Background and Clinical Presentation

Paget disease accounts for less than 2% of vulvar neoplasms. The average age in most series is approximately 65 years old; the majority of patients are older than 50 years old when diagnosed. The most common symptom is vulvar pruritus, which predates diagnosis by 1 to 17 years. Paget disease of the vulva, or any site, is characterized by infiltration of the squamous mucosa or adnexa by mucin-producing neoplastic cells. The disease presumably originates in the appendages, and evidence supports both an apocrine and eccrine ductal origin. In the breast, this process is usually associated with an underlying intraductal or invasive adenocarcinoma. However, in the vulva, the majority of cases are not associated with invasion; approximately 20% have a coexisting invasive adenocarcinoma, which is either the source of or sequelae to the intraepithelial lesion.

The disease may involve the labium majus or minus, perineum, or anus and clinically appears as an eczematoid, erythematous, sometimes ulcerated lesion ( Fig. 7.2 ).

Clinical appearance of Paget disease of the vulva. The patient’s left vulva is erythematous and superficially ulcerated.

Diagnostic Criteria

Histologically, vulvar Paget disease is characterized by large oval to polyhedral cells with pale cytoplasm, large nuclei, and small nucleoli. The cells are arranged either singly or in large clusters or nests within the epithelium, where they may be interspersed with normal squamous epithelial cells with or without hyperkeratosis and squamous pearls ( Fig. 7.3 ). Extensive sectioning will virtually always uncover focal involvement of the adnexal glands, and it is this constant feature that further supports an origin in these structures ( Fig. 7.4 ). The tumor cells are characteristically positive for mucin, CK-7, carcinoembryonic antigen (CEA), and Her-2-neu ( Fig. 7.5 ).

Paget disease of the vulva. A, There is replacement of the squamous epithelium by large mucin-filled columnar cells. B, Same image as A shown at a higher power. C, In some foci, the Paget cells are scattered and less conspicuous. D, An immunostain for cytokeratin 7 (CK7) highlights Paget cells.

Paget disease with adnexal involvement. A, Superficial adnexal extension. B, Involvement of deeper structures.

Markers for Paget disease. A, A mucicarmine stain highlights individual cells. B, Cytokeratin (CK)-7 staining. C, Strong immunopositivity for carcinoembryonic antigen (CEA). D, Staining for Her-2-neu.

Differential Diagnosis

Important considerations in the laboratory and clinical management of Paget disease include the following:

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  Associated squamous lesions: Brainard and Hart reported a diverse array of squamous epithelial alterations associated with Paget disease of the vulva. Most were benign squamous proliferations, including acanthosis (termed squamous hyperplasia not otherwise specified [NOS] ), and mixed stromal epithelial alterations, including “fibroepithelioma-like hyperplasia” and papillomatous hyperplasia ( Fig. 7.6A and B ). The authors suggested that these alterations should prompt a search for Paget disease, although the specificity of these changes is unknown. However, they also observed occasional coexisting squamous neoplasms, including rare HPV-positive squamous carcinomas in association with Paget disease.

  
  

  
  

  
  

  

  
  

  
  

  A, Epithelial hyperplasia associated with Paget disease with dense stromal fibrosis. B, Note the dense fibrous appearance of the intervening stroma at higher power. Other patterns that may cause diagnostic confusion include: acantholysis with tombstones simulating an acantholytic dermatosis (C) and Pagetoid vulvar intraepithelial neoplasia (VIN) (D).

  
  
  
  
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  Excluding mimics: Paget disease must be distinguished from several other entities. The first is malignant melanoma (see Chapter 8 , Fig. 8.20 , Fig. 8.21 , Fig. 8.22 , Fig. 8.23 , Fig. 8.24 , Fig. 8.25 ). Both Paget disease and melanoma invade the epidermis, extend into skin appendages, and may even be sloughed in the superficial keratin. Although they can be distinguished by a mucin stain, immunostaining with HMB-45 (melanoma) and CEA (Paget disease) will confirm the diagnosis. The second is misclassification as an acantholytic dermatosis (see Fig. 7.6C ). A third is pagetoid vulvar intraepithelial neoplasia (VIN) of squamous origin (see Fig. 7.6D ). This can be distinguished by markers of squamous (p63) differentiation and the absence of mucin.

