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The histopathologic characteristics of reactions caused by the many novel anticancer agents are under-recognized. We report a case of a 67-year-old female with locally advanced metastatic breast cancer, who initially presented with an extensive reticulated erythematous patch on the trunk caused by intravascular metastases confirmed by a skin biopsy. Owing to disease progression, she was started on ixabepilone, a mitotic inhibitor. While receiving ixabepilone, another skin biopsy was obtained and initially interpreted as extramammary Paget's disease. However, the biopsy showed metaphase arrest of numerous keratinocytes in the basilar and suprabasilar epidermis. Atypical epithelial cells were only present in the intravascular spaces similar to the initial biopsy. Given the temporal association between the initiation of ixabepilone therapy and the epidermal mitotic arrest, a diagnosis of chemotherapy reaction to ixabepilone was rendered. Ixabepilone is an analog of epothilone, a microtubule stabilizer causing mitotic arrest of the cell cycle approved for the treatment of metastatic and locally advanced treatment-resistant breast cancer. The demonstration of epidermal mitotic arrest caused by ixabepilone is without precedent. The case emphasizes the importance of considering a chemotherapy reaction in the histologic differential diagnosis of epidermal mitotic arrest in a cancer patient receiving chemotherapy.

Background Phosphatidylinositol 3-kinase (PI3K), Ras-related C3 botulinum toxin substrate 1 (Rac1) and P21-activated protein kinase 1 (PAK1) appear to play important roles in the pathogenesis of several tumors, but their expressions in extramammary Paget's disease (EMPD) have not been investigated yet. Objectives To investigate the potential contribution of the PI3K, Rac1 and PAK1 to the development of EMPD. Methods Thirty-five paraffin-embedded EMPD specimens were subjected to immunohistochemical staining for PI3K (85α), Rac1 and pPAK1. Results All the 35 primary EMPD specimens, including 20 non-invasive EMPD, 13 invasive EMPD and 2 metastatic lymph nodes, showed cytoplasm overexpression of PI3K (85α), Rac1 and pPAK1. The expression (% positive cells) of PI3K(85α), Rac1 and pPAK1 (90.1 ± 8.6, 91.4 ± 9.5 and 89.6 ± 10.8% ) in EMPD were significantly higher than in apocrine glands of normal skin ( 20.1 ± 11.9, 29.8 ± 8.9, 41.1 ± 13.4%), and the expression in invasive EMPD with lymph node metastasis (98.2 ± 1.7, 98.8 ± 0.7 and 98.4 ± 0.9%) are significantly higher than in invasive EMPD without lymph node metastasis (94.1 ± 2.6, 96.5 ± 1.7 and 95.3 ± 1.1%) and non-invasive EMPD (85.2 ± 8.4, 87.1 ± 9.9 and 83.1 ± 10.6%). There were significant positive correlations of the expression levels between PI3K (85α) and Rac1, as well as between Rac1 and pPAK1 in EMPD. Conclusions These results indicate that PI3K, Rac1 and PAK1 may play important roles in the pathogenesis of EMPD.

Background: The Wnt (wingless-type MMTV integration site) gene family encodes secretory signaling molecules that play a diverse biological role in the regulation of normal and pathological processes, including cell growth, differentiation and oncogenesis. However, the role of Wnt genes in the development of extramammary Paget's disease remains unknown. Objective: To investigate the expression of Wnt-1, Wnt-5α and their downstream genes, β-catenin and c-Myc, in extramammary Paget's disease. Methods: Paraffin-embedded specimens of extramammary Paget's disease (33 specimens from 22 patients), including 7 specimens with dermal invasion and 4 with lymph node metastasis, were examined immunohistochemically for Wnt-1, Wnt-5α, β-catenin and c-Myc. Seven normal genital skin specimens served as controls. Results: The expression levels of Wnt-1 and β-catenin in extramammary Paget's disease were significantly correlated with each other; however, their expression levels in the invasive extramammary Paget's disease were similar to those of wholly intraepithelial extramammary Paget's disease. Nuclear expression of c-Myc was significantly higher in the invasive extramammary Paget's disease in comparison with intraepithelial extramammary Paget's disease. Interestingly, the expression of Wnt-5α in invasive extramammary Paget's disease was significantly downregulated compared to wholly intraepithelial extramammary Paget's disease. Conclusion: The Wnt-1/β-catenin pathway may not play an important role in the progression of extramammary Paget's disease. The loss of Wnt-5α, however, may play a role in the invasiveness of extramammary Paget's disease. Xie L, Hayashida S, Furue M. Loss of Wnt-5α is associated with an invasive phenotype of extramammary Paget's disease.

