Are You Confident of the Diagnosis?
What you should be alert for in the history
Be alert for a slowly enlarging warty tumor in the oral cavity of a smoker.
Characteristic findings on physical examination
Characteristic findings include multiple, exuberant, confluent, cauliflower-like growths on the oral mucosa (Figure 1).
Expected results of diagnostic studies
Classic histology shows blunt projections of well-differentiated stratified squamous epithelium with deep bulbous rete ridges exhibiting minimal atypia (Figure 2, Figure 3).
The projections extend into the dermis and deeper layers, which often form keratin-filled cysts and sinuses. There is an edematous stroma, filled with chronic inflammatory cells surrounding the ridges.
The margins of these lesions can show a deep epithelial “pushing” border, marking an aggressive growth pattern and local connective tissue destruction. A prominent granular layer with hyperkeratosis and parakeratosis is also characteristic and the basement membrane is intact. The keratinocytes are often enlarged, with minimal dysplasia and prominent nuclei and nucleoli. Local tumor invasion is marked by bulbous islands comprising benign-appearing epithelium adjacent to intact basement membranes. These tumors spread by local invasion and rarely metastasize.
Immunoperoxidase staining is positive for p53, bcl-2, and Ki-67; p53 and Ki-67 staining is positive in the lower third of the epidermis, primarily in the basal cells.
Magnetic resonance imaging (MRI) may be considered, to define the extent of the tumor and to determine whether underlying bone or other structures are involved.
Computed tomography (CT) may be used to demonstrate the exact location and extent of the tumor for preoperative staging and surgical exicison.
Squamous cell carcinoma can be differentiated with immunoperoxidase staining, which shows full thickness positivity for p53, Ki-67, and bcl-2. Other conditions to be ruled out include: viral infections of the mouth, nongenital warts, verruca vulgaris, and speckled leukoplakia.
Who is at Risk for Developing this Disease?
Lesions have been diagnosed more frequently in men than in women. Patients between 60 and 80 years of age are preferentially affected. Immunodeficiency and smoking predispose to the disease.
What is the Cause of the Disease?
Oral florid papillomatosis was first described in 1965 by Archard et al. and Witkop and Niswander in patients from North American and South American Indian populations.
Oral florid papillomatosis is one variant of verrucous carcinoma (VC). A direct causal relationship between human papillomavirus (HPV) and VC has not been proven; 41% of the verrucous leukoplakias tested for HPV are HPV DNA positive. HPV 16 is the most frequently identified type.
Systemic Implications and Complications
Though metastasis via lymph nodes is rare, the tumor is locally destructive and can cause substantial morbidity.
Treatment is difficult and there is a high recurrence rate after therapy.
Surgery is the preferred method, and traditional excision is preferred over Mohs micrographic surgery. Radiotherapy and cryotherapy may also be used, although irradiated verrucous leukoplakias may have an increased risk of malignant conversion.
Systemic therapy consists of photodynamic therapy using a topical application of 20% 5-aminolevulinic acid (ALA), followed by multiple 3-minute fractionated irradiations with a light-emitting diode (LED). The following therapies have been recommended:
–Photosensitizer photocarcinorin (5mg/kg) intravenously and irradiation with a 635nm laser beam of 177mW/cm2 intensity and 106.2J/cm2 energy density monthly for 3 months
–Intralesional injection of bleomycin
–Oral retinoids, including etretinate, acitretin, and isotretinoin, have been used in case reports. Treatment efficacy is varied and there is no recommended dosing regimen time.
–Methotrexate 12.5mg/day orally daily, two successive days a week for several months, with reassessments every 3-6 months, for several courses of therapy until resolution.
Optimal Therapeutic Approach for this Disease
The most prevalent treatment in the United States is surgery, followed by surgery combined with irradiation and irradiation alone. Radiation therapy is generally considered a last resort, as it has been reported to increase the risk of anaplastic transformation. The systemic therapies listed above have anecdotal evidence of working but have yet to be validated by randomized clinical trials.
