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Background
This cancer shares many histologic similarity with Paget's disease of the breast. Clinically, patients present with itchy pink to red scaly areas, resembling a chronic eczema. There may be scattered islands of white hyperkeratosis. These areas may be scattered and multicentric, involving the vulva and perineum. It is a slow growing and progressive cancer which requries a wide local excision. In addition, there are occasional cases which are really underlying invasive adenocarcinomas which have secondarily spread to the overlying skin in 10-20% of cases. Underlying adenocarcinoma in 10-20% of cases represent secondary metastasis to the skin, not true extramammary Paget's disease. In these cases, the pathologist must perform a diligent search to identify a primary adenocarcinoma.
OUTLINE
EPIDEMIOLOGY CHARACTERIZATION INCIDENCE Rare AGE RANGE-MEDIAN Postmenopausal F Usually Caucasian
DISEASE ASSOCIATIONS CHARACTERIZATION Hidradenoma papilliferum Am J Dermatopathol 2000;22:439-442
May be a coincidental finding
PATHOGENESIS CHARACTERIZATION GENERAL These cells are neoplastic apocrine cells,derived from apocrine glands CLEAR CELLS OF TOKER
- Vulvar Clear Cells of Toker: Precursors of Extramammary Paget's Disease.
Willman JH, Golitz LE, Fitzpatrick JE.
From the Departments of *Pathology and daggerDermatology, University of Colorado Health Sciences Center, Denver, Colorado.
Am J Dermatopathol. 2005 Jun;27(3):185-188. Abstract quote
Clear cells of Toker are intraepithelial cells with clear to pale staining cytoplasm and bland cytologic features found with H&E staining in approximately 10% of normal nipples. Toker cells have been hypothesized as a precursor of extramammary Paget's disease (EMPD), although Toker cells have not been identified as a normal component of genital skin.
Using immunohistochemistry, we studied 11 vulvectomies for the presence of Toker cells in association with mammary-like glands of the vulva (MLG). A retrospective study of 11 vulvectomies was performed using routine hematoxylin and eosin staining, as well as immunohistochemical staining for cytokeratin 7 (CK7). Control sections of skin not involving the milk line from age-matched patients were also examined.
Four of eleven vulvectomies (36%) demonstrated Toker cells with CK7 staining. Toker cells were associated with the openings of the ducts of mammary-like glands of the vulva. Toker cells were not seen in control tissues. Toker cells occur as a normal constituent of genital skin in association with mammary-like glands of the vulva. Previous morphologic, immunohistochemical, and ultrastructural evidence have pointed to Toker cells as a precursor of EMPD.
The demonstration of Toker cells in genital skin strengthens the evidence of their role in the development of EMPD.E-CADHERIN
Department of Obstetrics and Gynaecology, Royal Free and University College Medical School (Hampstead Campus), University College London, London, UK.
The growth and metastasis of many cancers is due in part to loss of cell-cell adhesion. E-cadherin, plakoglobin and beta-catenin are important in cell adhesion. Our aim was to examine the presence of these molecules in Paget's disease of the vulva and Paget's disease of the breast, and to correlate any differences in their expression with the presence of invasive disease or an underlying carcinoma.
Sixty-three archival cases of Paget's disease of the vulva, including eight associated with invasive disease, and 23 archival cases of Paget's disease of breast, which included 10 cases with ductal carcinoma in situ alone, four cases with both ductal carcinoma in situ and invasive carcinoma, and five cases with underlying invasive carcinoma alone, were analysed immunohistochemically for expression of E-cadherin, plakoglobin and beta-catenin proteins. The respective mRNAs were also detected by in situ hybridisation using digoxigenin-labelled cRNA probes. Seventy-six percent (41/54) of Paget's disease of vulva cases had >50% of Paget cells expressing the E-cadherin protein, compared with 28 % (2/7) of Paget's disease vulva with invasive disease. This result was significant, with a P-value of 0.039. Twenty-five percent (14/55) of the intraepidermal Paget's disease of the vulva cases had >50% of Paget cells expressing the plakoglobin protein, compared with 12% (1/8) of cases of Paget's disease of vulva with invasive disease, and for beta-catenin, 9% (5/55) of the non-invasive Paget's disease of the vulva had >50% of Paget cells expressing beta-catenin, compared with 12% (1/8) of Paget's disease of the vulva cases with invasive disease. Sixty-five percent (15/23) of the Paget's disease of the breast had >50% of Paget cells expressing E-cadherin, and for plakoglobin and beta-catenin it was 17% (4/23) and 28% (6/21), respectively. The results were not significant.
The results suggest that reduced expression of E-cadherin may have a role to play in the pathogenesis of invasive Paget's disease of the vulva. Abnormal plakoglobin expression may be involved in the formation of some cases of Paget's of the vulva and the breast.
- Liu H,
- Urabe K,
- Uchi H,
- Takeuchi S,
- Nakahara T,
- Dainichi T,
- Tu Y,
- Furue M,
- Moroi Y.
Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Background: Stat5 has been shown to regulate the proliferation and inhibition of apoptosis in cancer cells. E-cadherin plays an important role in maintaining epithelial stability and is widely regarded as a prognostic marker in many types of human cancers. The expression of Stat5 has not been investigated in extramammary Paget's disease (EMPD).
Objectives: To study the expression of Stat5a and E-cadherin protein in EMPD and to evaluate the relationships between them.
Methods: Thirty-six tissue samples from 34 cases with primary EMPD were subjected to immunohistochemical staining for Stat5a and E-cadherin.
