Immunohistochemical studies of breast and extra-mammary Paget's disease indicate an apocrine differentiation

Using the PAP technique, paraffin-embedded and formalin-fixed tissue sections taken from 11 patients suffering from Paget's disease (5 mammary, 6 extramammary cases) were stained with antibodies against keratin, actin, S 100 protein, CEA, HMFG 1, cytokeratin 6 and 18 (Dako-CK-1), as well as the lectin SBA. We did not find any differences between mammary and extramammary Paget's disease. In both forms of the disease, all tumor cells showed reaction to antibodies against HMFG 1 and CEA and, in 50 to 100%, to the lectin SBA. The other antibodies investigated did not react with Paget's cells. Since HMFG 1 and Dako-CK-1 are selective markers of apocrine and eccrine sweat gland structures, respectively, our results suggest apocrine differentiation of both mammary and extramammary Paget's disease. At the same time, our findings rule out a possible histogenesis of Paget's cells from melanocytes (positive for S 100 protein) or keratinocytes (positive for Dako-CK-1 and antikeratin).     

Expression of differentiation antigens in mammary and extramammary Paget''s disease

Seven cases of mammary and twelve cases of extramammary Paget's disease were studied for the presence of carcinoembryonic antigen (CEA) and apocrine epithelial antigen (AEA) using the immunoperoxidase technique. CEA was found in the Paget cells in five out of seven mammary and in all twelve cases of extramammary Paget's disease, whereas the AEA reaction was positive in six mammary and all extramammary cases. The same antigens were also found in the cells of intraductal or ductal adenocarcinomas of the breast associated with mammary Paget's disease, suggesting a common origin for the cells. In the cases of extramammary Paget's disease studied no underlying malignant neoplasms could be detected. Our findings support the suggestion that Paget cells originate in sweat gland ducts and undergo an apocrine differentiation.     

Lectin-binding sites in Paget''s disease

The presence and distribution of lectin-binding sites on neoplastic cells of Paget's disease was studied using fluorescein isothiocyanate (FITC)-conjugated peanut agglutinin (PNA), and FITC-conjugated wheatgerm agglutinin (WGA), and compared with such lectin-binding sites on keratinocytes, and cells of eccrine glands, apocrine glands, and mammary glands. Neoplastic cells of both mammary and extramammary Paget's disease showed cytoplasmic staining with both lectins. There were however fewer stained cells in mammary Paget's disease than in extramammary Paget's disease. The cytoplasmic staining of lectin-binding sites in cells of apocrine glands was in sharp contrast to the cell-surface staining seen on keratinocytes, or cells of eccrine glands or mammary glands. These results indicate that the lectin-binding sites of neoplastic cells of Paget's disease more closely resemble those of cells of apocrine glands than of keratinocytes, cells of eccrine glands or cells of mammary glands.     

A case of giant extramammary Paget's disease of the genital area with squamous-cell carcinoma

Extramammary Paget's disease is a primary carcinoma with apocrine differentiation that begins within the epidermis. Extramammary Paget's disease and squamous-cell carcinoma (SCC) have different neoplastic origins and are different both clinically and histologically. Until now the concurrence of extramammary Paget's disease and SCC in the same area has not been reported to our knowledge. We report on a 76-year-old man with extramammary Paget's disease affecting a large region of the genital area with SCC within the same area. A skin biopsy specimen showed the coexistence of typical Paget's disease and highly differentiated SCC invading the dermis. Immunohistochemical staining of both cell types was completely different.     

Ultrastructural study of extramammary Paget's disease—histologically showing transition from bowenoid pattern to Paget's disease pattern

Histoiogical, immunohistochemical, and ultrastructural studies were performed on two cases of histologically unusual extramammary Paget's disease. Histologically, the central area of the lesions showed a bowenoid pattern, and the peripheral area showed typical extramammary Paget's disease. The transition zone showed an intermediate pattern. All these areas were positive for CHA and EMA, and negative for S-100 protein. Ultrastructually. in the intermediate pattern, the tumour cells had abundant cytoplasmic glycogen, and the widened intercellular spaces contained numerous glycogen particles, which were probably secreted hy the tumour cells. It is well known that eccrine glands, but not apocrine glands, secrete glycogen particles. Therefore, the present findings suggest that some cases of extramammary Paget's disease are a proliferation of germinative cells with eccrine gland differentiation.     

