A detailed clinical examination is paramount, and most BCC can be diagnosed by their appearance. A skin biopsy is usually performed to provide histologic confirmation of the diagnosis. Shave biopsies, punch biopsies, and excisional biopsies can be used for the diagnosis of BCC.

Surgical options for BCCs at low risk for recurrence include conventional surgical excision, Mohs surgery, and electrodesiccation and curettage (ED&C). Typically, surgical excision of the BCC is the preferred option and can often be performed under local anesthesia. Generally, surgical excision of the trunk, extremity, or small facial BCCs of the head or neck with anywhere from 1 to 10 mm margins has been associated with 5-year cure rates exceeding 95 %; therefore, 3–5 mm surgical margins are commonly used for the excision of these lesions [8]. Infiltrative/morpheaform lesions may require wider (5–10 mm) margins due to their indistinct borders. Mohs surgery is usually reserved for lesions that exhibit features associated with an increased risk for recurrence and for locations in which tissue sparing is of great value due to cosmetic or functional concerns. When standard surgical excision is performed, all extremity lesions should be removed in a longitudinal fashion. While a longitudinal incision of the extremity may not be the most cosmetic, it allows for an easier re-excision if the lesion recurs and also disrupts less lymphatic tissue so that lymphedema is minimized (See Chap. 1, Fig. 2.2). The concept of longitudinal excisions of the extremities is critical for all NMSCs and should be considered the standard. Cryosurgery may be used for small superficial lesions, but for larger nodules, its use is infrequent. With proper lesion selection and operator skill/experience, ED&C is capable of achieving a high cure rate.

Photodynamic therapy (PDT) is a nonsurgical treatment option for superficial BCCs. The three components of PDT are a light source; exogenous photosensitizer, such as aminolevulinic acid or methyl-aminolevulinic acid; and oxygen. Excellent response rates have been reported for this modality in selected BCC.

The superficial nature of early BCCs allows for effective topical treatments of these lesions. Options for topical therapy include 5-fluorouracil (5-FU) and imiquimod. 5-FU is a pyrimidine analogue that induces cell cycle arrest and apoptosis. Extensive experience with topical 5-FU indicates that this treatment should be restricted to superficial BCCs in non-critical locations. Imiquimod 5 % cream is an immune response modifier that is approved by the US Food and Drug Administration for the treatment of superficial BCCs in low-risk sites. Topical agents require active patient participation and close practitioner surveillance to prevent BCC progression and/or recurrence. All nonresponding lesions should be biopsied for persistent or recurrent disease. Radiation therapy (RT) is utilized as a primary modality in patients who are poor surgical candidates. As an adjuvant therapy, radiation therapy can achieve good results with excellent cosmetic results if applied appropriately especially in patients with high risk of recurrence. A randomized study in 347 patients receiving either surgery or RT as primary treatment of BCC found RT to result in higher recurrence rates than surgery alone (7.5 % vs 0.7 %) [9]. For multiple recurrent BCC that have failed to be cleared by surgical excisions, RT is often a useful option, particularly for microscopically involved margins.

Advances in the understanding of the molecular mechanisms that lead to BCC formation has led to the FDA recently approving a novel agent Vismodegib, a first-in-class Hedgehog pathway inhibitor. This agent can be used for refractory locally advanced BCCs that have failed all other options or for the rare metastatic BCC patient. While this treatment is currently quite expensive, the results can be significant in clearing the tumors. Multiple side effects have been reported with this agent which may limit its use in certain patients.

Close follow-up is required following treatment to diagnose both local recurrences and new skin cancers and to assess posttreatment outcomes. Most dermatologists recommend reevaluation every 3–6 months for the first year following treatment and then every 6–12 months thereafter. About 30–50 % of patients may develop another NMSC within 5 years. Therefore, close skin surveillance is mandatory.

Squamous cell carcinoma (SCC) is the second most common type of NMSC, accounting for approximately 20 % of all NMSC cases. SCCs can arise de novo, but unlike BCCs, SCCs often arise from precursor lesions that show partial-thickness epidermal dysplasia, such as actinic keratosis (AK). AK presents as slightly scaly papules with ill-defined borders, on sun-exposed skin. Seborrheic keratosis is tan to dark brown stuck-on appearing benign, warty growths located anywhere on the body. The rate of malignant transformation from AK to SCC is estimated to range from 0.025 % to 16 % per year for an individual lesion [10]. Intraepithelial SCC or carcinoma in situ is believed to be the next step in the progression to invasive SCC. Risk factors for developing SCC include sun exposure, radiation, chronic inflammation, immunosuppression, and virally induced.

SCC typically develops on areas that are commonly exposed to the sun, including the head and neck, scalp, face, dorsum of hand, shoulder, and chest. The majority of these lesions occur on the head and neck areas. SCCs appear as ill-defined keratotic papules and nodules which may be ulcerated. They can be reddish brown, erythematous, or flesh colored. Occasionally, cutaneous horns from hyperkeratosis may be seen, and bleeding can occur with SCC. A typical SCC in the background of extensive AK is compared to a locally advanced SCC as depicted in Fig. 2.2a, b. Histologically, they show nests of atypical keratinocytes with dermal invasion. In situ lesions, also known as Bowen’s disease, are characterized by full-thickness atypical epidermal involvement. Histologic grading is divided into well, moderately, or poorly differentiated. Poorly differentiated lesions have a higher recurrence (28.6 % versus 13.6 %) and metastatic rate (32.8 % versus 9.2 %) compared to well-differentiated lesions [11].

