Triple extramammary Paget's disease. Immunohistochemical studies

A 75-year-old man developed three lesions of Paget's disease which involved the pubic area and both axillae. Histologically, there was no invasion into the dermis in any of the three lesions. Various kinds of histochemical and immunohistochemical studies including those for carcinoembryonic antigen showed that both genital and axillary lesions were identical in nature. Cases with triple involvement of Paget's disease are thought to be extremely rare in the literature.     

Depigmented extramammary Paget's disease

BACKGROUND: Depigmented extramammary Paget's disease (EMPD) has been reported in a few cases. Depigmented macules or patches may be the only presenting sign or may coexist with the classical erythematous lesions. OBJECTIVES: To investigate the occurrence rate and clinical presentation of depigmentation in EMPD. METHODS: All pathology-proven cases of EMPD diagnosed in our department during 1990-2003 were retrieved. The clinical photographs were reviewed for evidence of local depigmentation. The pathological diagnosis of EMPD in the whitish lesions was confirmed by positive expression of cytokeratin 7 or carcinoembryonic antigen, and/or the presence of intracytoplasmic mucin. RESULTS: Of 19 cases of EMPD, six (30%) manifested depigmented lesions which were confirmed to be EMPD pathologically. In two patients, the hypopigmentation was associated with erythematous lesions at the initial presentation. In four others, the depigmentation developed later as local recurrence after excision, cryotherapy, photodynamic therapy or radiotherapy. The progressive enlargement of the depigmentation and the appearance of separate new white lesions in these four cases suggested that the localized depigmentation was unlikely to be simple postinflammatory hypopigmentation. CONCLUSIONS: Our study suggests that depigmented EMPD may not be rare. Localized depigmentation in the genital area can be an early sign of EMPD and its local recurrence. In patients with an established diagnosis of EMPD, appearance of new white lesions and continuous enlargement of depigmented patches should not be dismissed as simple treatment-induced postinflammatory hypopigmentation or another type of hypopigmented lesion without biopsy confirmation.     

Immunohistochemical analysis of human milk fat globulin expression in extramammary Paget's disease

Primary extramammary Paget's disease is thought to be an intraepidermal carcinoma indicating apocrine secretory differentiation. In addition to expression in breast tissue, human milk fat globulin (HMFG) is expressed in the normal apocrine glands and tumours with apocrine differentiation. In this study HMFG expression in extramammary Paget's disease was analysed immunohistochemically in 18 cases of primary extramammary Paget's disease and two cases of secondary extramammary Paget's disease. The proportion and staining pattern of positive tumour cells with the anti-HMFG antibody was variable in each case. Cytoplasmic staining was observed frequently in dermal invasion and metastasis of Paget cells. The variabilities were thought to be due to modulation of the cellular localization of the cell surface component, HMFG, according to changes in cellular differentiation or malignant potency.     

Mammary and extramammary Paget's disease

Ten cases of mammary Paget's disease and 10 cases of extramammary Paget's disease were studied for differences of histologic features in them. Based on the epidermal changes alone, Paget cells in 90% of specimens from lesions of extramammary Paget's disease had abundant mucin that stained well, whereas Paget cells in only 40% of specimens from mammary Paget's disease stained for mucin and faintly at that. In 60% they did not stain at all. The conclusion derived from these observations is that the mucin in Paget cells of extramammary Paget's disease is different from that found in cells of mammary Paget's disease. The Paget cells in these two conditions seem to have different origins, i.e., those of mammary Paget's disease ascend to the epidermis from lactiferous ducts, whereas those of extramammary Paget's disease originate in the epidermis itself.     

Multilocular extramammary Paget's disease]

Paget cells were found histologically in a patient with erythemato-erosive lesions on the genitoperineale areas. These cells were also observed in the right axillary skin within a tiny depigmented spot and even in the left axillary skin which was macroscopically almost intact. There were no signs of metastatic or deep-seated adnexal adenocarcinoma. Treatment consisted of radical operation of the pathological lesions with skin grafting and removal of one testicle. After the operation the x-ray irradiation was performed.     

Mammary and extramammary Paget's disease

Paget''s disease, described by Sir James Paget in 1874, is classified as mammary and extramammary. The mammary type is rare and often associated with intraductal cancer (93-100% of cases). It is more prevalent in postmenopausal women and it appears as an eczematoid, erythematous, moist or crusted lesion, with or without fine scaling, infiltration and inversion of the nipple. It must be distinguished from erosive adenomatosis of the nipple, cutaneous extension of breast carcinoma, psoriasis, atopic dermatitis, contact dermatitis, chronic eczema, lactiferous ducts ectasia, Bowen''s disease, basal cell carcinoma, melanoma and intraductal papilloma. Diagnosis is histological and prognosis and treatment depend on the type of underlying breast cancer. Extramammary Paget''s disease is considered an adenocarcinoma originating from the skin or skin appendages in areas with apocrine glands. The primary location is the vulvar area, followed by the perianal region, scrotum, penis and axillae. It starts as an erythematous plaque of indolent growth, with well-defined edges, fine scaling, excoriations, exulcerations and lichenification. In most cases it is not associated with cancer, although there are publications linking it to tumors of the vulva, vagina, cervix and corpus uteri, bladder, ovary, gallbladder, liver, breast, colon and rectum. Differential diagnoses are candidiasis, psoriasis and chronic lichen simplex. Histopathology confirms the diagnosis. Before treatment begins, associated malignancies should be investigated. Surgical excision and micrographic surgery are the best treatment options, although recurrences are frequent.     