Extramammary Paget's disease: diagnosis and disease pattern.

Extramammary Paget's disease is a rare cutaneous disorder. We report the clinical and histochemical features of five such cases. In all the cases studied, the lesions were located on the perineum of elderly women. None of the cases showed malignant proliferation invading the dermis. Recent observations suggest that extramammary Paget's disease is a disease of the apocrine glands. Immunoreactants to identify apocrine glands have been developed and can be used to confirm the diagnosis of extramammary Paget's disease.     

Cells of extramammary Paget's disease express cytokeratins different from those of epidermal cells

The patterns of expression of cytokeratin polypeptides which are closely correlated to routes of differentiation of epithelial cells were studied in extramammary Paget's disease. Cytokeratins of uninvolved and involved epidermis were analyzed by two-dimensional gel electrophoresis of microdissected tissue preparations as well as by immunofluorescence microscopy using cytokeratin antibodies with different specificities. In uninvolved epidermis, cytokeratins Nos. 1, 5, 6, 10, 11, 14, and 16, characteristic of keratinocytes, were found. Epidermis infiltrated by Paget's cells contained the same components and, in addition, cytokeratins Nos. 7, 8, 18, and 19, the latter being characteristic of simple and glandular epithelia, including apocrine and eccrine skin glands. By immunohistochemistry, broad-spectrum antibodies to cytokeratins decorated both keratinocytes and Paget's cells. Antibodies selective for cytokeratins Nos. 1, 10, and 11 stained suprabasal keratinocytes but not Paget's cells. In contrast, antibodies to cytokeratin No. 18 were negative on keratinocytes but the Paget's cells were selectively stained, as were the secretory cells but not the ductal cells in apocrine and eccrine glands. The results show that the cytoskeleton of Paget's cells is different from that of keratinocytes and ductal cells of skin glands and suggest that these tumor cells express the glandular type cytokeratins Nos. 7, 8, 18, and 19. This provides cell biologic support for a relationship of cells of Paget's disease to secretory cells of apocrine and eccrine glands. The histogenesis of extramammary Paget's cells is discussed in relation to these findings.     

The expression of CD23 in cutaneous non-lymphoid neoplasms

BACKGROUND: Cluster designation 23 (CD23) is generally used as a lymphoid marker. Its utility in cutaneous epithelial tumors has never been studied. In our routine practice, we observed that CD23 reacted strongly with eccrine and apocrine secretory coils. METHODS: Immunohistochemical staining of CD23 was performed in a total of 131 cases of apocrine, eccrine, follicular and other cutaneous non-lymphoid tumors. RESULTS: CD23 expression was detected in all benign apocrine tumors and in half of benign eccrine tumors, particularly those derived from secretory coils. CD23 staining was seen in 42% (8/19) of microcystic adnexal carcinoma (MAC), while no staining was observed in tumor cells of desmoplastic trichoepithelioma, morpheaform basal cell carcinoma and syringoma. All mammary and extramammary Paget's disease were labeled with CD23. In comparison, pagetoid Bowen's disease, melanoma in situ and sebaceous carcinoma exhibited negative staining. In addition, CD23 reacted diffusely with cutaneous mucinous eccrine carcinoma in a manner similar to breast or colonic adenocarcinoma. CONCLUSION: CD23 appears to be a reliable immunohistochemical marker of the eccrine/apocrine secretory coil and helpful in identifying sweat gland tumors of such origin. It is of ancillary value in differentiating MAC from its mimicker. CD23 is a useful addition to the diagnostic immunohistochemical panels for Paget's disease.     

Immunohistochemical stains in extramammary Paget's disease.

