Pathology

Paget`s disease of the Breast. Differential diagnosis using additional IHC-panel. Literature review and own observations.

Global Journal of Pathology & Laboratory Medicine
Volume 1, Issue 2, June 2021, Pages: 25-49
Received: July 11, 2021, Reviewed: July 13, 2021, Accepted: July 21, 2021, Published: August 25, 2021

Unified Citation Journals, Pathology 2021, https://doi.org/10.52402/Pathology205
ISSN 2754-0952

Dr. MV Mnikhovich1.4File:ORCID iD.svg - Wikimedia Commons, Dr. AV Romanov1File:ORCID iD.svg - Wikimedia Commons, Dr. LM Mikhaleva1File:ORCID iD.svg - Wikimedia Commons, Dr. TV Bezuglova1File:ORCID iD.svg - Wikimedia Commons,
Dr.
TN Sotnikova 2File:ORCID iD.svg - Wikimedia Commons, Dr. AR Shurdumov 3File:ORCID iD.svg - Wikimedia Commons

  1. Research Institute of Human Morphology, Moscow, Russia
  2. Davydovsky Moscow city Hospital, Moscow, Russia
  3. Sechenov First Moscow State Medical University
  4. Department of Pathological Anatomy and Clinical Pathological Anatomy with a course in histology Medico-Biological University of Innovation and Continuing Education named after A.I. Burnazyan FMBA of Russia, Moscow, Russia
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1. Abstract:
In 1874, Sir James Paget described a tumor that was later called Paget’s disease of the breast. Currently, Paget’s disease of the breast is a rare type of cancer that affects the skin of the nipple and usually the areola. Moreover, it should be noted that, as a rule, this cancer is associated with other breast carcinomas, such as: ductal carcinoma in situ or invasive cancer.

We have carried out a massive analysis of the literature, including research work from the early twentieth century, as well as modern data, in order to obtain an extended differential diagnosis of Paget’s disease of the breast. We also present our own clinical and morphological observations as informative images of the corresponding breast conditions. Paget’s disease of the breast must be differentiated from the following conditions: normal or atypical Toker cells, melanoma of the nipple, squamous cell carcinoma of the nipple. In addition, one should keep in mind such a diagnosis as Weisner Nevus (Bap-oma), a detailed differential diagnosis, in relation to which is also given.

Conclusion: We have developed a wide differential diagnostic IHC panel that simplifies the diagnosis of Paget’s disease of the breast. We recommend using such stains as: CD138, P53, CK8, Ck7, HER2 / Neu, EMA / MUC1, HMB-45, Melan A, S-100, P-63, P16 and BAP1.

Keywords: Paget`s breast disease, Toker cells, Differential diagnosis in breast pathology, Bowen’s disease, melanoma, BAP-1oma.=

2. Introduction:
James Page, a British surgeon, and pathologist, first described Paget’s disease in 1874. At that time, he described a disease that manifested itself as itching, irritation, erythema, and liquid discharge from the nipples, and which was associated with the underlying neoplasia of the mammary gland. [1-4] Today, Paget’s mammary disease is defined as a rare type of carcinoma that affects the skin of the nipple and usually the areola. Furthermore, the majority of patients with Paget’s disease also have one or more tumors nearby from the Paget’s carcinoma focus. These tumors are most often ductal carcinoma in situ or invasive cancer. [1-3] It should be kept in mind that Paget’s carcinoma is found not only in the mammary gland, but there is also extramammary Paget’s disease, which has its own characteristics.[4-5]. Paget’s carcinoma of the breast is more common in women due to the prevalence of breast cancer [5]. Paget’s carcinoma accounts for 1 – 4% of all breast cancers. [6]. Most often, the disease occurs in postmenopausal women, often during the sixth decade of life (mean age 57 years), but also occurs in adolescents [7] and even in elderly patients [8].

2 Pathogenesis:
2.1 History overview
For almost 200 years of studying the disease, dozens of different theories of pathogenesis have been proposed, refuted, and again proposed:

Parasitic theory:
In the 1889 year. Jean Darier et al gave a very detailed description of the histopathological changes that occur in Paget’s mammary disease. The authors considered Paget’s cells to be parasitic (sporospermia or coccidia сells), which provoked Paget’s carcinoma. Wickham (1890), Lang (1905), Rawogli (1894), Fabri, and Trautman (1904) supported this theory, but the etiology was seen not in sporospermia or coccidia, but in pathogenic fungal yeasts.