BACKGROUND Extramammary Paget's disease (EMPD) is a rare neoplasm of apocrine gland-bearing skin. It is known that over-expression of survivin and human telomerase reverse transcriptase (hTERT) correlates with malignancies. We investigated the expression of hTERT and survivin by Paget's cells and their role in the tissue invasion and recurrence of EMPD. METHOD Forty-two patients were enrolled into the study. Expression of survivin and hTERT were analyzed by immunohistochemistry and in situ hybridization techniques. The variables including the expression level of survivin and hTERT, gender, age, lesion location, invasion level and number of surgeries were statistically analyzed using Fisher's exact test. RESULTS Survivin was positively stained in 18 of 22 cases (81.8%), and hTERT in 18 of 29 cases (62.1%). Significantly higher level of survivin expression was detected in patients with multiple surgeries than those with single one (p = 0.0458). Expression of hTERT was significantly higher in the patients with micro-invasive and invasive lesions than those with non-invasive lesions (p = 0.0478). CONCLUSIONS Over-expression of survivin and hTERT correlated strongly with recurrence and local invasion of EMPD lesions. EMPD has male gender predominance in Oriental population.

Background: Extramammary Paget's disease (EMPD) is an uncommon skin neoplasm characterized by Paget's cells with pale-staining cytoplasm in the epidermis, and cases with distinguished acantholysis but lacking characteristic Paget's cells were rarely reported in the literature. Methods: An 80-year-old male with lesion on scrotum was screened histologically and immunohistologically for the diagnosis of his tumor. Results: Histological examination showed acanthosis with cellular atypia and focal acantholysis, consistent with acantholytic squamous cell carcinoma in situ (SCCIS). No characteristic Paget's cells were observed in low magnification. Immunohistochemical staining showed carcinoembryonic antigen (CEA), cytokeratin 7 (CK7) and cytokeratin 8 (CK8) to be strongly expressed in the nests and singly arranged large tumor cells, and the surrounding epidermis was positive for CK5/6 and negative for CEA. Sporadic periodic acid-schiff (PAS)-positive cells could be seen in some areas. Conclusions: These findings strongly indicated the diagnosis of EMPD mimicking acantholytic SCCIS. Du X, Yin X, Zhou N, Zhang G, Shi H, Cao S. Extramammary Paget's disease mimicking acantholytic squamous cell carcinoma in situ: a case report.

Extramammary Paget's disease (EMPD) is a rare malignant neoplasm with a predilection for the apocrine-rich anogenital skin and less commonly for the axilla. The tumor rarely occurs in non-apocrine bearing regions where it is referred to as ectopic EMPD. Here, we report a case of a patient that presented with a poorly circumscribed, erythematous plaque with patchy alopecia on the scalp. Histology showed pagetoid infiltration of the epidermis by atypical single and nested cells with abundant amphophilic cytoplasm with nuclear hyperchromasia, extending along the adnexae. Immunohistochemistry showed that the tumor cells stained positively for mucicarmine, periodic acid schiff, cytokeratin-7, polyclonal carcinoembryonic antigen, epithelial membrane antigen, gross cystic disease fluid protein, androgen receptor and Her-2-neu; and negatively for S-100, HMB-45, CDX-2, thyroid transcription factor-1, estrogen receptor and progesterone receptor, thus, establishing the diagnosis of ectopic EMPD. Subsequent workup showed no underlying malignancy. To our knowledge, we report the second case, and the first in the English literature, of an ectopic EMPD involving the scalp without any associated malignancy.