Results: Twenty-nine of 30 in situ EMPD specimens were positive for Stat5a expression, and the staining pattern for Stat5a was mainly nuclear in the majority of Paget's cells. All four invasive specimens and two metastatic lymph node specimens were negative for Stat5a. Twenty-six of 30 in situ EMPD specimens expressed E-cadherin in more than 50% of tumor cells, and three of 30 in situ EMPD specimens expressed E-cadherin in less than 50% of tumor cells. One in situ EMPD specimen and one invasive specimen expressed E-cadherin in less than 25% of tumor cells. Three invasive specimens and two metastatic lymph node specimens were negative, with occasional membranous staining for E-cadherin. There is a significant correlation between the expression of Stat5a and E-cadherin.
Conclusions: Our results showed that these proteins were found in in situ lesions, and it is speculated that these proteins may play some role in the prognosis/invasion of EMPD.HER2
- Extramammary Paget's disease: analysis of growth signal pathway from the human epidermal growth factor receptor 2 protein.
Ogawa T, Nagashima Y, Wada H, Akimoto K, Chiba Y, Nagatani T, Inayama Y, Yao M, Aoki I, Ikezawa Z.
Department of Environmental Immunodermatology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Hum Pathol. 2005 Dec;36(12):1273-80. Epub 2005 Oct 28. Abstract quote
Paget's disease is a skin cancer characterized by characteristic (Paget) cells scattered in the epidermis. Although its prognosis is generally favorable with surgical resection, the clinical outcome turns unfavorable in cases with recurrence and metastasis. Therefore, establishment of effective therapeutic regimens is required for advanced Paget's disease.
The human epidermal growth factor receptor 2 (HER2) protein, a transmembrane growth factor receptor, is frequently overexpressed in malignancies, causing activation of the phosphatidylinositol 3 kinase (PI3K) and extracellular signal-regulated kinase (ERK) signal pathways. Recently, HER2-targeting molecular therapy using trastuzumab (Herceptin; Genentech, Inc, South San Francisco, Calif) was revealed to be effective in advanced breast cancers overexpressing HER2 protein. Here, we analyzed the correlation between activation of the HER2 signal pathways and clinicopathologic parameters of 36 extramammary Paget's disease samples from 34 Japanese patients, using immunohistochemical analyses for HER2, phosphorylated HER2, phosphorylated AKT, and phosphorylated ERK proteins.
We found overexpression of the HER2 protein in 19.4% (7) of the lesions, 3 of which showed HER2 amplification by chromogenic in situ hybridization. Phosphorylated HER2 protein was detected in 12 lesions (33.3%), including 2 of the 7 HER2-overexpressing lesions. Phosphorylated AKT was detected in approximately 75.0% (27/36) and phosphorylated ERK in 38.9% (14/36). Both HER2 and AKT were simultaneously phosphorylated in 9 cases (25.0%) and HER2 and ERK in 9 cases (25.0%), but all 3 molecules were phosphorylated in only 1 sample. Phosphorylated ERK correlated with the maximum diameter of the tumors (P < .025), but other immunohistochemical parameters failed to show any correlation with clinicopathologic features.
These results suggest the contribution of the HER2 signaling pathway to the pathogenesis and progression of some cases of extramammary Paget's disease, for which clinical use of molecular target therapy against the HER2 pathway is warranted.
- p185(HER2) overexpression and HER2 oncogene amplification in recurrent vulvar Paget's disease.
Reich O, Liegl B, Tamussino K, Regauer S.
1Department of Obstetrics and Gynecology.
Mod Pathol. 2005 Mar;18(3):354-7. Abstract quote
We evaluated p186(Her2) overexpression and HER2 oncogene amplification in recurrent vulvar Paget's disease.
We identified six patients with recurrent vulvar Paget's disease in our archives. The number of recurrences ranged from 1 to 11 over a time period of 1-168 months. Recurrences were evaluated immunohistochemically for p185(Her2) overexpression with the HercepTest(R) and for HER2 oncogene amplification with fluorescence in situ hybridization. p185(Her2) overexpression was scored as 3 in two patients, as 2 in two patients, and as 1 in two patients. All patients with scores 2 and 3 showed HER2 oncogene amplification.
Overexpression of p185(Her2) and HER2 oncogene amplification appears to be common in recurrent vulvar Paget's disease.MUCIN GENES Differential Expression of Mucin Genes in Mammary and Extramammary Paget's Disease
Shih-Fan Kuan, M.D. , Ph.D. ; Anthony G. Montag, M.D. ; John Hart, M.D. ; Thomas Krausz, M.D. ; Wendy Recant, M.D.
From the Department of Pathology, University of Chicago Hospitals, Chicago, Illinois, U.S.A.
Am J Surg Pathol 2001;25:1469-1477 Abstract quote
Paget's disease (PD) of the skin is characterized by intraepidermal adenocarcinoma cells, which contain clear cytoplasm and abundant mucin. Nearly all cases of mammary PD (MPD) are associated with underlying ductal carcinoma of the breast, whereas in the majority of cases of extramammary PD (EMPD) no underlying regional malignancy is identified. Mucins are high molecular weight glycoproteins produced by epithelial cells. Different mucin genes are expressed in various types of tissues such as mammary glands, intestinal mucosa, and adnexal structures of the skin.
