Are You Confident of the Diagnosis?
What you should be alert for in the history
Verrucous carcinoma (VC) presents as a slow-growing but persistent warty tumor.
Characteristic findings on physical examination
A papillary nonulcerated grey-white or red mass with a very broad base of attachment. Any cutaneous area of the body may be affected, but 90% of VC lesions are found on the feet. VC normally occurs as a solitary lesion (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). 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 (Figure 3). The basement membrane is intact and 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. Ki-67 and p53 staining is positive in the lower third of the epidermis, primarily in the basal cells.
For proper diagnosis, both careful physical examination and deep surgical biopsy must be performed, as a superficial biopsy may result in misdiagnosis.
Verrucous hyperplasia (VH) cannot be distinguished from VC based on cytological features alone. A full clinical history and deep biopsy are required.
Histologically, VC shows ’pushing’ borders versus the infiltrative borders of squamous cell carcinoma (SCC). Additionally, VCs typically lack the loss of polarity and abundance of mitotic figures typically seen in SCC. Immunostaining may also be beneficial to distinguish between SCC and VC: p53 and Ki-67 expression can be found at all levels of the epidermis in SCC.
Proliferative verrucous leukoplakia (PVL) is a rare and aggressive clinicopathological entity that is persistent, often multifocal, and refractory to treatment with a high risk of recurrence and malignant transformation. Clinically it can begin as a flat white plaque and evolve slowly to an exophytic plaque with a verrucous or papillary surface.
PVL can involve any oral site, but the buccal mucosa and tongue are the most common. PVL lacks specific histological criteria, so epidemiology, clinical presentation, and histopathology must all be taken into account for diagnosis.
Late or advanced stages of PVL cannot be distinguished from VC or an exophytic papillary form of squamous cell carcinoma.
Other conditions to be aware of in the differential diagnosis include:
Reactive keratosis and epithelial hyperplasia
Infections, such as mycobacterium and blastomyces
Keratoacanthoma (KA): VC can often be distinguished by a proper clinical history, as KA has an ’eruptive’ nature and VC is more indolent and slow-growing
Who is at Risk for Developing this Disease?
VC is strongly associated with chronic use of tobacco, chronic alcohol abuse, or chewing betel nuts. There is also a strong relationship with human papillomavirus infection (HPV). VC is most often diagnosed in the seventh or eighth decades of life and reported predominantly in men. There is relatively rare malignancy comprising 0.6% of head and neck cancers.
What is the Cause of the Disease?
VC is a low-grade well-differentiated variant of squamous cell carcinoma of the mucosa and skin that was first described by Ackerman in 1948. Four main clinicopathologic types are based on the anatomic area of involvement: oroaerodigestive VC, anourogenital VC, palmoplantar VC, and VC at other cutaneous locations.
VC is associated with HPV infection, but the mechanism of HPV involvement in the etiology of VC is poorly understood. The presence of HPV may be identified in approximately 50% of VC lesions.
Oroaerodigestive VC is also known as Ackerman tumor, oral florid papillomatosis, oral florid verrucosis, giant mucocutaneous papillomatosis, and nonmetastasizing papillomatosis. HPV 6, 11, 16, and 18 have been linked. Chemical carcinogenesis, specifically due to tobacco and alcohol, has also been linked to VC.
Anourogenital VC is also known as the Buschke-Lownestein tumor. It is most commonly associated with low-risk HPV types 6 and 11, but high-risk HPV types have also been identified.
Palmoplantar VC and VC at other cutaneous locations have not been specifically linked to certain HPV types.
Systemic Implications and Complications
VCs rarely metastasize. VCs are locally invasive and have a high incidence of local recurrence.
Give the rare metastatic rate, but high risk of local destruction and recurrence, local tumor control is the foremost goal of treatment.
Surgical excision and Mohs micrographic (MMS) surgery represent the treatments of choice for cutaneous verrucous carcinomas.
Cryosurgery using liquid nitrogen is a safe and low-cost procedure for the ablation of selected verrucous carcinomas and is well tolerated by patients. However, as no histology will be provided, close follow-up is necessary to monitor for inadequate treatment or recurrence. This treatment method is the least preferred intervention as it is the least likely to result in a cure.
Curettage and electrodessication may be used in superficial and minimally invasive lesions. The main disadvantage of this method is a lack of margin control.
Radiation therapy offers the advantage of skin-sparing and avoidance of trauma, but has been occasionally associated with transformation to a high-grade SCC. Ionizing radiation therapy may be the only option for patients who cannot tolerate surgery. Radiation therapy is expensive and requires multiple visits. Furthermore, there is no margin-control.
