Extramammary Paget Disease 

Updated: Apr 18, 2017
Author: Blanca Anais Estupiñan; Chief Editor: Dirk M Elston, MD 

Overview

Background

Mammary Paget disease (PD) of the nipple was first described by Sir James Paget in 1874. Extramammary PD (EMPD) was first recognized and reported as a distinct clinical entity by Radcliffe Crocker in 1889. EMPD is morphologically and histologically identical to mammary PD of the nipple, the primary difference being the anatomic location. See the image below.

Photomicrograph of malignant melanoma in situ of s Photomicrograph of malignant melanoma in situ of skin displays prominent intraepidermal pagetoid spread. Note that melanoma cells are present in all layers of epidermis, mostly in single units. Cytoplasm of melanoma cells is vacuolated. Moderate upper dermal chronic inflammatory infiltrate is present (hematoxylin-eosin, original magnification ×250). S-100 protein and homatropine methylbromide immunostains are positive in melanoma cells, whereas carcinoembryonic antigen is negative. No epithelial mucin is seen in these tumor cells.

Crocker described a patient with erythematous patches on his penis and scrotum. Since he made this distinction, the term EMPD is more commonly used to describe the condition in women. This process targets the genital skin, perianal skin, and other cutaneous sites rich in apocrine glands. EMPD is not a common disorder, but it must be considered in the differential diagnosis of patients with chronic genital or perianal dermatitis.

Please see the following for more information:

  • Paget Disease

  • Mammary Paget Disease

  • Physical Medicine and Rehabilitation for Paget Disease

Pathophysiology and Etiology

Extramammary Paget disease (EMPD) arises as a primary cutaneous adenocarcinoma in most cases. The epidermis becomes infiltrated with neoplastic cells showing glandular differentiation. Tumor cells may originate from apocrine gland ducts or from keratinocytic stem cells.

Approximately 25% of the cases of EMPD (range, 9-32%) are associated with an underlying in situ or invasive neoplasm. In all patients, the neoplasm most likely to be associated with EMPD is an adnexal 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 Bartholin glands, urethra, bladder, vagina, cervix, endometrium, and prostate.

The anatomic location of EMPD plays a role in predicting the risk of associated carcinoma. For instance, genital disease is associated with carcinoma in about 4-7% of patients. Perianal disease is associated with underlying colorectal carcinoma in 25-35% of cases.

Rare cases of EMPD associated with tumors arising in distant organs without direct epithelial connection to the affected epidermis have been reported. Roy et al reported PD in a retrorectal dermoid cyst.[1] No clear evidence supports a causal link between these distant tumors and cutaneous EMPD.

The cause of primary EMPD is unknown. However, a minority of cases do represent a direct extension of an underlying adenocarcinoma along contiguous epithelium, while others suggest pluripotent stem cells or Toker cells may be potential precursors.

Epidemiology

Extramammary Paget disease (EMPD) is a rare condition; there are only several hundred cases in the world literature. It most commonly appears in individuals aged 50-60 years. Women are more commonly affected by EMPD than men. The female-to-male ratio was 4.5:1 in one series of 55 patients and 3:1 in another series of 197 patients.[2] EMPD is more frequently seen in whites and is rarely seen in the black population.[3]

Prognosis

The course of extramammary Paget disease (EMPD) may extend over a period of 10-15 years without evidence of cancer or metastases.[4] In a minority of patients, tumor cells infiltrate the dermis, adnexa, or lymph nodes. Both mortality and morbidity are increased in these patients because of the extensive surgical treatment or chemotherapy that they need.

The prognosis for EMPD heavily depends on early diagnosis with definitive surgical treatment. Full recovery is possible in patients with purely epidermal disease and negative margins after micrographic surgery. One study showed a mortality of 18% for patients without associated carcinoma and 46% for those with underlying carcinoma.

Perianal disease, dermal invasion, and two or more lymph node metastases are poor prognostic indicators. Other characteristics associated with worse survival include tumor thickness over 4 mm and distant metastasis. The recurrence rate of EMPD is 30%, even with margin control. The average time to recurrence is 2.5 years, with case reports of more than 10 years follow-up.

 

Presentation

History

The possibility of extramammary Paget disease (EMPD) should be carefully considered in any patient with chronic dermatitis of the groin, vulva, or perianal area. Patients with EMPD usually present with nonresolving eczematous lesions in the groin, genitalia, perineum, or perianal area.[5] The most common symptom of EMPD is intense pruritus; most patients have only pruritus in the affected area and no other symptoms. Pain and bleeding may occur in longer-standing lesions.

Physical Examination

At clinical examination, extramammary Paget disease (EMPD) may appear as chronic intertrigo or presumed tinea cruris. It may appear eczematous, and it has usually been present for several years before biopsy is performed to confirm the diagnosis. The genitalia, perineum, axillae, and external auditory canal are rich in apocrine glands; therefore, these are the usual sites of EMPD involvement, which is usually multifocal. In males, the penoscrotal area is most frequently involved, as is the vulva in women.