We studied the immunohistochemical expression of apomucin MUC1, MUC2, MUC5AC in MPD, and EMPD. MUC1 is commonly expressed in most cases of PD. MUC5AC is a unique mucin that is exhibited in the majority of cases of EMPD, but not in any MPD. Of the 13 patients with MPD who all had associated breast ductal carcinoma, both Paget cells and underlying ductal carcinoma exhibited the phenotype (MUC1+MUC2–MUC5AC–). This mucin phenotype is also expressed by Toker cells, which have been identified in the epidermis of five of 50 nipples in mastectomies without MPD. Of the three patients with perianal PD who all had associated rectal adenocarcinoma, Paget's cells expressed MUC2 constantly but expressed MUC1 and MUC5AC variably. Seven patients with intraepidermal vulvar PD and two patients with scrotal–penile PD had no identifiable underlying malignancy. Paget cells from all of these nine cases of EMPD expressed a uniform phenotype of mucin (MUC1+MUC2–MUC5AC+). One case of vulvar PD associated with underlying apocrine carcinoma had a phenotype (MUC1+MUC2–MUC5AC–) identical to that of normal apocrine glands. The skin appendage and Bartholin's glands from 20 normal-appearing vulvar skin samples and anal glands from 10 hemorrhoidectomies were also studied. Only Bartholin's gland expressed a mucin phenotype identical to that of intraepidermal EMPD.
The results of the present study indicate that 1) MPD may arise from either mammary glands or epidermal Toker cells, 2) intraepidermal EMPD in the anogenital areas may arise from ectopic MUC5AC+ cells originating from Bartholin's or some other unidentified glands, and 3) unique expression of MUC2 in perianal PD indicates its origin from colorectal mucosa. We conclude that the study of mucin gene expression is useful in identifying the histogenesis of PD.
HISTOLOGICAL TYPES CHARACTERIZATION General Intraepithelial cells larger than keratinocytes occasionally forming glandular spaces
Occasional mitotic figures
No cytoplasmic pigmentVARIANTS APOCRINE CARCINOMA
Extramammary Paget Disease of the Axilla Associated With Comedo-like Apocrine Carcinoma In Situ.Castelli E, Wollina U, Anzarone A, Morello V, Tomasino RM.
Institute of Pathology (E.C., A.L., V.M., R.M.T.), University of Palermo, Palermo, Italy; and Department of Dermatology (U.W.), Hospital Dresden-Friedrichstadt, Dresden, Germany.
Am J Dermatopathol 2002 Aug;24(4):351-7 Abstract quote Extramammary Paget disease of the axilla with underlying apocrine carcinoma has been reported only in six cases until now. This report deals with a seventh case characterized by the unique finding of comedo-like features evocative of large cell ductal breast carcinoma within an otherwise typical in situ apocrine carcinoma.
This is characterized by spiral-shaped foci of epithelial proliferation with decapitation secretion and central masses of necrotic debris. A possible connection between the solid neoplasm and the overlying Paget disease is illustrated by a few apocrine-follicular units colonized by both the Paget cells and the structured adenocarcinoma. Here, although they display the same immunohistologic pattern of glandular differentiation, the two populations seem to be cytologically different and do not show signs of gradual transition to one another. Thus, they give the impression of parallel but distinct processes, which is consistent with the hypothesis of proliferative induction of a preexisting intraepidermal scattered population from the underlying adnexal carcinoma.
The observed resemblance between apocrine carcinoma and comedo carcinoma of the breast, with its ontogenetic and phylogenetic implications, links not only the two neoplasms and the corresponding glands of origin but also mammary and extramammary Paget disease. This reinforces the unifying conception of Paget disease.
DEPIGMENTED Depigmented genital disease Br J Dermatol 1994;130:102
J Cutan Pathol 2001;28:105-108Extensive intraepithelial proliferation of atypical pagetoid cells with markedly reduced epidermal melanization but nearly normal numbers of melanocytes
Tumor cells strongly positive for AE1/AE3 with some cells showing a tadpole morphology, reminiscent of clear cell papulosis, suggesting a histiogenetic association
FIBROEPITHELIOMA CHANGES Proliferative Epidermal Lesions Associated With Anogenital Paget's Disease
Jennifer A. Brainard, M.D.; William R. Hart, M.D.
From the Department of Anatomic Pathology, Division of Pathology and Laboratory Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio, U.S.A.
Am J Surg Pathol 2000;24:543-552 Abstract quote
A series of 35 cases of Paget's disease (PD) of the vulva and perianal area were studied to characterize the spectrum of proliferative epidermal lesions that occur in this rare disease but generally have been overlooked. The study group consisted of 8 men and 27 women with a median age of 66 years. Nineteen patients (54%) had one or more benign proliferative epidermal lesions, including 7 of 22 patients (32%) with vulvar PD and 12 of 13 patients (92%) with perianal PD. Two patients also had malignant squamous cell neoplasms.
Three categories of epidermal hyperplasia were identified: (1) squamous hyperplasia NOS (34%), (2) fibroepithelioma-like hyperplasia (32%), and (3) papillomatous hyperplasia (29%).
Small nests of hyperplastic squamous cells protruding into the dermis simulated microinvasive squamous carcinoma in three of these cases. None of the nine papillomatous hyperplasias tested for HPV by in-situ hybridization were positive. The squamous hyperplasia NOS and the papillomatous hyperplasia did not show a predilection for an anatomic site. In contrast, fibroepithelioma-like hyperplasia occurred in 69% of perianal PD compared with only 9% of vulvar cases. There was no association between the type of epidermal hyperplasia and the presence of a regional internal cancer. Two patients with vulvar PD had malignant squamous lesions, including one with squamous cell carcinoma in-situ (CIS) of classic type and one patient with invasive squamous cell carcinoma (InvSCC); the latter also had invasive PD. The malignant squamous component in both patients was positive for HPV 16/18, whereas the associated Paget's cells were HPV-negative.
The finding of fibroepithelioma-like hyperplasia in the anogenital skin should prompt a thorough search for Paget's cells. Papillomatous hyperplasia may be misinterpreted as condyloma acuminatum when Paget's cells are few in number and have koilocytotic-like vacuolar change or for warty (condylomatous) carcinoma when pseudoinvasive foci are present. When Paget's cells are florid and diffusely infiltrate an acanthotic epidermis, classic CIS may be misdiagnosed. Cytokeratin 7 immunostain is an excellent marker for intraepithelial and invasive Paget's cells that aids in their distinction from hyperplastic and malignant squamous cells.
