Extramammary Paget's disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

Extamammary Paget’s disease (EMPD) is a rare non-melanocytic intraepidermal skin lesion. It usually involves the epidermis, but occasionally extends into the underlying dermis. It has predilection for apocrine gland-bearing areas: mostly the perineum, vulva, axilla, scrotum and penis. Extramammary Paget’s disease may be classified into two groups based on the origin of the Paget’s cells. Extramammary Paget’s disease may be classified into four subtypes based on site of origin and area affected. On gross pathology, plaque with an irregular border and erythematous or white lesion are characteristic findings of extramammary Paget’s disease. On microscopic histopathological analysis, the presence of Paget’s cells (large cells with abundant amphophilic or basophilic, finely granular cytoplasm and a large, centrally-located nucleus and prominent nucleolus) and signet ring cells are characteristic findings of extramammary Paget’s disease. Extramammary Paget’s disease is usually associated with adnexal apocrine carcinoma, which represents infiltration of the deeper adnexa by epidermal Paget cells. Neither the direct cause nor a prominent risk factor of extramammary Paget’s disease has been identified. Extramammary Paget’s disease is rare and the exact incidence is unknown. Extramammary Paget’s disease commonly affects individuals 50-60 years of age. Females are more commonly affected with the disease than males. The female to male ratio is approximately 3-4.5 to 1. It usually affects individuals of the Caucasian race, but it may occur in other races. Symptoms of extramammary Paget’s disease include pruritis, vulvar pain, vulvar bleeding, and burning sensation. Biopsy is diagnostic of extramammary Paget’s disease. Other diagnostic studies for extramammary Paget’s disease include fine needle aspirate and PAP smear. Treatment depends on the stage at diagnosis. Treatment often includes surgery and chemotherapy with either 5-fluorouracil, imiquimod, or combination of paclitaxel and trastuzumab.

Extramammary Paget’s disease was first discovered by Radcliffe Crocker in 1889.

Extramammary Paget’s disease may be classified into two groups based on the origin of the Paget’s cells. Extramammary Paget’s disease may be classified into four subtypes based on site of origin and area affected.

On gross pathology, plaque with an irregular border and erythematous or white lesion are characteristic findings of extramammary Paget’s disease. On microscopic histopathological analysis, Paget’s cells which are large cells with abundant amphophilic or basophilic, finely granular cytoplasm, the nucleus which is usually large, centrally situated, and sometimes contains a prominent nucleolus, and signet ring cells are characteristic findings of extramammary Paget’s disease. Extramammary Paget’s disease arises from keratinocytic stem cells or from apocrine gland ducts. Approximately 25% (range 9-32%) of the cases of extramammary Paget’s disease are associated with an underlying in situ or invasive neoplasm. Extramammary Paget’s disease is usually associated with adnexal apocrine carcinoma, which represents infiltration of the deeper adnexa by epidermal Paget cells.

The cause of extramammary Paget’s disease has not been identified.

Extramammary Paget’s disease must be differentiated from basal cell carcinoma, Bowen’s disease, cutaneous candidiasis, intertrigo, irritant contact dermatitis, lichen simplex chronicus, plaque psoriasis, tinea cruris, seborrhoeic dermatitis, lichen sclerosis, anogenital intraepithelial neoplasia, melanoma, histiocytosis, mycosis fungoides, leukoplakia, squamous cell carcinoma, condylomata accuminata, Crohn’s disease, and hidradenitis suppurativa.

Extramammary Paget’s disease is rare, and its exact incidence is unknown. Extramammary Paget’s disease commonly affects individuals 50-60 years of age. Females are more commonly affected with the disease than males. The female to male ratio is approximately 3-4.5 to 1. It usually affects individuals of the Caucasian race, but it may occur in other races.

There are no established risk factors for extramammary Paget’s disease.

According to the United States Preventive Services Task Force, screening for extramammary Paget’s disease is not recommended among the general population.

If left untreated, the disease is usually progressive. Common complications of extramammary Paget’s disease include recurrence of the tumor and metastasis. Depending on the extent of the tumor at the time of diagnosis, the prognosis may vary. The prognosis for primary extramammary Pagets’s disease confined to the epidermis is excellent. However, invasive primary extramammary Paget’s disease carries a poor prognosis, particularly if lymphovascular invasion is present.

Symptoms of extramammary Paget’s disease include pruritis, vulvar pain, vulvar bleeding, and burning sensation.

Common physical examination findings of extramammary Paget’s disease include well demarcated, erythematous or leucoplakic plaques present on the skin, characteristic ‘cake-icing’ appearance of vulval extramammary Paget’s disease (erythematous changes associated with white islands and bridges of hyperkeratotic epithelium), and lymphadenopathy.

Chest x-rays may be performed to detect metastases of extramammary Paget’s disease to the lungs.

Chest, abdomen, and pelvic CT scan may be helpful in the diagnosis of extramammary Paget’s disease. CT scan can confirm the exact location of the cancer and show the organs nearby, as well as lymph nodes and distant organs where the cancer might have spread.

