Materiały źródłowe

• #1 Mammary Paget Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK563228/

  Paget’s disease of the breast is an uncommon manifestation of underlying breast cancer in postmenopausal female patients. Underlying breast lesion is usually a ductal carcinoma in situ (DCIS) but can be invasive cancer. […] It is widely accepted that Paget disease is associated with some underlying breast malignancy, usually ductal carcinoma in situ (DCIS) or invasive ductal carcinoma. It is theorized that these malignant ductal epithelial cells migrate toward the skin through the lactiferous ducts and ductules. […] A couple of hypotheses have been proposed to explain the pathogenesis of PDB. […] Epidermotropic theory: proposes the Paget cell arises from an underlying mammary adenocarcinoma, with the neoplastic ductal epithelial cells migrating through the ductal system of the breast and reaching the epidermis of the nipple.

• #2 Mammary Paget disease. Paget disease of the nipple

  https://dermnetnz.org/topics/mammary-paget-disease

  Mammary Paget disease is an uncommon form of breast cancer, comprising 13% of all breast cancer presentations. […] Mammary Paget disease is nearly always associated with an underlying intraductal breast cancer located near the areola. […] There are two main theories proposed for the pathogenesis of mammary Paget disease. […] Epidermotropic theory this theory proposes that Paget cells arise in an underlying intraductal carcinoma and migrate along the lactiferous ducts to the nipple epidermis. […] In situ malignant transformation theory this suggests Paget cells are malignant keratinocytes of the nipple epidermis. […] Mammary Paget disease is almost always a skin sign of an underlying breast cancer. This may be an in-situ or invasive intraductal carcinoma. Metastases to lymph nodes and beyond may be present.

• #3 Paget’s Disease of the Breast

  http://www.aboutcancer.com/pagets_harris.htm

  There are two main theories for the origin of Paget’s disease. The epidermotropic theory, first described by Jacobeus, suggests that the Paget’s cells arise in breast ducts and spread by way of the lactiferous sinuses to the nipple epidermis. This view is supported by the fact that more than 97% of patients with Paget’s disease have an underlying breast carcinoma and that in the majority of cases, the immunophenotype of the Paget’s cell is the same as the breast cancer. […] The intraepidermal transformation theory proposes that the Paget’s cells arise in the terminal portion of the lactiferous duct at its junction with the epidermis; they are altered epidermal cells that have been transformed in situ. Support for this theory is found in the rare cases of Paget’s disease without an underlying breast carcinoma or cases in which the Paget’s disease and the underlying carcinoma appear to be separate tumors. […] Paget’s cells do not invade through the dermal basement membrane and therefore are a form of carcinoma in situ. Paget’s disease is frequently associated with a chronic inflammatory infiltrate in the dermis.

• #4 Paget’s disease of the nipple – PubMed

  https://pubmed.ncbi.nlm.nih.gov/23929251/

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

• #5 Mammary Paget disease. Paget disease of the nipple

  https://dermnetnz.org/topics/mammary-paget-disease

  Mammary Paget disease is an uncommon form of breast cancer, comprising 13% of all breast cancer presentations. […] Mammary Paget disease is nearly always associated with an underlying intraductal breast cancer located near the areola. […] There are two main theories proposed for the pathogenesis of mammary Paget disease. […] Epidermotropic theory this theory proposes that Paget cells arise in an underlying intraductal carcinoma and migrate along the lactiferous ducts to the nipple epidermis. […] In situ malignant transformation theory this suggests Paget cells are malignant keratinocytes of the nipple epidermis. […] Mammary Paget disease is almost always a skin sign of an underlying breast cancer. This may be an in-situ or invasive intraductal carcinoma. Metastases to lymph nodes and beyond may be present.

• #6 Paget Disease of the Breast – NCI

  https://www.cancer.gov/types/breast/paget-breast-fact-sheet

  Paget disease of the breast (also known as Paget disease of the nipple and mammary Paget disease) is a rare type of cancer involving the skin of the nipple and, usually, the darker circle of skin around it, which is called the areola. Most people with Paget disease of the breast also have one or more tumors inside the same breast. These breast tumors are either ductal carcinoma in situ or invasive breast cancer. […] Doctors do not fully understand what causes Paget disease of the breast. The most widely accepted theory is that cancer cells from a tumor inside the breast travel through the milk ducts to the nipple and areola. This would explain why Paget disease of the breast and tumors inside the same breast are almost always found together. […] A second theory is that cells in the nipple or areola become cancerous on their own. This would explain why a few people develop Paget disease of the breast without having a tumor inside the same breast. Moreover, it may be possible for Paget disease of the breast and tumors inside the same breast to develop independently.

• #7 Mammary Paget Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK563228/

  Paget’s disease of the breast is an uncommon manifestation of underlying breast cancer in postmenopausal female patients. Underlying breast lesion is usually a ductal carcinoma in situ (DCIS) but can be invasive cancer. […] It is widely accepted that Paget disease is associated with some underlying breast malignancy, usually ductal carcinoma in situ (DCIS) or invasive ductal carcinoma. It is theorized that these malignant ductal epithelial cells migrate toward the skin through the lactiferous ducts and ductules. […] A couple of hypotheses have been proposed to explain the pathogenesis of PDB. […] Epidermotropic theory: proposes the Paget cell arises from an underlying mammary adenocarcinoma, with the neoplastic ductal epithelial cells migrating through the ductal system of the breast and reaching the epidermis of the nipple.

• #8 Pathology Outlines – Paget disease

  https://www.pathologyoutlines.com/topic/breastmalignantpaget.html

  Mammary Paget disease (MPD) is a proliferation of malignant glandular epithelial cells (in situ carcinoma) in the nipple areolar epidermis (Histopathology 2020;77:181) […] 2 theories on the pathogenesis: […] Epidermotropic theory (most widely accepted): Paget cells are DCIS cells that migrate along the basement membrane of the nipple, supported by the presence of DCIS deeper in the breast identical to Paget cells in almost all cases; migration may be mediated through a motility factor heregulin α, produced by keratinocytes and exerting its effect via the HER2 receptor (J Natl Cancer Inst 2000;92:622) […] Transformation theory: Paget cells originate from malignant transformation of keratinocytes or Toker cells; it would explain rare cases (< 5%) in which cancer is not present in underlying breast (Intractable Rare Dis Res 2019;8:203) [...] When no parenchymal cancer is identified, there is a possibility that the underlying tumor has gone undetected / unsampled.

• #9 Paget’s disease of the breast in a male with lymphomatoid papulosis: a case report | Journal of Medical Case Reports | Full Text

  https://jmedicalcasereports.biomedcentral.com/articles/10.1186/1752-1947-5-43

  Paget’s disease is an eczematous skin change of the nipple that is usually associated with an underlying breast malignancy. […] We discuss the presentation, investigations, management and pathogenesis of Paget’s disease of the nipple. […] The pathogenesis of Paget’s disease is still a subject of debate with two main hypotheses. The epidermotropic hypothesis proposes that Paget’s cells originate from ductal epithelium, from where they migrate towards the epidermis. This hypothesis is supported by the association between Paget’s and an underlying breast carcinoma in the majority of patients. The second hypothesis, the intraepidermal transformation theory, considers the presence of malignant keratinocytes that originate from the areolar epidermis. Our case supports this origin since there was no underlying carcinoma.

• #10 Mammary Paget disease. Paget disease of the nipple

  https://dermnetnz.org/topics/mammary-paget-disease

  Mammary Paget disease is an uncommon form of breast cancer, comprising 13% of all breast cancer presentations. […] Mammary Paget disease is nearly always associated with an underlying intraductal breast cancer located near the areola. […] There are two main theories proposed for the pathogenesis of mammary Paget disease. […] Epidermotropic theory this theory proposes that Paget cells arise in an underlying intraductal carcinoma and migrate along the lactiferous ducts to the nipple epidermis. […] In situ malignant transformation theory this suggests Paget cells are malignant keratinocytes of the nipple epidermis. […] Mammary Paget disease is almost always a skin sign of an underlying breast cancer. This may be an in-situ or invasive intraductal carcinoma. Metastases to lymph nodes and beyond may be present.