Early skin changes may be subtle and vary according to location. Initially, only slight erythema, crusting, and increased maceration may be noted. Pruritus commonly leads to prominent excoriations and lichenification. In addition to pruritus, patients may describe a burning sensation or pain over the area of involvement. Lesional progression leads to a unilateral sharply marginated plaque with distinct erythema. Hypopigmentation or hyperpigmentation occurs, and small pale islands are often observed over the lesion. Superficial erosion or scaling may develop in mature lesions.

 

DDx

Diagnostic Considerations

Differential diagnosis includes squamous cell carcinoma, condyloma acuminata, hidradenitis suppurativa, and lichen sclerosis. Other considerations are listed below.

Differential Diagnoses

 

Workup

Approach Considerations

The diagnosis of extramammary Paget disease (EMPD) requires a high degree of clinical suspicion, especially with patients presenting with persistent eczematous lesions failing a 6-week trial of antieczema therapy. Skin biopsy with pathologic correlation is the basis of diagnosis.[6] Initially, a detailed review of systems and physical examination should be performed in all patients. The examination should include the following:

  • Palpation of all lymph nodes

  • Rectal examination

  • Sigmoidoscopy

  • Cystoscopy

Additionally, women require pelvic examination with a Papanicolaou test, breast examination, and colposcopy.

Imaging Studies

Imaging studies in extramammary Paget disease (EMPD) should be directed by the anatomic location of the involved skin and the sex of the patient. Imaging studies should be used to augment physical and endoscopic examination in assessing possible undetected internal malignancy.[2]

Positron emission tomography (PET) may be helpful in assessing regional lymph nodes and locating distal disease, especially in patients with dermal invasion noted on initial skin biopsy specimens.[7]

Skin Biopsy and Histologic Findings

Because extramammary Paget disease (EMPD) extends beyond the visibly involved margins, obviously involved skin should be examined by using transverse frozen sections or serial vertical sections. Perform skin biopsy to evaluate possible EMPD in patients in whom ongoing therapy is ineffective. See the image below.

Photomicrograph of malignant melanoma in situ of s Photomicrograph of malignant melanoma in situ of skin displays prominent intraepidermal pagetoid spread. Note that melanoma cells are present in all layers of epidermis, mostly in single units. Cytoplasm of melanoma cells is vacuolated. Moderate upper dermal chronic inflammatory infiltrate is present (hematoxylin-eosin, original magnification ×250). S-100 protein and homatropine methylbromide immunostains are positive in melanoma cells, whereas carcinoembryonic antigen is negative. No epithelial mucin is seen in these tumor cells.

The epidermis is diffusely infiltrated with large vacuolated cells that have a bluish cytoplasm; these are called Paget cells. These distinctive cells are found in the lower epidermis and may proliferate to the rete ridges and adnexa. The epidermis shows varying degrees of acanthosis, hyperkeratosis, and parakeratosis. With histochemical analysis, Paget cells are stained with sialomucin by using periodic acid–Schiff (PAS) followed by diastase digestion.

It is important to keep in mind the differential diagnosis of tumors with an epidermotropic growth pattern and the importance of immunohistochemical staining in the histologic workup of such tumors. The following should all be considered[8] :

  • Squamous cell carcinoma in situ

  • Melanoma

  • Mycosis fungoides

  • Eccrine porocarcinoma

  • Sebaceous carcinoma of the eyelid

  • Mammary Paget disease (PD) and EMPD

  • Merkel cell carcinoma

  • Epidermotropic metastases

Cytokeratin 20 (CK20) and BRST-2 are both positive in large subsets of primary and secondary EMPD. Studies have used immunohistochemical analysis of skin biopsy specimens to determine the significance of podoplanin, a mucinlike transmembrane protein, within peritumoral basal keratinocytes in EMPD patients.[9] Podoplanin expression is associated with increased tumor thickness, loss of E-cadherin, and the presence of invadopodia on keratinocyte plasma membranes, which are believed to degrade extracellular matrix and enhance tumor migration. Thus, immunohistochemically staining skin biopsy samples for podoplanin may prove useful in identifying aggressive EMPD and determining prognosis. Other molecular markers immunohistochemically identified in the current literature include gross cystic disease fluid protein 15 (GCDFP15) and mucin 5AC, ie, oligomeric mucus/gel-forming protein (MUC5AC).[10, 11]

Using HER2/neu and CDX2 may be beneficial to distinguish primary EMPD from secondary EMPD due to anorectal adenocarcinoma but not due to urothelial or prostatic malignancy.[12]

Staging

TNM (tumor, node, metastasis) classification is used to describe many solid tumors and determine staging. Currently, no TNM staging system exists for extramammary Paget disease (EMPD) in general. However, staging has been established for EMPD with perianal involvement and is as follows[13] :

