Reflectance confocal microscopy for diagnosis of mammary and extramammary Paget's disease.

BACKGROUND: Paget's disease is an intraepidermal adenocarcinoma that is difficult to diagnose clinically as it mimics inflammatory or infectious diseases. As a consequence, it may be clinically misdiagnosed resulting in a delay in appropriate management. Reflectance confocal microscopy allows the visualization of the upper layers of the skin and mucosa at cellular resolution. Paget's disease is characterized histologically by the presence of neoplastic cells scattered throughout all layers of the epidermis in a pattern similar to that also observed in melanoma (and termed Pagetoid spread). OBJECTIVE: In vivo confocal microscopy is an excellent diagnostic tool for detecting Pagetoid spread and for diagnosing melanoma. We therefore hypothesized that it may also assist in the diagnosis of Paget's disease. METHODS: In this study, we describe the confocal features of nine cases of extramammary Paget's disease and one case of mammary one. RESULTS: Large atypical Pagetoid cells were present singly and in clusters in all 10 cases and were readily visualized on ex vivo and in vivo confocal microscopy. The presence of Pagetoid spread and other confocal features, in the appropriate clinical context, is suggestive Paget's disease and should allow distinction from other inflammatory diseases that may appear similar clinically. CONCLUSION: The use of confocal microscopy is likely to facilitate earlier diagnosis of Paget's disease and the instigation of appropriate management with concomitant improvement in clinical outcomes.

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

Histological, 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 CEA and EMA, and negative for S-100 protein. Ultrastructurally, in the intermediate pattern, the tumour cells had abundant cytoplasmic glycogen, and the widened intercellular spaces contained numerous glycogen particles, which were probably secreted by 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: comparative histopathologic studies of intraductal carcinoma of the breast and apocrine adenocarcinoma.

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.

Cytologic, histologic, DNA ploidy and electron microscopic analyses of a case of vulvar Paget's disease.

The cells in a case of multifocal vulvar Paget's disease were studied by cytology, histology, ploidy analysis and electron microscopy. The Paget cells in smears were seen in an isolated or a sheetlike arrangement. The cells had peripherally located nuclei, prominent nucleoli and unevenly distributed melanin granules of various sizes in their cytoplasms. The histologic sections contained multifocal microscopic lesions that were larger than the macroscopic lesion. Paget cells in the histologic sections demonstrated positive cytoplasmic staining with the periodic acid-Schiff, Alcian blue, mucin, glandular cytokeratin, epithelial membrane antigen and carcinoembryonic antigen reactions. The nuclear DNA histogram of the Paget cells in the cytologic smears showed a polyploid pattern, with a sharp peak at 4c; the cells in sheets had a ploidy level between 2c and 4c while a few of the isolated cells had a ploidy level that extended past 8c. Various nuclear DNA patterns were observed in the histologic samples; a recurrent lesion was later found in an area adjacent to the primary lesions that had higher ploidy levels. Ultrastructurally, the Paget cells contained lysosomes and tiny electron-dense secretory granules in their cytoplasms, suggestive of a glandular cell origin. These findings suggest that Paget cells may be derived from the secretory portion of sweat glands.

Perianal Paget's disease.

An early case of perianal Paget's disease is described in a 59 year old female. Literature search revealed 57 documented cases up to 1987. Diagnosis is suspected on clinical features and needs to be always confirmed by biopsy with routine stains, and, in doubtful cases, also by electron microscopy and immunohistology. The extent of the primary disease and the presence of an associated adnexal or anorectal cancer must be established. Wide surgical excision of the primary lesion, preferably with frozen section examination of the excised margins and undersurface, is the preferred treatment. Associated adnexal or anorectal cancer is treated on merit. Recurrent disease is managed by further excision, topical chemotherapy and/or laser therapy. Prognosis depends on the extent of the primary lesion, on the adequacy of the primary excision, and on the presence of an associated adnexal or anorectal cancer. In apparently cured cases, long-term surveillance is recommended.

Clear cell papulosis of the skin. A new entity with histogenetic implications for cutaneous Paget's disease.

A new skin condition characterized by multiple white papular eruptions was observed in two young brothers. Histologic study revealed many benign pagetoid clear cells in the basal layer of the acanthotic epidermis with decreased pigmentation. These cells contained cytoplasmic mucin and were positive for keratin AE1/AE3, carcinoembryonic antigen, and epithelial membrane antigen. The staining pattern was identical to that of extramammary Paget's disease. The presence of mucin granules and cytoplasmic filaments corresponding to AE1/AE3 were confirmed ultrastructurally. Comparative histochemical and immunohistochemical studies with normal eccrine sweat glands, Toker's nipple clear cells, and Paget cells of mammary and extramammary Paget's disease suggest that these clear cells are an aberrant derivative of sweat-gland epithelial cells in the epidermis. AE1/AE3 is an excellent marker for the "clear cells" of both the condition described and the cells in the nipple. The term "clear cell papulosis" is proposed for this new entity. The clear cell identified provides evidence for the existence of potential precursor cells in the epidermis for cutaneous Paget's disease.

