Extramammary Paget disease (EMPD) of the vulva is a rare and slow-growing type of skin cancer that develops from glandular cells within the surface skin of the vulva. It is classified as an “in situ” cancer when the tumor cells stay within the top layer of skin (the epidermis), meaning they have not yet spread into deeper tissue or to other parts of the body. In a smaller proportion of cases, the tumor cells extend into the underlying tissue, and the disease is called invasive extramammary Paget disease.
Most cases are primary EMPD, meaning the tumor begins in the vulva itself. Less commonly, secondary EMPD represents spread to the vulvar skin from another nearby cancer, such as a cancer of the rectum, anus, bladder, or cervix. Distinguishing primary from secondary EMPD is important because it changes both the diagnostic workup and the management plan.
This article will help you understand what this diagnosis means on your pathology report, what each term means, and why it matters for your care.
What causes extramammary Paget disease?
The exact cause of primary EMPD is not fully known. The tumor cells are thought to arise from glandular cells associated with sweat glands in the vulvar skin, and they share some features with cells lining the milk ducts of the breast. Several factors are associated with the development of EMPD:
- Older age — EMPD is most commonly diagnosed in postmenopausal patients in their 60s, 70s, or 80s. It is uncommon in younger patients.
- Female sex — The vulva is the most common site of EMPD in women, accounting for the large majority of female cases.
- Underlying internal malignancies — In secondary EMPD, the tumor cells in the vulvar skin represent spread from a cancer arising in a nearby organ, most often the rectum, anus, bladder, or cervix. Identifying or excluding an underlying internal cancer is an important part of evaluating any new EMPD diagnosis.
- Other skin appendage abnormalities — Because EMPD arises from glandular skin cells, factors that affect these glands may contribute, though specific causes have not been identified.
EMPD is not caused by infection with human papillomavirus (HPV), and it is not contagious. There are no clearly established lifestyle risk factors.
What are the symptoms?
EMPD often develops slowly over years and can resemble common skin conditions, which sometimes delays the diagnosis. Symptoms commonly include:
- Persistent itching — Long-standing itching of the vulva that does not improve with usual treatments is the most common symptom.
- Red, eczema-like patches — The affected skin often appears red, scaly, and slightly raised. Some areas may look white or have a “strawberries and cream” pattern of red and white.
- Burning or soreness — Discomfort in the affected area, sometimes worsened by friction, urination, or sexual activity.
- Crusting or oozing — The surface of the skin may become cracked, weeping, or crusted over.
- Bleeding — Small amounts of bleeding may occur, especially if the skin has been scratched.
- A lump or thickened area — In more advanced disease, the affected skin may become noticeably thickened, raised, or ulcerated. A new lump in the groin may signal spread to a lymph node in invasive cases.
Because EMPD can mimic eczema, dermatitis, or fungal infection, patients are often treated for these conditions for months or years before a biopsy leads to the correct diagnosis. Any vulvar skin change that does not improve after several weeks of standard topical treatment should be evaluated with a biopsy.
How is the diagnosis made?
The diagnosis of EMPD is made when a pathologist examines a sample of vulvar skin under the microscope. The sample is typically obtained via a small biopsy of the area of concern during an office visit. If EMPD is confirmed on biopsy, the entire affected area is usually removed surgically through a wide local excision or vulvectomy, which allows the pathologist to assess the full extent of the disease and the surgical margins.
Because the abnormal cells in EMPD can resemble those in other skin cancers, the pathologist almost always performs additional tests, such as immunohistochemistry, to confirm the diagnosis and distinguish primary from secondary EMPD. The typical pattern in primary EMPD includes:
- Positive markers — Cytokeratin 7 (CK7), gross cystic disease fluid protein-15 (GCDFP-15), mucin (MUC1), carcinoembryonic antigen (CEA), and epithelial membrane antigen (EMA) are typically positive in the tumor cells.
- Negative markers — Cytokeratin 20 (CK20), p63, S100, HMB-45, and Melan-A are typically negative, helping to rule out other diagnoses such as squamous cell carcinoma or melanoma.
- Markers that distinguish primary from secondary EMPD — Secondary EMPD usually shows a different staining pattern that reflects the origin of the underlying cancer. For example, if the cells are positive for CK20 and CDX2, the disease may represent spread from a colorectal cancer. Positive uroplakin or GATA3 staining may suggest spread from a urothelial (bladder) cancer.
When EMPD of the vulva is diagnosed, additional tests are often performed to look for an associated internal cancer. These commonly include a colonoscopy, cystoscopy (an examination of the bladder), and cervical screening, particularly if the staining pattern raises concern for secondary disease or if the patient is at higher risk based on her medical history.