• #11 Invasive Paget’s Disease of the Breast: A case Report

  https://jbd.or.kr/journal/view.php?number=126

  Intramammary Pagets disease is an uncommon disease in which 90% of the cases are accompanied by invasive or noninvasive ductal carcinoma. It comprises approximately 0.7%-4.3% of all breast cancers. […] The pathogenesis of intramammary Pagets disease continues to be debated, with two main theories involved. The epidermotropic theory states that Pagets cells are ductal carcinoma cells that have migrated from the underlying breast parenchyma to the nipple epidermis, known as Pagetoid spread. In the in situ transformation theory, the Pagets cells arise as malignant cells in the nipple epidermis, independent from any other pathologic process within the breast parenchyma. […] Pagets cells do not invade through the dermal basement membrane and therefore are a form of carcinoma in situ. […] Intramammary Pagets disease generally shows intra-epidermal manifestation, although in very rare cases, tumor cells within the epidermis invade through the basement membrane of the skin into the dermis. […] There is no clear information on the clinical outcome or post-operative management of invasive intramammary Pagets disease due to its rare incidence. […] Due to its scarcity, there is still little information regarding its management and prognosis.

• #12 Paget’s Disease | Oncohema Key

  https://oncohemakey.com/pagets-disease/

  Pagets disease, a rare presentation of breast cancer accounts for 1% to 3% of all breast cancers. The majority of cases are associated with an underlying malignancy and prognosis is dependent upon the stage of the underlying cancer. The pathogenesis of Pagets disease is an interesting one because there are two main theories for the origin of Pagets disease. The most widely accepted one is the epidermotropic theory, first described by Jacobeus, who suggested that the Paget cells arise in breast ducts and spread through the lactiferous sinuses to the nipple epidermis. This view is supported by several observations. First of all, it is well documented that most patients with Pagets disease have an underlying breast carcinoma which is ductal in origin and that the immunohistochemical profile and pattern of gene expression in the Paget cell and the underlying cancer are similar. In addition, heregulin alpha, a motility factor released by normal epidermal keratinocytes can induce chemotaxis of the Paget cells to migrate into the overlying nipple epidermis. Because not all Pagets disease is associated with an underlying carcinoma, another theory, the intraepidermal transformation theory (in situ transformation theory) proposes that the Paget cells arise either in the terminal portion of the lactiferous duct at its junction with the epidermis or from multipotential cells in the epidermal basal layer. This in situ transformation theory is thought to occur in pre-existing benign intraepidermal clear cells of the nipple areolar complex, or Toker cells, which are thought to have migrated from nonneoplastic ducts. Support for this theory is found in the rare cases of Pagets disease without an underlying breast carcinoma or cases in which the Pagets disease and the underlying carcinoma appear to be separate tumors. Other studies have identified desmosomal attachments between the Paget cells and adjacent keratinocytes supporting the in situ development of the Paget cell. Histologically, Pagets disease is characterized by the infiltration of the nipple epidermis by Paget cells, described as large pale-staining cells with round or oval nuclei and prominent nucleoli. The cells are between the normal keratinocytes of the nipple epidermis, occurring singly in the superficial layers and in clusters toward the basement membrane. Paget cells do not invade through the dermal basement membrane and therefore are a form of carcinoma in situ. Pagets disease is often associated with a chronic inflammatory infiltrate in the dermis.

• #13 Patients with Nipple-Areola Paget’s Disease and Underlying Invasive Breast Carcinoma Have Very Poor Survival: A Matched Cohort Study | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0061455

  Pagets disease (PD) of the breast is a rare disease. The survival rate of PD was reported to depend on the characteristics of the underlying carcinoma. […] The pathogenesis of PD remains debatable. There are two theories about the origin of Pagets cells. The transformation theory proposes that Pagets cells are transformed in situ keratinocytes of the epidermis of the nipple. The migration theory is more widely accepted; it assumes that Pagets cells are ductal carcinoma cells that have migrated from the underlying mammary ducts to the epidermis of the nipple. It seems that both theories could be supported by our study. […] Patients with PD and underlying IBC tended to have a greater chance of lymph node involvement, lower hormone receptor expression, higher HER2 expression and worse survival compared to those without PD. The subsequent matched study confirmed that the survival of patients with PD and underlying IBC was reduced compared to patients with IBC with similar prognostic factors (stage and characteristics). This finding suggests that PD itself is an indicator of poor survival.

• #14 Pathology Outlines – Paget disease

  https://www.pathologyoutlines.com/topic/breastmalignantpaget.html

  Mammary Paget disease (MPD) is a proliferation of malignant glandular epithelial cells (in situ carcinoma) in the nipple areolar epidermis (Histopathology 2020;77:181) […] 2 theories on the pathogenesis: […] Epidermotropic theory (most widely accepted): Paget cells are DCIS cells that migrate along the basement membrane of the nipple, supported by the presence of DCIS deeper in the breast identical to Paget cells in almost all cases; migration may be mediated through a motility factor heregulin α, produced by keratinocytes and exerting its effect via the HER2 receptor (J Natl Cancer Inst 2000;92:622) […] Transformation theory: Paget cells originate from malignant transformation of keratinocytes or Toker cells; it would explain rare cases (< 5%) in which cancer is not present in underlying breast (Intractable Rare Dis Res 2019;8:203) [...] When no parenchymal cancer is identified, there is a possibility that the underlying tumor has gone undetected / unsampled.

• #15 Paget’s Disease | Oncohema Key

  https://oncohemakey.com/pagets-disease/

  Pagets disease, a rare presentation of breast cancer accounts for 1% to 3% of all breast cancers. The majority of cases are associated with an underlying malignancy and prognosis is dependent upon the stage of the underlying cancer. The pathogenesis of Pagets disease is an interesting one because there are two main theories for the origin of Pagets disease. The most widely accepted one is the epidermotropic theory, first described by Jacobeus, who suggested that the Paget cells arise in breast ducts and spread through the lactiferous sinuses to the nipple epidermis. This view is supported by several observations. First of all, it is well documented that most patients with Pagets disease have an underlying breast carcinoma which is ductal in origin and that the immunohistochemical profile and pattern of gene expression in the Paget cell and the underlying cancer are similar. In addition, heregulin alpha, a motility factor released by normal epidermal keratinocytes can induce chemotaxis of the Paget cells to migrate into the overlying nipple epidermis. Because not all Pagets disease is associated with an underlying carcinoma, another theory, the intraepidermal transformation theory (in situ transformation theory) proposes that the Paget cells arise either in the terminal portion of the lactiferous duct at its junction with the epidermis or from multipotential cells in the epidermal basal layer. This in situ transformation theory is thought to occur in pre-existing benign intraepidermal clear cells of the nipple areolar complex, or Toker cells, which are thought to have migrated from nonneoplastic ducts. Support for this theory is found in the rare cases of Pagets disease without an underlying breast carcinoma or cases in which the Pagets disease and the underlying carcinoma appear to be separate tumors. Other studies have identified desmosomal attachments between the Paget cells and adjacent keratinocytes supporting the in situ development of the Paget cell. Histologically, Pagets disease is characterized by the infiltration of the nipple epidermis by Paget cells, described as large pale-staining cells with round or oval nuclei and prominent nucleoli. The cells are between the normal keratinocytes of the nipple epidermis, occurring singly in the superficial layers and in clusters toward the basement membrane. Paget cells do not invade through the dermal basement membrane and therefore are a form of carcinoma in situ. Pagets disease is often associated with a chronic inflammatory infiltrate in the dermis.

• #16 Case Report: Rare case of advanced metastatic… | F1000Research

  https://f1000research.com/articles/12-1498

  A rare type of breast cancer is called Pagets disease of the breast. It is a nipple-areolar complex condition that frequently coexists with in situ or invasive cancer. The epidermotropic theory states that Pagets cells are ductal cancer cells that have moved from the breast parenchyma to the nipple epidermis. The in situ transformation idea says that without any other pathologic process in the breast parenchyma. Pagets disease is a malignant disease. The nipple-areolar complex initially develops eczematous alterations due to the disease, and in later stages, the nipple-areolar complex will be destroyed by ulceration. Pagets nipple illness may be connected to primary invasive or in situ breast cancer. The generally recognized migratory idea states that ductal carcinoma in situ cells migrate from the primary tumor to the nipple and surrounding skin via milk ducts. The underlying duct carcinoma cells share similarities with Paget cells in terms of HER2 oncogene positive and epithelial cell characteristics. The precise mechanisms are less clear, although interactions between the HER2 on the tumor cells and the heregulin-alpha protein produced by nipple epidermal keratinocytes have been linked to the chemotaxis. The biopsy is crucial for making a Pagets disease diagnosis. A clinical breast exam can detect an associated breast lump in about 50% of people with Pagets disease. In Pagets disease, CD138 and p53 are regarded as positive and detrimental in the typically present Toker cells. What is extremely unusual about this case is the malignancy had spread to the adjacent structures and led to malignant pleural effusion.