Fibroepithelioma-like changes occurring in perianal Paget's disease with rectal mucinous carcinoma: case report and review of 49 cases of extramammary Paget's disease.Ishida-Yamamoto A, Sato K, Wada T, Takahashi H, Toyota N, Shibaki T, Yamazaki K, Tokusashi Y, Miyokawa N, Iizuka H.
Department of Dermatology, Asahikawa Medical College, Asahikawa, Japan, South 6th Avenue Dermatology Clinic, Asahikawa, Japan, First Departmentof Surgery, Asahikawa Medical College, Asahikawa, Japan, Department of Surgical Pathology, Asahikawa Medical College, Asahikawa, Japan.
J Cutan Pathol 2002 Mar;29(3):185-189 Abstract quote BACKGROUND: Anogenital Paget's disease (PD) may be accompanied by varying degrees of epidermal hyperplasia. The histological changes can be reminiscent of fibroepithelioma of Pinkus.
METHODS: We present a case of perianal PD associated with fibroepitheliomatous epidermal hyperplasia in a 76-year-old-man with an underlying rectal mucinous carcinoma. We also carried out a retrospective analysis of 51 biopsies from 49 cases of extramammary PD to see whether particular epidermal changes occur in association with PD in different anatomic locations.
RESULTS: A tumor, 3 cm in diameter, was noted in the patient's perianal skin. Histologically, it was composed of anastomosing thin epithelial strands with follicular differentiation. Paget's cells were distributed in the epithelial strands of this tumor as well as in the surrounding epidermis and anal epithelia. In our series of extramammary PD, epidermis was hyperplastic in two of two perianal cases, 26 of 43 genital skin samples, and one of six axillary PD biopsies. The stroma beneath the hyperplastic epidermis tended to be rich in thin collagen fibers and fibroblasts.
CONCLUSIONS: Anogenital PD was more frequently associated with epidermal hyperplasia than axillary PD. Fibroepitheliomatous hyperplasia may be induced by the altered stroma associated with PD.
SPECIAL STAINS/
IMMUNO-
PEROXIDASE/
OTHERCHARACTERIZATION Paget cells Positive for:
CAM5.2
EMA
Low MW Cytokeratin (35betaH11)
Mucicarmine
CK7
GCDFP15ANDROGEN RECEPTORS
Mod Pathol. 2005 Oct;18(10):1283-8. Abstract quote
Mammary Paget's disease and extramammary Paget's disease are rare intraepithelial neoplasms. Mammary Paget's disease is almost exclusively associated with underlying invasive breast carcinoma or high-grade ductal carcinoma in situ (DCIS G3).
Extramammary Paget's disease arises in areas rich in apocrine glands and is suspected to have apocrine gland origin.
The aim of the study was to investigate the presence of estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR) and Her2/neu in a large number of cases.
We investigated 58 cases of mammary and 23 cases of extramammary Paget's disease. Formalin-fixed and paraffin-embedded tissues were analyzed using antibodies against AR, PR, ER and Her2/neu according to standardized procedures. In mammary Paget's disease, positive immunoreactions for Her2/neu, AR and ER were observed in 56 of 58 (97%), 51 of 58 (88%), and respectively in six of 58 (10%) cases. All cases of mammary Paget's disease were negative for PR and showed a coexpression of Her2/neu and AR in 51 out of 58 cases (88%). In extramammary Paget's disease, positive immunoreactions for AR, Her2/neu and ER were observed in 18 of 23 (78%), 12 of 23 (52%), and respectively in 1 of 23 (4%) cases. All cases of extramammary Paget's disease were negative for PR and showed a coexpression of AR and Her2/neu in 12 out of 23 cases (52%). In contrast to ER and PR, AR and Her2/neu are commonly expressed in mammary and extramammary Paget's disease.
The knowledge about frequent expression of AR in Paget's disease could lead to the development of a new adjuvant therapy, particularly in patients with recurrent disease.BD ProEX C
Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
The differential diagnosis of perineal biopsies can include squamous intraepithelial lesions, extramammary Paget's disease, and melanoma. Less frequently two of these lesions coexist. BD ProEx C is a recently developed immunoassay that targets expression of two genes shown to be associated with cervical cancer. Immunostaining for ProEx C has been validated in cervical cytology and positive staining has also been shown to be strongly associated with human papilloma virus (HPV)-induced cervical and anal intraepithelial neoplasia in biopsies.
We observed positive staining for ProEx C in Paget cells in all of 26 cases of Paget's disease irrespective of tissue site (extramammary, mammary) and in melanoma cells in all of 12 cases of primary perineal melanoma with immunostaining in >50% of malignant cells in 73% of Paget disease cases and 43% of perineal melanoma cases. Positive staining was heterogeneous and exclusively nuclear in all cases.
In situ hybridization was negative for low-risk and high-risk HPV subtypes in all Paget and melanoma cases that were tested. Currently neither of these lesions is known to be HPV related although according to the literature the possibility of a role for HPV in melanoma is still unsettled. Relevant literature is reviewed.Ber-EP4
Department of Dermatology, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
BACKGROUND: While cytokeratin 7 is a reliable marker for most cases of Paget's disease, it is not 100% sensitive. Moreover, cases of cytokeratin 7-positive pagetoid squamous cell carcinoma in situ are reported in the literature. The monoclonal antibody Ber-EP4 is diagnostically highly reliable in the differentiation between basal cell carcinoma and cutaneous squamous cell carcinoma. Here we report its application in the differential diagnosis of cutaneous pagetoid neoplasms.