Theory of degenerative skin changes:
In 1902 year. Darier has safely abandoned the previously stated parasitic theory. Since then, he believed that Paget’s disease arises from the epidermis and excretory ducts of the mammary gland, due to their degenerative and dystrophic changes, and Paget’s cells are special epithelial elements, having undergone a specific type of cellular degeneration. Vignolo-Lutati, Sekiguchi, Elbogen (1909), Stahr (1928) supported this theory of the development of Paget’s cancer.
Afterward, this theory was refuted by indisputable evidence of the cancerous nature of Paget`s cells, and not degenerative, as the above authors believed.

Theory of precancerous condition:
James Paget himself attributed the pathology he described to a precancerous condition of the mammary gland. He believed that eczematous damage to the nipple and areola gave rise to a cancerous nodule in the breast tissue.
“The development of breast carcinoma as a consequence of a chronic skin disease is so constant that it can be assumed, it must be feared, and in some cases, it can be foreseen.”
Paget J. On disease of the mammary areola precending cancer of the mammary gland. «St. Barthol. Hosp.» 1874, n10, p89.
V.L. Bogolyubov (1907), A.P. Shanin (1932), A.V. Melnikov (1933), and other famous Russian pathologists believed that Paget’s disease must exist for a long time in the form of nipple eczema before breast carcinoma develops.
And only after this does the malignant nature of the disease begin to manifest itself in the form of regional and distant metastasis.
It is worth noting that in addition to the above, there is a huge number of theories of the pathogenesis of Paget’s disease of the breast, such as: The theory of the emergence of Paget’s carcinoma from apocrine sweat glands, the theory of the development of Paget’s carcinoma due to metastasis of breast carcinoma in the epidermis of the nipple and others, currently only of historical significance.

2.2 Actual leading theories of pathogenesis
At the present time, 2 main theories of Paget’s breast disease histopathogenesis are leading: Epidermotropic and Malignant Transformation theory [9-16].
A schematic representation of both theories is given below. (Fig. 1)

Fig. 1 Schematic representation of the leading theories of the pathogenesis of Paget's breast disease.

Fig. 1 Schematic representation of the leading theories of the pathogenesis of Paget’s breast disease

2.2.1 Epidermotropic theory:
Professor of pathology at the University of Glasgow, Sir Robert Muir, suggested that tumor cells are capable of moving into the superficial layers of the epidermis through the excretory ducts of the mammary gland In 1935 [9].
This gave rise to research in these fields of theories of the pathogenesis of Paget’s carcinoma. It is now widely believed that Paget’s breast disease is often associated with underlying breast carcinoma.
Through histopathological examination, Robert Muir described the intraepidermal migration of malignant ductal epithelial cells through the mammary ducts and called this process Epidermotropism. [9-10]. (Fig. 2)
Currently, most scientists support this theory.

Fig. 2 Schematic representation of the epidermotropic theory of carcinogenesis in Paget's carcinoma. Malignant Pagets cells

Fig. 2 Schematic representation of the epidermotropic theory of carcinogenesis in Paget’s carcinoma. Malignant Paget`s cells pass from the lumen of the milk duct into the epidermis of the overlying nipple through retrograde spreading of Paget`s cells. Robert Scwartz et al. 2017 adapted scheme.

It is generally accepted that heregulin molecules are the cause for this chemotaxis, and mainly heregulin-alpha, which express normal cells of the epidermis and which interact with heterodimers of the HER group receptors.
The binding of heregulin-alpha to the receptor complex on Paget cells leads to chemotaxis of these cells, which migrate to the overlying layers of the nipple epidermis. [11]  (Fig.3).
In addition, it should be noted that due to the above-mentioned mechanism, heregulins are able to control tumor metastasis. So it was proved that blockade of Heregulin-alpha expression sharply reduces the oncogenic potential of a breast carcinoma including Paget`s breast carcinoma.  [14].

Fig. 3 The mechanism of epidermotropism of Paget cells.

Fig. 3 The mechanism of epidermotropism of Paget cells. Schelfhout V et al. 2000 adapted scheme

2.2.2 Malignant transformation theory:
It is assumed that Paget’s cells may originate from glandular stem cells or Toker epidermal cells. [12] Toker’s cells have been found in about 10% of normal nipples [13] Like the Paget cells of both the mammary and extramammary regions, Toker cells contain a pronounced transparent (vacuolated) cytoplasm, however, they lack figures of mitosis and any atypia, therefore they are considered benign analogs of Paget cells.
Below are microscopic images of Paget’s breast  carcinoma (Fig. 4) and Toker giant cells (Fig. 5)

Fig. 4 Giant Paget cells large tumor cells with mitotic figures and atypia.