• #17 Paget’s disease of the breast pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Paget%27s_disease_of_the_breast_pathophysiology

  The pathogenesis of Pagets disease of the breast still remains controversial. […] The commonly accepted hypothesis is that most cases of Paget’s disease of the breast originate from in situ or invasive ductal carcinoma of the underlying breast tissue. This is supported by two different theories: […] According to this hypothesis malignant epithelial cells from intraductal carcinoma, extend into the overlying epidermis through mammary duct epithelium and proliferate in the epidermis causing thickening of the nipple and areolar skin. […] Normal epidermal keratinocytes produce and release the mobility factor heregulin-alpha which is chemotactic for heregulin receptors (Her-2) and coreceptors Her 3 and Her 4 which are produced by Pagets cells. This is thought to result in migration of these cells to the nipple epidermis.

• #18 Paget`s disease of the Breast. Differential diagnosis using additional IHC-panel. Literature review and own observations. – Unified Citation Journals

  https://ucjournals.com/pagets-disease-of-the-breast-differential-diagnosis-using-additional-ihc-panel-literature-review-and-own-observations/

  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. […] At the present time, 2 main theories of Pagets breast disease histopathogenesis are leading: Epidermotropic and Malignant Transformation theory. […] 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. This gave rise to research in these fields of theories of the pathogenesis of Pagets carcinoma. […] 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.

• #19 Androgen receptors are frequently expressed in mammary and extramammary Paget’s disease | Modern Pathology

  https://www.nature.com/articles/3800437

  The frequent expression of AR and common coexpression of AR and Her2/neu in mammary Paget’s disease and extramammary Paget’s disease raise the important question of the role of androgen, Her2/neu, and their receptors in the pathogenesis and biology of Paget’s disease. […] The knowledge about frequent expression of AR in Paget’s disease may play a significant role in the development of new adjuvant therapeutic strategies in future, particularly in patients with recurrent diseases.

• #20 Mammary Paget Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK563228/

  Transformation theory: proposes that the PDB arises from epidermal keratinocytes independent of underlying breast malignancy and actually represents an epidermal carcinoma in situ. […] The histologic hallmark of PDB is the presence of Paget cells, which are malignant, intraepithelial adenocarcinoma cells of variable sizes usually large in size, present singly or in the form of small groups within the epidermis of the nipple. […] Immunohistochemical (IHC) staining for a nipple biopsy that does not involve tissue from the underlying mass is very helpful to differentiate from other similar lesions, especially if squamous cell carcinoma of epidermis and melanoma are the in the list of differential diagnosis.

• #21 :: Journal of Breast Disease

  https://www.jbd.or.kr/m/journal/view.php?number=126

  Intramammary Pagets disease is an uncommon disease in which 90% of the cases are accompanied by invasive or noninvasive ductal carcinoma. […] The pathogenesis of intramammary Pagets disease continues to be debated, with two main theories involved. The epidermotropic theory states that Pagets cells are ductal carcinoma cells that have migrated from the underlying breast parenchyma to the nipple epidermis, known as Pagetoid spread. […] In the in situ transformation theory, the Pagets cells arise as malignant cells in the nipple epidermis, independent from any other pathologic process within the breast parenchyma. […] Pagets cells do not invade through the dermal basement membrane and therefore are a form of carcinoma in situ. […] Intramammary Pagets disease with dermal invasion has been reported rarely worldwide, and its management and prognosis remain unknown.

• #22 SciELO Brazil – Mammary and extramammary Paget’s disease Mammary and extramammary Paget’s disease

  https://www.scielo.br/j/abd/a/x8tdYkztBBpp5vg8RzZ5bCd/

  The second theory, the degeneration of preexisting cells, considers that Paget cells are keratinocytes that have undergone malignant transformation and that the disease is an in situ carcinoma regardless of the underlying intraductal carcinoma. […] A third theory attempts to combine the two previous ones, suggesting that Paget cells can originate in both ways already mentioned, depending on local circumstances. […] Recent studies have shown that the expression of NY-BR-1, a breast differentiation antigen, may have a role in MPD’s pathogenesis.

• #23 Pathology Outlines – Paget disease

  https://www.pathologyoutlines.com/topic/breastmalignantpaget.html

  Mammary Paget disease (MPD) is a proliferation of malignant glandular epithelial cells (in situ carcinoma) in the nipple areolar epidermis (Histopathology 2020;77:181) […] 2 theories on the pathogenesis: […] Epidermotropic theory (most widely accepted): Paget cells are DCIS cells that migrate along the basement membrane of the nipple, supported by the presence of DCIS deeper in the breast identical to Paget cells in almost all cases; migration may be mediated through a motility factor heregulin α, produced by keratinocytes and exerting its effect via the HER2 receptor (J Natl Cancer Inst 2000;92:622) […] Transformation theory: Paget cells originate from malignant transformation of keratinocytes or Toker cells; it would explain rare cases (< 5%) in which cancer is not present in underlying breast (Intractable Rare Dis Res 2019;8:203) [...] When no parenchymal cancer is identified, there is a possibility that the underlying tumor has gone undetected / unsampled.

• #24 Paget’s disease of the breast pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Paget%27s_disease_of_the_breast_pathophysiology

  According to this hypothesis Paget cells are keratinocytes that have undergone malignant transformation. […] Thus it is speculated that Paget’s disease is an in situ carcinoma and is independent from any underlying parenchymal carcinoma. […] It is assumed that the underlying intraductal carcinoma coexisting with this disease is unrelated to the overlying eczematous change. […] Cases in which there is no underlying malignancy nor there is any dermal invasion. […] Cases of collision tumors in which breast cancer is located peripheral to the nipple lesion, suggesting two concurrent but separate processes. […] Cases suggesting the Paget cells may have originated intraepidermally, by the presence of microvilli and desmosomal attachments between Paget cells and keratinocytes. […] Cases in which there is genetic variation between Paget cells and cells of the underlying carcinoma.

• #25 Paget’s Disease | Oncohema Key

  https://oncohemakey.com/pagets-disease/

  Pagets disease, a rare presentation of breast cancer accounts for 1% to 3% of all breast cancers. The majority of cases are associated with an underlying malignancy and prognosis is dependent upon the stage of the underlying cancer. The pathogenesis of Pagets disease is an interesting one because there are two main theories for the origin of Pagets disease. The most widely accepted one is the epidermotropic theory, first described by Jacobeus, who suggested that the Paget cells arise in breast ducts and spread through the lactiferous sinuses to the nipple epidermis. This view is supported by several observations. First of all, it is well documented that most patients with Pagets disease have an underlying breast carcinoma which is ductal in origin and that the immunohistochemical profile and pattern of gene expression in the Paget cell and the underlying cancer are similar. In addition, heregulin alpha, a motility factor released by normal epidermal keratinocytes can induce chemotaxis of the Paget cells to migrate into the overlying nipple epidermis. Because not all Pagets disease is associated with an underlying carcinoma, another theory, the intraepidermal transformation theory (in situ transformation theory) proposes that the Paget cells arise either in the terminal portion of the lactiferous duct at its junction with the epidermis or from multipotential cells in the epidermal basal layer. This in situ transformation theory is thought to occur in pre-existing benign intraepidermal clear cells of the nipple areolar complex, or Toker cells, which are thought to have migrated from nonneoplastic ducts. Support for this theory is found in the rare cases of Pagets disease without an underlying breast carcinoma or cases in which the Pagets disease and the underlying carcinoma appear to be separate tumors. Other studies have identified desmosomal attachments between the Paget cells and adjacent keratinocytes supporting the in situ development of the Paget cell. Histologically, Pagets disease is characterized by the infiltration of the nipple epidermis by Paget cells, described as large pale-staining cells with round or oval nuclei and prominent nucleoli. The cells are between the normal keratinocytes of the nipple epidermis, occurring singly in the superficial layers and in clusters toward the basement membrane. Paget cells do not invade through the dermal basement membrane and therefore are a form of carcinoma in situ. Pagets disease is often associated with a chronic inflammatory infiltrate in the dermis.