What does extramammary Paget disease look like under the microscope?
Under the microscope, EMPD has a characteristic appearance:
- Paget cells — The tumor is made up of large, round cells (called Paget cells) with abundant pale or light pink cytoplasm and a large nucleus that often contains a visible nucleolus.
- Scattered distribution within the epidermis — The Paget cells are typically scattered as single cells or small clusters throughout the epidermis (the top layer of the vulvar skin), often more concentrated in the lower layers.
- Background skin changes — The surrounding skin frequently shows reactive changes, including thickening of the epidermis and a mild inflammatory infiltrate in the underlying tissue.
- Confinement to the epidermis (in situ disease) — When EMPD is non-invasive, the Paget cells stay within the epidermis and do not extend below the basement membrane.
- Extension into deeper tissue (invasive disease) — In invasive EMPD, the Paget cells break through the basement membrane and extend into the dermis or, less commonly, the subcutaneous tissue.
Invasion
The term invasion refers to the movement of tumor cells from their starting location (the epidermis, in EMPD) into the deeper layers of skin (the dermis or subcutaneous tissue). The distinction between in situ and invasive EMPD is critically important because it changes both the prognosis and the discussion about further treatment.
- In situ EMPD — The Paget cells are confined to the epidermis and cannot, by definition, spread to lymph nodes or distant organs. In situ EMPD is the most common form of the disease, and the prognosis is excellent with adequate surgical removal, although recurrences are common.
- Invasive EMPD — The Paget cells have invaded into the dermis or deeper tissue. Once invasion has occurred, the cancer has the potential to spread to lymph nodes (most commonly the inguinal nodes in the groin) and to distant organs. The depth of invasion (typically measured in millimeters) is important: tumors that invade more than 1 mm into the dermis are more likely to spread.
Your pathology report will state whether your EMPD is in situ or invasive and, if invasive, will describe the depth of invasion.
Surgical margins
A margin is the cut edge of tissue removed during surgery. The pathologist examines all of the margins under the microscope to determine whether any Paget cells are present at the cut edges of the specimen.
- Negative margin — No Paget cells are present at the cut edge of the tissue. Most reports also describe how far the closest Paget cells are from the margin, usually in millimeters.
- Positive margin — Paget cells extend to the cut edge of the tissue. This means some abnormal cells may still remain and increases the risk that the disease will return in the same area.
Margins are particularly important in EMPD because the disease often extends well beyond what is visible to the naked eye. Microscopic “skip lesions” (small islands of Paget cells beyond the apparent edge of the lesion) can lead to positive margins even when the surgery appears to have removed the entire visible area. This is one of the reasons EMPD has a relatively high recurrence rate. When margins are positive, the team often discusses further surgical treatment.
Lymph nodes
Lymph nodes are small immune organs that filter fluid as it returns from the body’s tissues. Lymph node assessment is only relevant for invasive EMPD, because in situ disease cannot spread to lymph nodes. When invasion is present and the depth of invasion is greater than 1 mm, or when other high-risk features are present, the team may discuss removing one or more lymph nodes in the groin to look for spread.
The vulva drains first into the inguinal lymph nodes in the groin. For invasive EMPD, a sentinel lymph node biopsy or a more extensive inguinofemoral lymph node dissection may be considered. The pathology report describes the number of lymph nodes examined, the number that contain tumor cells, the size of any tumor deposits, and whether tumor cells have broken through the outer wall of a lymph node into the surrounding tissue (a finding called extranodal extension, which is associated with a higher risk of recurrence).
Biomarker and molecular testing
Biomarker testing is most relevant in invasive, recurrent, or metastatic EMPD, where the results help determine eligibility for specific systemic therapies.
HER2
HER2 (human epidermal growth factor receptor 2) is a protein that some cancer cells produce in larger-than-normal amounts. HER2 is overexpressed in approximately 30 to 60% of EMPD cases, and the rate is higher in invasive and metastatic tumors. HER2 testing is performed by immunohistochemistry and, in equivocal cases, confirmed with in situ hybridization (FISH or CISH). When HER2 is overexpressed (a 3+ result by immunohistochemistry, or a positive in situ hybridization result), the team may discuss HER2-targeted therapy with drugs such as trastuzumab. HER2-targeted therapy can be an important option for invasive or recurrent disease that has not responded to other treatments.
Androgen receptor and other markers
The androgen receptor is positive in a substantial proportion of EMPD cases, and there is growing interest in androgen receptor-directed therapy for advanced disease. Other markers, including those involved in DNA repair pathways, are being studied as potential treatment targets. The role of these tests is evolving, and not all are part of routine clinical practice.
