Extramammary Paget disease

Published on 19/03/2015 by admin

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Extramammary Paget disease

Lori D. Prok and James E. Fitzpatrick

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Extramammary Paget disease (EMPD) was first described by Crocker in 1889, when he noted skin lesions affecting the penis and scrotum of a male patient that were identical to the nipple disease described by Paget in 1874. Although an uncommon malignancy, EMPD should be included in the clinical differential diagnosis of any chronic dermatitis of the groin or perineum. EMPD most commonly affects postmenopausal Caucasian women, but can also be seen in men of all ethnicities. It typically presents as chronic, often sharply demarcated, erythematous scaling plaques of apocrine gland-bearing skin, including the genitalia, axillae, umbilicus, and external auditory canal. Pruritus is the most common presenting symptom. Primary EMPD results from epidermal infiltration of neoplastic glandular cells. Recent evidence supports the role of Toker cells (clear cells found in 10% of normal nipples, and recently identified in tissue of the milk line and the vulva) as the pathologic cell in this disease. Secondary EMPD accounts for approximately 25% of cases and is the result of direct cutaneous extension of an underlying adenocarcinoma, most commonly of the genitourinary system or from the anal canal.

Management strategy

Clinical suspicion of EMPD should prompt an immediate skin biopsy. Histologically, neoplastic cells are characterized by pale vacuolated cytoplasm and large pleomorphic nuclei, which can be seen infiltrating all levels of the epidermis. Extension into adnexal structures is common. Historically the diagnosis was established by demonstrating the presence of sialomucin with positive staining with mucicarmine, colloidal iron, periodic acid–Schiff, and Alcian blue at pH 2.5. While these studies can still be utilized, the diagnosis is now usually established by immunoperoxidase studies to demonstrate positivity for carcinoembryonic antigen (CEA), epithelial membrane antigen, CK7, gross cystic disease fluid protein-15 and/or Ber-EP4 to differentiate EMPD from pagetoid variants of squamous cell carcinoma in situ and melanoma in situ. CK7 positivity is also supportive of a diagnosis of primary EMPD, since it is less commonly expressed in secondary EMPD. In select cases it is used in tandem with CK20 since CK20 positivity is more commonly seen in secondary EMPD. Recent studies have also demonstrated that HER2/neu over-expression is useful both in helping to establish a diagnosis of EMPD but also in identifying invasive cases that might be responsive to trastuzumab.

A full-body skin examination and lymph node evaluation should be performed in all patients with EMPD. Patients should then have appropriate evaluation for underlying malignancy, including age- and gender-appropriate screening (Papanicolaou smear, fecal occult blood, colonoscopy, cystoscopy, and prostate-specific antigen). Additional investigations (imaging, colposcopy, etc.) are guided by screening results and the anatomic location of cutaneous lesions. Patients who have invasive EMPD (extension into the dermis and/or lymphatic vessels) should be considered for sentinel lymph node biopsy.

EMPD is treated locally with surgical excision, with adjuvant therapies in selected cases. Mohs micrographic surgery is the preferred technique, offering the most reliable margin control, maximal tissue preservation, and lowest recurrence rates. However, this technique is still limited by non-contiguous tumor spread and the high likelihood of EMPD involving clinically normal-appearing skin.

Specific investigations

First-line therapies

image Wide local excision, with or without lymph node dissection B
image Frozen section-guided wide local excision B
image Mohs micrographic surgery B

Second-line therapies

image Photodynamic therapy C
image Systemic chemotherapy E
image Radiation therapy D
image Topical imiquimod D

Third-line therapies

image Topical 5-fluorouracil and retinoic acid E
image Intralesional interferon-α2b E
image Laser therapy E
image Androgen receptor antagonist E

Androgen-deprivation regimen for multiple bone metastases of EMPD.

Yoneyama K, Kamada N, Kinoshita K. Br J Dermatol 2005; 153: 853–5.