METHODS: Biopsy samples from 21 cases of extramammary Paget's disease, 12 pagetoid squamous cell carcinomas in situ and 10 pagetoid melanomas in situ of the superficial spreading type were examined immunohistochemically with Ber-EP4, 34betaE12 and HMB-45.
RESULTS: Ber-EP4 selectively labeled all cases of extramammary Paget's disease but none of the other pagetoid neoplasms. The majority of cases (18 = 85.7%) displayed strong and three (14.3%) showed moderate immunoreactivity.
CONCLUSIONS: Ber-EP4 reliably differentiates extramammary Paget's disease from pagetoid squamous cell carcinoma in situ and pagetoid melanoma in situ. The antibody should be included along with a panel of other markers when evaluating for pagetoid cutaneous neoplasms in order to avoid a possible misdiagnosis of pagetoid squamous cell carcinoma in situ.MATRILYSIN
- Matrilysin-1 (MMP-7) and MMP-19 are expressed by Paget's cells in extramammary Paget's disease.
Kuivanen T, Tanskanen M, Jahkola T, Impola U, Asko-Seljavaara S, Saarialho-Kere U.
Department of Dermatology, Helsinki University Central Hospital and Biomedicum Helsinki, Helsinki, Finland.
J Cutan Pathol. 2004 Aug;31(7):483-91. Abstract quote
BACKGROUND: Extramammary Paget's disease (EMPD) is a rare malignant neoplasm of apocrine gland bearing skin characterized by intraepidermal proliferation of adenocarcinoma cells. Tumor growth depends on the ability of tumor cells to migrate by proteolysis and on angiogenesis. The matrix metalloproteinase (MMP) enzymes have been implicated in both of these processes in other types of skin cancer. METHODS: The expression of MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-13, and MMP-19 was analyzed by immuno- histochemistry and/or in situ hybridization in 27 EMPD and five mammary PD (MMPD) specimens. The distribution of laminin-5 (LN-5) and tenascin-C, two extracellular matrix proteins associated with tumor invasion, was studied by immunohistochemistry.
RESULTS: MMP-7 (matrilysin-1) and MMP-19 were the most frequently expressed MMPs in Paget's cells. Overexpression of MMP-2, MMP-9, or MMP-13, which is seen in many cancers, was not evident in EMPD. LN-5 and tenascin-C positivity did not correlate with the level of invasion. MMP-7, MMP-13, and MMP-19 were detected abundantly in MMPD, while MMP-9 was absent.
CONCLUSIONS: MMP expression did not generally associate with the level of invasion of EMPD. In three samples positive for MMP-7 and four samples positive for MMP-19, an underlying carcinoma was detected, suggesting the importance of these two MMPs as predictors of secondary EMPD or the putative origin of Paget's cells from the dermal adenocarcinoma cells of apocrine duct origin.MUCIN
The ectopic expression of gastric mucin in extramammary and mammary Paget's disease.Kondo Y, Kashima K, Daa T, Fujiwara S, Nakayama I, Yokoyama S.
Department of Pathology, Oita Medical University, Oita, Japan.
Am J Surg Pathol 2002 May;26(5):617-23 Abstract quote The immunohistochemical analysis of the ectopic expression of gastric mucin has been used as a valuable tool for the identification of several neoplasms.
We performed an immunohistochemical examination of the expression of gastric, intestinal, and mammary-type mucins in 25 lesions from patients with extramammary Paget's disease (ExMPD) and in 10 lesions from patients with mammary Paget's disease (MPD). All ExMPD lesions were immunopositive for HGM-45, a marker of gastric surface mucous cells, whereas only 40% of MPD lesions were weakly immunopositive. No markers for gastric-gland mucous cells were found in almost all ExMPD and MPD lesions, and markers for intestinal mucin were recognized in only a few lesions. Antibodies specific for MUC1, a marker of mammary-type mucin, gave positive results in both ExMPD and MPD lesions at a higher frequency than antibodies specific for gross cystic disease fluid protein-15. Our analysis indicates that Paget's cells contain gastric surface-type mucin in ExMPD and they contain mammary-type mucin in both ExMPD and MPD.
The ectopic localization of mucosubstances may be a further step in the understanding of these lesions. Moreover, antibodies against MUC1 seem to be a useful tool for the diagnosis of both ExMPD and MPD.
SYNDECAN-1
Immunolabeling pattern of syndecan-1 expression may distinguish pagetoid Bowen's disease, extramammary Paget's disease, and pagetoid malignant melanoma in situ.
Bayer-Garner IB, Reed JA.
Marshfield Clinic, Marshfield, WI, and Baylor College of Medicine, Houston, TX, USA.
J Cutan Pathol. 2004 Feb;31(2):169-73. Abstract quote
The differential diagnosis of pagetoid cells within the epidermis rests primarily between pagetoid Bowen's disease (PBD), extramammary Paget's disease (EPD), and pagetoid malignant melanoma (MIS) in situ. Although morphologic clues are often helpful in differentiating these lesions, the use of immunohistochemistry is often necessary to arrive at the correct diagnosis.
Syndecan-1 is a cell-surface proteoglycan that mediates adhesion between cells and the extracellular matrix, and between cells themselves. Twenty-two cases of PBD, four cases of intraepidermal EPD, and 13 cases of MIS were examined for syndecan-1 immunoreactivity. Cell-membrane syndecan-1 immunoreactivity was evident in PBD, cytoplasmic syndecan-1 immunoreactivity was evident in EPD, whereas immunoreactivity for syndecan-1 was not present in MIS.
The patterns of syndecan-1 immunoreactivity in these lesions may be a useful adjunct in the differentiation of PBD, EPD, and MIS.ZIRCONYL HEMATOXYLIN
Zirconyl hematoxylin vs. alcian blue staining in a case of extramammary Paget's disease.Smith AA, Silver TM.