• #26 Mammary Paget’s disease occurring after mastectomy | World Journal of Surgical Oncology | Full Text

  https://wjso.biomedcentral.com/articles/10.1186/1477-7819-4-51

  Mammary Paget’s disease accounts for 23% of all neoplastic conditions of the breast and, in most cases (up to 90%), microscopic examination shows intraepithelial (usually intraepidermal) infiltration by neoplastic cells with glandular differentiation. Most cases originate from in situ or invasive ductal carcinoma in the underlying breast tissue, but rare cases appear to have originated primarily within the nipple epidermis. […] The presence of an associated invasive tumour obviously drives the therapeutic decision-making process. Immunohistochemistry can be very helpful in diagnosing mammary Paget’s disease, particularly in cases like ours with an unusual clinical appearance, because pathologists can make some immunohistochemical analysis using particular markers, some of which are quite sensitive or specific.

• #27 Paget’s disease of the breast pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Paget%27s_disease_of_the_breast_pathophysiology

  According to this hypothesis Paget cells are keratinocytes that have undergone malignant transformation. […] Thus it is speculated that Paget’s disease is an in situ carcinoma and is independent from any underlying parenchymal carcinoma. […] It is assumed that the underlying intraductal carcinoma coexisting with this disease is unrelated to the overlying eczematous change. […] Cases in which there is no underlying malignancy nor there is any dermal invasion. […] Cases of collision tumors in which breast cancer is located peripheral to the nipple lesion, suggesting two concurrent but separate processes. […] Cases suggesting the Paget cells may have originated intraepidermally, by the presence of microvilli and desmosomal attachments between Paget cells and keratinocytes. […] Cases in which there is genetic variation between Paget cells and cells of the underlying carcinoma.

• #28 Paget`s disease of the Breast. Differential diagnosis using additional IHC-panel. Literature review and own observations. – Unified Citation Journals

  https://ucjournals.com/pagets-disease-of-the-breast-differential-diagnosis-using-additional-ihc-panel-literature-review-and-own-observations/

  Malignant transformation theory: It is assumed that Pagets cells may originate from glandular stem cells or Toker epidermal cells. […] 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 Pagets cells and the underlying ductal carcinoma express the same phenotypic apomucins that are also expressed by Toker cells. […] 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 Pagets cells are genetically different from underlying breast carcinoma cells. […] The concept of Tumor colision was introduced between Pagets 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 Pagets breast carcinoma.

• #29 Paget`s disease of the Breast. Differential diagnosis using additional IHC-panel. Literature review and own observations. – Unified Citation Journals

  https://ucjournals.com/pagets-disease-of-the-breast-differential-diagnosis-using-additional-ihc-panel-literature-review-and-own-observations/

  Malignant transformation theory: It is assumed that Pagets cells may originate from glandular stem cells or Toker epidermal cells. […] 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 Pagets cells and the underlying ductal carcinoma express the same phenotypic apomucins that are also expressed by Toker cells. […] 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 Pagets cells are genetically different from underlying breast carcinoma cells. […] The concept of Tumor colision was introduced between Pagets 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 Pagets breast carcinoma.

• #30 Paget’s disease of the breast pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Paget%27s_disease_of_the_breast_pathophysiology

  According to this hypothesis Paget cells are keratinocytes that have undergone malignant transformation. […] Thus it is speculated that Paget’s disease is an in situ carcinoma and is independent from any underlying parenchymal carcinoma. […] It is assumed that the underlying intraductal carcinoma coexisting with this disease is unrelated to the overlying eczematous change. […] Cases in which there is no underlying malignancy nor there is any dermal invasion. […] Cases of collision tumors in which breast cancer is located peripheral to the nipple lesion, suggesting two concurrent but separate processes. […] Cases suggesting the Paget cells may have originated intraepidermally, by the presence of microvilli and desmosomal attachments between Paget cells and keratinocytes. […] Cases in which there is genetic variation between Paget cells and cells of the underlying carcinoma.

• #31 Paget’s Disease of the Breast and Extramammary Paget’s Disease – Dermatology Advisor

  https://www.dermatologyadvisor.com/home/decision-support-in-medicine/dermatology/pagets-disease-of-the-breast-and-extramammary-pagets-disease/

  MPD and EMPD are neoplastic processes. The causes and cells of origin are controversial. […] MPD is largely believed to originate from underlying ductal carcinoma of the breast. Some, however, question whether Toker cells beget MPD, especially in the uncommon instances of MPD arising without underlying breast carcinoma. Toker cells are found intraepidermally in 10% of normal nipples. Their abundant cytoplasm and ability to appear singly or in clusters can mirror the appearance of MPD on pathology. Even immunostains of Toker cells and Pagets cells of MPD can overlap, leaving the pathologist to rely more heavily on the pleomorphism and atypical nuclei of Pagets cells to make the correct diagnosis. […] In contrast, EMPD is thought to arise from one of two pathways, known as primary and secondary forms. Primary EMPD is believed to arise from intraepidermal ducts of apocrine glands or pluripotent keratinocyte stem cells. The secondary form, observed in roughly 25% of reported EMPD cases, results from contiguous spread from an underlying neoplastic dermal adnexal gland or nearby organ, especially one from the urogenital and gastrointestinal tract.

• #32 Paget’s Disease | Oncohema Key

  https://oncohemakey.com/pagets-disease/

  Pagets disease, a rare presentation of breast cancer accounts for 1% to 3% of all breast cancers. The majority of cases are associated with an underlying malignancy and prognosis is dependent upon the stage of the underlying cancer. The pathogenesis of Pagets disease is an interesting one because there are two main theories for the origin of Pagets disease. The most widely accepted one is the epidermotropic theory, first described by Jacobeus, who suggested that the Paget cells arise in breast ducts and spread through the lactiferous sinuses to the nipple epidermis. This view is supported by several observations. First of all, it is well documented that most patients with Pagets disease have an underlying breast carcinoma which is ductal in origin and that the immunohistochemical profile and pattern of gene expression in the Paget cell and the underlying cancer are similar. In addition, heregulin alpha, a motility factor released by normal epidermal keratinocytes can induce chemotaxis of the Paget cells to migrate into the overlying nipple epidermis. Because not all Pagets disease is associated with an underlying carcinoma, another theory, the intraepidermal transformation theory (in situ transformation theory) proposes that the Paget cells arise either in the terminal portion of the lactiferous duct at its junction with the epidermis or from multipotential cells in the epidermal basal layer. This in situ transformation theory is thought to occur in pre-existing benign intraepidermal clear cells of the nipple areolar complex, or Toker cells, which are thought to have migrated from nonneoplastic ducts. Support for this theory is found in the rare cases of Pagets disease without an underlying breast carcinoma or cases in which the Pagets disease and the underlying carcinoma appear to be separate tumors. Other studies have identified desmosomal attachments between the Paget cells and adjacent keratinocytes supporting the in situ development of the Paget cell. Histologically, Pagets disease is characterized by the infiltration of the nipple epidermis by Paget cells, described as large pale-staining cells with round or oval nuclei and prominent nucleoli. The cells are between the normal keratinocytes of the nipple epidermis, occurring singly in the superficial layers and in clusters toward the basement membrane. Paget cells do not invade through the dermal basement membrane and therefore are a form of carcinoma in situ. Pagets disease is often associated with a chronic inflammatory infiltrate in the dermis.

• #33 SciELO Brazil – Mammary and extramammary Paget’s disease Mammary and extramammary Paget’s disease

  https://www.scielo.br/j/abd/a/x8tdYkztBBpp5vg8RzZ5bCd/

  The second theory, the degeneration of preexisting cells, considers that Paget cells are keratinocytes that have undergone malignant transformation and that the disease is an in situ carcinoma regardless of the underlying intraductal carcinoma. […] A third theory attempts to combine the two previous ones, suggesting that Paget cells can originate in both ways already mentioned, depending on local circumstances. […] Recent studies have shown that the expression of NY-BR-1, a breast differentiation antigen, may have a role in MPD’s pathogenesis.

• #34 Mammary Paget’s Disease: An Update

  https://www.mdpi.com/2072-6694/14/10/2422

  Mammary Paget’s Disease is a non-invasive cutaneous malignancy of the breast involving the nipple-areolar complex that is commonly mistaken for benign breast conditions, leading to delay in diagnosis. […] Two main theories have been proposed for how MPD arises: the epidermotropic theory and the intraepidermal origin theory. The epidermotropic theory states that Paget cells originate from underlying intraductal carcinoma cells that migrated along the basement membrane into the nipple. This theory is supported by the high incidence of MPD with underlying ductal carcinoma in situ (DCIS). […] The intraepidermal origin theory states that Paget cells result from malignant transformation of pluripotent keratinocyte stem cells or cells of apocrine gland ducts in the absence of underlying carcinoma, which also provides an explanation for cases of MPD where the nipple is spared. […] A hybrid theory proposes that Paget cells can originate either epidermotrophically or intraepidermally, depending on the circumstances and local conditions.