  • Stage I: Paget cells located in perianal epidermis and adnexa without underlying carcinoma
  • Stage IIA: Cutaneous Paget disease associated with adnexal carcinoma
  • Stage IIB: Cutaneous Paget disease associated with anorectal carcinoma
  • Stage III: Paget disease associated with underlying carcinoma that has metastasized to nearby lymph nodes
  • Stage IV: Paget disease associated with underlying carcinoma that has distant metastases

A 2016 retrospective review of patients with EMPD proposed the staging system detailed below[14] :

  • Stage I: Tumor thickness less than 4 mm without lymphovascular invasion
  • Stage II: Tumor thickness greater than 4 mm or lymphovascular invasion
  • Stage IIIa: Any tumor thickness plus one regional lymph node metastasis
  • Stage IIIb: Any tumor thickness plus two regional lymph node metastases
  • Stage IV: Any tumor thickness plus distant organ metastasis or distant lymph node metastasis

 

 

Treatment

Chemotherapy

Three separate reports describe successful treatment of extramammary Paget disease (EMPD) with 5-fluorouracil,[15] imiquimod,[16, 17, 18, 19, 20] and a combination of paclitaxel and trastuzumab.[21]

Specifically, imiquimod 5% cream applied 3 times weekly for 16 weeks induced complete resolution in a patient with perineal EMPD. One case report describes two patients with recurrent and extensive EMPD achieving complete remission after 5-aminolevulinic acid (5-ALA) photodynamic therapy and topical imiquimod.[22] Lesions were treated with 20% 5-ALA photodynamic therapy every 2 weeks for a total of 6 cycles followed by topical imiquimod every other day for 3 months. Topical imiquimod is considered a possible treatment option, especially when surgery is a challenge or contraindicated. However, more studies are needed to confirm the use of topical therapies for patients with EMPD.[23]

Surgical Excision

Margin-controlled surgical excision of all the involved epidermis is the most effective treatment. Extramammary Paget disease (EMPD) extends beyond the visibly involved margins. Obviously involved skin should be examined by using transverse frozen sections or serial vertical sections (see Workup). Multiple scouting biopsies performed before surgery may aid in planning a more precise initial excision.[3]

Multifocal disease is a challenge for any surgical method that relies on contiguous tumor spread for effective margin control—even micrographic surgery. Currently, wide radical excision with 5-cm margins or Mohs micrographic surgery are the recommended excision options. When operating in the anogenital region, providers must consider the aesthetic and functional consequences patients may face after radical excision. However, Mohs micrographic surgery offers lower recurrence rates after excision of primary tumors, with a smaller margin of normal skin removed.[24, 25] The recurrence rate of primary tumors after standard surgical excision is 30-60%. The rate after excision with Mohs micrographic surgery is 8-26%. The average time to recurrence is 2.5 years, with case reports of more than 10 years follow-up. Although long-term outcomes are improved using Mohs micrographic surgery, some patients may not be able to afford the higher treatment costs. Additional studies have explored minimal surgical therapy as a third excision treatment option and have reported success with 1-cm excisional borders in well-circumscribed EMPD.[26]

 

Consultations and Long-Term Monitoring

Depending on the anatomic location of extramammary Paget disease (EMPD), treatment should be coordinated with an appropriate surgical subspecialist (eg, a urologist, a colorectal surgeon, or a gynecologist). Optimally, the consultant would have some experience treating this specific condition. Further consultation with a radiologist and a gastroenterologist may also be required to order appropriate screening examinations for internal malignancy.

Patients with EMPD require follow-up examination every 3 months after surgery to assess possible recurrence. This routine should continue for at least 24 months, after which time examinations may be done annually. Consider repeating other endoscopic or imaging studies on a regular basis according to the specific recommendations of the consultants.

A 2017 study found serum cytokeratin 19 fragment 21-1 (CYFRA 21-1) levels to be useful in monitoring tumor burden and treatment response. Compared with carcinoembryonic antigen (CEA) monitoring, CYFRA 21-1 levels were more sensitive in detecting tumor reduction as well as recurrence, with a corresponding decrease and increase in serum concentration, respectively.[27]

 

Medication

Medication Summary

Topical imiquimod is considered a possible treatment option, when surgery is a challenge or contraindicated. However, more studies are needed to confirm the use of topical therapies for patients with extramammary Paget disease (EMPD).

Fluorouracil is used topically. It interferes with DNA synthesis by blocking methylation of deoxyuridylic acid via inhibition of thymidylate synthetase and, subsequently, cell proliferation. For lesions on bald scalp or extremities, longer treatment is often necessary.

Immunomodulators

Class Summary

These agents modulate key factors of the immune system.

Imiquimod (Aldara, Zyclara)

Immune response modifier with an unknown mechanism of action. Indicated to treat clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses on the face or scalp.

Antineoplastics, Antimetabolite

Class Summary

These agents inhibit cell growth and proliferation.

Fluorouracil (Carac, Efudex, Fluoroplex)

Fluorouracil is used topically. It interferes with DNA synthesis by blocking methylation of deoxyuridylic acid via inhibition of thymidylate synthetase and, subsequently, cell proliferation. For lesions on bald scalp or extremities, longer treatment is often necessary.