School of Graduate Medical Sciences, Barry University, Miami Shores, FL, and Virginia Commonwealth University, Richmond, VA, USA.
J Cutan Pathol. 2003 Jul;30(6):401-4. Abstract quote BACKGROUND: Despite its occasional unavailability, alcian blue has long been the stain of choice for the pathognomonic mucin-secreting cells of extramammary Paget's disease. Zirconyl hematoxylin is a recently developed substitute for alcian blue, which is made from common laboratory materials.
METHODS: We have stained sections from three different areas of the same case of extramammary Paget's disease with zirconyl hematoxylin, destained in 7% HCl in ethanol, restained with alcian blue at pH 2.5, destained in 2.5% trifluoroacetic acid in dichloromethane, and restained with zirconyl hematoxylin.
RESULTS: Each staining procedure stained the same cells.
CONCLUSIONS: Zirconyl hematoxylin is a useful alternative to alcian blue in the diagnosis of extramammary Paget's disease.
CYTOKERATIN
Keratin profile of intraepidermal cells in Paget's disease, extramammary Paget's disease, and pagetoid squamous cell carcinoma in situ.Lau J, Kohler S.
Department of Dermatology, and Department of Pathology, Stanford University, Stanford, CA, USA.
J Cutan Pathol. 2003 Aug;30(7):449-54. Abstract quote BACKGROUND: Although the histopathologic differential diagnosis of pagetoid neoplasms is broad, unique histopathologic identifiers and clinical correlation can often identify the process. However, in the case of mammary Paget's disease (MPD) or extramammary Paget's disease (EPD) without an obvious underlying malignancy, distinction from pagetoid squamous cell carcinoma in situ (PSCCIS) can be challenging. Our goal was to better define the immunohistochemical staining patterns of these three entities in the hope of determining distinctive staining patterns.
METHODS: We evaluated nine cases of PSCCIS, five cases of MPD, and 10 cases of EPD with the immunohistochemical antibodies CAM 5.2 and CK 5/6. In addition, only PSCCIS was stained with CK 7, as the staining patterns of CK 7 in MPD and EPD are well known from prior studies.
RESULTS: CAM 5.2 diffusely stained all cases of MPD and EPD and failed to stain any case of PSCCIS. Furthermore, CK 7 only focally stained two of the 10 cases of PSCCIS. CK 5/6 was difficult to interpret due to the high functional background staining of the normal keratinocytes in the epidermis.
CONCLUSIONS: Based on these results, our data supports the use of CAM 5.2 and CK 7 immunoperoxidase markers in differentiating between difficult cases of PSCCIS and MPD or EPD. An antibody panel consisting of S-100, CAM 5.2, and CK 7 will aid in the accurate diagnosis of almost all pagetoid neoplasms of the breast or genital skin.
Cytokeratin Subset Immunostaining in Rectal Adenocarcinoma and Normal Anal Glands
Preetha Ramalingam, MD, William R. Hart, MD, and John R. Goldblum, MD
From the Division of Pathology and Laboratory Medicine, Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, Ohio.
Arch Pathol Lab Med 2001;125:1074–1077. Abstract quote
Context. —A large percentage of cases of perianal Paget disease are associated with an internal cancer, most commonly rectal adenocarcinoma. Immunostains for cytokeratin 7, cytokeratin 20, and gross cystic disease fluid protein 15 are useful in identifying cases associated with rectal adenocarcinoma. The Paget cells and rectal adenocarcinoma cells of these lesions typically have a cytokeratin 7+/cytokeratin 20+/gross cystic disease fluid protein 15 immunophenotype. It is not known whether rectal adenocarcinoma unassociated with perianal Paget disease has the same cytokeratin profile as rectal adenocarcinoma associated with perianal Paget disease.
Objective. —To evaluate the immunohistochemical cytokeratin 7 and 20 profile of resected rectal adenocarcinoma unassociated with perianal Paget disease as well as that of normal anal glands from hemorrhoidectomy specimens.
Design. —We performed immunohistochemistry for cytokeratins 7 and 20 on tissues from 30 cases of rectal adenocarcinoma unassociated with perianal Paget disease and 12 hemorrhoidectomy specimens from 12 cases with normal anal glands. We defined positive staining as any immunoreactivity within the neoplastic cells.
Results.—Twenty-six of 30 cases of rectal adenocarcinoma (87%) had a cytokeratin 7 /cytokeratin 20+ immunophenotype, similar to the immunophenotype of cases of nonrectal large intestine adenocarcinoma. In 4 cases (13%), neoplastic cells coexpressed cytokeratins 7 and 20. Anal glands stained strongly for cytokeratin 7 but were negative for cytokeratin 20 in all cases, and the anal transitional zone mucosa had a similar immunophenotype.
Conclusions. —Rectal adenocarcinoma unassociated with perianal Paget disease has a cytokeratin profile similar to that of nonrectal large intestine adenocarcinoma. These data suggest that rectal adenocarcinoma unassociated with perianal Paget disease has a different cytokeratin profile than rectal adenocarcinoma associated with perianal Paget disease.
RCAS1 RCAS1 antigen is highly expressed in extramammary Paget's disease and in advanced stage squamous cell carcinoma of the skin.
Takahashi H, Iizuka H, Nakashima M, Wada T, Asano K, Ishida-Yamamoto A, Watanabe T.
Department of Dermatology, Asahikawa Medical College, 2-1-1-1 Midorigaokahigashi,0788510, Asahikawa, Japan.