Clinical workup includes a complete history and physical examination, with emphasis on full skin and regional lymph node examinations. Patients may have concurrent cancer located in various sites, and individuals with SCC may be at increased risk of developing BCC and/or melanoma.

A skin biopsy is performed, making sure to obtain full-thickness sample down to the deep reticular dermis. Punch biopsies are simple to perform in the clinic under local anesthesia and yield good full-thickness samples for pathologic evaluation (Fig. 2.3). Imaging studies are rarely necessary and typically reserved only for locally advanced or clinically detected metastatic lesions.

The presence of palpable lymph nodes identified by clinical examination or imaging studies should prompt a fine-needle aspiration for diagnosis. Regional nodal involvement significantly increases the risk of recurrence and mortality and is often associated with other histologic findings including lymphovascular invasion, poor differentiation, and perineural invasion (Fig. 2.4a, b). A fine-needle aspiration or core biopsy is generally sufficient for pathologic diagnosis, and excisional biopsies are discouraged as they may confound future definitive surgical interventions. Fortunately, the rate of lymph node metastasis from cutaneous SCC is estimated to only be 0.1 % for early lesions, but increases with more advanced lesions.

The American Joint Committee on Cancer (AJCC) TNM staging classification for cutaneous squamous cell carcinoma is listed in Table 2.1 [7].

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine malignancy that arises in the dermoepidermal junction. It commonly affects elderly Caucasians and was originally described by Toker in 1972 as trabecular carcinoma of the skin. Other names include Toker tumor, primary small cell carcinoma of the skin, primary cutaneous neuroendocrine tumor, and malignant trichodiscoma. Although rare, MCC incidence rates are increasing rapidly. The tumor often appears as an asymptomatic erythematous nodule and may resemble a basal cell carcinoma, a common misdiagnosis both clinically and histologically (Fig. 2.5). The pathogenesis of MCC is controversial. One thought is it arises from Merkel cells, which are part of the amine precursor uptake and decarboxylation system located in the basal layer of the epidermis and hair follicles. Another hypothesis is that MCCs originate from immature stem cells that acquire neuroendocrine features during malignant transformation.

MCCs can be characterized by AEIOU features: Asymptomatic/lack of tenderness, Expanding rapidly, Immune suppression, Older than 50 years, and Ultraviolet-exposed site on a person with fair skin [22]. In a SEER data review of 1,034 patients, MCC was more common in males and patients geographically located in sun-exposed climates; 94 % were Caucasian, 76 % were older than 65 years (median 75), and 48 % occurred on the head [23]. MCC has been shown to be more common in immunosuppressed populations such as solid organ transplant recipients and HIV patients. Accordingly, MCC can be aggressive and should be considered to have a high lethal potential with an estimated 1 in 3 patients succumbing to the disease. Of the patients for which MCC is the cause of mortality, half of the patients will die within 4 years of the initial diagnosis.

In 2008, Merkel cell polyomavirus (MCV) was discovered and found to be integrated into the host genome of over 80 % of patients with MCC, and this association has been validated by multiple other studies [24]. An increased incidence of MCCs was found in patients with chronic lymphocytic leukemia (CLL) who are relatively immunosuppressed and have a high rate of MCV detected in their MCC tumors [22].

When MCC is suspected, a punch biopsy or full-thickness biopsy should be performed. There are three main histologic patterns: (1) solid type- most common type, composed of irregular groups of tumor cells interconnected by strands of connective tissue; (2) trabecular type- well-defined cords of cells that form invading columns or cords; and (3) diffuse type- exhibits poor cohesion and a lymphoma-like diffuse type of growth. The pathologic diagnosis is difficult due to its similarity to small round blue cell tumors (small cell carcinoma of the lung, cutaneous large cell lymphoma, neuroblastoma, metastatic carcinoid, amelanotic melanoma, sweat gland carcinoma, Langerhans cell histiocytosis, and Ewing sarcoma). Hematoxylin and eosin (H&E) staining should be confirmed by immunohistochemistry (IHC). CK-20 is both sensitive and specific for MCC with a positivity in 89–100 % cases, and thyroid transcription factor 1 (TTF-1) is consistently negative in MCC [25].

Histologic features that may have prognostic significance include: tumor thickness, presence of lymphovascular invasion, and tumor growth pattern. The AJCC lists site-specific prognostic factors: measured thickness (depth), tumor base transection status, profound immune suppression, tumor infiltrating lymphocytes in the primary tumor, growth pattern of primary tumor, size of tumor nests in regional lymph nodes, clinical status of regional lymph nodes, regional lymph nodes pathologic extracapsular extension, isolated tumor cells in regional lymph node(s) [7]. The majority of patients die from distant metastases involving liver, bone, lung, brain, or distant lymph nodes. Tumors greater than 2 cm in diameter at the time of diagnosis have been shown to have a negative influence on survival.