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
Lack features of squamous differentiation
No visible intercellular bridges
No transition to surrounding squamous cells
Most cases mucin positive Underlying chronic inflammation common
Epidermal hyperplasia and hyperkeratosis and parakeratosis frequently present
Present in half of 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
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
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
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
Staging
TNM for vulva or skin, depending upon the site
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.