Fig. 4 Giant Paget cells: large tumor cells with mitotic figures and atypia

Fig. 5 Toker's giant cells are also large cells, with a voluminous light cytoplasm, but without pleomorphism, mitotic figures can rarely be observed, but atypical mitoses are absent

Fig. 5 Toker’s giant cells are also large cells, with a voluminous light cytoplasm, but without pleomorphism, mitotic figures can rarely be observed, but atypical mitoses are absent

S.F. Kuan et al in 2001 reported the immunohistochemical expression of apomucins such as  MUC1, MUC2, and MUC5AC in Paget cells and concluded that both Paget’s cells and the underlying ductal carcinoma express the same phenotypic apomucins that are also expressed by Toker cells. They concluded about the interconnection of the above structures. [15] However, L. Morandi et al two years later in 2003 reported that chromosomal changes observed in Paget`s cells are different from those observed in cells of underlying breast carcinoma. They suggested that Paget’s cells are genetically different from underlying breast carcinoma cells. [16].

The concept of “Tumor colision” was introduced between Paget’s breast carcinoma and the underlying ductal carcinoma. However, this concept is based on only a few observations, so further research is needed to confirm or refute the theory of “tumor collision” in the context of oncogenesis of Paget’s breast carcinoma.
It is also necessary to take into account the existence of the so-called hyperplastic and atypical Toker cells (Fig. 6), which introduce some difficulties in the pathomorphological diagnosis of Paget’s breast disease. [17]

Fig. 6 Atypical toker cells. There is Pagetoid spread of cells in the epidermis, but without dermal invasion. Well visible nucleoli, giant multinucleated atypical cells are visible.

Fig. 6 Atypical toker cells. There is  Pagetoid spread of cells in the epidermis, but without dermal invasion. Well visible nucleoli, giant multinucleated atypical cells are visible

3. MORPHOLOGY:
3.1 Gross examination:
Paget’s mammary disease is characterized by scaly, erythematous, thickened, crusty plaques located on the nipple, with a tendency to spread to surrounding areas. In this case, the spread of the tumor occurs not only in the nearest (for example, the areola) but also in relatively distant areas, so axillary Paget сarcinoma can arise from the axillary auxiliary tissue of the mammary gland.  [18] Nipple changes are associated with breast carcinoma (ie, infiltrating ductal carcinoma in situ) in more than 98% of patients; however, two-thirds of patients have a palpable breast tumor. Gross images of Paget’s carcinoma are shown in Figures 7 and 8.

Fig. 7 Gross view of Paget's breast disease. There are slight ulcerative lesion of the nipple and the presence of pale overlays.

Fig.7 Gross view of Paget’s breast disease. There are slight ulcerative lesion of the nipple and the presence of pale overlays

Fig. 8 Gross view of Paget's breast disease. There are severe ulceration of the nipple and crusting.

Fig. 8 Gross view of Paget’s breast disease. There are severe ulceration of the nipple and crusting

The erythematous spot is usually sharply demarcated. Nipple retraction or palpable nodules indicate underlying breast carcinoma.
Serous spotting from the nipple may be present. The size of the lesion varies from 3 mm to 15 cm in diameter; the average size is 2.8 cm in diameter. Nipple intussusception is sometimes observed. As a rule, the lesion in Paget’s disease is unilateral; however, Sahoo S, Green G et al reported bilateral lesions in Paget’s breast disease. [19] Additionally, it is necessary to take into account and remember the existence of a special Pigmented form of Paget’s breast disease. Pigmented forms of Paget’s breast disease of both breast and extra-mammary localization are rare tumors in both men and women.
These diseases can mimic malignant melanoma both clinically and histopathologically. They can also mimic melanoma during dermatoscopy. [20] At the same time, during histological examination, an increase in the number of benign melanocytes is observed, which can interfere with the correct diagnosis and lead to an incorrect interpretation of this form of Paget’s breast disease as malignant melanoma. [21].
A macroscopic view of the Pigment Form of Paget`s breast carcinoma is shown in Figure 9.