Long-term results can be poor, with atrophy, hypopigmentation, telangiectasia, and radiation necrosis.
Other treatments that have been used for cutaneous VC with variable success include topical or systemic chemotherapy (bleomycin, 5-fluorouracil, cisplatin, methotrexate), carbon-dioxide laser, intralesional interferon alfa, imiquimod, and photodynamic therapy. Large scale randomized clinical trials are needed to better assess these treatments.
Optimal Therapeutic Approach for this Disease
Surgical resection is the treatment of choice with histologically confirmed tumor-free resection margins.
Lymphadenectomy should only be performed in cases of suspicious lymphadenopathy. Lymphadenopathy may be present secondary to reactive changes and not metastatic disease, especially when VC affects the cervical region.
Radiation therapy is contraindicated because of the risk of anaplastic transformation and possible subsequent lymphatic spread.
All other therapeutic modalities including chemotherapy, immunotherapy, and local therapies, are not recommended.
After surgical resection, the final pathological diagnosis should involve staff from multiple disciplines. Because of the nature to misdiagnose this entity, deep surgical biopsy along with a good clinical history and picture are necessary to ensure correct diagnosis.
Skin examinations at 3-12 month intervals after treatment should be initiated to monitor for recurrence.
Unusual Clinical Scenarios to Consider in Patient Management
Though the foot is the most common area for VC, VC of the hand have similar presentation. The incidence of infiltrating adjacent bone is documented at 5-10% in all cases, but is reported to be higher in VC of the hand (~20%).
What is the Evidence?
Dubina, M, Goldenberg, G. “Viral-associated nonmelanoma skin cancers: a review”. Am J Dermatopathol. vol. 31. 2009. pp. 561-73. (Several types of 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.)
Gertler, R, Werber, KD. “Management of verrucous carcinoma of the hand: a case report”. International Journal of Dermatology. vol. 48. 2009. pp. 1233-1235. (Case report of a large VC of the right palm which was completely surgically resected with good outcome. Based on this and the 15 previously published cases of VC, radical resection is treatment of choice with histologically confirmed tumor-free margins. Lymphadenectomy should only be performed in case of suspicious lymphadenopathy.)
Santoro, A, Pannone, G, Contaldo, M, Sanguedolce, F, Esposito, V, Serpico, R. “A Troubling diagnosis of verrucous squamous cell carcinoma (“the bad kind” of keratosis) and the need of clinical and pathological correlations: a review of the literature with a case report”. Journal of Skin Cancer. 2011. pp. 1-4. (VC (Ackerman tumor) is an uncommon, exophytic, low-grade well-differentiated variant of SCC. In oral cavity is often called 'snuff-dipper's carcinoma' as it is associated with chewing tobacco and use of snuff. In addition to oral cavity, can also occur in genitalia and skin, and has also been associated with HPV. This is a literature review and case presentation of VC highlighting the underdiagnosis of VC and need for involvement from various disciplines to properly manage these patients, given the difficulty of the clinicohistopathological diagnosis.)
Mercer, SE, Khalil, D, Emanuel, PO, Goldenberg, G. “Verrucous Carcinoma Masquerading as a Giant Fibroepithelial Polyp”. International Journal of Surgical Pathology. vol. 18. 2010. pp. 347-351. (VC is a low-grade well-differentiated variant of squamous cell carcinoma that typically repesents distinctly as a large cauliflower-like growth with histological features of acanthosis, parakeratosis, minimal cytological atypia, and deep pushing borders. It has been associated with 'low-risk' HPV types (6,11) and 'high-risk' HPV types (16,18). This is a review of VC and case report of VC presenting as a giant fibroepithelial polyp.)
Zeina, B, Sakka, N, Mansoor, S. “Verrucous Carcinoma”. eMedicine Dermatology. (General overview of VC, including background, pathophysiology, frequency, morbidity/mortality, epidemiology, clinical presentation and DDx. Diagnosis, treatment options and follow-up recommendations also included.
Thomas, P. “Shopper “Proliferative verrucous leukoplakia: an aggressive form of oral leukoplakia””. Journal of Dental Hygiene. (This article describes the clinical aspects and histologic features of a case that demonstrated the typical behavior pattern in a long-standing, persistent lesion of PVL of the mandibular gingiva that ultimately developed into squamous cell carcinoma. Prognosis is poor for this seemingly harmless-appearing white lesion of the oral mucosa.
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