Well Differentiated Squamous Cell Carcinoma with Verrucous Clinical Presentation

Presentation A 49-year-old White female was referred for evaluation of a warty lesion, which had been present on her abdomen for 3 months. It had not responded to liquid nitrogen treatment or over-the-counter wart treatments. The lesion had gradually become more irritated and had increased in size. The patient had a 10-year history of rheumatoid arthritis and ankylosing spondylitis. The patient’s medications included immunosuppressive treatments, including prednisone for 10 years, adalimumab (Humira, Abbott Laboratories, Abbott Park, Ill) for 2 years, and nabumetone (Relafen, GlaxoSmithKline, Research Triangle Park, NC) for 3 years. Physical Examination Physical examination revealed a healthy looking White female who was alert and oriented. There was a 5mm x 8mm verrucous lesion on the right lower quadrant of her abdomen (Figure 1). The surrounding skin was erythematous and indurated. The overlying hyperkeratotic crust was removed to reveal a 5mm x 8mm ulcer with an inflamed and indurated margin. Rheumatoid arthritis-related joint deformities were present. The remainder of the general skin examination was otherwise unremarkable. Diagnosis A biopsy was performed, and the pathology report resulted in a diagnosis of well differentiated squamous cell carcinoma (Figure 2). Discussion Cutaneous squamous cell carcinoma (SCC) is a malignant proliferation of the keratinocytes of the epidermis. Squamous cell carcinoma in general is divided into nonverrucous and verrucous forms.^1,2 This terminology is not based on clinical appearance but on histopathology. Verrucous carcinoma is a warty, slow growing tumor, which is more likely to cause destruction and compression of underlying tissues than to metastasize.^1,3Etiology. The incidence of SCC is 12 per 100,000 in White males, 7 per 100,000 in White females, and 1 per 100,000 African Americans in the continental United States. In Hawaii, however, the incidence in Whites is 62 per 100,000. Squamous cell carcinoma is strongly related to sunlight exposure. It can also occur as a result of other exogenous carcinogens (Table 1). The incidence of SCC increases with age and is inversely related to the degree of skin pigmentation. Most SCCs in light-skinned people occur on the photodistributed areas, such as the head, neck, and upper extremities. A small number of SCCs arises on apparently healthy skin.⁴ The frequent demonstration of tumor suppressor gene mutations, including the P53 gene located on chromosome 17p, has highlighted a genetic element to the etiology of SCC.¹ In a study on 8 pathologic specimens of verrucous carcinoma, abnormal expression of P53 tumor suppressor protein was a common event and probably plays a crucial role in the pathogenesis of this tumor.⁵ A combination of potentially carcinogenic stimuli, such as ultraviolet radiation (UVR), chemical carcinogens, x-ray exposure, or chronic scars, may be at work in the same patient and/or act synergistically with other factors, including inherited/acquired immunosupression and viral oncogenesis, to increase the potential for skin cancers. Clinical presentations. Table 2 outlines the most common clinical presentation of SCC. Verrucous carcinoma is a clinicopathologic variant of SCC. It is known by a number of names, including Ackerman’s tumor, Buschke-Loewenstein tumor, florid oral papillomatosis, epithelioma cuniculatum, carcinoma cuniculatum, and cutis papillomatosis carcinoides of Gottron.³ Verrucous carcinoma is a subtype of low-grade SCC and not simply SCC with a verrucous clinical presentation.¹ Its apparent clinical benignity may lead to a lengthy period of misdiagnosis.³ It is unlikely to spread to distant lymph nodes but rather to destroy local tissues, such as the nose, mandible, or penis, as it slowly but relentlessly extends into underlying structures. At times, it might be foul smelling with a cauliflower-like appearance. It may affect any cutaneous or mucous areas of the body; however, there is a predilection for the feet, particularly the soles. It also has a tendency to occur in moist and/or chronically inflamed areas.⁶Differential diagnosis. Verrucous SCC. The warty morphology of verrucous SCC is often mistaken for verruca vulgaris or verrucous seborrheic keratosis. On the soles, it is often misdiagnosed as a plantar wart. When it extends into underlying tissues, it may be mistaken for a benign adnexal tumor or even an epidermoid cyst.³Histopathology: verrucous SCC versus well differentiated SCC. Electron microscopy studies have revealed that verrucous carcinoma is a well-differentiated SCC.⁷ On histology, verrucous carcinoma is characterized by exophytic and endophytic aggregations of bulbous proliferations of epithelium that often invade the dermis in a “pushing” pattern as opposed to “infiltrative.” These proliferations are usually composed of large pale staining keratinocytes. Nuclear atypia and mitotic activity are variable and often accentuated at the periphery of the lesion. Hyperkeratosis and parakeratosis are present overlying the bulbous proliferation. Unlike SCC, keratin pearl formation is uncommon. Having said this, histological distinction of verrucous carcinoma from verruca vulgaris can be at times very difficult, and clinicopathologic correlation is of paramount importance in such instances.⁸ Well differentiated SCC is characterized histologically by aggregates of atypical squamous epithelium that exhibit premature keratinization and keratin pearl formation. High mitotic activity, acantholysis, and infiltrative pattern are variably seen. Often, the tumor arises in association with actinic keratosis or Bowen’s disease. Well circumscribed and symmetrical tumors with crateriform morphology and central keratin are often referred to as SCC of the keratoacanthoma type. Treatment Treatment for SCC is based on tumor characteristics, such as size, shape, location, histopathology, and the nature of the skin from which the tumor arises. Excision, Mohs surgery, radiation, and electrosurgery are standard treatment for carcinomas. With verrucous carcinoma, radiation therapy is contraindicated due to reported higher risks for transformation to poorly differentiated SCC and potential for metastasis. Management Initially, an excisional biopsy was performed. The diagnosis of well differentiated SCC was made based on the pathology report. The patient was referred for Mohs surgery. The tumor was completely removed with satisfactory clear margins. She will be followed closely for the development of any new tumors. In this particular case, chronic immunosuppression treatment may have contributed to the development of SCC.