  
  
  
  
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    Another pitfall is direct extension of an urothelial carcinoma to the vulvar mucosa. This rare disorder may be impossible to distinguish from Paget disease on first examination. The distinction is made immunohistochemically by a staining profile of GCDFP+ and CK7+/CK20− in vulvar Paget disease versus GDFP− CK7+/CK20+ in urothelial neoplasia ( Figs. 7.5 and 7.7 ). Keep in mind that GATA3 is expressed in both Paget disease and urothelial carcinoma.

    
    

    
    

    
    

    

    
    

    
    

    A, Urothelial carcinoma simulating Paget disease. B, Following staining for low-molecular-weight cytokeratins (CKs).

    
    

  
  
  
  
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  Excluding invasion on histologic examination: Because Paget disease develops at the epithelial–stromal interface and extends into adnexal structures, the exclusion of invasion may be particularly difficult for the pathologist. This problem is greatest when individual cells are seen in the superficial stroma or when inflammation obscures the tumor cell stromal interface. Invasion is characterized by dis-cohesive groups of tumors cells infiltrating into the underlying dermis or submucosa ( Fig. 7.8 ).

  
  

  
  

  
  

  

  
  

  
  

  A, Paget disease confined to the epithelium. B, Invasion of the stroma as poorly differentiated cohesive aggregates. C, Early stromal invasion. D, Deeply invasive Paget disease.

  
  
  
  
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  The possibility of an underlying invasive neoplasm: In the majority of cases of Paget disease associated with cancer, the underlying cancer is diagnosed initially and is of similar histology. Rarely, squamous carcinomas have been reported in association with Paget disease. One case of primary carcinoma of the Bartholin gland with secondary involvement of the overlying epithelium has been reported. Mortality is closely related to the depth of invasion.

  
  
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  Depth of invasion: Crawford et al. correlated outcome with depth of invasion in 10 cases of invasive vulvar Paget disease. Of seven patients with dermal invasion less than 1.0 mm, none died of their disease. Of three patients with invasion exceeding 1.0 mm, all had nodal metastases. This underscores the importance of carefully staging patients with any invasion present. One study noted that invasion of the reticular dermis produced a sharp drop in survival (100% to 33%).

  
  
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  Extent of epithelial spread: The major problem posed by Paget disease is the extensive distribution of the lesion. Inasmuch as Paget disease spreads freely through the network of epithelia, conventional excision will frequently be inadequate and the lesion will recur. Adamson and Reisenfield emphasized this problem in their observation that clinically uninvolved skin frequently contained histologic evidence of neoplasia. Moreover, uninvolved skin adjacent to negative margins could also be involved. However, Taylor et al. noted that if careful histologic examination revealed negative margins, recurrence rates were low. Pierie et al. noted recurrences in 42% and significant association with positive margins requiring as many as six excisions in some patients. This underscores the importance of margin assessment ( Fig. 7.9 ).

  
  

  
  

  
  

  

  
  

  
  

  A, Paget disease involving inked margin (left). B, Paget disease involving the inked margin, highlighted by a cytokeratin (CK)-7 stain.

  
  
  
  
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  Risk of subsequent invasion: The risk of subsequent invasion is low once concurrent invasive tumor has been excluded. Hart and McMillan noted a single patient who was followed for nearly 11 years. In these unusual cases, the invasion occurs via disruption of the basement membrane with primary dermal invasion.

  
  
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  Risk of breast or other carcinomas: Friedrich et al. summarized the literature and noted that of 78 reported cases of vulvar Paget disease, 14 were associated with carcinoma of the breast. In a few cases, there was coexisting Paget disease at both sites. Aside from the similarity in embryogenesis and functional anatomy in the two sites, the reason for this frequent association is unknown. It should be stressed that the ratio (14 : 78) could reflect biased reporting inasmuch as coexisting breast and vulvar neoplasms may be the subject of case reports. Pierie et al. noted either breast or other carcinomas in 42% of patients. Overall mortality was not increased compared with patients of similar age, however.

Management

The majority of patients are treated by local excision and reconstruction if necessary, but nonsurgical approaches with follow-up are also permitted. Some reports have attempted management with imiquimod with some success. As mentioned previously, Paget disease may coexist with or mimic squamous carcinoma in situ. Management of vulvar Paget disease should entail the exclusion of underlying cancer, careful histologic mapping to determine whether residual disease is present, and careful follow-up with the expectation that the disease will recur.