• #35 Paget`s disease of the Breast. Differential diagnosis using additional IHC-panel. Literature review and own observations. – Unified Citation Journals

  https://ucjournals.com/pagets-disease-of-the-breast-differential-diagnosis-using-additional-ihc-panel-literature-review-and-own-observations/

  2 Pathogenesis: 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 Pagets mammary disease. The authors considered Pagets cells to be parasitic (sporospermia or coccidia ells), which provoked Pagets carcinoma. […] Theory of degenerative skin changes: In 1902 year. Darier has safely abandoned the previously stated parasitic theory. Since then, he believed that Pagets disease arises from the epidermis and excretory ducts of the mammary gland, due to their degenerative and dystrophic changes, and Pagets cells are special epithelial elements, having undergone a specific type of cellular degeneration.

• #36 Paget`s disease of the Breast. Differential diagnosis using additional IHC-panel. Literature review and own observations. – Unified Citation Journals

  https://ucjournals.com/pagets-disease-of-the-breast-differential-diagnosis-using-additional-ihc-panel-literature-review-and-own-observations/

  2 Pathogenesis: 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 Pagets mammary disease. The authors considered Pagets cells to be parasitic (sporospermia or coccidia ells), which provoked Pagets carcinoma. […] Theory of degenerative skin changes: In 1902 year. Darier has safely abandoned the previously stated parasitic theory. Since then, he believed that Pagets disease arises from the epidermis and excretory ducts of the mammary gland, due to their degenerative and dystrophic changes, and Pagets cells are special epithelial elements, having undergone a specific type of cellular degeneration.

• #37 Paget`s disease of the Breast. Differential diagnosis using additional IHC-panel. Literature review and own observations. – Unified Citation Journals

  https://ucjournals.com/pagets-disease-of-the-breast-differential-diagnosis-using-additional-ihc-panel-literature-review-and-own-observations/

  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. […] At the present time, 2 main theories of Pagets breast disease histopathogenesis are leading: Epidermotropic and Malignant Transformation theory. […] 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. This gave rise to research in these fields of theories of the pathogenesis of Pagets carcinoma. […] 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.

• #38

  https://link.springer.com/article/10.1007/BF01807036

  The paraffin sections from 20 nipples with Paget’s disease (10 central intraductal and 10 invasive ductal carcinomas) were analyzed for human papilloma virus (HPV) DNA of the low- and intermediate/high-risk groups. […] Our results showed for the first time that this type of virus did not contribute to the pathogenesis of Paget’s disease.

• #39 Paget’s disease of the breast – VALINTERMED treatment in Valencia

  https://valintermed.com/en/medlibrary/disease-of-the-mammary-gland/

  Paget’s disease can occur both in isolated cases and in combination with other forms of cancer, which emphasizes the need for a comprehensive approach to its diagnosis and treatment. […] One of the significant contributions to the study of PPD was made in the 1980s, when it was established that skin changes can be associated with extravasation of malignant cells from the internal activity of the mammary gland. […] In addition, the TP53 gene, which is responsible for the control of apoptosis and cell division, also plays an important role in the pathogenesis of this disease. […] It is important to differentiate other diseases such as eczema, dermatitis, and infectious processes. […] The overall strategy is a comprehensive assessment of the patient’s condition, including surgical removal of the tumor, radiation therapy, and pharmacological therapy.

• #40 Androgen receptors are frequently expressed in mammary and extramammary Paget’s disease | Modern Pathology

  https://www.nature.com/articles/3800437

  The frequent expression of AR and common coexpression of AR and Her2/neu in mammary Paget’s disease and extramammary Paget’s disease raise the important question of the role of androgen, Her2/neu, and their receptors in the pathogenesis and biology of Paget’s disease. […] The knowledge about frequent expression of AR in Paget’s disease may play a significant role in the development of new adjuvant therapeutic strategies in future, particularly in patients with recurrent diseases.

• #41 Androgen receptors are frequently expressed in mammary and extramammary Paget’s disease | Modern Pathology

  https://www.nature.com/articles/3800437

  Mammary Paget’s disease and extramammary Paget’s disease are rare intraepithelial neoplasms. […] 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. […] 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. […] Normal apocrine glands of the skin and sebaceous glands are known to express androgen receptors; they are, however, negative for estrogen receptors (ERs) and progesterone receptors (PRs). […] Our study, to the best of our knowledge, is the first reporting common expression of AR in mammary Paget’s disease.

• #42 Androgen receptors are frequently expressed in mammary and extramammary Paget’s disease | Modern Pathology

  https://www.nature.com/articles/3800437

  The frequent expression of AR and common coexpression of AR and Her2/neu in mammary Paget’s disease and extramammary Paget’s disease raise the important question of the role of androgen, Her2/neu, and their receptors in the pathogenesis and biology of Paget’s disease. […] The knowledge about frequent expression of AR in Paget’s disease may play a significant role in the development of new adjuvant therapeutic strategies in future, particularly in patients with recurrent diseases.

• #43 SciELO Brazil – Mammary and extramammary Paget’s disease Mammary and extramammary Paget’s disease

  https://www.scielo.br/j/abd/a/x8tdYkztBBpp5vg8RzZ5bCd/

  The second theory, the degeneration of preexisting cells, considers that Paget cells are keratinocytes that have undergone malignant transformation and that the disease is an in situ carcinoma regardless of the underlying intraductal carcinoma. […] A third theory attempts to combine the two previous ones, suggesting that Paget cells can originate in both ways already mentioned, depending on local circumstances. […] Recent studies have shown that the expression of NY-BR-1, a breast differentiation antigen, may have a role in MPD’s pathogenesis.

• #44 Paget’s Disease of the Breast | CancerIndex

  http://www.cancerindex.org/clink3pb.htm

  Paget’s disease of the breast is characterized by eczematous changes of the nipple-areolar complex and is associated with an underlying in situ or invasive breast carcinoma in most cases. […] Recognition of Paget’s disease clinically and pathologically is critical as the superficial lesion may be the only sign of an underlying ductal carcinoma and its presence may be of prognostic significance. […] In breast cancer, COX-2 expression is associated with poor prognostic factors. […] We suggest that COX-2 expression and inflammatory processes may play a role in pathogenesis of the Paget’s disease of the breast.

• #45 Mammary Paget Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK563228/

  Transformation theory: proposes that the PDB arises from epidermal keratinocytes independent of underlying breast malignancy and actually represents an epidermal carcinoma in situ. […] The histologic hallmark of PDB is the presence of Paget cells, which are malignant, intraepithelial adenocarcinoma cells of variable sizes usually large in size, present singly or in the form of small groups within the epidermis of the nipple. […] Immunohistochemical (IHC) staining for a nipple biopsy that does not involve tissue from the underlying mass is very helpful to differentiate from other similar lesions, especially if squamous cell carcinoma of epidermis and melanoma are the in the list of differential diagnosis.

• #46 Paget’s Disease | Oncohema Key

  https://oncohemakey.com/pagets-disease/

  Pagets disease, a rare presentation of breast cancer accounts for 1% to 3% of all breast cancers. The majority of cases are associated with an underlying malignancy and prognosis is dependent upon the stage of the underlying cancer. The pathogenesis of Pagets disease is an interesting one because there are two main theories for the origin of Pagets disease. The most widely accepted one is the epidermotropic theory, first described by Jacobeus, who suggested that the Paget cells arise in breast ducts and spread through the lactiferous sinuses to the nipple epidermis. This view is supported by several observations. First of all, it is well documented that most patients with Pagets disease have an underlying breast carcinoma which is ductal in origin and that the immunohistochemical profile and pattern of gene expression in the Paget cell and the underlying cancer are similar. In addition, heregulin alpha, a motility factor released by normal epidermal keratinocytes can induce chemotaxis of the Paget cells to migrate into the overlying nipple epidermis. Because not all Pagets disease is associated with an underlying carcinoma, another theory, the intraepidermal transformation theory (in situ transformation theory) proposes that the Paget cells arise either in the terminal portion of the lactiferous duct at its junction with the epidermis or from multipotential cells in the epidermal basal layer. This in situ transformation theory is thought to occur in pre-existing benign intraepidermal clear cells of the nipple areolar complex, or Toker cells, which are thought to have migrated from nonneoplastic ducts. Support for this theory is found in the rare cases of Pagets disease without an underlying breast carcinoma or cases in which the Pagets disease and the underlying carcinoma appear to be separate tumors. Other studies have identified desmosomal attachments between the Paget cells and adjacent keratinocytes supporting the in situ development of the Paget cell. Histologically, Pagets disease is characterized by the infiltration of the nipple epidermis by Paget cells, described as large pale-staining cells with round or oval nuclei and prominent nucleoli. The cells are between the normal keratinocytes of the nipple epidermis, occurring singly in the superficial layers and in clusters toward the basement membrane. Paget cells do not invade through the dermal basement membrane and therefore are a form of carcinoma in situ. Pagets disease is often associated with a chronic inflammatory infiltrate in the dermis.