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.     

Microscopically controlled surgery for extramammary Paget's disease.

In five cases of extramammary Paget's disease (EMPD), the neoplasms were removed under complete microscopical control by means of fixed-tissue chemosurgical technique in one case and fresh-tissue technique in four cases. In each lesion there were histologically involved areas extending several centimeters into clinically normal-appearing skin. All patients have been free of the disease for periods from four months to nine years. Other authors using conventional surgery have reported a recurrence rate of 44%. Microscopically controlled surgery offers the most reliable method of removing all of the neoplastic tissue EMPD and preserves as much normal tissue as possible.     

Immunohistochemical analysis of the mammalian target of rapamycin signalling pathway in extramammary Paget's disease

Background We have previously observed that persistent activation of the serine/threonine kinase, protein kinase B (AKT) is a frequent event in extramammary Paget’s disease (EMPD). AKT promotes cell proliferation by its ability to coordinate mitogenic signalling with energy‐ and nutrient‐sensing pathways that control protein synthesis through the atypical serine/threonine kinase, mammalian target of rapamycin (mTOR). CDK2, a member of the serine/threonine kinase family of cyclin‐dependent kinases, is a key regulator of G₁–S cell cycle progression, and has recently been shown to be one of the targets of AKT. The AKT–mTOR–p70 ribosomal protein S6 kinase (p70S6K) pathway has been described in some human malignancies, but not in EMPD. Objective To investigate the immunohistochemical staining of the AKT–mTOR–p70S6K pathway in EMPD and to evaluate the relationships among the components. Methods Samples of primary EMPD tissue were subjected to immunohistological staining with phosphorylated (p)‐AKT, p‐mTOR, p‐4E‐binding protein 1 (p‐4EBP1), p‐p70S6K/S6K1, p‐ribosomal protein S6 (p‐S6) and CDK2. Ten normal skin samples served as a control. Results Of the 32 EMPD tissue samples, 29, 27, 26, 29, 26 and 32 samples were positive for p‐AKT, p‐mTOR, p‐4EBP1, p‐p70S6K/S6K1, p‐S6 and CDK2 staining, respectively. All these cell signalling molecules showed higher positivity in invasive EMPD than in EMPD in situ. There were significant correlations between p‐AKT, p‐mTOR, p‐4EBP1, p‐p70S6K/S6K1 and p‐S6 and CDK2. Conclusions The activation of the AKT–mTOR–p70S6K pathway may play an important role in the pathogenesis of EMPD. The high expression of the components of the pathway was highly correlated with CDK2 expression, suggesting that the AKT/mTOR pathway may induce the malignant transition through CDK2 in EMPD. The AKT–mTOR–p70S6K pathway might be a potential therapeutic target in EMPD.     

Immunohistochemical studies of normal sweat glands, sweat gland tumors and extramammary Paget's diseases. II. Immunohistochemical studies of sweat gland tumors and extramammary Paget's diseases

Localizations of 18 antigens were analyzed in 41 cases with benign sweat gland tumors (13 with eccrine acrospiroma, 4 with eccrine spiradenoma, 2 with hidroacanthoma simplex, 9 with chondroid syringoma, 4 with syringocystadenoma papilliferum, 1 with tubular apocrine adenoma, 1 with papillary eccrine adenoma, 1 with apocrine cystadenoma, 1 with cylindroma, 5 with syringoma), 14 with malignant sweat gland tumors (7 with eccrine porocarcinoma, 3 with eccrine duct carcinoma, 3 with apocrine gland carcinoma, 1 with mucinous carcinoma) and 13 with extramammary Paget's disease. The results I obtained were compared with those in the normal sweat glands for determination of a differentiation of each tumor.     

Comparative genomic hybridization in extramammary Paget's disease

BACKGROUND: Extramammary Paget's disease (EMPD) is a distinct skin cancer of unknown histogenesis. Data from genome-wide surveys for chromosomal aberrations in EMPD are limited. OBJECTIVES: To identify chromosomal aberrations that are present in EMPD. METHODS: Fifteen cases of EMPD were analysed by comparative genomic hybridization (CGH). We used pooled DNA CGH, instead of studying a single sample. In addition, immunohistochemistry was performed for detection of androgen receptor (AR). RESULTS: The most recurrent change was amplification at chromosomes Xcent-q21 and 19, and loss at 10q24-qter. In addition, expression of AR, located in chromosome X, was found in six cases. CONCLUSIONS: Results suggest that AR may play a role in EMPD tumorigenesis.