J Dermatol Sci 2001 Jun;26(2):140-4 Abstract quote
Receptor-binding cancer antigen expressed on SiSo cells (RCAS1), which is a type II membrane protein expressed on cervical carcinoma cells, induces apoptosis in RCAS1 receptor expressing cells. RCAS1 is thus presumed to protect tumor cells from immune surveillance by infiltrating RCAS1 receptor-positive immunocytes (Sonoda et al. Int J Oncol 1995; 6: 1899-1904; Nakashima et al. Nature Med 1999; 5: 938-942).
We performed immunohistochemical analysis of RCAS1 expression in various skin tumors. RCAS1 was not detected in normal human epidermis.
One of 21 seborrheic keratosis (4.8%), one of 12 actinic keratosis (8.3%), two of 16 keratoacanthomas (12.5%), and two of 14 basal cell carcinomas (14.2%) expressed RCAS1. RCAS1 was not detected in Bowen's disease (0/17). RCAS1 was positive in 45 of 61 (73.8%) squamous cell carcinomas. Interestingly, the expression of RCAS1 was mostly correlated with clinical stages of squamous cell carcinoma. It was found that 46.1% of stage I, 61.1% of stage II, 85.7% of stage III, and 83.3% of stage IV squamous cell carcinomas were RCAS1-positive. In addition, RCAS1 was found to be highly expressed in extramammary Paget's disease. Fifty nine of 63 extramammary Paget's disease samples (93.7%) were positive for RCAS1. Fifty eight (92%) showed co-expression of RCAS1 and carcinoembryonic antigen (CEA). While two of 24 cases of melanoma (8.3%) expressed RCAS1 antigen, none of 20 cases of nevus pigmentosus showed positive staining.
These results indicate that RCAS1 is a highly sensitive marker for extramammary Paget's disease. RCAS1 is also expressed in various skin tumors including squamous cell carcinoma, where positive correlation with clinical staging was documented.
UROPLAKIN-III
Uroplakin-III to distinguish primary vulvar Paget disease from Paget disease secondary to urothelial carcinoma.Brown HM, Wilkinson EJ.
Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville 32610, USA.
Hum Pathol 2002 May;33(5):545-8 Abstract quote Paget disease of the vulva can be mimicked by several disease entities histopathologically, but most of these entities can be clinically distinguished from vulvar Paget disease. However, vulvar Paget disease is in itself a heterogeneous group of epithelial neoplasms that can be similar both clinically and histopathologically.
The subtypes of vulvar Paget disease include primary Paget disease arising from a pluripotent stem cell within the epithelium of the vulva, and secondary Paget disease of the vulva. Secondary vulvar Paget disease results from spread of an internal malignancy, most commonly from an anorectal adenocarcinoma or urothelial carcinoma of the bladder or urethra, to the vulvar epithelium. We have recently proposed that these lesions be classified as primary (of cutaneous origin) or secondary (of extracutaneous origin). These subtypes can present similarly as eczematoid skin lesions and may appear similar on routine hematoxylin and eosin-stained slides. Immunohistochemical studies can help differentiate between them. Our current study includes 17 patients with a pathologic diagnosis of vulvar Paget disease.
We performed a panel of immunohistochemical stains, including cytokeratin (CK) 7 and 20, carcinoembryonic antigen (CEA), gross cystic disease fluid protein-15 (GCDFP-15), and uroplakin-III (UP-III). Of these 17 patients, 14 (80%) had primary intraepithelial cutaneous Paget disease, 13 without invasion and 1 with associated invasion. Three patients had urothelial carcinoma with spread to the vulva, manifesting as secondary vulvar Paget disease. Immunohistochemically, primary vulvar Paget disease is immunoreactive for CK 7 and GCDFP-15, but uncommonly for CK 20. Vulvar Paget disease secondary to anorectal carcinoma demonstrates CK 20 immunoreactivity but is usually nonreactive for CK 7 and consistently nonimmunoreactive for GCDFP-15.
Vulvar Paget disease secondary to urothelial carcinoma is immunoreactive for CK 7 and CK 20 but nonimmunoreactive for GCDFP-15. In addition, we propose the use of a new, commercially available antibody, UP-III, which is specific for urothelium and, in our experience, is immunoreactive in secondary vulvar Paget disease of urothelial origin. The distinction between these 3 types of Paget and Paget-like lesions is essential in that the specific diagnosis has a significant influence on current treatment. The difference in surgical approach to the subtypes of vulvar Paget disease justifies classifying them into distinct lesions, which may be aided by the use of immunohistochemistry, including UP-III.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES BOWEN'S DISEASE Mucicarmine negative CLEAR CELL PAPULOSIS Am J Surg Pathol 1987;11:827
Br J Dermatol 1998;138:678Tadpole shaped cells
MELANOMA S100 positive TOKER'S CLEAR CELLS OF THE NIPPLE Cancer 1970;25:601
Clear cells of Toker in accessory nipples.Willman JH, Golitz LE, Fitzpatrick JE.
Department of Pathology, and Department of Dermatology, University of Colorado Health Sciences Center, Denver, CO, USA.
J Cutan Pathol 2003 Apr;30(4):256-60 Abstract quote BACKGROUND: Clear cells of Toker are intraepithelial cells with clear to pale staining cytoplasm and bland cytologic features found in approximately 10% of normal nipples. Toker cells have been hypothesized as a precursor of extramammary Paget's disease (EMPD), although the distribution of Toker cells outside of the nipples has not been studied. Using immunohistochemistry, we studied 20 cases of accessory nipples for the presence of Toker cells.
METHODS: A retrospective study of 20 cases of accessory nipples was performed using routine hemotoxylin and eosin staining, as well as immunohistochemical staining for CK7, CK20, EMA, and GCDFP-15.