The histologic and immunohistochemical characteristics of 49 skin biopsy specimens from 49 patients with extramammary Paget's disease were studied. Patients with extramammary Paget's disease with and without underlying malignant disease were identified. Associated malignant lesions, present in 16 patients (33%), were transitional cell carcinoma of the bladder (n = 8), adenocarcinoma underlying the skin (n = 3), adenocarcinoma of the anus (n = 1), adenocarcinoma of the vulva (n = 1), apocrine carcinoma (n = 1), prostate carcinoma (n = 1), and carcinoma metastatic to the lung (n = 1). The main histologic feature was the presence of Paget's cells, predominantly at the base of the epidermis. In 6% of the cases, well-defined nests of large Paget's cells mimicked melanocytic nests. Carcinoembryonic antigen and Cam 5.2 (a monoclonal antibody that stains 40-kDa, 45-kDa, and 52.5-kDa low molecular weight keratins) were localized to the Paget's cells in 42 of 45 (93%) and 29 of 41 cases (71%), respectively. Forty-four of 46 lesions (96%) were mucin positive, as determined by Hale's colloidal iron stain. Absence of staining for colloidal iron and carcinoembryonic antigen occurred somewhat more frequently in patients with underlying malignant disease than in patients without tumors (13% vs. 0% mucin negative and 13% vs. 3% carcinoembryonic antigen negative, respectively). Although immunohistochemical staining for low molecular weight keratin may be used to confirm the diagnosis of extramammary Paget's disease, Cam 5.2 is not as sensitive as the colloidal iron or carcinoembryonic antigen stain.     

Expression of moesin and its associated molecule CD44 in epithelial skin tumors

Moesin, one of the ERM (ezrin; radixin; moesin) family members, is directly associated with the cytoplasmic domain of CD44, which is now thought to be related to the metastatic potential of tumor cells. Using immunohistochemistry we investigated the expression of moesin in normal epidermis and various kinds of epithelial skin tumors: squamous cell carcinoma, verrucous carcinoma, Bowen's disease, solar keratosis, keratoacanthoma, basal cell carcinoma, and extramammary Paget's disease. Normal skin showed positive epidermal staining for moesin with the exception of the stratum corneum. The expression of moesin varied with the type of skin tumor. In basal cell carcinoma, Bowen's disease, and extramammary Paget's disease, moesin expression was either faint or negative. In contrast to Bowen's disease, invasive squamous cell carcinoma showed more intense and heterogeneous staining of the cytoplasm and the cell membrane. Verrucous carcinoma was weakly positive, with a tendency for the moesin to be distributed in the cell membrane. The staining pattern of moesin varied among the different kinds of epithelial skin tumors, and its expression was generally similar to that of the standard form of CD44. These results suggest that moesin is closely inter-related with CD44 in epithelial skin cells as seen in other cellular systems, and that the variable pattern of moesin staining among the skin tumor cells could reflect expression disorders associated with the transformation.     

Extramammary Paget''s disease:

We examined 32 cases (38 lesions) of extramammary Paget's disease (EMPD) in relation to comparative studies on intraductal carcinoma of the breast (ductal carcinoma in situ, DCIS) and apocrine adenocarcinoma (AAC). Lesions included scrotum (18 lesions), vulva (8), axilla (6), groin (3), penis (2) and chest wall (1), and the distribution was compatible with that of apocrine or supernumerary mammary glands. Histologically, extra-mammary Paget's and DCIS cells exhibited a large amount of a pale-stained cytoplasm. The cytoplasm of AAC cells frequently contained granules, was eosinophilic and differed from that of Paget's or DCIS cells. Immunohistochemical studies revealed positive reactions for polyclonal and monoclonal antibodies to carcinoembryonic antigen in all EMPD and most DCIS, but not in AAC. Recent studies have shown that extramammary Paget's cells exhibit characteristics of glandular epithelial cells and that most cases of EMPD are not accompanied by an underlying carcinoma. The results obtained in this study, coupled with data on the frequency of the supernumerary breasts, lead to the speculation that extramammary Paget's cells originate from ectopic mammary glands or from pluripotential germinative cells in the epidermis, capable of differentiating toward the mammary glands.     