Fig. 9 Pigmented form of Paget`s breast carcinoma.

 Fig. 9 Pigmented form of Paget`s breast carcinoma.

There is a black prominent mass of the nipple with slight areas of gray overlays. It is necessary to keep this form of Paget’s carcinoma in mind due to the possible misdiagnosis with melanoma.
TNM staging of Paget breast disease is often associated with and classified according to the underlying carcinoma. [34].

3.2 Microscopic examination:
Hyperkeratosis, parakeratosis and acanthosis may be detected in the epidermis.   Large, rounded or elliptoid, malignant tumor cells with varying degrees of atypia may be found, in all layers of the epidermis and also in the deeper layers of the skin. Tumor cells are pale or brightly eosinophilic, contain large vesicular hyperchromatic nuclei with pronounced nucleoli. Also sometimes there are prominent mitotic figures, rarely atypical mitoses.
In addition, Paget cells often compress the basal keratinocytes that lie between Paget’s cells and the papillary dermis. Paget cells are located singly or in the nests. Microscopic images of Paget’s mammary carcinoma are given below in Figures 10-12.

Fig. 10 Paget`s cells often compress the basal keratinocytes that lie between Paget cells and the papillary dermis. Paget cells are located singly or in the form of nests with sparse duct formations.

Fig. 10 Paget`s cells often compress the basal keratinocytes that lie between Paget cells and the papillary dermis. Paget cells are located singly or in the form of nests with sparse duct formations.

Fig. 11 Dermal pseudo-invasion of Paget's cells. It is noteworthy that this is not a true dermal invasion, but only pseudo-immersion into the dermis along the adnexal ducts.

Fig. 11 Dermal pseudo-invasion of Paget’s cells. It is noteworthy that this is not a true dermal invasion, but only pseudo-immersion into the dermis along the adnexal ducts.

Fig. 12 Dermal pseudo-invasion of Paget's cells. Same case as Fig. 11, different field of view.

Fig. 12 Dermal pseudo-invasion of Paget’s cells. Same case as Fig. 11, different field of view

The cytoplasm of Paget cells often contains PAS-positive granules, indicating the presence of neutral mucopolysaccharides. Less often, acidic mucopolysaccharides (sialomucin), which are identified in the Alcian blue reaction or in the aldehyde-fuchsin stain.
Paget`s cells are able to completely (or almost completely) replace normal keratinocytes in ulcerated areas. It should be kept in mind that Paget cells do not penetrate directly into the dermis; however, they often extend along the epithelium of the sebaceous and sweat glands.

3.2.1 Histologic forms of Paget`s breast disease:
Adenocarcinoma-like type which has columnar cells, similar to metastatic adenocarcinoma to the skin.
Fusiform type. Tumor cells are angular, elongated, nested and grow in compact masses.
Anaplastic type. The cells resemble cells found in Bowen’s disease. Pleomorphic tumor cells can be present in the distorted epidermis in all layers. Apoptotic (necrotic) tumor cells, mitotic figures, and multinucleated tumor cells are common. Positive IHC staining for markers such as CEA, epithelial membrane antigen (EMA) and c-erb B-2 promotes the diagnosis of Paget breast disease and interferes with the diagnosis of Bowen’s disease.
Acantholytic type. This subtype may overlap with the anaplastic form. Acantholysis may lead to misinterpretation of the diagnosis as another acantholytic lesion affecting the skin of the nipple and areola.
Pigment type. As mentioned earlier, rare cases of Paget’s pigmented mammary carcinoma have been reported. [24, 25] Pigmented Paget cells are DOPA negative. Melanin pigment is transferred from melanocytes to Paget’s malignant cells. The number of melanocytes in these foci does not increase.
In addition, a reticular variant of Paget’s pigmented carcinoma has recently been described. [24, 25].
Equally important is that the majority of cases of Paget’s mammary carcinoma (in both men and women) are associated with underlying cancer. As a rule, it is a poorly differentiated ductal carcinoma in situ (Fig. 13), invasive carcinoma is less common, or both at once. [24-28]

Fig. 13. A & B

Fig.13.
A. Paget’s carcinoma focus (left), as well as ductal intraepithelial hyperplasia (right), express HER-2.
B. Underlying perineural invasion in invasive ductal carcinoma of no special type distant from previous focus.