Chest, abdomen, and pelvic MRI scan may be helpful in the diagnosis of EMPD.

Other imaging studies for EMPD include bone scan, ultrasound scan, PET scan, cystoscopy, sigmoidoscopy, colonoscopy, mammography, and colposcopy, which demonstrates metastases and underlying invasive carcinomas.

Biopsy is diagnostic of extramammary Paget’s disease. Other diagnostic studies for extramammary Paget’s disease include fine needle aspirate and Pap smear.

Treatment depends on the stage at diagnosis. Chemotherapy with either 5-fluorouracil, imiquimod, or combination of paclitaxel and trastuzumab has been evaluated for the treatment of extramammary Paget’s disease.

Surgery is the first line treatment for extramammary Paget’s disease.

There are no primary preventive measures against extramammary Paget’s disease.

Secondary prevention strategies following extramammary Paget’s disease include an annual complete physical examination, proctosigmoidoscopy and punch biopsy of any new lesion. Colonoscopy should be carried out at every two to three year intervals.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

Extramammary Paget’s disease was first discovered by Radcliffe Crocker in 1889.^[1]

• Extramammary Paget’s disease was first discovered by Radcliffe Crocker in 1889.
• Crocker described a patient with erythematous patches on penis and scrotum.^[1]
• Perianal extramammary Paget’s disease—also called perianal Paget disease — was first reported in 1893 by Darier and Coulillaud.
• The first case of vulval extramammary Paget’s disease was described in 1901.^[2][3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

Extramammary Paget’s disease may be classified into two groups based on the origin of the Paget’s cells. Extramammary Paget’s disease may be classified into four subtypes based on site of origin and area affected.

The classification of extramammary Paget’s disease based on the site and area affeced is shown below in a tabular form:

• Extramammary Paget’s disease may be classified based on the origin of the Paget’s cells according to a classification system proposed by Wilkinson and Brown into two groups: primary (cutaneous) and secondary (non-cutaneous).

• Classification of extramammary Paget’s disease into two groups is shown below in a tabular form:^[13]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

On gross pathology, a plaque with an irregular border and erythematous or white skin lesion are characteristic findings of extramammary Paget’s disease. On microscopic histopathological analysis, Paget’s cells (large cells with abundant amphophilic or basophilic, finely granular cytoplasm, large centrally-located nucleus with prominent nucleolus) and signet ring cells are characteristic findings of extramammary Paget’s disease. Extramammary Paget’s disease arises from keratinocytic stem cells or from apocrine gland ducts. Approximately 25% (range 9-32%) of the cases of extramammary Paget’s disease are associated with an underlying in situ or invasive neoplasm. The neoplasm most likely to be associated with extramammary Paget’s disease is an adnexal apocrine carcinoma, which usually represents infiltration of the deeper adnexa by epidermal Paget’s cells.^[1][2]

On gross pathology, the following are characteristic findings of extramammary Paget’s disease:^[2]

• Plaque with an irregular border
• Erythematous or white lesion
• Eczematous appearance
• May have a ring-shaped appearance

• Paget’s cells are large cells with abundant amphophilic or basophilic, finely granular cytoplasm, which tend to stand out in contrast to the surrounding epithelial cells.
• The nucleus is usually large, centrally situated, and sometimes contains a prominent nucleolus. Prominent nuclear atypia and pleomorphism are present.
• Signet ring cells may be present in small numbers and mitotic figures are more frequent.
• The Paget’s cells may be dispersed singly or form clusters, solid nests, or glandular structures. The majority of cells are concentrated in the lower strata, but there may be infiltration into upper strata of the epidermis, often being observed in the pilosebaceous apparatus.
• Cells may be present in sweat gland ducts, leading to confusion as to whether the lesion has spread from a local apocrine neoplasm or has arisen within the epidermis. A dense inflammatory infiltrate is often seen associated with the epidermal malignancy.
• In approximately more than 90% of cases of extramammary Paget’s disease the tumor cells contain cytoplasmic mucin, stain positively with periodic acid Schiff (PAS) and mucicarmine reagent. Only 40% of cases of mammary Paget’s disease show any intracellular mucin and staining is generally weaker than in extramammary Paget’s disease.
• Cytological examination of skin scrapings from lesions of Paget’s disease reveals eccentric nuclei and single malignant cells with vacuolated cytoplasm, three dimensional cell aggregates, and acinar groups consistent with glandular differentiation. However, the material obtained is variably cellular and often shows a background of keratinous debris, which may lead to confusion with squamous neoplasia or inflammatory skin conditions or squamous neoplasia. Hence, it may be more appropriate to biopsy lesions.^[3]