Cluster designation 5 staining of normal and non-lymphoid neoplastic skin

BACKGROUND: Immunohistochemical staining for cluster designation 5 (CD5) has been found to label a variety of non-lymphoid tumors. METHODS: A variety of eccrine, apocrine, follicular, epithelial, and pagetoid lesions were selected and stained with an anti-CD5 monoclonal antibody (Novocastra Labs, Newcastle upon Tyne, UK, clone 4C7) by immunohistochemistry. The intensity of positive cytoplasmic staining was graded semiquantitatively (1+ weak staining, 2+ strong staining). Additionally, the percentage of positive lesional cells was placed in one of four categories: >75%, 25-75%, 1-25%, and <1%. RESULTS: Within normal skin, CD5 labeled lymphocytes, apocrine glands, deep dermal eccrine glands, and smooth muscle (weak). The majority of benign and malignant apocrine lesions demonstrated strong focal (36%, n=11)-to-diffuse (64%, n=16) staining. In contrast, labeling of benign eccrine tumors was more focal, tending to localize around ducts (79%, n=19). Microcystic adnexal carcinoma demonstrated focal staining of deeper ductal structures (71%, n=7), whereas desmoplastic trichoepithelioma and basal cell carcinoma showed only rare positive cells. All cases of mammary (n=7) and extramammary (n=8) Paget's disease labeled diffusely for CD5. Pagetoid Bowen's disease (n=6), intraepidermal sebaceous carcinoma (n=3), nor melanoma in situ (n=6) showed any CD5 staining. CONCLUSIONS: Immunohistochemical staining for CD5 is extremely useful in the differential diagnosis of pagetoid epidermal lesions and will mark mammary and extramammary Paget's disease, but not pagetoid Bowen's disease, melanoma in situ, or sebaceous carcinoma.     

原发性乳房外Paget病中E钙黏蛋白的检测

目的观察乳房外Paget病中E钙黏蛋白的表达并分析其在肿瘤侵袭过程中的意义。方法应用免疫组化方法分别对28例原发性原位乳房外Paget病(A组)和17例原发性侵袭性乳房外Paget病(B组)标本中的E钙黏蛋白进行检测。结果原发性原位乳房外Paget病标本中E钙黏蛋白的表达较周边正常皮肤标本中表达下调,其中28例原发性原位乳房外Paget病标本中,E钙黏蛋白阴性表达的占28.6%(8/28),低表达的占46.4%(13/28),高表达的占25.0%(7/28),17例原发性侵袭性乳房外Paget病标本表达分别为17.6%(3/17),58.8%(10/17),23.6%(4/17),9例肿瘤边缘正常皮肤和2例正常阴囊皮肤中E钙黏蛋白全部高表达,正常皮肤组与两组乳房外Paget病中E钙黏蛋白的表达差异有显著性(P<0.01),而两组乳房外Paget病之间的表达差异无显著性(P>0.05)。结论E钙黏蛋白表达的下调与原发性乳房外Paget病的发病有关,但可能与侵袭过程没有必然的联系。     

Immunohistochemical staining properties of keratin type intermediate filaments in mammary and extramammary Paget's disease

Utilizing three different anti-keratin antibodies and the avidin-biotin peroxidase complex system on sections of formalin-fixed paraffin-embedded tissues and on cryostat sections, immunohistochemical localization of keratin type intermediate filaments in mammary Paget's disease and extramammary Paget's disease was investigated. Anti-keratin antibodies EAB-903 and EAB-904, which recognize 66K and 57K dalton keratin peptides, did not decorate any Paget's cells in either mammary or extramammary Paget's disease. On the other hand, anti-keratin antibody MAK-6, which recognizes 52.5K, 50K, 48K, 45K and 40K daltons keratin peptides, did decorate Paget's cells in both Paget's diseases. These staining properties of Paget's cells were the same as those of secretory cells in normal human sweat glands and mammary glands. Anti-keratin antibody MAK-6 is thought to be useful in the diagnosis of mammary and extramammary Paget's diseases.     

Immunohistochemical analysis of human milk fat globulin 1 and cytokeratin expression in median raphe cyst of the penis

Because median raphe cyst of the penis shares histological findings with apocrine cystadenoma, some cases were thought to be erroneously reported as apocrine cystadenoma of the penis. Further, there is some controversy as to whether the entity, apocrine cystadenoma of the penis, exists or not. Nine cases of median raphe cyst which were clinically unequivocal from their location on the ventral aspects of the penis, were analysed immunohistochemically by using an antibody against human milk fat globulin 1 (HMFG) and a panel of monoclonal anti-cytokeratin antibodies. HMFG expression was not observed in eight out of nine cases of median raphe cyst of the penis, and the remaining case showed a faint expression of HMFG focally in its luminal surface, while conventional apocrine cystadenoma in extra-genital area expressed HMFG definitively in our previous study. Our results suggest a possibility that apocrine cystadenoma of the penis is very rare or not present. Therefore, we thought that HMFG expression should be examined in the cases in which apocrine cystadenoma on the penis is reported.     