It is also important to keep in mind that allergic contact dermatitis, as well as simple (irritant) contact dermatitis, and some other skin diseases (drug rash of the nipple and areola area) are histopathological manifestations of inflammatory dermatosis. Under these conditions, it is much more difficult to identify Paget cells, and in some cases, it is completely impossible.

3.2.2 IHC profile:
Paget’s cells almost always express molecules such as low molecular weight keratins, EMA, c-erb B-2, and polyclonal pCEA. Increased expression of HER-2 family proteins, and variable expression of ER, PR receptors are also often detected.
In addition, it is worth noting the expression of such molecules as CD138, CK7, CK8, as well as the variable expression of cell proliferation regulators such as proteins of the P53 and S100 families. [26, 28].
The corresponding IHC characteristics of Paget’s breast carcinoma are presented in figures 14-17.

Fig. 14 Strong expression of CAM5.2 in Paget`s cells.

Fig. 14 Strong expression of CAM5.2 in Paget`s cells. It should be kept in mind that this marker is very sensitive, but it is not 100% specific. Interpretation of the diagnosis is possible only after a comprehensive study of the sample.

Fig. 15. Strong membrane expression of E-cadherin indicates a high connection between cells and the absence of acantholysis.

Fig.15. Strong membrane expression of E-cadherin indicates a high connection between cells and the absence of acantholysis.

Fig. 16 Paget cells are also characterized by weak expression of mucins, including MUC1.

Fig. 16 Paget cells are also characterized by weak expression of mucins, including MUC1

Fig. 17 Paget cells are also characterized by high expression of GATA3, as in other breast tumors, including ductal carcinomas.

Fig. 17 Paget cells are also characterized by high expression of GATA3, as in other breast tumors, including ductal carcinomas. A number of authors consider the expression of GATA3 as one of the indirect confirmations of Paget’s epidermotropic theory of Paget`s breast disease carcinogenesis.

A brief summary of the main characteristics of Paget’s breast disease is given below (Table 1.)

Table 1. Main characteristics of Paget`s breast disease

Epidemiology  Wide age range (26-88 years old)
1-4% of the number of diagnosed breast cancer
Gross examination: Limited erythema, eczema, crusts.
Bloody / serous discharge, nipple retraction and palpable underlying swelling are possible.
Microscopic examination: Hyper / para-keratoses, Paget cells are found in the epidermis. Prominent normal and rare pathological mitoses.
Often associated with underlying carcinoma (High-grade DCIS, invasive carcinoma, or both)
Histochemistry study: Often PAS-positive granules within Paget cells (neutral polysaccharides)
Less commonly Alcian blue – positive granules (acidic mucopolysaccharides, sialomucins)
IHC study: Strong Expression of  low molecular weight cytokeratins, EMA, c-erb B-2, polyclonal pCEA, HER-2 family proteins,
Variable expression of ER, PR receptors, Cd138, CK7 / 8, as well as P53 and S100.

4. Differential diagnosis:
4.1 Paget’s Disease of the Breast Versus Toker Cells
Toker cells of the nipple are the most similar morphologically and immunohistochemically with Paget cells, which can present significant differential diagnostic problems (especially when they are present in large numbers). The main differential diagnostic differences between Paget cells in and Toker cells are presented in Table 2.
Typical visual and IHC-associated distinguishing characteristics are presented in Figures 18-20.

Table 2. Differential diagnosis of Toker cells and Paget cells.

Toker cell Paget cells
Morphology As a rule, Toker’s cells are devoid of pleomorphism, prominent nucleoli, and vesicular chromatin. [29].

Toker cells have round nuclei and are usually concentrated along with the basal layer of the epidermis, but can also be found in surface layers.

There are pleomorphism of cells and nuclei, prominent nucleoli, vesicular chromatin. Paget cells can be localized in any layer epidermis, but no dermal invasion. Although they may pseudo-immersion into the dermis along the excretory ducts of the sebaceous and sweat glands.
Underlying carcinoma As a rule, there is no association Toker cells with breast carcinoma. Paget`s breast is Typically associated with high-grade DCIS, invasive cancer, or both.
Mitoses Less More
IHC Positive expression: СK7
Negative expression: HER2 / Neu
Less expression in comparison with Paget cells [28] There are Hyperplastic and atypical tocker cells that are capable of expressing HER2 / neu and PR, ER, and, most likely, the degree of atypia is directly related to the expression [30].
Differential Diagnosis of such Toker cells is extremely difficult. Ki67 are useful markers for distinguishing these two conditions.
Strong Expression of  low molecular weight cytokeratins, EMA, c-erb B-2, polyclonal pCEA, HER-2 family proteins,

 

Variable expression of ER, PR receptors, Cd138, CK7 / 8, as well as P53 and S100.