RESULTS: Thirteen out of 20 accessory nipples (65%) demonstrated Toker cells with CK7 staining. Toker cells in six of the 13 cases were also positive for EMA. Only one case with Toker cells showed immunoreactivity for antibodies to GCDFP-15.
CONCLUSIONS: Toker cells occur outside the normal nipple epidermis in the epidermis of accessory nipples. The distribution of Toker cells along the milk line correlates with the distribution of most cases of EMPD along the milk line, especially in the groin and axillae. Further studies are necessary to define the relationship between Toker cells and EMPD.Pagetoid Dyskeratosis of the Cervix An Incidental Histologic Finding in Uterine Prolapse
J. Fernando Val-Bernal, M.D., Ph.D.; Jesús Pinto, M.D.; M. Francisca Garijo, M.D., Ph.D.; M. Soledad Gómez, Pharm.D.
From the Department of Anatomical Pathology, Marqués de Valdecilla University Hospital, Medical Faculty, University of Cantabria, Santander, Spain.
Am J Surg Pathol 2000;24:1518-1523 Abstract quote
Pagetoid dyskeratosis, is considered a reactive process in which a small part of the normal population of keratinocytes is induced to proliferate. The lesion is characterized by pale cells resembling those of Paget's disease within the epidermis. These cells have been seen as an incidental finding in a variety of benign papules most commonly located in intertriginous areas. Among the inductors of the lesion, friction is suspected. To the best of our knowledge, these pale cells have not been reported in the cervix.
We describe the location of the lesion in the ectocervix and the incidence of this lesion in a group of 100 unselected patients surgically treated for uterine prolapse. Another group of 100 unselected patients treated for uterine leiomyoma was used as a control. Pagetoid dyskeratosis was found in 37 cases (37%) of uterine prolapse and in five cases (5%) of uterine leiomyomas. The lesion is more common in uterine prolapse (p <0.001) and is not significantly associated with cornification of the epithelium (p = 0.72343). The cells of pagetoid dyskeratosis show an immunohistochemical profile different from the surrounding squamous cells characterized by premature keratinization. Pagetoid dyskeratosis cells have shown positivity for high molecular weight cytokeratin and negative reaction for low molecular weight cytokeratin, epithelial membrane antigen, carcinoembryonic antigen, and human papilloma virus. Pagetoid dyskeratosis cells must be distinguished from artefactual clear cells, glycogen-rich cells, koilocytes, extramammary Paget's disease cells, and pagetoid spread of carcinoma cells to the cervix. In cases in which pagetoid dyskeratosis shows a florid expression, there is a hazard of overdiagnosis.
The pathologist should be aware of the histologic features of pagetoid dyskeratosis in the ectocervix to avoid misdiagnosis and unnecessary treatment. Routine histologic study is usually sufficient to identify the lesion.
Benign mucinous metaplasia of the penis. A lesion resembling extramammary Paget's disease
J.Fernando Val-Bernal and EmiliaHernández-Nieto
Anatomical Pathology Department, Marqués de Valdecilla University Hospital, Medical Faculty, University of Cantabria, Santander, Spain
J Cutan Pathol 2000;27 (2), 76-79 Abstract quote
Benign mucinous metaplasia in the surface epithelium of the genital area is rare and has only been reported once in the vulva. A unique case of benign mucinous metaplasia of the prepuce in a 65-year-old man is reported here. The lesion measured 0.6 cm, was located in the mucous surface of the foreskin, and showed acid mucin containing cells.
We regard benign mucinous metaplasia as a reactive rather than a neoplastic process. The main lesions to be considered in the differential diagnosis are mucinous syringometaplasia, extramammary Paget's disease, cutaneous squamous cell carcinoma in situ with mucinous metaplasia, superficial spreading malignant melanoma, and epidermotropic metastasis.
The confinement of mucin-containing cells to the epidermis, the absence of nuclear atypia, the basal orientation of the nuclei, the predominant location of the cells in the upper layers of the epithelium, and the fact that the mucinous cells are replacing the squamous epithelium rather that infiltrating it, all assist in recognizing mucinous metaplasia of the penis as a specific and benign entity.
PROGNOSIS AND TREATMENT CHARACTERIZATION Treatment Wide local excision MOHS SURGERY
- Extramammary Paget's disease: surgical treatment with Mohs micrographic surgery.
Hendi A, Brodland DG, Zitelli JA.
Department of Dermatology, Mayo Clinic, USA.
J Am Acad Dermatol. 2004 Nov;51(5):767-73. Abstract quote
BACKGROUND: Extramammary Paget's disease (EMPD) is an uncommon tumor that has a high rate of recurrence after conventional surgical treatments.
OBJECTIVE: Our purpose was to establish the efficacy of Mohs micrographic surgery (MMS) in the treatment of EMPD, and to make treatment recommendations with regard to surgical margins. We also attempted to summarize the published recurrence rates of EMPD after standard surgical management.
METHODS: In a retrospective chart review, pertinent demographic data, tumor data, treatment characteristics, and follow-up data were tabulated. A search of the literature for recurrence rates after MMS and non-MMS surgical treatment modalities was performed.
RESULTS: The recurrence rate after treatment with MMS was 16% for primary EMPD and 50% for recurrent EMPD. The 5-year tumor-free rates (Kaplan-Meier analysis) were 80% for primary tumors and 56% for recurrent tumors. Using MMS, the salvage rate (and, hence, overall cure rate) was 100%. Margins of 5 cm were required to clear 97% of the tumors. The recurrence rate after non-MMS (from the literature) is 33% to 60%.
CONCLUSION: MMS is effective, and superior to standard surgical management in the treatment of EMPD. We recommend a 5-cm margin of normal skin if MMS cannot be offered.Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fifth Edition. Mosby Elesevier 2008
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