Extramammary Paget Disease Workup

Updated: Apr 18, 2017
  • Author: Blanca Anais Estupiñan; 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 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.

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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. [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]

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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. 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]

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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) 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

 

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