Extramammary Pagets Disease: Symptoms, Types, Causes and Treatment

Extramammary Paget’s disease (EMPD) is a rare and often misunderstood skin cancer that primarily affects areas rich in apocrine glands, such as the genital, perianal, and axillary regions. While its name links it to the more common mammary (breast) Paget’s disease, EMPD presents unique challenges in diagnosis, management, and understanding of its origins. This article offers a comprehensive, evidence-based exploration of EMPD, including its symptoms, types, causes, and treatment options.

Symptoms of Extramammary Pagets Disease

Recognizing EMPD can be challenging, as its symptoms often mimic common skin conditions. Early identification is crucial, given the disease's potential to invade deeper tissues or be associated with underlying malignancies.

Symptom	Description	Common Sites	Source(s)
Erythematous	Red, inflamed patches or plaques	Vulva, perianal, axilla	2 3 8
Eczematous	Scaly, itchy, or crusted lesions	Genital, perianal	1 2 3 8
Ulceration	Erosions or open sores	Affected skin	3 8
Pigmentation	Light brown or blue-gray spots in some cases	Lesion surface	2

Table 1: Key Symptoms

Overview of EMPD Symptoms

EMPD typically presents as a persistent, well-demarcated, red or pink patch on the skin, especially in areas with apocrine glands such as the vulva, scrotum, perianal region, penis, and axilla. The affected area may be itchy, sore, or tender. Some lesions develop scaling, crusting, or ulceration, and in pigmented variants, brown or blue-gray dots may be seen 2 3 8. Due to its variable appearance, EMPD is often misdiagnosed as eczema, psoriasis, fungal infection, or dermatitis.

Detailed Symptom Breakdown

Erythema and Plaques

• The hallmark of EMPD is an erythematous (red) patch or plaque, often with well-defined borders 2 3.
• Sometimes the patch is moist, weeping, or appears eroded.

Eczematous Changes

• The lesion may resemble eczema, with scaling and itching 1 8.
• This similarity leads to frequent delays in correct diagnosis.

Ulceration and Crusting

• In advanced cases, the surface may become ulcerated or develop a crust 3 8.
• These changes can indicate disease progression or invasive potential.

Pigmentation Variants

• Some EMPD lesions are pigmented, showing light brown or blue-gray areas.
• Dermoscopic examination can reveal distinctive patterns, aiding in diagnosis 2.

Anatomical Sites

• EMPD is most often seen in the vulva for women and the scrotum or perianal area for men, but can occur wherever apocrine glands are present 2 3 8.

Symptom Duration and Delay

• Patients often experience symptoms for months or years before diagnosis, due to misattribution to benign skin disorders 8.

Types of Extramammary Pagets Disease

EMPD is not a single entity; its classification has implications for prognosis, treatment, and cancer association.

Type	Defining Feature	Cancer Association	Source(s)
Primary	Originates in the epidermis or skin	Sometimes, but less often associated with underlying carcinoma	4 6 9 16
Secondary	Due to spread from underlying malignancy	Usually a sign of internal or skin cancer	4 6 16
Intraepidermal	Confined to superficial skin layers	Low risk of metastasis	16
Invasive	Invades deeper dermis or beyond	Higher metastatic risk	3 8 16

Table 2: Types of EMPD

Defining EMPD Types

Primary vs Secondary EMPD

• Primary EMPD arises within the skin itself, generally from apocrine gland-bearing areas. Most cases are primary and have no underlying carcinoma 4 6 9.
• Secondary EMPD results from the spread of an underlying malignancy (e.g., colorectal, urothelial, or other skin cancers) to the epidermis 4 6 16.

Intraepidermal vs Invasive EMPD

• Intraepidermal EMPD is limited to the upper skin layers (epidermis), with a lower risk of spreading to lymph nodes or other organs 16.
• Invasive EMPD extends into the dermis or subcutaneous tissue and is associated with a higher risk of metastasis, requiring more aggressive treatment 3 8 16.

Clinical Importance of EMPD Types

• Accurate classification is crucial for treatment planning and prognosis 16.
• Baseline screening for internal malignancies is recommended, especially when secondary EMPD is suspected 16.
• Invasive disease may present as nodular or ulcerated areas within the lesion, highlighting the importance of multiple biopsies for diagnosis 16.

Causes of Extramammary Pagets Disease

The cause of EMPD remains a subject of active research and debate, involving both cellular origin and genetic factors.

Cause/Origin	Description	Evidence/Notes	Source(s)
Apocrine glands	Derives from apocrine (sweat) gland cells	Supported by immunohistochemistry	2 5 9
Ectopic mammary glands	Possible origin from misplaced mammary tissue	Speculative, based on anatomical distribution	9
Follicular stem cells	Involvement of hair follicle stem cells	Suggested by marker studies	10
Chromatin remodeling mutations	Genetic alterations (e.g., KMT2C, ARID2)	Early events in oncogenesis	7
Underlying malignancies	Secondary EMPD from distant cancer	Less common than primary	4 6 16

Table 3: Causes and Origins

Cellular and Histological Origins

Apocrine Gland Derivation

• Most evidence points to EMPD arising from apocrine gland cells, based on immunohistochemical markers such as GCDFP-15 and carcinoembryonic antigen, which are present in apocrine and Paget cells 2 5 9.

