Extramammary Paget disease

Extramammary Paget disease
Diagnosis in short
Extramammary Paget's disease. H&E stain.
LM	large epithelioid cells - nested or single - in the epidermis, clear/pale cytoplasm (occasionally eosinophilic), large nucleoli
LM DDx	benign Toker cell hyperplasia, malignant melanoma, Bowen's disease, apocrine carcinoma of the skin
IHC	CK7 +ve, CEA +ve, S-100 -ve, CK5/6 -ve, HER2 +ve
Gross	erythema, +/-weeping, +/-crusted
Site	vulva, penis, scrotum, others
Symptoms	pruritis (itchy)
Prognosis	typically benign - usually not associated with an underlying malignancy (unlike Paget's disease of the breast)
Clin. DDx	contact dermatitis, lichen sclerosus

Extramammary Paget disease, abbreviated EMPD, is a skin disease. As the name suggests, there is also a Paget disease of the breast.

There is also a Paget disease of the bone - just to make things confusing. This is dealt with in the bone article and has nothing (from a pathologic perspective) to do with the Paget disease discussed in this article

General

• Two types
  • Primary Extramammary Paget disease - a malignancy of the cutaneous apocrine glands
    • Arises in apocrine rich areas - usually the vulva but also the groin, inguinal area, perineum, penis or scrotum. and rarely axilla or eye.
    • Usually entirely intraepidermal but may be associated with an underlying apocrine gland carcinoma (in contrast to mammary Paget disease which is usually associated with underlying mammary carcinoma).
  • Secondary Extramammary Paget disease - intraepidermal spread from a distant tumor
    • Usually of urothelial or colorectal origin.
    • Arises in the perineal areas near these organs

Clinical:

• Pruritis.
• R/O VIN
• R/O vulvitis

Gross

Features:

• Plaque with an irregular border.
• Erythematous or white.

Clinical DDx:

• Lichen sclerosus.
• Vulvar intraepithelial neoplasia
• Vulvar squamous cell carcinoma in situ
• Other vulvitis

Images

• Scrotal EMPD (nih.gov).

Microscopic

Features:

• Epitheliod morphology (round/ovoid).
• Cells nested or single.
• Classically Paget cells ride above the basal cell layer
• But the process can fill the entire epidermis
• Clear/pale cytoplasm key feature - may also be eosinophilic.
• Large nucleoli.

Images

• Paget disease - low mag. (WC).
• Paget disease - high mag. (WC).

• 

  Anus Pagets Disease - (SKB)

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  Anus Pagets Disease - (SKB)

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  Anus Pagets Disease - (SKB)

DDx

• Malignant melanoma in situ.
• Bowen disease - Pagetoid squamous cell carcinoma in situ.
• Pagetoid vulvar intraepithelial neoplasia
• Vulvar squamous cell carcinoma.

Notice that mammary Paget disease and Toker cell hyperplasia are not part of this DDX (wrong locations) except possibly in the rare case of EMPD arising in the axilla where mammary arising from a ectopic nipple or ectopic breast tissue may be a consideration. Notice that EMPD is not really part of the DDX of pagetoid cutaneous squamous cell carcinoma arising on typical sun damaged skin (arm, cheek, leg) - if it's from an apocrine rich area - it's not EMPD.

Stains

• Mucicarmine stain +ve.

IHC

• Extramammary Paget disease is a 'big' diagnosis in that the diagnosis will have significant clinical consequences. So a large panel of immuno is required to nail down the diangosis.

• Is the lesion epithelial or melanocytic? (S100, Melan A)
• Is the lesion adenocarcinoma or squamous cell carcinoma?
  • Low molecular weight (CK7, cam5.2) or high molecular weight keratins (34BE12, CK5/6)?
  • Adenocarcinoma markers? - CEA, BerEP4
  • Nuclear differentiation markers? - p63 (squamous) vs GATA3 (adnexal)
• Is the lesion primary or secondary?
  • Secondary extramammary Paget disease may be CK20 positive (urothelial or rectal)
  • If CK20 is positive are other organ specific markers positive? - CDX2 - colorectal or GATA3 - urothelial

Panel: You can not rely on any one marker - a panel is required

• A carcinoma marker - CEA or BerEP4 or both
• Differential keratins - low molecular weight (glandular) cam5.2, CK7 vs high molecular weight (squamous) 34BE12, CK5/6
• CK7 and CK20 - where does it come from?
• S100 and Melan A - exclude melanoma in situ
• Differentiation markers GATA - apocrine and urothelial; p63 - squamous, CDX2 - colorectal

• • Notice urothelial origin Paget can show immunos patterns "transitional" between glandular and squamous epithelium
    • A CK20 negative urothelial origin EMPD could show a similar immunoprofile as a primary cutaneous EMPD.
  • Notice that you do not need to include markers for mammary Paget disease or Toker cells.
  • Do not rely on CK7 alone as CK7 may be positive in pagetoid squamous cell carcinoma in situ or extramammary Paget disease
  • p16 is not helpful in distinguishing between VIN and EMPD as may be positive in either. Urothelial carcioma can also be positive for this marker

Roughly and with caveats........

• Primary cutaneous extramammary Paget disease - CK7+, CK20-, BerEP4+, CEA+, S100-, MelanA-, 34BE12-, CK5/6-, p63-, GATA+, CDX2-
• Secondary extramammary Paget disease - colorectal origin - CK7-, CK20+, BerEP4+, CEA+, S100-, MelanA-, 34BE12-, CK5/6-, p63-, GATA-, CDX2+
• Secondary extramammary Paget disease - urothelial origin - CK7+, CK20+/-, BerEP4-/+, CEA-/+, S100-, MelanA-, 34BE12+, CK5/6+/-, p63+, GATA+, CDX2-
• Pagetoid VIN or squamous cell carcinoma in situ - CK7-, CK20-, BerEP4-, CEA-, S100-, MelanA-, 34BE12+, CK5/6+ p63+, GATA-, CDX2-
• Melanoma in situ - CK7-, CK20-, BerEP4-, CEA-, S100+, MelanA+, 34BE12-, CK5/6- p63-, GATA-, CDX2-

See also

• Paget disease.