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Extramammary Paget Disease

Definition

  • Intraepithelial involvement of the skin by (non-squamous) carcinoma cells

Diagnostic Criteria

  • Intraepithelial population of large atypical cells (Paget cells) distinct from surrounding normal epithelial cells
    • Large nuclei, prominent nucleoli
    • Abundant pale cytoplasm
    • Scattered individually and in clusters
      • May form small acini
    • Lack features of squamous differentiation
      • No visible intercellular bridges
      • No transition to surrounding squamous cells
  • Most cases mucin positive
    • May form signet rings
  • Underlying chronic inflammation common
  • Epidermal hyperplasia and hyperkeratosis and parakeratosis frequently present
    • Present in half of cases
      • >90% of anal cases
    • Three patterns described
      • Squamous hyperplasia NOS
        • May result in pseudoepitheliomatous hyperplasia
      • Fibroepithelioma-like
        • Anastomosing network of rete ridges
        • Especially frequent in perianal cases
      • Papillomatous
        • HPV negative
    • Paget cells may be shrunken and pyknotic
  • Extramammary Paget disease can be separated into primary and secondary types
    • Primary type not associated with underlying deep carcinoma
      • Positive for GCDFP15 and negative for CK20 (see Supplemental Studies and Differential Diagnosis at left sidebar)
      • Invasion is uncommon, but can occur
    • Secondary type is associated with an underlying internal carcinoma
      • Negative for GCDFP15 and frequently CK20 positive
      • Phenotype may depend upon nature of underlying carcinoma
      • Most common underlying carcinomas
        • Rectal adenocarcinoma
        • Urothelial (transitional cell) carcinoma
  • Most common locations
    • Vulva
    • Anal/perianal
    • Scrotum and penis
    • Inguinal
Teri A Longacre MD
Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting/updates : 10/7/10

Supplemental studies

Immunohistology

  • Markers useful for separating Paget disease from other processes
    • CK7 is the most useful marker as it is not expressed by the surrounding epidermal cells
      • Normal Toker cells and Merkel cells are positive for CK7 and must be distinguished morphologically
      • CAM5.2 may be useful as a substitute as it is nearly as specific
      • Other anti-keratins and EMA will stain most Paget cells but are not as specific
    • BerEp4 has been proposed as a useful marker
      • Extramammary Paget disease is 100%
      • Squamous cell carcinoma in situ is negative
      • One report, needs confirmation
    • High molecular weight cytokeratin (HMWCK) and p63 are useful complementary markers
      • Squamous carcinoma in situ is nearly always positive while Paget cells are nearly always negative
    • S100 may be expressed by Paget cells so it is not a perfect marker to rule out melanoma
      • MelanA is better
  • Markers useful for separating primary from secondary Paget disease
    • GCDFP15 (BRST2) and CK20 are useful for separating primary from secondary Paget disease
    • In secondary Paget disease the phenotype may depend upon the nature of the underlying carcinoma
      • Most cases with underlying rectal adenocarcinoma are reported to be CK7+20+, even though 90% of rectal adenocarcinomas are CK7-20+

       

      Primary Paget Disease Secondary Paget Disease

      GCDFP15

      90% 7%

      CK7

      100% 70%

      CK20

      12% >95%

      HMWCK

      0% See note

      p63

      0% See note

      CDX2

      0% See note
        • The phenotype of secondary Paget disease is variable, depending upon the nature of the underlying carcinoma
            • Rectal adenocarcinoma is CK7 variable, CK20+, CDX2+, p63-
            • Urothelial carcinoma is usually CK7+, CK20+, CDX2-, p63+

           

Differential Diagnosis

Pagetoid Squamous Cell Carcinoma In Situ / HSIL Extramammary Paget Disease
Atypical cells usually merge with surrounding keratinocytes Discrete population of atypical cells
Atypical cells may keratinize Atypical cells may form lumens or be mucin positive
Desmosomes and keratohyaline granules may be visible in atypical cells Desmosomes and keratohyaline granules not present
HMWCK+, p63+, CK7 neg, BerEp4 neg CK7 >90%+, p63 & HMWCK neg (positive if underlying urothelial carcinoma), BerEp4+
GCDFP15 neg GCDFP15 positive if primary, variable if secondary

 

Melanoma In Situ of the Anus Extramammary Paget Disease
Substantial proportion of atypical cells sit directly on the epidermal basement membrane Atypical cells at all levels but frequently have at least one layer of normal cells separating them from the basement membrane
No lumen formation or mucin positivity Atypical cells may form lumens or be mucin positive
CK7 and other keratins negative CK7 and other broad spectrum antikeratins >95%+
HMB45 and MelanA 60-95%+ HMB45 and MelanA negative
Rare cases of Paget disease are pigmented

Grading / Staging

Grading

  • Not applicable

Staging

  • TNM for vulva or skin, depending upon the site
    • If no invasion, use pTis
    • Different criteria for separating pT1a and pT1b
      • Vulva TNM separates at 1 mm for superficial invasion
      • Skin TNM separates at 2 mm for superficial invasion

Classification / Lists

Anal Tumors and Neoplasms

Extension from rectal lesions must be ruled out

Bibliography

  • Hamilton SR, Aaltonen LA eds. Pathology and genetics of tumours of the digestive system. World Health Organization classification of tumours, Vol. 2. Lyon: IARC Press 2000.
  • Balachandra B, Marcus V, Jass JR. Poorly differentiated tumours of the anus canus: a diagnostic strategy for the surgical pathologist. Histopathology. 2007 Jan;50(1):163-74.
  • Ragnarsson-Olding BK, Nilsson PJ, Olding LB, Nilsson BR. Primary ano-rectal malignant melanomas within a population-based national patient series in Sweden during 40 years. Acta Oncol. 2008 May 19:1-7.
  • Homsi J, Garrett C. Melanoma of the anus canus: a case series. Dis Colon Rectum. 2007 Jul;50(7):1004-10.
  • Chute DJ, Cousar JB, Mills SE. Anorectal malignant melanoma: morphologic and immunohistochemical features. Am J Clin Pathol. 2006 Jul;126(1):93-100.
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