乳房外Paget病中汗腺病理及免疫组化分析

目的：分析乳房外Paget病(EMPD)中汗腺上皮组织CK7和CEA的表达及临床意义。方法：应用免疫组化SP法对15例EMPD皮损和周边正常皮肤CK7和CEA的表达进行检测。结果：15例中有8例在汗腺腺体及导管部见CK7和CEA呈阳性，其中仅5例发现汗腺上皮细胞呈异常改变。结论：免疫组化方法在诊断和鉴别诊断EMPD中汗腺上皮细胞的不典型增生具有一定价值。     

Two cases of cutaneous apocrine ductal carcinoma of the axilla. Case report and review of the literature

We report 2 cases of cutaneous apocrine ductal carcinoma (CADC) of the axilla in a 64- and a 54-year-old male. Histological examination revealed 2 solid, ductal and glandular tumors with decapitation secretion. Tumor cells showed cellular and nuclear atypism, and infiltrative growth of tumor cell nests was also observed. Although there were no characteristic features of extramammary Paget's disease on the overlying skin, case 1 exhibited a typical Paget's phenomenon. We concluded that the Paget's phenomenon of case 1 was a result of upward extension of the tumor in the dermis. The neoplastic cells of both cases were immunohistochemically positive for gross cystic disease fluid protein, lysozyme, CD15 and carcinoembryonic antigen but negative for S-100 protein. Based on these findings, we concluded that these tumors were cutaneous apocrine ductal carcinomas. There was no evidence of tumor remnants in the axilla, and the patients have shown no signs of local recurrence or metastasis. We also reviewed the literature and summarize here the clinical features of CADC. Copyright (R) 2000 S. Karger AG, Basel     

Expression of prostate-specific antigen and androgen receptor in extramammary Paget's disease and carcinoma

Prostate-specific antigen (PSA) is a kallikrein-like serine proteinase (human kallikrein 3) produced by epithelial cells of both benign and malignant prostate tissue. In this study, PSA expression was histologically examined in tissue specimens from 34 patients with extramammary Paget's disease (EPD; 31 cases) and extramammary Paget's carcinoma (EPC; three cases), but no associated prostate carcinoma. Tumour cells positive for PSA were found in 17 of the 34 cases. Based on this finding, we examined serum PSA level in the three EPC cases. A high level of serum PSA was observed in one case of EPC, which was correlated with disease progression. Because some reports suggest that 50-80% cases of EPD/EPC express androgen receptor (AR), we also examined expression of AR. Immunohistological staining showed correlation of PSA and AR in expression. These results suggest that PSA and the androgen signalling pathway may be involved in the pathogenesis of EPD.     

Extramammary Paget's disease of the perianal and perineal regions. Evidence of apocrine derivation

A case of perianal and perineal extramammary Paget's disease in a male is reported. The presence of gross cystic disease fluid protein--a new marker of apocrine epithelia--in Paget's cells provides additional insight into the histopathogenesis of this condition. This marker may be a valuable diagnostic adjunct in evaluating intra-epithelial malignancies at a variety of anatomic sites.     

Extramammary Paget's cells: further evidence of sweat gland derivation

Tissue from a 66-year-old male patient with extramammary Paget's disease of the right side of the scrotum and the right groin was studied for the presence of several antigens with the immunoperoxidase technic. Adenokeratin (cytokeratin No. 18) and carcinoembryonic antigens were positive in Paget's cells, whereas squamokeratin (cytokeratin No. 10) was expressed only in normal epidermal cells. Langerhans cells were decreased in the region of the tumor. Many transferrin receptors were present on the tumor cells, indicating a high cellular proliferation rate. Enzyme histochemical studies of the extramammary Paget's cells showed positive reactions for several enzymes typical of sweat glands, except for leucine aminopeptidase, which was negative. A comparison with three other cases showed that these enzyme reactions varied greatly from case to case. Both immunohistochemical and enzyme histochemical findings provide further evidence that extramammary Paget's cells are related to sweat gland epithelial cells, with variable expression of cellular characteristics.