• #47 Mammary Paget’s Disease of the Nipple: Relatively Common but Still Unknown to Many

  https://www.kjfm.or.kr/journal/view.php?number=4391

  Mammary Pagets disease is clinically defined as skin inflammation of the nipple area and is an adenocarcinoma of the epidermis of the nipple. The pathogenesis of mammary Pagets disease is relatively unknown; nonetheless, there are two popular theories that support the underlying carcinoma and de novo carcinogenesis. […] Mammary Pagets disease is an adenocarcinoma that arises within the epidermis of the nipple and/or areola of the breast. Histopathologically, it is characterized by malignant glandular epithelial cells with clear and abundant cytoplasm known as Paget cells. These cells contain mucin together with pleomorphic and hyperchromatic nuclei. They are situated within the squamous epithelium of the nipple that may extend into the areola and adjacent skin. […] Mammary Pagets disease is associated with carcinoma of the underlying lactipherous ducts. The skin lesions progress slowly over months as scaly, fissured, or oozing erythema of the nipple and areola. Advanced lesions may appear as well-demarcated, eczema-like plaques with a pink or red hue.

• #48 Paget’s Disease | Oncohema Key

  https://oncohemakey.com/pagets-disease/

  Pagets disease, a rare presentation of breast cancer accounts for 1% to 3% of all breast cancers. The majority of cases are associated with an underlying malignancy and prognosis is dependent upon the stage of the underlying cancer. The pathogenesis of Pagets disease is an interesting one because there are two main theories for the origin of Pagets disease. The most widely accepted one is the epidermotropic theory, first described by Jacobeus, who suggested that the Paget cells arise in breast ducts and spread through the lactiferous sinuses to the nipple epidermis. This view is supported by several observations. First of all, it is well documented that most patients with Pagets disease have an underlying breast carcinoma which is ductal in origin and that the immunohistochemical profile and pattern of gene expression in the Paget cell and the underlying cancer are similar. In addition, heregulin alpha, a motility factor released by normal epidermal keratinocytes can induce chemotaxis of the Paget cells to migrate into the overlying nipple epidermis. Because not all Pagets disease is associated with an underlying carcinoma, another theory, the intraepidermal transformation theory (in situ transformation theory) proposes that the Paget cells arise either in the terminal portion of the lactiferous duct at its junction with the epidermis or from multipotential cells in the epidermal basal layer. This in situ transformation theory is thought to occur in pre-existing benign intraepidermal clear cells of the nipple areolar complex, or Toker cells, which are thought to have migrated from nonneoplastic ducts. Support for this theory is found in the rare cases of Pagets disease without an underlying breast carcinoma or cases in which the Pagets disease and the underlying carcinoma appear to be separate tumors. Other studies have identified desmosomal attachments between the Paget cells and adjacent keratinocytes supporting the in situ development of the Paget cell. Histologically, Pagets disease is characterized by the infiltration of the nipple epidermis by Paget cells, described as large pale-staining cells with round or oval nuclei and prominent nucleoli. The cells are between the normal keratinocytes of the nipple epidermis, occurring singly in the superficial layers and in clusters toward the basement membrane. Paget cells do not invade through the dermal basement membrane and therefore are a form of carcinoma in situ. Pagets disease is often associated with a chronic inflammatory infiltrate in the dermis.

• #49 :: Journal of Breast Disease

  https://www.jbd.or.kr/m/journal/view.php?number=126

  Intramammary Pagets disease is an uncommon disease in which 90% of the cases are accompanied by invasive or noninvasive ductal carcinoma. […] The pathogenesis of intramammary Pagets disease continues to be debated, with two main theories involved. The epidermotropic theory states that Pagets cells are ductal carcinoma cells that have migrated from the underlying breast parenchyma to the nipple epidermis, known as Pagetoid spread. […] In the in situ transformation theory, the Pagets cells arise as malignant cells in the nipple epidermis, independent from any other pathologic process within the breast parenchyma. […] Pagets cells do not invade through the dermal basement membrane and therefore are a form of carcinoma in situ. […] Intramammary Pagets disease with dermal invasion has been reported rarely worldwide, and its management and prognosis remain unknown.

• #50 :: Journal of Breast Disease

  https://www.jbd.or.kr/m/journal/view.php?number=126

  The morphological and clinical features of intra- and extramammary Pagets disease are similar; however, they differ in invasiveness. […] In extramammary Pagets disease, superficial invasion into the dermis has been reported in up to 16% of patients, and dermal invasion predicts regional lymph node metastasis and a poor prognosis. […] Intramammary Pagets disease generally shows intra-epidermal manifestation, although in very rare cases, tumor cells within the epidermis invade through the basement membrane of the skin into the dermis. […] When there is intramammary Pagets disease only, it is managed as a ductal carcinoma in situ. […] Traditionally, management of intramammary Pagets disease has been considered to be total mastectomy with ipsilateral axillary dissection. […] However, we do not have clear evidence regarding the treatments effectiveness, due to the rare incidence of the disease and a lack of research.

• #51 Invasive Paget’s Disease of the Breast: A case Report

  https://jbd.or.kr/journal/view.php?number=126

  Intramammary Pagets disease is an uncommon disease in which 90% of the cases are accompanied by invasive or noninvasive ductal carcinoma. It comprises approximately 0.7%-4.3% of all breast cancers. […] The pathogenesis of intramammary Pagets disease continues to be debated, with two main theories involved. The epidermotropic theory states that Pagets cells are ductal carcinoma cells that have migrated from the underlying breast parenchyma to the nipple epidermis, known as Pagetoid spread. In the in situ transformation theory, the Pagets cells arise as malignant cells in the nipple epidermis, independent from any other pathologic process within the breast parenchyma. […] Pagets cells do not invade through the dermal basement membrane and therefore are a form of carcinoma in situ. […] Intramammary Pagets disease generally shows intra-epidermal manifestation, although in very rare cases, tumor cells within the epidermis invade through the basement membrane of the skin into the dermis. […] There is no clear information on the clinical outcome or post-operative management of invasive intramammary Pagets disease due to its rare incidence. […] Due to its scarcity, there is still little information regarding its management and prognosis.

• #52 Paget’s Disease | Oncohema Key

  https://oncohemakey.com/pagets-disease/

  Pagets disease, a rare presentation of breast cancer accounts for 1% to 3% of all breast cancers. The majority of cases are associated with an underlying malignancy and prognosis is dependent upon the stage of the underlying cancer. The pathogenesis of Pagets disease is an interesting one because there are two main theories for the origin of Pagets disease. The most widely accepted one is the epidermotropic theory, first described by Jacobeus, who suggested that the Paget cells arise in breast ducts and spread through the lactiferous sinuses to the nipple epidermis. This view is supported by several observations. First of all, it is well documented that most patients with Pagets disease have an underlying breast carcinoma which is ductal in origin and that the immunohistochemical profile and pattern of gene expression in the Paget cell and the underlying cancer are similar. In addition, heregulin alpha, a motility factor released by normal epidermal keratinocytes can induce chemotaxis of the Paget cells to migrate into the overlying nipple epidermis. Because not all Pagets disease is associated with an underlying carcinoma, another theory, the intraepidermal transformation theory (in situ transformation theory) proposes that the Paget cells arise either in the terminal portion of the lactiferous duct at its junction with the epidermis or from multipotential cells in the epidermal basal layer. This in situ transformation theory is thought to occur in pre-existing benign intraepidermal clear cells of the nipple areolar complex, or Toker cells, which are thought to have migrated from nonneoplastic ducts. Support for this theory is found in the rare cases of Pagets disease without an underlying breast carcinoma or cases in which the Pagets disease and the underlying carcinoma appear to be separate tumors. Other studies have identified desmosomal attachments between the Paget cells and adjacent keratinocytes supporting the in situ development of the Paget cell. Histologically, Pagets disease is characterized by the infiltration of the nipple epidermis by Paget cells, described as large pale-staining cells with round or oval nuclei and prominent nucleoli. The cells are between the normal keratinocytes of the nipple epidermis, occurring singly in the superficial layers and in clusters toward the basement membrane. Paget cells do not invade through the dermal basement membrane and therefore are a form of carcinoma in situ. Pagets disease is often associated with a chronic inflammatory infiltrate in the dermis.