Patients should be carefully monitored for recurrence, regardless of the therapy they receive. HPV subtype testing can be perfromed on biopsy specimens. This is not routunely done, due to expense.
Unusual Clinical Scenarios to Consider in Patient Management
The apparent benign clinical appearance may result in misdiagnosis. Though it is slow growing and unlikely to metastasize, the tumor is locally destructive and results in substantialmorbidity. Malignant transformation of oral florid papillomatosis during topical immunotherapy with imiquimod 5% was described in one patient.
Therapy is challenging because of recurrences and potential anaplastic transformation after radiation therapy.
If HPV is determined to be an etiologic agent, the development of a subunit vaccine directed against viral oncoproteins may be a further long-term goal.
What is the Evidence?
Dubina, M, Goldenberg, G. “Viral-associated nonmelanoma skin cancers: a review”. Am J Dermatopathol. vol. 31. Aug 2009. pp. 561-73. (Several types of nonmelanoma skin cancers [NMSC] and precancerous lesions have an associated viral pathogenesis, including epidermodysplasia verruciformis, verrucous carcinoma, bowenoid papulosis, Kaposi sarcoma, squamous cell carcinoma, and Merkel cell carcinoma. This is a literature review focusing on the histologic aspects of viral-associated skin malignancies, as well as the epidemiology, etiology, and clinical aspects of the diagnoses.)
Lu , YG, Wu , JJ, Lei, X, Zhu, TY, He, Y, Chen, L. “Treatment of oral florid papillomatosis with systemic adminsitration of photocarcinorin: an effective photodynamic therapy.”. Photomed Laser Surg. vol. 28. 2010. pp. 831-3. (Case report evaluating the treatment of oral florid papillomatosis with systemic administration of photosensitizer photocarcinorin [PsD-007)] 5mg/kg IV, followed by 10 minutes of irradiation with a 635nm laser beam of 177 mW/cm(2) intensity and 106.2J/cm(2) energy density. This therapy was given once a month for 3 months. After 3 cycles, the small lesions disappeared and the larger ones were reduced by 80%, with minimal adverse effects.)
Wenzel, K, Saka, B, Zimmerman, R, Gundlach, KKH, Barten, M, Gross, G. “Malignant conversion of florid oral and labial papillomatosis during topical immunotherapy with imiquimod”. Med Microbiol Immunol. vol. 192. 2003. pp. 161-4. (Case report of a 61-year-old woman with recurrent oral florid papillomatosis. Overnight treatment with a topical 5% immiquod cream three times weekly was initiated, but due to severe irritation and pain, the application was dropped to 4 hours per night, three times a week, followed by 2-week therapy-free intervals. After four cycles of 3-week therapy, the lesions remained large. A biopsy showed squamous cell carcinoma. Two years of after surgical removal, no metastases or recurrence were noted.)
Schwartz, RA, Barnett, CR. “Oral florid papillomatosis”. eMedicine Dermatology. (General overview of oral florid papillomatosis, including background, pathophysiology, frequency, morbidity/mortality, epidemiology, clinical presentation and differential diagnosis. Treatment options and follow-up recommendations are also included.)
Ben, Kanee. “Oral florid papillomatosis complicated by verrucous squamous carcinoma. Treatment with methotrexate”. Arch Derm. vol. 99. 1969. pp. 196-202. (Oral florid papillomatosis in an immunocompetent elderly patient with verrucous squamous carcinoma, treated with intermittent courses of methotrexate, with favorable response.)
Samitz, MH, Acherman, AB, Lantis, LR. “Squamous cell carcinoma arising at the site of oral florid papillomatosis”. Arch Dermatol. vol. 96. 1967. pp. 286-9. (First published case report of squamous cell carcinoma arising at the site of oral florid papillomatosis. The typical clinical features of oral florid papillomatosis are reviewed, including multiple confluent cauliflower-like lesions confined to the oral mucous membranes, an exuberant aggressive growth pattern, refractoriness to many forms of nonsurgical therapy, and recurrence after surgical removal.)
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