What is the prognosis?
The prognosis for EMPD depends most strongly on whether the disease is in situ or invasive at the time of diagnosis, and on whether any underlying internal cancer is present.
- In situ EMPD has an excellent prognosis. The cells cannot spread to lymph nodes or distant organs, and survival is generally not affected by the disease itself. However, recurrence after surgical removal is common — reported in approximately one-third of patients — because microscopic skip lesions often extend beyond the visible disease.
- Invasive EMPD carries a meaningfully higher risk. The prognosis depends on the depth of invasion, the presence of lymph node involvement, and the HER2 status. Tumors with a depth of invasion of 1 mm or less and negative lymph nodes have a favorable outlook. Deeper invasion, larger size, lymph node involvement, and extranodal extension are all associated with worse outcomes.
- The prognosis of secondary EMPD is largely determined by the stage of the underlying internal cancer (such as colorectal, urothelial, or cervical cancer) rather than by the EMPD itself.
Several features in the pathology report influence the chance of recurrence:
- Margin status — Negative margins are associated with a lower risk of recurrence. Positive margins, or Paget cells close to the margin, increase the risk.
- Multifocal disease — EMPD often involves multiple separate areas of the vulva, which increases the chance of recurrence even after complete excision.
- Depth of invasion (when present) — Deeper invasion is associated with a higher risk of spread.
- Lymph node involvement — The presence of tumor cells in lymph nodes substantially worsens the prognosis.
- HER2 status — HER2 overexpression is associated with more aggressive behavior but may also identify patients who can benefit from HER2-targeted therapy.
What happens after this diagnosis?
Once EMPD of the vulva is diagnosed, the gynecologic oncology team will discuss treatment options with the patient. Decisions depend on whether the disease is in situ or invasive, the extent of involvement, the patient’s age and overall health, and whether an underlying internal cancer is identified.
Options that the team may consider include:
- Wide local excision — The standard surgical approach for EMPD is wide local excision of the affected area with a generous margin of normal-appearing surrounding skin. The goal is to remove all visible disease and any microscopic skip lesions.
- Mohs micrographic surgery — A specialized form of surgery in which the tissue is examined under the microscope during the operation, allowing the surgeon to confirm that the margins are clear before completing the procedure. Mohs surgery may improve the likelihood of achieving negative margins in EMPD.
- Repeat excision for positive margins — When margins are positive, the team may discuss a repeat excision to confirm complete removal.
- Topical imiquimod cream — Imiquimod is an immune-activating cream used as a non-surgical option for in situ EMPD, particularly for patients who cannot undergo surgery or have small or recurrent lesions. Response rates vary, and recurrence is common.
- Photodynamic therapy and laser therapy — Both are non-surgical options that have been used for selected patients with in situ disease. Their role is generally limited to specific clinical situations.
- Radiation therapy — May be considered for patients who are not surgical candidates, for selected cases with positive margins, or for invasive disease with high-risk features.
- Systemic therapy for invasive or metastatic disease — For invasive disease that has spread or that recurs after local treatment, the medical oncology team discusses systemic options. HER2-targeted therapy (such as trastuzumab) is a particularly important consideration when the tumor is HER2-positive. Conventional chemotherapy and enrollment in clinical trials may also be discussed.
- Screening for associated internal cancers — Because EMPD of the vulva can be secondary to or associated with cancers of nearby internal organs, your team will typically discuss screening tests such as colonoscopy, cystoscopy, and cervical screening, especially around the time of diagnosis.
Because EMPD has a high rate of recurrence, long-term follow-up with a clinician experienced in vulvar disease is essential. Surveillance typically includes regular vulvar examinations and prompt evaluation of any new symptoms or visible changes.
Questions to ask your doctor
- Was my EMPD found to be in situ (non-invasive) or invasive?
- If invasive, how deep was the invasion, and were any lymph nodes involved?
- Was the disease primary or secondary EMPD?
- Were the surgical margins negative or positive?
- Was HER2 testing performed, and if so, what was the result?
- What additional tests will I need to look for an associated internal cancer (colonoscopy, cystoscopy, cervical screening)?
- What treatment options would you discuss with me based on my findings?
- If I have positive margins, would you recommend further surgery, imiquimod cream, or another approach?
- What is the chance that my EMPD will come back after treatment?
- How often will I need follow-up examinations, and what will they involve?
- What symptoms should I watch for between scheduled visits?
- Are there topical treatments or skin care routines that you recommend for me?
- Should I see a specialist in vulvar disease or a multidisciplinary team for ongoing care?
- Are there clinical trials available that might be appropriate for my situation?
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