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.

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.

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.

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.

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.

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.

Background: The histogenesis of extramammary Paget’s disease (EMPD) is still controversial. Benign pagetoid cells of the nipple first described by Toker and the similar clear cells found in white maculopapules of clear cell papulosis (CCP) have been proposed to be potential precursor cells giving rise to EMPD and primary intraepidermal Paget’s disease in the nipple. The observation of a rare case of depigmented EMPD provided us with a chance to examine further the interesting Toker’s clear cell/CCP hypothesis. Methods: We performed pathologic studies, including Fontana-Masson stain and immunostaining for AE1/AE3 and S100P, on a new case of depigmented EMPD manifesting a 4×3 cm hypopigmented-depigmented patch on the root of the penis. Results: The lesion showed extensive intraepithelial proliferation of atypical pagetoid cells with markedly reduced epidermal melaninization but nearly normal numbers of melanocytes. The tumor cells were strongly positive for AE1/AE3 by immunostaining. Some tumor cells displayed tadpole-like morphology resembling the pagetoid cells of CCP. Such morphology was not observed in two random examples of non-depigmented genital EMPD. Conclusions: The findings of tadpole-shaped pagetoid cells and depigmentation in the present case suggest that depigmented EMPD may be histogenetically related to CCP. Depigmented EMPD should be considered in the differential diagnosis of vitiligo, depigmented mycosis fungoides and lichen sclerosus located along the milk line.

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.

Background: Neurotrophin (NT) systems appear to play important roles in the pathogenesis of several tumors, but their expression in extramammary Paget's disease (EPD) has not been investigated. Methods: Thirty-four paraffin-embedded EPD specimens (32 primary EPD and 2 metastatic to lymph nodes) were subject to immunohistochemical staining for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT3, NT4, their high-affinity receptors (TrkA, TrkB and TrkC) and the common low-affinity receptor, p75 NT receptor (p75). Results: All 34 EPD specimens, including 2 metastatic to lymph nodes, showed cytoplasmic overexpression of NGF, BDNF, TrkA and TrkB. The expression (% positive cells) of NGF, BDNF, NT3, NT4, TrkA and TrkB (81.6 ± 14.9, 86.0 ± 10.4, 89.6 ± 14.9, 87.8 ± 17.9, 83 ± 14.4 and 86.2 ± 11.7%) in EPD was significantly higher than in normal skin (21.6 ± 6.5, 27.6 ± 4.5, 19.7 ± 10.1, 8.2 ± 10.0, 25.0 ± 5.3 and 25.4 ± 6.4%), and the expression of these factors in invasive EPD was significantly higher than in noninvasive EPD. Interestingly, Paget cells were negative for p75 and TrkC in all the 34 EPD specimens. Conclusions: These results suggest that overexpression of NGF, BDNF and their high-affinity receptors (TrkA and TrkB) might play a role in the pathogenesis of EPD. Qian Y, Takeuchi S, Chen S-J, Dugu L, Tsuji G, Xie L, Nakahara T, Moroi Y, Tu Y-T, Furue M. Nerve growth factor, brain-derived neurotrophic factor and their high-affinity receptors are overexpressed in extramammary Paget's disease.

Pigmented Paget's disease is a rare variant that is often confused clinically and histologically with melanoma in situ. Herein, we describe a case of pigmented extramammary Paget's disease involving the axilla of a 79-year-old white male thought initially to represent malignant melanoma clinically and histologically. Review of the literature reveals that pigmented variant of Paget's disease, either mammary or extramammary, could be initially misdiagnosed as melanoma unless this entity is considered in the differential diagnosis, and additional confirmatory studies are performed.