Fig. 18 Toker cells in the epidermis. These cells have less pleomorphism and mitoses (unlike Paget cells) and rare nucleoli.

Fig. 18 Toker cells in the epidermis. These cells have less pleomorphism and mitoses (unlike Paget cells) and rare nucleoli

Fig. 19 Hyperplastic Toker's cells in the epidermis. Pronounced pleomorphism of cells and nuclei, prominent nucleoli, figures of mitosis, but less in comparison with Paget cells

Fig. 19 Hyperplastic  Toker’s cells in the epidermis. Pronounced pleomorphism of cells and nuclei, prominent nucleoli, figures of mitosis, but less in comparison with Paget cells

Fig. 20 Toker cells have variable, but less pronounced expression of Ki-67 in comparison with Paget cells.

Fig. 20 Toker cells have variable, but less pronounced expression of Ki-67 in comparison with Paget cells.
A.Ki-67 expressed by Toker Cells
B. Different field of view of the same case

As we have already mentioned, there are reasons to consider Toker cells precursors of Paget cells:

  1. There is Paget breast carcinoma that is not associated with the underlying breast carcinoma.
  2. Paget’s extramammary carcinoma is usually not associated with the underlying carcinoma.
  3. There are rare cases of invasive adenocarcinoma from primary Paget’s disease.
  4. Van Der Putt et al. In 1995 reported a case of Paget’s breast carcinoma from hyperplasia of Toker cells [31].

4.2 Paget’s Disease of the Breast Versus Melanoma
The main differential diagnostic criteria for Melanoma and Paget`s breast disease  are Below (Table 3.)  Microscopic images of Pagetoid melanoma are also presented (Figs. 21-22).

Table 3. Differential diagnosis of Melanoma and Paget cells

Melanoma Paget`s breast disease
Morphology Atypical melanocytes often are located predominantly as single cells, although nests may also be present. Individual melanocytes often form confluent proliferation along with the basal layer and attract additional structures. Rete ridges may be presented.
Melanocytes vary greatly in size and the amount of cytoplasmic melanin (maybe even absent), as well as nuclear atypia. Giant Star-burst cells may be seen. [32]
There are a pleomorphism of cells and nuclei, prominent nucleoli, vesicular chromatin. Paget cells can be localized in any layer epidermis, but no dermal invasion. Although they may

pseudo-immersion into the dermis along the excretory ducts of the sebaceous and sweat glands.

Mitoses Multiple mitoses including atypical As a rule fewer mitoses including atypical
IHC Positive expression: HMB-45+, Melan A+, S 100+
Negative expression: Ck7-, Her2/neu-.
Positive expression: CK7, HER2/Neu,
Variable expression  PR, ER, S-100
Negative expression: HMB-45, Melan A.

Fig. 21 A-B. Melanoma of the nipple. Melanocytes vary greatly in size as well as nuclear atypia. Note the lack of melanin depositions.

Fig. 21 A-B. Melanoma of the nipple. Melanocytes vary greatly in size as well as nuclear atypia. Note the lack of melanin depositions

Fig. 22 IHC study of the above case.

Fig. 22 IHC study of the above case.

  1. Strong broad expression of Melan A
  2. Even stronger expression of S100

4.3 Paget`s disease of the breast versus Bowen disease
The main differential diagnostic criteria for Bowen Disease and Paget’s breast disease are given below (Table 4.). Corresponding microscopic images are also shown (Fig. 23-24).

Table 4. Differential diagnosis of Bowen disease and Paget’s Breast disease.

Bowen disease
Squamous carcinoma in situ
Paget`s breast disease
Morphology Squamous cell differentiation with diffuse atypia
Atypical cells are found in all layers but without dermal or myoepithelial progression.
Pagetoid cells with abundant pale cytoplasm and large pleomorphic nuclei are widespread in the epidermis.
Mucin stains are negative.
There are pleomorphism of cells and nuclei, prominent nucleoli, vesicular chromatin. Paget cells can be localized in any layer epidermis, but no dermal invasion. Although they may pseudo-immersion into the dermis along the excretory ducts of the sebaceous and sweat glands.
Mitoses Equally Equally
IHC Positive expression: EMA, P63/P40
Negative expression: S100, Ck7, Her2/neu.[33-34]
Positive expression: CK7, HER2/Neu,
Variable expression  PR, ER, S-100, p63/p40

Fig. 23. Bowen`s disease of the nipple.

