Squamous Cell Carcinoma

Clinical features
Approximately 200,000 cases of cutaneous squamous cell carcinoma occur in the US per year resulting in ~2000 deaths (Miller and Weinstock, 1994). Excessive ultraviolet radiation exposure, immunosuppression, human papilloma virus infection, certain chronic dermatoses, and topical arsenic exposure are all risk factors for developing squamous cell carcinoma (Schwartz and Stoll, 1999). Solid organ transplant recipients commonly develop squamous cell carcinoma in the setting of immunosuppression and in some instances develop several hundred separate primary tumors over the span of a several years (Jensen et al., 1999).

Most squamous cell carcinomas arise on the sun-damaged skin of the head and neck, with fewer lesions arising on the extremities and occasional tumors occurring on the trunk. Early lesions frequently present as a red, scaly spots. Later lesions may form nodules or firm plaques, either of which can ulcerate ( http://tray.dermatology.uiowa.edu). Diagnosis is established by biopsy and histopathological confirmation. Complete excision is curative in the vast majority of cases. Occasionally squamous cell carcinoma will invade along the perineural layer of peripheral nerves and will extend well beyond the clinically apparent mass. Local recurrence is more common in these instances and when present on the head, direct intracranial extension may occur. Metastases to draining lymph nodes occurs in a minority of cases and disseminated disease is the cause of most squamous cell carcinoma-related deaths. Higher rates of metastasis (~15%) are observed with primary lesions of the lips or ears (Rowe et al., 1992). Radiation therapy is helpful in some cases of locally recurrent disease in which complete resection is difficult to achieve and in cases of limited metastatic disease.

Pathology

The development of squamous cell carcinoma is frequently a multistep process. Early lesions tend to be either actinic keratoses, with atypia of the basal keratinocytic layer of the epidermis or squamous cell carcinoma in situ, in which keratinocytic atypia spans the full thickness epidermis.

actinic keratoses	squamous cell carcinoma in situ

>These precursors are frequently present adjacent to invasive squamous cell carcinomas which invade the dermis as nests, islands, or cords squamous cells with or occasionally as individual cells. Several grading schemes have been developed for squamous cell carcinoma and incorporate the extent of keratinization (a form of differentiation) and nuclear atypia (Broders, 1932). A widely used scheme divides tumors into well, moderately, or poorly differentiated.

well differentiated	moderately differentiated	poorly differentiated

Although poorly differentiated tumors tend to behave more aggressively, well-differentiated tumors can also give rise to metastasis and result in death. Several histologic variants of squamous cell carcinoma have been documented, including verrucous, spindle cell and pseudovascular.

spindle cell	pseudovascular

Frequently an actinic keratosis or squamous cell carcinoma overlies the invasive component and the two are focally contiguous. Occasionally squamous tumors arise rapidly, have a crater-form morphology and spontaneously regress. These tumors are known as keratoacanthomas. Some craterform squamous lesions do not regress, but continue to invade and grow and represent invasive squamous cell carcinomas.

Human papilloma virus (HPV) infects squamous epithelia at various sites including the cervix, vagina, vulva, anorectal junction, skin, oral mucosa, and pharynx. Different HPV types tend to cause different clinical manifestations, for example HPV types 1-4 are associated with cutaneous warts, types 6, 11,16, and 18 are associated with genital-mucosal lesions, and types 5 and 8 are found in lesions from persons with epidermodysplasia veruciformis (EV), a rare inherited susceptibility to HPV infection (Lowy and Androphy, 1999). Although many of the resultant lesions are benign, some are precursors for invasive squamous cell carcinoma. Types 16 and 18 are most often present in squamous cell carcinomas arising in the cervix and at other genital-mucosal sites. Two gene products E6, and E7 have been shown to play key roles in transformation by HPV. E6 inhibits the function of p53 by directing its ubiquitination and degradation, while E7 inhibits the Rb pathway (Munger, 2002).

Some of the genetic changes that play a role in squamous cell carcinoma formation and progression have been defined. TP53 is mutated in the majority of both early lesions (actinic keratoses) as well as in invasive squamous cell carcinomas (Ortonne, 2002). The p110a subunit of the PI3-kinase (PIK3CA) is amplified in about 30% of squamous cell carcinomas (Singh et al., 2002). Chromosomal aberrations are common in squamous cell carcinoma with chromosomes 8, 1, 11, 3, 13, 5 and 7 most frequently altered (Jin et al., 1995) Squamous cell carcinoma may occur as a manifestation of certain inherited conditions including xeroderma pigmentosum and X-linked dyskeratosis congenita (OMIM #305000)

Mouse models of squamous cell carcinoma

Figure 16. Squamous papilloma arising in a DMBA/TPA treated mouse.
Figure 17. Well differentiated squamous cell carcinoma arising in a squamous papilloma.
Figure 18. Spindle cell squamous carcinoma arising in a UV irradiated mouse.

Transgenic mice have been constructed that have a predisposition for forming squamous cell carcinoma. Most models have used cytokeratin promoters active in the basal layer of the epidermis such as K5 or K14. One model of inducible model of precancerous squamous lesions has been developed by subrabasal keratinocytic expression of the c-myc/estrogen receptor fusion protein. Topical administration of 4-hydroxytamoxifen resulted in squamous proliferation with atypia, morphologically resembling squamous cell carcinoma in situ, which resolved in the absence of tamoxifen application.