Background: Activating transcription factor 2 (ATF2) and signal transducer and activator of transcription 3 (STAT3) play important roles in the pathogenesis of various tumors, but ATF2 expression/activation and the relationship with STAT3 activation have not yet been investigated in extramammary Paget’s disease (EMPD). Objective: To investigate potential contributions of ATF2 and STAT3 pathways to the pathogenesis of EMPD. Method: Paraffin-embedded 45 EMPD specimens (43 primary EMPD and 2 nodal metastases) were subjected to immunohistochemical staining for ATF2, phosphorylated (p)-ATF2 and p-STAT3. Results: P-ATF2 expression in advanced EMPD, non-invasive EMPD and normal skin (NS) controls were 97.9 ± 1.8%, 82.0 ± 23.4% and 45.8 ± 3.2%, respectively, and p-STAT3 expression in advanced EMPD, non-invasive EMPD and NS were 97.0 ± 2.9%, 83.2 ± 23.3% and 50.1 ± 6.7%, respectively. P-ATF2 and p-STAT3 expressions in EMPD were significantly higher than those in NS, indicating a possible contribution of these pathways to the tumor development. P-ATF2 and p-STAT3 expressions in advanced EMPD were significantly higher than those in non-invasive EMPD, possibly indicating that these pathways might also contribute to the tumor invasion and/or metastasis. We also found an exceptionally high positive correlation between p-ATF2 and p-STAT3 expressions in EMPD. Conclusions: P-ATF2 and p-STAT3 are concordantly overexpressed in EMPD and their expressions may possibly be associated with the tumor stage.

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.

Background: Pale cells resembling those of paget's disease have been seen as an incidental finding within the epidermis in a variety of benign papules most commonly located in intertriginous areas. This lesion, called pagetoid dyskeratosis, is considered a reactive process in which a small part of the normal population of keratinocytes is induced to proliferate. Among the inductors friction is suspected. As far as we know, these cells have not been reported in the penis. Methods: Here we describe the location of the lesion in the foreskin and the incidence of this lesion in a group of 281 unselected patiets surgically treated for phimosis. In selected cases histochemical staining and immunohistochemical studies were performed. Results: Pagetoid dyskeratosis was found in 105 cases (37.4%) but only in 5 cases (1.8%) the lesion was conspicuous. The cells of pagetoid dyskeratosis show an immunohistochemical profile different from the surrounding keratinocytes characterized by premature keratinization. Pagetoid dyskeratosis cells must be distinguished from the artefactual clear cells of the epidermis, from reactive melanocytes, and from pale-cell acanthosis. In cases in which pagetoid dyskeratosis shows a florid expression there is a hazard of overdiagnosis to the patient. The main differential diagnosis includes extramammary Paget's disease, pagetoid squamous cell carcinoma in situ, epidermotropic metastasis, superficial spreading malignant melanoma, clear cell papulosis, and penile koilocytoses. Conclusions: The pathologist should be familiar with the histologic features of pagetoid dyskeratosis in the foreskin in order to avoid misdiagnosis and unnecessary treatment. Routine histologic study is usually sufficient to identify the lesion.

An unusual case of primary adenocarcinoma of the vulva is described. It combined features of the three different types of adenocarcinoma of the skin of the vulva which are currently recognized, i.e. sweat gland carcinoma, adenocarcinoma derived from supernumerary mammary glands, and extramammary Paget's disease (EMPD). Central in this tumor was a recently recognized type of cutaneous gland which appeared special for the anogenital region and was distinguished because it combined morphological features of eccrine, apocrine and mammary glands. As it most resembles mammary glands, it is named "mammary-like gland". On the basis of the case presented and of a critical review of the literature, it was concluded that, with the exception of a few sweat gland carcinomas similar to those elsewhere in the skin, adenocarcinomas of the skin of the vulva form a single category of neoplasms with a variable expression of features reminiscent of eccrine, apocrine and mammary gland carcinomas. The data strongly suggested a common derivation from the mammary-like gland or, in cases of EMPD, its related germinative cells in the epidermis.