Fig. 23. Bowen`s disease of the nipple.
Pagetoid cells with abundant pale cytoplasm and large pleomorphic nuclei are widespread in the epidermis

Fig. 24 IHC study of the above case. Strong diffuse expression of p63

Fig. 24 IHC study of the above case. Strong diffuse expression of p63

4.4 Paget`s disease of the breast versus Weisner nevus
BAP1-ohma (Wiesner nevus) is a melanocytic tumor that occurs in middle age (extremely rare in children) and has a mutation in BRCA1, which manifests itself in negative expression of the BAP1 marker in IHC studies. [35-37].

The tumor has two main patterns, which occur with different frequencies and different expressions:

  • Fusiform cells, including Spitzoid-type cells
  • Epithelioid cells, including Pagetoid cells
    [36-37]

Hence, BAP1-oma with a large number of Pagetoid cells can easily be misdiagnosed with extramammary Paget’s disease. [37]. Especially in the context of limited clinical data.
Key differential diagnostic criteria between Paget`s breast disease and Weisner`s nevus are shown in the table below (Table 5). A microscopic image of the BAP1-ohm is shown in figures 26-27

Table 5. Differential diagnosis of BAP1-oma and Paget`s breast disease

Bap1-oma with pagetoid cells Extramamamry Paget`s disease
Morphology Pagetoid differentiation with diffuse atypia
Atypical cells are found in all layers, in some cases dermal invasion is possible.
Mucin stains are negative.
There are pleomorphism of cells and nuclei, prominent nucleoli, vesicular chromatin.
Paget cells may be localized in any layers of the epidermis, but do not have any dermal invasion. Although they can pseudo-immersed in the dermis along the excretory ducts of the sebaceous and sweat glands.
Melanin inclusions, PAS +, Alcian blue + inclusions may be present.
Mitosis Equally Equally
IHC Positive expression: EMA, P16,  S100, Melan A
Negative expression: Ck7, Her2/neu.
A characteristic and necessary criterion for the diagnosis is negative BAP1 expression
 Positive expression: CK7, HER2/Neu,
Variable expression: PR, ER, BAP1
Negatoive expression: HMB-45-, Melan A-, S-100+/-

Fig. 25. BAP1-oma with Pagetoid cells. Pagetoid cells infiltrate all layers of the epidermis. Prominent pleo- and polymorphism. [37]

Fig. 25. BAP1-oma with Pagetoid cells. Pagetoid cells infiltrate all layers of the epidermis. Prominent pleo- and polymorphism. [37]

Fig. 26 IHC study of Weisner nevus.

Fig. 26 IHC study of Weisner nevus
Note absolutely lack of BAP1 expression. [38]

5. Conclusion:
Thus, we have created an extended algorithm for the differential diagnosis of Paget’s carcinoma. A summary of all of the above conditions is shown in Table 6.

 Table 6. Summary: differential IHC diagnostics of Paget’s carcinoma

CD138 P53 CK8 Ck7 HER2 / New EMA / MUC1 HMB- 45,

Melan A

S- 100 P-63 P16 BAP1
Paget`s breast disease + +/- + + + + +- + +/-
Toker cells +/- + +/- + +/- +/- +/-
Melanoma +/- +/- + + +/- +/-
BAP-1 Bapoma

(Weisner nevus)

+/- +/- +/- + +/- +/-
Bowen`s disease

(SCC in situ)

+ +/-

 

+ +/- +/-

Positive  expression: +
Variable expression: +/-:
Lack of expression: –

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To citation of this article: Dr. M.V. Mnikhovich, Dr. A.V. Romanov, Dr. L.M. Mikhaleva, Dr. T.V. Bezuglova, Dr. T.N. Sotnikova, Dr. AR Shurdumov, Paget`s disease of the Breast. Differential diagnosis using additional IHC-panel. Literature review and own observations., Global Journal of Pathology & Laboratory Medicine

Dr. Maxim Valerievich

Candidate of Medical Sciences, Associate Professor, Leading Researcher of the Central Pathoanatomical Laboratory of the FGBNU Research Institute of Human Morphology

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