Comment
Extramammary Paget disease is a rare intraepithelial adenocarcinoma with a predilection for white females and an average age of onset of 50 to 80 years.1-3 The vulva, perianal region, scrotum, penis, and perineum are the most commonly affected sites.1-3 Clinically, EMPD presents as a chronic, well-demarcated, scaly, and often expanding plaque. The incidence of EMPD is unknown, as there are only a few hundred cases reported in the literature.2
Extramammary Paget disease can occur primarily, arising in the epidermis at the sweat-gland level or from primitive epidermal basal cells, or secondarily due to pagetoid spread of malignant cells from an adjacent or contiguous underlying adnexal adenocarcinoma or visceral malignancy.2 While primary EMPD is not associated with an underlying adenocarcinoma, it may become invasive, infiltrate the dermis, or metastasize via the lymphatics.2 Secondary EMPD is associated with underlying malignancy most often originating in the gastrointestinal or genitourinary tracts.1,2
Currently, treatment of primary EMPD typically is surgical with wide local excision or Mohs micrographic surgery.1,2 However, margins often are positive, and the local recurrence rate is high (ie, 33%–66%).2,3 There are a variety of other therapies that have been reported in the literature, including radiation, topical chemotherapeutics (eg, imiquimod, 5-fluorouracil, bleomycin), photodynamic therapy, and CO2 laser ablation.1,3 To our knowledge, there are no randomized controlled trials that compare surgery with other treatment options for EMPD.
Despite recurrence of EMPD with involvement of the anal canal, our patient refused further surgical intervention, as it would have required anal resection and radiotherapy due to the potentially negative impact on sphincter function. While investigating minimally invasive treatment options, we found several citations in the literature highlighting positive response with imiquimod cream 5% in patients with vulvar and periscrotal EMPD.4,5 A large, systematic review that analyzed 63 cases of vulvar EMPD—nearly half of which were recurrences of a prior malignancy—reported a response rate of 52% to 80% following treatment with imiquimod.5 Almost 70% of patients achieved complete clearance while applying imiquimod 3 to 4 times weekly for a median of 4 months; however, little has been written about the effectiveness of topical imiquimod in EMPD. Knight et al6 reported the case of a 40-year-old woman with perianal EMPD who was treated with imiquimod 3 times weekly for 16 weeks. At the end of treatment, the patient was completely clear of disease both clinically and histologically on random biopsies of the perianal skin; however, the EMPD later recurred with lymph node metastasis 18 months after stopping treatment.6
Given the growing evidence demonstrating disease control of EMPD with topical imiquimod, we elected to utilize this agent in combination with oral cimetidine in our patient. Cimetidine, an H2 receptor antagonist, has been shown to have antineoplastic properties in a broad range of preclinical and clinical studies for a number of different malignancies.7 Four distinct mechanisms of action have been shown. Cimetidine, which blocks the histamine pathway, has been shown to have a direct antiproliferative action on cancer cells.7 Histamine has been associated with increased regulatory T-cell activity, decreased antigen-presenting activity of dendritic cells, reduced natural killer cell activity, and increased myeloid-derived suppressor cell activity, which create an immunosuppressive tumor microenvironment in the setting of cancer. By blocking histamine and thus reversing this immunosuppressive environment, cimetidine demonstrates immunomodulatory effects.7 Cimetidine also has demonstrated an inhibitory effect on cancer cell adhesion to endothelial cells, which is noted to be independent of histamine-blocking activity.7 Finally, an antiangiogenic action is attributed to blocking of the upregulation of vascular endothelial growth factor that is normally induced by histamine.7
Cimetidine’s antineoplastic properties, specifically in the setting of colorectal cancer,8 were particularly compelling given our patient’s EMPD involvement of the anal canal. The most impressive clinical trial data showed a dramatically increased survival rate for colorectal cancer patients treated with oral cimetidine (800 mg once daily) and oral 5-fluorouracil (200 mg once daily) for 1 year following curative resection. The cimetidine-treated group had a 10-year survival rate of 84.6% versus 49.8% for the 5-fluorouracil–only group.8
Conclusion
We present this case of recurrent perianal and anal EMPD treated successfully with imiquimod cream 5% and oral cimetidine to highlight a potential alternative treatment regimen for poor surgical candidates with EMPD.