We report a case of inflammatory stage vulvar lichen sclerosus et atrophicans (LSA) with histopathologic features simulating both patch stage mycosis fungoides (MF) and extramammary Paget’s disease. The patient is a 79-year-old woman with an erythematous plaque on her vulva. A punch biopsy was performed that revealed mild psoriasiform hyperplasia of the epidermis with spongiosis, marked interface vacuolar alteration, scattered individual necrotic keratinocytes and Civatte bodies. A band-like mixed inflammatory infiltrate was present in the papillary/upper dermis with prominent intraepidermal lymphocytes. Some intraepidermal lymphocytes showed atypical nuclear contours simulating the cells seen in MF. The presence of numerous intraepidermal epithelioid cells with a pagetoid distribution raised the possibility of extramammary Paget’s disease. A panel of immunohistochemical (IHC) stains showed a reactive lichenoid mixed population of lymphocytes with numerous intraepidermal Langerhans cells. This confirmed the diagnosis of the inflammatory stage of lichen sclerosus. The presence of prominent epithelioid Langerhans cells with activated small lymphocytes represents an immune response in LSA and could cause diagnostic confusion with neoplastic conditions. IHC staining can confirm cell type and rule out MF and extramammary Paget’s disease.

We present a 69-year-old woman with a sebaceous carcinoma of the left upper eyelid, which originated from the Meibomian gland of the tarsal plate. The intraepidermal extension involved not only the conjunctival epithelium but also the overlying skin with subsequent extension into the dermis. The discussion will include diagnostic, both clinical and microscopic, considerations along with comparison to mammary Paget’s disease. Just as mammary Paget’s disease, which originates from the glands in the dermis eventuating in the seeding of the overlying epidermis, so too does sebaceous carcinoma of the eyelid. Accordingly, just as mammary Paget’s disease is often misdiagnosed as an inflammatory condition, so too is sebaceous carcinoma.

We evaluated the usefulness of immunohistological staining for S-100 protein in differentiating mammary and extramammary Paget's disease from primary malignant melanoma of superficial spreading (pagetoid) type. This technique was compared to both the mucicarmine and periodic acid-Schiff (PAS) methods. The tumor cells of 10 melanomas contained abundant cytoplasmic S- 100 protein. In tissues from mammary and extramammary Paget's disease, S-100 protein was detected in myoepithelial cells, Langerhans cells, and Schwann cells of cutaneous nerves, but was not present in tumor cells. The mucicarmine stain was most useful for vulvar Paget's disease, mucicarminophilic material being present in 9/10 cases. In mammary Paget's disease, only 2/8 cases stained by the mucicarmine technique. Cytoplasmic PAS-positive material was present in the tumor cells of 9/10 cases of vulvar Paget's disease, but was noted in only 1/9 cases of mammary Paget's disease. Melanoma cells from two cases stained weakly with both mucicarmine and PAS indicating that these stains are not specific for Paget's disease in this comparison. The PAS and mucicarmine stains are helpful in differentiating anogenital Paget's disease from pagetoid melanoma, but are less useful in mammary Paget's disease. Immunohistological demonstration of S-100 protein provides an additional diagnostic tool to aid the separation of Paget's disease from pagetoid melanoma.

An autopsied case of extramammary Paget's disease associated with the elevation of serum CEA level is reported. An abnormally high level of serum CEA was found in 46% of patients with this disease.

The coexistence of two tumors, porocarcinoma and extramammary Paget's disease (EMP) in one tissue section, facilitates a subtle but distinct differentiation of the two cell types. The adjacent occurrence of the two tumors perhaps indicates a common origin in their benign form. The biologic mechanism of the Pagetoid phenomenon is demonstrated.