Abstract
We evaluated p186Her2 overexpression and HER2 oncogene amplification in recurrent vulvar Paget's disease. We identified six patients with recurrent vulvar Paget's disease in our archives. The number of recurrences ranged from 1 to 11 over a time period of 1–168 months. Recurrences were evaluated immunohistochemically for p185Her2 overexpression with the HercepTestR and for HER2 oncogene amplification with fluorescence in situ hybridization. p185Her2 overexpression was scored as 3 in two patients, as 2 in two patients, and as 1 in two patients. All patients with scores 2 and 3 showed HER2 oncogene amplification. Overexpression of p185Her2 and HER2 oncogene amplification appears to be common in recurrent vulvar Paget's disease.
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Main
Paget's disease of the vulva is an uncommon carcinoma of apocrine gland origin. Most cases are limited to the epidermis and mucosa, but some invade the dermis. Definitive treatment of vulvar Paget's disease is often difficult because of the anatomical and surgical limitations in this region. Surgical excision is associated with recurrence rates of up to 60%.1, 2, 3 This is often due to positive resection margins, but it has also been suggested that Paget's disease arises multifocally from pluripotent stem cells.
Human epidermal growth factor receptor 2 (HER2) oncogene, encoding for the 185-kDa transmembrane glycoprotein receptor (p185Her2), is involved in transformation and progression of many human cancers, including Paget's disease.4, 5, 6, 7, 8, 9 Tanskanen et al5 reported HER2 oncogene amplification and p185Her2 overexpression in seven of 13 primary vulvar Paget's disease, but p185Her2 expression in recurrent Paget's disease has not been studied. We analyzed p185Her2 overexpression and HER2 oncogene amplification in six patients with recurrent vulvar Paget's disease.
Materials and methods
Among the 11 patients with primary Paget's disease identified in the archives of our institutions, six had recurrent disease. All vulvar tissues of the primary and recurrent vulvar Paget's disease were analyzed immunohistochemically with HercepTestR (DAKO, Denmark), an FDA-approved assay of p185Her2 overexpression. Staining results were scored as score 0 (negative; no staining is observed, or membrane staining in less than 10% of the tumor cells); score 1 (negative; faint/barely perceptible focal membrane staining in more than 10% of tumor cells); score 2 (positive; weak to moderate staining of the complete cell membrane in more than 10% of the tumor cells) and score 3 (positive; strong staining of the complete membrane in more than 10% of the tumor cells). Positive and negative controls were used to validate each run of the assay. All cases with a score 2 and 3 were further analyzed with fluorescence in situ hybridization (FISH, PathVysion HER2-DNA probe kit; Vysis, Downers Grove, IL, USA).
Results
All six patients with recurrences had positive surgical margins in the initial and recurrent excisions (Figure 1). Recurrences were seen as early as 1 month after primary surgery. Two patients had one recurrence, two patients had two, and one patient had three recurrences. One patient had 11 resections of recurrent disease over a period of 168 months after primary vulvectomy (Table 1 ). Three patients developed invasive disease in their recurrences after 9, 58 and 168 months, respectively (pt. 1, 4 and 5). p185Her2 overexpression was scored as 3 in two patients, as score 2 in two patients, and as score 1 in 2 patients (Figure 2a–d). All patients with score 2 and score 3 showed HER2 oncogene amplification (Figure 3). The recurrences showed the same scores as the corresponding primary tumors (Table 1). Analysis of the five tumors that did not recur showed a score 3 and HER2 oncogene amplification in three patients, while two patients were negative for p185Her2 overexpression.
Discussion
This is the first report of p185Her2 overexpression and HER2 oncogene amplification in recurrent Paget's disease of the vulva. In a large retrospective series of 100 women with Paget's disease treated in eight institutions, 34% of patients developed recurrences in the median time of 3 years.1 This is partly due to the apparently multifocal nature of the disease and partly to the difficulties in recognizing the extent of the lesions clinically. Recurrences have also been described in skin grafts from other parts of the body.10 The mechanism by which Paget's cells spread intraepidermally and infiltrate the dermis seems to be induced by a mobility factor (heregulin-alpha) that acts through the p185Her2 receptor.11 The major problem with the recurrences was the extension of the Paget's disease to surrounding nongenital skin such as the inner side of the thigh, perianal skin and mons pubis, rendering surgical revision excision difficult.
Trastuzumab is a recombinant DNA-derived humanized human monoclonal immunoglobulin G (IgG) antibody that binds to the antigen of p185Her2. Immunotherapy with trastuzumab is a well-tolerated option for first-line treatment of women with metastatic breast cancer and presently under investigation for several other cancers.12 Possible antiproliferative mechanisms of trastuzumab include downregulation of HER2 receptors, activation of immune effector cells (antibody-dependent cell-mediated cytotoxicity), reduction of S-phase cell-cycle progression, and reduction of vascular endothelial growth factor for angiogenesis.13 However, trastuzumab is generally confined only to patients whose tumors stain at score 3 level or with gene amplification detected by FISH.
In conclusion, overexpression of p185Her2 and HER2 oncogene amplification appears to be common in primary and recurrent vulvar Paget's disease including the invasive components. These results suggest that a clinical trial of trastuzumab for women with high-risk Paget's disease of the vulva is justified.
References
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Reich, O., Liegl, B., Tamussino, K. et al. p185HER2 overexpression and HER2 oncogene amplification in recurrent vulvar Paget's disease. Mod Pathol 18, 354–357 (2005). https://doi.org/10.1038/modpathol.3800243
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DOI: https://doi.org/10.1038/modpathol.3800243
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