• #53 Paget’s Disease of the Breast

  http://www.aboutcancer.com/pagets_harris.htm

  There are two main theories for the origin of Paget’s disease. The epidermotropic theory, first described by Jacobeus, suggests that the Paget’s cells arise in breast ducts and spread by way of the lactiferous sinuses to the nipple epidermis. This view is supported by the fact that more than 97% of patients with Paget’s disease have an underlying breast carcinoma and that in the majority of cases, the immunophenotype of the Paget’s cell is the same as the breast cancer. […] The intraepidermal transformation theory proposes that the Paget’s cells arise in the terminal portion of the lactiferous duct at its junction with the epidermis; they are altered epidermal cells that have been transformed in situ. Support for this theory is found in the rare cases of Paget’s disease without an underlying breast carcinoma or cases in which the Paget’s disease and the underlying carcinoma appear to be separate tumors. […] Paget’s cells do not invade through the dermal basement membrane and therefore are a form of carcinoma in situ. Paget’s disease is frequently associated with a chronic inflammatory infiltrate in the dermis.

• #54 Paget’s Disease | Oncohema Key

  https://oncohemakey.com/pagets-disease/

  Pagets disease, a rare presentation of breast cancer accounts for 1% to 3% of all breast cancers. The majority of cases are associated with an underlying malignancy and prognosis is dependent upon the stage of the underlying cancer. The pathogenesis of Pagets disease is an interesting one because there are two main theories for the origin of Pagets disease. The most widely accepted one is the epidermotropic theory, first described by Jacobeus, who suggested that the Paget cells arise in breast ducts and spread through the lactiferous sinuses to the nipple epidermis. This view is supported by several observations. First of all, it is well documented that most patients with Pagets disease have an underlying breast carcinoma which is ductal in origin and that the immunohistochemical profile and pattern of gene expression in the Paget cell and the underlying cancer are similar. In addition, heregulin alpha, a motility factor released by normal epidermal keratinocytes can induce chemotaxis of the Paget cells to migrate into the overlying nipple epidermis. Because not all Pagets disease is associated with an underlying carcinoma, another theory, the intraepidermal transformation theory (in situ transformation theory) proposes that the Paget cells arise either in the terminal portion of the lactiferous duct at its junction with the epidermis or from multipotential cells in the epidermal basal layer. This in situ transformation theory is thought to occur in pre-existing benign intraepidermal clear cells of the nipple areolar complex, or Toker cells, which are thought to have migrated from nonneoplastic ducts. Support for this theory is found in the rare cases of Pagets disease without an underlying breast carcinoma or cases in which the Pagets disease and the underlying carcinoma appear to be separate tumors. Other studies have identified desmosomal attachments between the Paget cells and adjacent keratinocytes supporting the in situ development of the Paget cell. Histologically, Pagets disease is characterized by the infiltration of the nipple epidermis by Paget cells, described as large pale-staining cells with round or oval nuclei and prominent nucleoli. The cells are between the normal keratinocytes of the nipple epidermis, occurring singly in the superficial layers and in clusters toward the basement membrane. Paget cells do not invade through the dermal basement membrane and therefore are a form of carcinoma in situ. Pagets disease is often associated with a chronic inflammatory infiltrate in the dermis.

• #55 Mammary Paget Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK563228/

  Transformation theory: proposes that the PDB arises from epidermal keratinocytes independent of underlying breast malignancy and actually represents an epidermal carcinoma in situ. […] The histologic hallmark of PDB is the presence of Paget cells, which are malignant, intraepithelial adenocarcinoma cells of variable sizes usually large in size, present singly or in the form of small groups within the epidermis of the nipple. […] Immunohistochemical (IHC) staining for a nipple biopsy that does not involve tissue from the underlying mass is very helpful to differentiate from other similar lesions, especially if squamous cell carcinoma of epidermis and melanoma are the in the list of differential diagnosis.

• #56 Mammary Paget disease. Paget disease of the nipple

  https://dermnetnz.org/topics/mammary-paget-disease

  A skin biopsy will show the typical foamy Paget cells in the epidermis. […] A wedge biopsy of the nipple extends more deeply into the breast tissue and aids diagnosis of the underlying cancer. […] Immunohistochemistry is used to determine hormone receptor status (oestrogen receptor, progesterone receptor) and human epidermal growth receptor 2 (HER2) that can influence treatment.

• #57 Synchronous bilateral Paget’s disease of the breast: A case report

  https://www.spandidos-publications.com/10.3892/ol.2012.676

  Conversely, the intraepidermal transformation hypothesis states that malignant keratinocytes originate from the areolar epidermis. […] Currently, the epidermotropic hypothesis is more widely accepted. However, findings of our case support the intraepidermal transformation hypothesis, since there is no underlying carcinoma. […] The above-mentioned theories are plausible; however, each theory of pathogenesis entails a markedly different approach to treatment.

• #58 Accuracy of mammography and magnetic resonance imaging to diagnose underlying malignancy in Paget’s disease of the nipple: a systematic review and meta-analysis – Madsen – Annals of Breast Surgery

  https://abs.amegroups.org/article/view/7229/html

  Pagets disease (PD) of the nipple is a less common type of breast cancer. Often it is accompanied by underlying malignancy and identification of this prior to surgery plays an important role in the surgical assessment. […] Multiple studies suggest that up to 90% of the cases of PD are associated with underlying malignancy in the mamma. […] Since the majority of PD cases are associated with an underlying malignancy, the epidermotropic theory is the most widely accepted theory regarding pathogenesis. This theory proposes a migration of tumour cells originating from DCIS or IDC in the mamma through the lactiferous ducts to the epidermis on the nipple-areolar complex (NAC). Histologically, the cells are seen as characteristic big, round so-called Paget cells. The second theory, the transformation theory, proposes that PD cells are transformed in situ keratinocytes of the nipple epidermis.

• #59 Accuracy of mammography and magnetic resonance imaging to diagnose underlying malignancy in Paget’s disease of the nipple: a systematic review and meta-analysis – Madsen – Annals of Breast Surgery

  https://abs.amegroups.org/article/view/7229/html

  This study demonstrated that MRI is a significantly more accurate tool to diagnose underlying malignancy in patients with PD compared to MMG. […] Identification of underlying malignancy was found to be significantly more accurate when MRI was used in addition to MMG. Adding MRI seems therefore to improve surgical treatment of patients with PD and a negative MMG.

• #60 Synchronous bilateral Paget’s disease of the breast: A case report

  https://www.spandidos-publications.com/10.3892/ol.2012.676

  Conversely, the intraepidermal transformation hypothesis states that malignant keratinocytes originate from the areolar epidermis. […] Currently, the epidermotropic hypothesis is more widely accepted. However, findings of our case support the intraepidermal transformation hypothesis, since there is no underlying carcinoma. […] The above-mentioned theories are plausible; however, each theory of pathogenesis entails a markedly different approach to treatment.

• #61 Invasive Paget’s Disease of the Breast: A case Report

  https://jbd.or.kr/journal/view.php?number=126

  Intramammary Pagets disease is an uncommon disease in which 90% of the cases are accompanied by invasive or noninvasive ductal carcinoma. It comprises approximately 0.7%-4.3% of all breast cancers. […] The pathogenesis of intramammary Pagets disease continues to be debated, with two main theories involved. The epidermotropic theory states that Pagets cells are ductal carcinoma cells that have migrated from the underlying breast parenchyma to the nipple epidermis, known as Pagetoid spread. In the in situ transformation theory, the Pagets cells arise as malignant cells in the nipple epidermis, independent from any other pathologic process within the breast parenchyma. […] Pagets cells do not invade through the dermal basement membrane and therefore are a form of carcinoma in situ. […] Intramammary Pagets disease generally shows intra-epidermal manifestation, although in very rare cases, tumor cells within the epidermis invade through the basement membrane of the skin into the dermis. […] There is no clear information on the clinical outcome or post-operative management of invasive intramammary Pagets disease due to its rare incidence. […] Due to its scarcity, there is still little information regarding its management and prognosis.