• In majority of cases extramammary Paget’s disease (EMPD) arises as a primary cutaneous adenocarcinoma. The epidermis becomes infiltrated with neoplastic cells showing glandular differentiation. Tumor cells may originate from keratinocytic stem cells or from apocrine gland ducts. The cause of primary extramammary Paget’s disease (EMPD) is unknown. However, a minority of cases do represent a direct extension of an underlying carcinoma along contiguous epithelium.
• Approximately 25% (range, 9-32%) of the cases of EMPD are associated with an underlying in situ or invasive neoplasm. The neoplasm most likely to be associated with EMPD is an apocrine carcinoma. This associated neoplasm probably represents infiltration of the deeper adnexa by epidermal Paget cells. Other malignancies besides cutaneous adnexal carcinoma that may be associated with EMPD include carcinomas of the urethra, Bartholin’s glands, vagina, bladder, cervix, endometrium, and prostate
• The anatomic location of extramammary Pagets’s disease (EMPD) plays a role in predicting the risk of associated carcinoma. For example, genital disease is associated with carcinoma in about approximately 4-7% of patients. Perianal disease is associated with underlying colorectal carcinoma in approximately 25-35% of cases.^[1]
• Rare cases of EMPD which are associated with tumors arising in distant organs without direct epithelial connection to the affected epidermis have been reported.

• Immunohistochemistry has been used both to identify the likely cell of origin and to diagnose Paget’s disease.^{[4] [5]}
• Paget’s cells typically stain for markers of eccrine and apocrine derivation including gross cystic disease fluid protein (GCDFP-15), low molecular weight cytokeratins (CK), periodic acid-Schiff (PAS) and carcinoembryonic antigen (CEA). Staining for S100 is negative.^[6][7][8]
• There are antigenic differences between primary intraepidermal Paget’s disease (CK7 positive, CK20 negative, GCDFP-15 positive) and Paget’s disease that has spread from an associated internal carcinoma (CK7 negative, CK20 positive, GCDFP-15 negative).
• The main histological diagnoses to exclude in the vulva are anogenital intraepithelial neoplasia (S100 negative, PAS negative) and superficial spreading malignant melanoma (S100 positive, PAS negative, CEA negative, cytokeratin negative).

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

The direct cause of extramammary Paget’s disease has not been identified.

• The direct cause of Extramammary Paget’s disease (EMPD) is unknown.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

Extramammary Paget’s disease must be differentiated from basal cell carcinoma, Bowen’s disease, cutaneous candidiasis, intertrigo, irritant contact dermatitis, lichen simplex chronicus, plaque psoriasis, tinea cruris, seborrhoeic dermatitis, lichen sclerosis, anogenital intraepithelial neoplasia, melanoma, histiocytosis, mycosis fungoides, leukoplakia, squamous cell carcinoma, condylomata accuminata, Crohn’s disease, and hidradenitis suppurativa.^[1]

Extramammary Paget’s disease must be differentiated from the following disease conditions:^[1]

• Basal Cell Carcinoma
• Bowen’s Disease
• Cutaneous Candidiasis
• Intertrigo
• Irritant contact dermatitis
• Lichen simplex chronicus
• Plaque Psoriasis
• Tinea Cruris
• Seborrhoeic dermatitis
• Lichen sclerosis
• Anogenital Intraepithelial Neoplasia
• Melanoma
• Histiocytosis
• Mycosis fungoides
• Leucoplakia
• Squamous Cell Carcinoma
• Condylomata Accuminata
• Crohn’s Disease
• Hidradenitis suppurativa

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

Extramammary Paget’s disease is rare, and its exact incidence is unknown. Extramammary Paget’s disease commonly affects individuals 50-60 years of age. Females are more commonly affected with the disease than males. The female to male ratio is approximately 3-4.5 to 1. It usually affects individuals of the Caucasian race, but it may occur in other races.

• Extramammary Paget’s disease is rare, and the exact incidence is unknown.
• The incidence of extramammary Paget’s disease is estimated to be 0.10 per 100,000 individuals.
• However, in older reports, it represented 6.5% of all cases of all Paget diseases.

• The peak age incidence of vulvar extramammary Paget’s disease is approximately 50-65 years.^[1][2]
• The median age for a diagnosis of scrotal and penile disease is approximately 70-75 years.

Females are more commonly affected with extramammary Paget’s disease than males. The female to male ratio is approximately 3-4.5 to 1.^[3]

Extramammary Paget’s disease usually affects individuals of the Caucasian race, but it may occur in other races.^[4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

There are no established risk factors for extramammary Paget’s disease.

There are no established risk factors for extramammary Paget’s disease.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

According to the United States Preventive Services Task Force, screening for extramammary Paget’s disease is not recommended among the general population.

• Routine screening for extramammary Paget’s disease in general population is not recommended.^[1]
• However, approximately 10% of patients with Paget’s disease of the vulva have an underlying second malignancy. These include colorectal cancer, cervical cancer, breast cancer, as well as carcinoma of the transitional epithelium from the renal pelvis to urethra. Routine screening with colonoscopy, Pap test, and mammogram may therefore be recommended in these patients.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The prognosis of extramamary Paget’s disease depends on the following:

• Whether or not the tumor can be removed by surgery

• The stage of the cancer: the size of the tumor, whether the cancer has spread outside the vulva or penis

• The patient’s general health

• Whether the cancer has just been diagnosed or has recurred

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 complications and prognosis