[A case of perineal (extramammary) Paget's disease].

A case of perineal Paget's disease in a 67-year-old male patient is reported. The perineal polyp, having shown no increase in size for 3 years, wks resected. The microscopic features of the polyp was comprised of clusters of a pale, large tumor cell (Paget cell) only in the epidermis. The skin that was resected around the polyp showed almost the same histological appearance as the polyp, except for an infiltration of tumor cells forming a small gland structure on the minimal region of the dermis. Both the Paget's cells and these tumor cells showed positive for mucin staining. Ultrastructurally, we confirmed two types of Paget's cells, one containing much granules and the other lacking in these granules but rich in other organelles. Further, the Paget's cells formed lumen and intercellular canaliculus, suggesting a differentiation to the eccrine sweat gland. From our findings and a review of the literature, we favor presuming that extramammary Paget's disease without a cancer of the neighbouring organs originates from the epidermis and extends to the dermis.

Mammary and extramammary Paget's disease. An immunocytochemical and ultrastructural study.

Twenty-one cases of Paget's disease have been studied using histochemical, ultrastructural, and immunohistochemical methods. Eight of the tumors involved the nipple, and 13 were extramammary (11 vulvar and two anal). The antibodies used were directed against different classes of cytokeratin proteins, epithelial membrane antigen, carcinoembryonic antigen, gross cystic disease fluid protein-15, and S-100 protein. The findings of this study provide conclusive evidence that Paget's cells, regardless of their location, are adenocarcinoma cells. Intracytoplasmic mucin is scanty in Paget's cells within the nipple, but typically plentiful in the extramammary sites where the cells are frequently signet-ring cells. The common mechanism for the evolution of Paget's disease is extension of cells from an underlying carcinoma, but the possibility that some cases, particularly in the vulva, develop from intraepithelial precursors cannot be excluded.

Ultrastructure of preneoplastic lesions of the vulva.

Ultrastructural analysis using electron microscopy was performed on 16 cases of preneoplastic lesions of the vulva. They included specimens from patients with condylomatous dysplasia, carcinoma in situ, melanoma in situ and extramammary Paget's disease. Each showed significant differences from normal in the ultrastructural details.

[Associated Paget's disease of the vulva and of the nipple in the same patient: pathology with ultrastructural study (author's transl)]. / Association d'une maladie de Paget mammaire et vulvaire. Etude optique, ultrastructurale et cytochimique.

A case of Paget's disease of the vulva associated with Paget's disease of the nipple is reported. When the patient was 74-year-old, Paget's disease of the vulva was diagnosed; four years later, Paget's disease of the nipple was detected. Paget's disease of the vulva, although recurrent, is devoid of underlying infiltrating carcinoma. Eccrine sweats glands show different type of lesions consistent with pagetoid extension, in situ carcinoma and epithelial papillary proliferation. Ultrastructural study demonstrates dense granules within Paget's cells. A positive Thiery's cytochemical reaction indicates that these granules contain glycoprotein. Paget's disease of the nipple is associated with an intraductal carcinoma (cribriform type). Some feature of intralobular carcinoma is also observed. No foci of infiltration are found. Oestrogen receptors are detected by the histofluorescence technique of Sin Hang Lee. Few receptors are seen within the intraductal neoplastic cells and within the Paget's cells whereas no receptor at all, are observed within the keratinocytes. Several reports emphasized the relationship between vulvar Paget's disease and infiltrating breast carcinoma. Associated vulvar and nipple Paget's disease is rather rare and was just observed in two cases. These two observations were associated with a mammary infiltrating carcinoma whereas in our case, it remains an in situ carcinoma.

The cytoplasmic mucin in Paget cells of extramammary Paget's disease.

The cytoplasmic mucin in the Paget cells of extramammary Paget's disease was examined with a battery of histochemical techniques. The staining methods used were alcian blue, azure A and periodic acid-Schiff. In a further attempt to identify various polyanions, staining was carried out with alcian blue containing various concentrations of electrolyte. Methylation, saponification, borohydride reduction, acid hydrolysis, and digestion with diastase, sialidase, chondroitinase ABC, or nucleases were also employed. The results obtained suggest that the cytoplasmic mucin in the Paget cells is sialomucin without side-chain substituent.