cells (Tregs) which are immunosuppressive and thus may allow tumors to evade destruction by the immune system and continue to grow. Additionally, SCCs do not express E-selectin on tumor vessels, and therefore cutaneous lymphocyte antigen (CLA) 4+ skin-homing memory T-cells cannot enter the tumor tissue [44]. The CLA4+ cells are crucial for immune surveillance. In mice, treatment of SCCs with imiquimod reverses many of these effects; this results in expression of vascular E-selectin, decreased Treg density [44], and increased CLA4+ effector T-cells with resultant inter- feron-g (IFN-g) production and resulting tumor regression [45]. Thus, the development and growth of invasive squamous cell carcinoma appears to involve complex genetic and immunologic alterations within the tumor and the surrounding microenvironment, all of which serve as potential portals for further understanding of high-risk disease and the development of novel therapies.

Summary: Clinical Disease Spectrum

•The spectrum of cutaneous neoplasms with squamous dysplasia is broad ranging from superficial focal actinic keratoses to highly aggressive, invasive SCC. The etiology of a particular tumor may correlate with a specific presentation and course, as in bowenoid papulosis and verrucous carcinoma. Understanding variations in presentation and diagnosis allows for appropriate diagnosis and management of the SCC disease spectrum.

17.3Clinical Disease Spectrum

Evaluation of the patient with known or suspected cutaneous SCC involves obtaining a thorough history evaluating for common risk factors and those associated with high-risk disease. While most typical SCCs are brought to the physicians’ attention by the patient or relative and are generally asymptomatic, a careful history can help distinguish those patients at high risk for recurrence and metastases. Rate of growth should be assessed, as well as symptoms of numbness, tingling, pain, or weakness, which may reflect the presence of perineural involvement (PNI); this has prognostic and management implications [46]. History of immunosuppression, especially exposure

Fig. 17.1 Dermally invasive SCCs on a background of diffuse actinic damage and SCCIS on the posterior legs

to immunomodulatory drugs or diagnosis of chronic lymphocytic leukemia (CLL), should be obtained as high-risk disease is more common in these patients.

17.3.1 Actinic Keratosis

Actinic keratoses (AK) are the third most common diagnosis made on dermatologic consultation [47]. Clinically, they are typically rough, keratotic skin-colored papules 2–6 mm in diameter. Patients with diffuse actinic damage are more likely to develop multiple SCCs. Such patients with multiple tumors in a background of diffuse actinic damage (Fig. 17.1) can be considered clinical entities in and of themselves, requiring special consideration with regard to evaluation and management. These patients with diffuse precancerous and cancerous lesions can present a management challenge. Referral to a

high-risk or immunosuppression dermatology subspecialty clinic for close follow-up and field therapy may be considered. See the section on field cancerization below for a step-wise approach to management.

17.3.2 Squamous Cell Carcinoma In Situ

Squamous cell carcinoma in situ is a histologic diagnosis defined by full thickness keratinocyte atypia. The breadth of the lesion is often not considered pathologically. Thus, a small microscopic focus of full-thickness atypia seen in a background of actinic keratosis is still diagnosed as SCCIS. The natural history of SCCIS, including the percentage of SCCIS lesions that progress to invasive SCC, is not known. However, it is assumed they have the potential for invasion, similar to actinic keratoses, so treatment is generally advised. Clinically, SCCIS may be indistinguishable from AK. Classic Bowen’s disease is a well-demarcated pink plaque of SCCIS arising in a non- sun-exposed area. An example of this is erythroplasia of Queyrat, Bowen’s disease of the glans penis. Also occurring in the genital region, bowenoid papulosis presents with hyperpigmented papules of the pubic region, with histologic findings identical to Bowen’s disease. It is most commonly associated with HPV 16 and 18. The significance of distinguishing the particular clinical variant of SCCIS is relevant when implementing treatment plans, as these entities have different potentials for invasion; the risk of developing invasive disease in erythroplasia of Queyrat is reported to be 30% [48, 49] while that potential for bowenoid papulosis is less than 1% [50]. Thus, clinicopathologic correlation is quite important in developing management and follow-up plans for the various subtypes of SCCIS.

17.3.3 Invasive Squamous Cell Carcinoma

Fig. 17.2 SCC with associated hyperkeratosis

Fig. 17.3 Exophytic SCC without hyperkeratosis on a background of actinically damaged skin

Typical invasive cutaneous SCC arises most commonly on sun-exposed skin of the head and neck or distal extremities and presents as a firm pink keratotic papule or plaque (Fig. 17.2). They may also be exophytic without hyperkeratosis (Figs. 17.3 and 17.4, superior) or relatively flat and ill defined (Fig. 17.4, inferior). The presence of a nodule lacking surface change should raise suspicion of a metastatic tumor.

Cutaneous SCCs commonly associated with HPV includeperiungualandanogenitaldisease.Theperiungual

Fig. 17.4 Two clinical presentations of SCC: A large friable exophytic tumor with hemorrhagic crust removed on the anterior central scalp (superior) and a thinner but more ill-defined lesion just above the left temple (inferior)