Extramammary Paget Disease Workup

Updated: Jul 21, 2021
  • Author: Richard Harold "Hal" Flowers, IV, MD; Chief Editor: Dirk M Elston, MD  more...
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Workup

Approach Considerations

The diagnosis of extramammary Paget disease (EMPD) requires a high degree of clinical suspicion, especially in patients presenting with persistent eczematous lesions failing a 6-week trial of topical therapies. Skin biopsy with pathologic correlation is the basis of diagnosis. [18]  A detailed review of systems and physical examination should be performed in all patients following a diagnosis of EMPD. 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.

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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. [7]

Positron-emission tomography (PET) may be helpful in assessing regional lymph nodes and locating distant disease, especially in patients with dermal invasion noted on initial skin biopsy specimens. [19]

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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. A skin biopsy specimen should be obtained for initial diagnosis. Repeat biopsies are warranted to evaluate possible EMPD in patients in whom ongoing therapy is ineffective.

On histologic examination of EMPD, the epidermis is diffusely infiltrated with large vacuolated cells that have a bluish cytoplasm called Paget cells (see the images below). There are two types of Paget cells: classic type (type A) and signet-ring type (type B). The classic type is characterized by vesicular nuclei with prominent nucleoli and abundant pale cytoplasm, while the signet-ring type is characterized by an eccentrically displaced nucleus with large cytoplasmic mucin droplets. [20, 21] 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) stain followed by diastase digestion.

Classic histology of extramammary Paget disease (E Classic histology of extramammary Paget disease (EMPD). Clusters of large cells with pale, vacuolated cytoplasm scattered throughout the epidermis.
High power image of extramammary Paget disease (EM High power image of extramammary Paget disease (EMPD). Clusters of large cells with pale, vacuolated cytoplasm scattered throughout the epidermis.

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 [22] :

  • 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

Immunohistochemical staining can be used to identify Paget cells, differentiate primary from secondary EMPD, and distinguish the condition from other malignant processes, including melanoma or squamous cell carcinoma in situ. [3]

When Paget cells are noted in the epidermis, cytokeratin (CK)–7 and CK20 can be extremely helpful in characterizing the diagnosis. CK7 is extremely sensitive (though poorly specific) in identifying EMPD cells. Cancers of the urothelial and gastrointestinal tracts, which can show pagetoid spread, strongly express CK20, while EMPD does not. It follows that primary EMPD typically stains positive for CK7 and negative CK20, while secondary EMPD stains positive for both. [23] When the diagnosis remains in doubt, gross cystic disease fluid protein 15 (GCDFP-15) is another stain that shows specificity for secondary EMPD. Although unable to differentiate primary from secondary disease, epithelial membrane antigen (EMA), PAS, and carcinoembryonic antigen (CEA) stains are also sometimes used to identify Paget cells. [23] The dermatopathologist may select a combination of these stains in order to make the diagnosis.

More recently, studies on genetic and protein expression profiles of EMPD cells are providing useful prognostic information. HER2, Ki-67, cyclin D1, and MUC5AC are some of the more promising markers of tumor differentiation. In preliminary studies, expression of any or all of these markers has been associated with more aggressive tumors. [23] Owing to cost and access issues, routine use of these studies is not standard practice at this time.

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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). However, staging has been established for EMPD with perianal involvement and is as follows [24] :

  • 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 [25] :

  • 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
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