What is extramammary Paget disease of skin?
Extramammary Paget disease of the skin is an uncommon intraepithelial adenocarcinoma usually of the anogenital or axillary skin.
Extramammary Paget disease is classified into primary and secondary disease:
- Primary extramammary Paget disease of skin is of cutaneous origin
- Secondary extramammary Paget disease of skin is associated with a primary adenocarcinoma elsewhere in the body.
Extramammary Paget disease of the skin is differentiated from mammary Paget disease which has a similar appearance involving the nipple or areola, but is a manifestation of an underlying breast cancer.
Who gets extramammary Paget disease of skin?
Extramammary Paget disease generally affects individuals over 50 years of age, with a peak at 65 years. It is more common in Caucasians than other ethnicities. In Asian populations, there is a marked male predominance, in contrast to the female predominance seen in Caucasian populations. In males, Asians and Pacific Islanders are the predominant groups affected, followed by Caucasians, and is rarely seen in African Americans.
What causes extramammary Paget disease of skin?
The cause of extramammary Paget disease remains poorly understood, however it is most commonly located in apocrine gland-rich skin.
- The cell of origin in primary extramammary Paget disease is of epidermal origin, with possible candidates including a pluripotent keratinocyte stem cell, Toker cell, or apocrine gland duct cells.
- Secondary extramammary Paget disease results from direct extension or metastasis from another site such as adenocarcinoma of the rectum, bladder, urethra, prostate, endocervix, or stomach. An underlying rectal adenocarcinoma can be found in one third of cases of perianal extramammary Paget disease.
What are the clinical features of extramammary Paget disease of skin?
Extramammary Paget disease most commonly presents as an asymmetrical or unilateral, red or pink, scaly plaque on the vulva in women or perianally in men. It is typically slow growing with irregular, poorly defined margins, often leading to misdiagnosis as an inflammatory dermatosis.
- Paget disease is usually itchy, leading to secondary changes of excoriations and lichenification.
- Burning, pain, and irritation are also commonly described symptoms.
- Hyperpigmentation and/or leukoplakia can be present.
- Weepy erosions, maceration, and crusting may be seen.
- In later stages, nodules may develop indicating invasive disease.
- In women, the most common site is the vulva (65% of all cases).
- The perianal region is involved in 20% of all cases, and is the most common site affected in men. The scrotum, groin, and penis are less commonly involved.
- Extramammary Paget disease rarely presents in the axilla.
Extramammary Paget disease of a non-apocrine-rich region is extremely rare and is termed ectopic extramammary Paget disease. Sites reported have included the scalp, umbilicus, thigh, and face.
Due to the non-specific clinical features, diagnosis of extramammary Paget disease is often delayed by months or years.
Dermoscopy of extramammary Paget disease has been reported to show two unique features — white small round clods with white structureless areas ('cloud-like structureless areas') and thick branching white lines with intermingled white clods ('lava lake structures').
Pigmented extramammary Paget disease can be difficult to distinguish from superficial spreading melanoma, even on dermoscopy. The combination of a linear arrangement of brown globules and a white negative pigment network may be useful clues seen in pigmented extramammary Paget disease.
Extramammary Paget disease
See more images on Mammary and extramammary Paget disease of the skin images
What is the differential diagnosis for extramammary Paget disease of skin?
The differential diagnosis for extramammary Paget disease of the skin includes common inflammatory dermatoses, infections, and other malignancies.
- Atopic dermatitis — usually bilateral, affects a younger patient, and responds quickly to a topical steroid or calcineurin inhibitor.
- Flexural psoriasis — characterised by symmetrical non-scaly well-defined pink plaques, which may be pruritic or non-pruritic. Other sites would typically also be affected.
- Tinea cruris — usually asymmetrical with a scaly edge, and does not resolve with topical steroids. A skin scraping for fungal microscopy and culture will help to distinguish this.
- Candidiasis — typically presents as bright red erythematous patches with satellite lesions.
- Intraepidermal squamous cell carcinoma
- Mucosal melanoma or cutaneous superficial spreading melanoma when pigmented.
- Other genital skin diseases.
How is extramammary Paget disease of skin diagnosed?
The possibility of extramammary Paget disease must be considered for a chronic skin change in the anogenital region that does not respond to standard topical treatment for dermatitis within 4-6 weeks.
Diagnosis requires a skin biopsy for histopathological confirmation. See extramammary Paget disease pathology.
Once a diagnosis of extramammary Paget disease is made on histology, evaluation for an underlying internal malignancy is required.
Investigations may include:
- Evaluation of lymph nodes by ultrasound scan or fine needle aspirate
- Cervical and breast screening
- Pelvic imaging for underlying cancer
- Colonoscopy (for perianal Paget disease)
- Cystoscopy (for periurethral Paget disease)
- Prostate specific antigen (PSA) test and prostate examination in men.
What is the treatment of extramammary Paget disease of skin?
Surgery, including wide local excision and Mohs micrographic surgery, is the standard treatment for extramammary Paget disease. Surgical procedures tend to be extensive; radical vulvectomy may be required. Despite this, there is a high rate of recurrence due to multifocal disease and poorly defined margins clinically. Mohs micrographic surgery results in a lower recurrence rate compared to wide local excision. Recurrent extramammary Paget disease is usually retreated surgically. Reconstruction may require a skin graft or flap repair.
Sentinel lymph node biopsy may be considered if Paget cells have extended into the reticular dermis or are seen within lymphatics or vascular spaces.
Imiquimod cream is showing good evidence as a useful non-surgical treatment at initial presentation, for recurrent disease, or for those who are not surgical candidates.
Radiotherapy, either alone or as an adjuvant therapy, has also been used with some responses.
Other less successful non-surgical treatments have included:
- Photodynamic therapy — useful only for very small lesions
- 5-fluorouracil cream
- CO2 and other forms of laser ablation
There are a small number of reports of successful use of trastuzumab for extramammary Paget disease with HER-2 overexpression.
Treatment of metastatic extramammary Paget disease has not been standardised due to the rarity of the condition. Surgery, chemotherapy, radiotherapy, and trastuzumab have been tried.
Any underlying cancer identified on screening will also require appropriate treatment.
What is the outlook for extramammary Paget disease of skin?
In general, patients with extramammary Paget disease have a good prognosis with a 5-year overall survival rate of 75–95%. However, quality of life can be significantly impacted after radical surgery.
Although extramammary Paget disease is usually intraepithelial, it can progress to invasive disease with metastases.
Risk factors associated with a poor prognosis include:
- Perianal disease in males aged over 75 years
- Nodules in the tumour
- Lymph node involvement either clinically or on histology
- Paget cells infiltrating the reticular dermis or deeper.
Outcome is also affected by the associated primary underlying cancer.
What is the follow-up for extramammary Paget disease of skin?
Due to the high recurrence rate (30–60%), long-term follow-up is recommended to monitor for local disease recurrence, the development of internal malignancy, regional lymphadenopathy, or distant metastasis.