Case report of EMPD with multiple bone metastases successfully suppressed with anti-androgen bicalutamide and LH-RH agonist leuprorelin. Tumor markers decreased and bone scintigraphy evidence of metastasis disappeared within 2 months. When tumor markers rose at day 70, other anti-androgens and systemic chemotherapy failed. Bone metastases reappeared, and the patient ultimately died 14 months after the start of anti-androgen therapy. The authors postulate that the rapid development of resistance to the androgen-deprivation therapy suggests that mutation or amplification in the androgen receptor gene occurred in this case, as seen in cases of prostate cancer.

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Extramammary Paget disease

Lori D. Prok and James E. Fitzpatrick

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Extramammary Paget disease (EMPD) was first described by Crocker in 1889, when he noted skin lesions affecting the penis and scrotum of a male patient that were identical to the nipple disease described by Paget in 1874. Although an uncommon malignancy, EMPD should be included in the clinical differential diagnosis of any chronic dermatitis of the groin or perineum. EMPD most commonly affects postmenopausal Caucasian women, but can also be seen in men of all ethnicities. It typically presents as chronic, often sharply demarcated, erythematous scaling plaques of apocrine gland-bearing skin, including the genitalia, axillae, umbilicus, and external auditory canal. Pruritus is the most common presenting symptom. Primary EMPD results from epidermal infiltration of neoplastic glandular cells. Recent evidence supports the role of Toker cells (clear cells found in 10% of normal nipples, and recently identified in tissue of the milk line and the vulva) as the pathologic cell in this disease. Secondary EMPD accounts for approximately 25% of cases and is the result of direct cutaneous extension of an underlying adenocarcinoma, most commonly of the genitourinary system or from the anal canal.

Management strategy

Clinical suspicion of EMPD should prompt an immediate skin biopsy. Histologically, neoplastic cells are characterized by pale vacuolated cytoplasm and large pleomorphic nuclei, which can be seen infiltrating all levels of the epidermis. Extension into adnexal structures is common. Historically the diagnosis was established by demonstrating the presence of sialomucin with positive staining with mucicarmine, colloidal iron, periodic acid–Schiff, and Alcian blue at pH 2.5. While these studies can still be utilized, the diagnosis is now usually established by immunoperoxidase studies to demonstrate positivity for carcinoembryonic antigen (CEA), epithelial membrane antigen, CK7, gross cystic disease fluid protein-15 and/or Ber-EP4 to differentiate EMPD from pagetoid variants of squamous cell carcinoma in situ and melanoma in situ. CK7 positivity is also supportive of a diagnosis of primary EMPD, since it is less commonly expressed in secondary EMPD. In select cases it is used in tandem with CK20 since CK20 positivity is more commonly seen in secondary EMPD. Recent studies have also demonstrated that HER2/neu over-expression is useful both in helping to establish a diagnosis of EMPD but also in identifying invasive cases that might be responsive to trastuzumab.

A full-body skin examination and lymph node evaluation should be performed in all patients with EMPD. Patients should then have appropriate evaluation for underlying malignancy, including age- and gender-appropriate screening (Papanicolaou smear, fecal occult blood, colonoscopy, cystoscopy, and prostate-specific antigen). Additional investigations (imaging, colposcopy, etc.) are guided by screening results and the anatomic location of cutaneous lesions. Patients who have invasive EMPD (extension into the dermis and/or lymphatic vessels) should be considered for sentinel lymph node biopsy.

EMPD is treated locally with surgical excision, with adjuvant therapies in selected cases. Mohs micrographic surgery is the preferred technique, offering the most reliable margin control, maximal tissue preservation, and lowest recurrence rates. However, this technique is still limited by non-contiguous tumor spread and the high likelihood of EMPD involving clinically normal-appearing skin.

Specific investigations

First-line therapies

image Wide local excision, with or without lymph node dissection B
image Frozen section-guided wide local excision B
image Mohs micrographic surgery B

Indications for lymph node dissection in the treatment of EMPD.
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