Other Theories

• Some cases may arise from ectopic mammary glands (remnants of mammary tissue outside the breast) or from pluripotent epidermal cells capable of glandular differentiation 9.
• Follicular stem cell origin has been proposed, particularly due to EMPD’s involvement of adnexal (hair follicle) structures and high recurrence rates 10.

Genetic and Molecular Insights

• Recent genomic studies show frequent mutations in chromatin remodeling genes (e.g., KMT2C, ARID2), suggesting these alterations are early events in EMPD development and may represent diagnostic or therapeutic targets 7.
• Primary EMPD and associated invasive carcinomas usually have distinct genetic mutations, indicating they arise independently 7.

Association with Malignancy

• While primary EMPD is not always linked to internal cancer, secondary EMPD is a manifestation of an underlying malignancy, most often of the anorectal, genitourinary, or skin origin 4 6 16.
• Therefore, a thorough search for underlying tumors is necessary upon diagnosis, especially in older adults 16.

Treatment of Extramammary Pagets Disease

The management of EMPD is complex, requiring individualized approaches based on disease extent, invasiveness, and patient factors. High recurrence rates and the risk of associated malignancy make ongoing surveillance vital.

Treatment	Indication/Use	Efficacy/Notes	Source(s)
Mohs Surgery	Localized, non-metastatic EMPD	Highest cure and lowest recurrence rates	12 14 16
Wide Local Excision	Standard for resectable lesions	Higher recurrence than Mohs	12 14 15 16
Radiotherapy	Non-surgical candidates, palliation	Well-tolerated, variable results	15 16
Photodynamic Therapy	Superficial, non-invasive EMPD	Variable, less effective for invasive disease	13 16
Topical therapies	Non-surgical, superficial disease	Imiquimod, laser, others; less evidence	16
Systemic therapies	Metastatic or unresectable EMPD	Chemotherapy, targeted agents	16
Surveillance	All patients	Essential due to recurrence risk	8 16

Table 4: EMPD Treatment Options

Surgical Approaches

Mohs Micrographic Surgery

• Mohs surgery is the most effective treatment for localized EMPD, offering the lowest recurrence rates (5-year recurrence-free survival up to 91%) 12 14 16.
• It allows precise removal of cancerous tissue while sparing as much healthy tissue as possible.
• Recommended when available, especially for primary, non-invasive EMPD 12 14.

Wide Local Excision

• Traditionally the standard treatment, especially when Mohs is unavailable.
• Has higher recurrence rates (33–60%) compared to Mohs (16%) 12 14.
• Large surgical margins (up to 5 cm) may be needed due to subclinical spread 12.

Nonsurgical and Adjunctive Treatments

Radiotherapy

• Used for patients who cannot undergo surgery, for palliation, or when disease is unresectable.
• Can be effective and well-tolerated, but data is limited to small series 15 16.

Photodynamic Therapy and Topical Treatments

• Photodynamic therapy, imiquimod cream, carbon dioxide laser, and other modalities have been used for superficial, intraepidermal disease 13 16.
• Results are variable; these are considered when surgery is contraindicated 16.

Systemic Therapy

• For metastatic or unresectable disease, chemotherapy or targeted agents may be used, tailored to the tumor’s molecular profile 16.

Surveillance and Follow-Up

• High recurrence rates, even after aggressive treatment, necessitate close follow-up for at least 5 years 8 16.
• Surveillance includes physical exams, imaging, and occasionally repeat biopsies 16.

Multidisciplinary Care

• Because of the risk of underlying or synchronous malignancy, care involves dermatologists, surgeons, oncologists, and, where appropriate, urologists or gynecologists 8 16.

Conclusion

Extramammary Paget’s disease is a rare but significant skin cancer requiring a high index of suspicion for diagnosis, careful classification, and individualized treatment. Its complexity is underscored by frequent misdiagnosis, variable origins, and a tendency to recur. Advances in molecular understanding and surgical techniques continue to improve outcomes.

Key Takeaways:

• EMPD often masquerades as benign skin conditions, delaying diagnosis.
• Symptoms include persistent red, scaly, itchy, or ulcerated plaques, most commonly in apocrine-rich areas.
• EMPD is classified as primary or secondary, and as intraepidermal or invasive, each with different implications.
• Most cases originate from apocrine glands, with genetic mutations in chromatin remodeling genes playing a key role.
• Mohs micrographic surgery offers the best cure rates; wide local excision, radiotherapy, and topical treatments are alternatives.
• Vigilant, long-term surveillance is essential due to high recurrence risk and possible association with other cancers.

Understanding and managing EMPD relies on a multidisciplinary, patient-centered approach, integrating the latest clinical and molecular insights for optimal care.