• #62 :: Journal of Breast Disease

  https://www.jbd.or.kr/m/journal/view.php?number=126

  There are also several studies comparing invasive intramammary Pagets disease with the noninvasive type. […] Due to its scarcity, there is still little information regarding its management and prognosis. […] Further studies are necessary to determine the usefulness of sentinel lymph node biopsy and establish management protocols for invasive intramammary Pagets disease.

• #63 Patients with Nipple-Areola Paget’s Disease and Underlying Invasive Breast Carcinoma Have Very Poor Survival: A Matched Cohort Study | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0061455

  Pagets disease (PD) of the breast is a rare disease. The survival rate of PD was reported to depend on the characteristics of the underlying carcinoma. […] The pathogenesis of PD remains debatable. There are two theories about the origin of Pagets cells. The transformation theory proposes that Pagets cells are transformed in situ keratinocytes of the epidermis of the nipple. The migration theory is more widely accepted; it assumes that Pagets cells are ductal carcinoma cells that have migrated from the underlying mammary ducts to the epidermis of the nipple. It seems that both theories could be supported by our study. […] Patients with PD and underlying IBC tended to have a greater chance of lymph node involvement, lower hormone receptor expression, higher HER2 expression and worse survival compared to those without PD. The subsequent matched study confirmed that the survival of patients with PD and underlying IBC was reduced compared to patients with IBC with similar prognostic factors (stage and characteristics). This finding suggests that PD itself is an indicator of poor survival.

• #64 Mammary Paget’s Disease of the Nipple: Relatively Common but Still Unknown to Many

  https://www.kjfm.or.kr/journal/view.php?number=4391

  Pagets breast disease is characterized histologically by an epidermal migration and intraductal spread of Pagets cells. It was demonstrated that the outcome of patients with Pagets disease of the breast could be determined by the presence or absence of invasive cancer in the underlying breast tissue. […] The prognosis of mammary Pagets disease depends on the presence or absence of an underlying carcinoma and the stage of the disease. It was reported that the 5-year recurrence-free survival is 75%-90% for those with DCIS and 63%-75% for those with invasive carcinoma. Meanwhile, the 5-year overall survival rates are 94%-98% and 73%-93% in the presence of DCIS and invasive carcinoma, respectively.

• #65 Androgen receptors are frequently expressed in mammary and extramammary Paget’s disease | Modern Pathology

  https://www.nature.com/articles/3800437

  The frequent expression of AR and common coexpression of AR and Her2/neu in mammary Paget’s disease and extramammary Paget’s disease raise the important question of the role of androgen, Her2/neu, and their receptors in the pathogenesis and biology of Paget’s disease. […] The knowledge about frequent expression of AR in Paget’s disease may play a significant role in the development of new adjuvant therapeutic strategies in future, particularly in patients with recurrent diseases.

• #66 Mammary Paget Disease – MD Searchlight

  https://mdsearchlight.com/skin-problems-and-treatments/mammary-paget-disease/?utm_source=pubmedlink&utm_campaign=MDS&utm_content=34019

  At present, there is no evidence to suggest that hormone therapies, such as tamoxifen or aromatase inhibitors, can lower the risk of local disease recurrence in patients with Pagets disease of the breast who have received breast-conserving therapy and who dont have any underlying invasive carcinoma or DCIS. […] Recommendations for hormone therapy and other forms of additional treatment, like chemotherapy and trastuzumab, should be made based on the characteristics of any associated invasive carcinoma or DCIS. […] A new procedure known as photodynamic therapy has been tested recently in clinical trials for the treatment of Pagets disease. […] This method uses a drug called a photosensitizer along with special type of light that can destroy affected cells. […] Initial results suggest that photodynamic therapy is a safe, well-tolerated and possibly less invasive alternative to surgery, but more research is needed to validate its effectiveness and long-term safety.

• #67 Patients with Nipple-Areola Paget’s Disease and Underlying Invasive Breast Carcinoma Have Very Poor Survival: A Matched Cohort Study | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0061455

  Pagets disease (PD) of the breast is a rare disease. The survival rate of PD was reported to depend on the characteristics of the underlying carcinoma. […] The pathogenesis of PD remains debatable. There are two theories about the origin of Pagets cells. The transformation theory proposes that Pagets cells are transformed in situ keratinocytes of the epidermis of the nipple. The migration theory is more widely accepted; it assumes that Pagets cells are ductal carcinoma cells that have migrated from the underlying mammary ducts to the epidermis of the nipple. It seems that both theories could be supported by our study. […] Patients with PD and underlying IBC tended to have a greater chance of lymph node involvement, lower hormone receptor expression, higher HER2 expression and worse survival compared to those without PD. The subsequent matched study confirmed that the survival of patients with PD and underlying IBC was reduced compared to patients with IBC with similar prognostic factors (stage and characteristics). This finding suggests that PD itself is an indicator of poor survival.

• #68 Mammary Paget’s Disease: An Update

  https://www.mdpi.com/2072-6694/14/10/2422

  Mammary Paget’s Disease is a non-invasive cutaneous malignancy of the breast involving the nipple-areolar complex that is commonly mistaken for benign breast conditions, leading to delay in diagnosis. […] Two main theories have been proposed for how MPD arises: the epidermotropic theory and the intraepidermal origin theory. The epidermotropic theory states that Paget cells originate from underlying intraductal carcinoma cells that migrated along the basement membrane into the nipple. This theory is supported by the high incidence of MPD with underlying ductal carcinoma in situ (DCIS). […] The intraepidermal origin theory states that Paget cells result from malignant transformation of pluripotent keratinocyte stem cells or cells of apocrine gland ducts in the absence of underlying carcinoma, which also provides an explanation for cases of MPD where the nipple is spared. […] A hybrid theory proposes that Paget cells can originate either epidermotrophically or intraepidermally, depending on the circumstances and local conditions.

• #69 Mammary Paget’s Disease of the Nipple: Relatively Common but Still Unknown to Many

  https://www.kci.go.kr/kciportal/landing/article.kci?arti_id=ART002487976

  Mammary Pagets disease is clinically defined as skin inflammation of the nipple area and is an adenocarcinoma of the epidermis of the nipple. The pathogenesis of mammary Pagets disease is relatively unknown; nonetheless, there are two popular theories that support the underlying carcinoma and de novo carcinogenesis. […] For the attending medical practitioner, mammary Pagets disease poses a diagnostic and therapeutic dilemma, especially in the absence of a clinically palpable breast mass. […] A full evaluation and assessment of the patient were conducted, and mammary Pagets disease was diagnosed.

• #70 :: Journal of Breast Disease

  https://www.jbd.or.kr/m/journal/view.php?number=126

  There are also several studies comparing invasive intramammary Pagets disease with the noninvasive type. […] Due to its scarcity, there is still little information regarding its management and prognosis. […] Further studies are necessary to determine the usefulness of sentinel lymph node biopsy and establish management protocols for invasive intramammary Pagets disease.

• #71 Invasive Paget’s Disease of the Breast: A case Report

  https://jbd.or.kr/journal/view.php?number=126

  Intramammary Pagets disease is an uncommon disease in which 90% of the cases are accompanied by invasive or noninvasive ductal carcinoma. It comprises approximately 0.7%-4.3% of all breast cancers. […] The pathogenesis of intramammary Pagets disease continues to be debated, with two main theories involved. The epidermotropic theory states that Pagets cells are ductal carcinoma cells that have migrated from the underlying breast parenchyma to the nipple epidermis, known as Pagetoid spread. In the in situ transformation theory, the Pagets cells arise as malignant cells in the nipple epidermis, independent from any other pathologic process within the breast parenchyma. […] Pagets cells do not invade through the dermal basement membrane and therefore are a form of carcinoma in situ. […] Intramammary Pagets disease generally shows intra-epidermal manifestation, although in very rare cases, tumor cells within the epidermis invade through the basement membrane of the skin into the dermis. […] There is no clear information on the clinical outcome or post-operative management of invasive intramammary Pagets disease due to its rare incidence. […] Due to its scarcity, there is still little information regarding its management and prognosis.

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