variant is often mistaken for a recalcitrant wart frequently causing a delay in diagnosis. Clinicians should have a low threshold for biopsy, particularly when initial treatment fails [51]. Anogenital SCCs commonly present as moist red, indurated, or ulcerated plaques.

The keratoacanthoma (KA) type of squamous cell carcinoma is a well differentiated, rapidly growing crateriform nodule with a central keratin plug. It is considered a self-healing neoplasm with a particular history and histologic architecture. While the metastatic potential of a keratoacanthoma is minimal, KA can be indistinguishable histologically from invasive SCC [52]. Given the potential morbidity and mortality of an error in diagnosis or predicted biologic behavior, KA is best considered and treated as a well-differenti- ated SCC taking the patient, the history, and the risks and benefits of treatment into consideration.

Verrucous carcinoma is a slow-growing variant of invasive SCC that can be locally destructive but has low metastatic potential. When found in the anogenital region, these lesions are referred to as Buschke– Lowenstein tumors. When found in the mouth, they are termed oral florid papillomatosis, and on the foot, epithelioma cuniculatum. Despite their low metastatic potential, their propensity toward local destruction can be quite severe, particularly in immunosuppressed patients.

17.3.4 Differential Diagnosis

The differential diagnosis of cutaneous SCC includes its precursor lesions, actinic keratoses, and SCCIS, as well as basal cell carcinoma and verruca. Atypical fibroxanthoma and merkel cell carcinoma may present similarly to some SCCs and often occur in similar locations. Additionally, ulcerative diseases, such as pyoderma gangrenosum, may be in the clinical differential in the case of a non-healing ulcer. Biopsy is required for definitive diagnosis and, given the ease and low morbidity associated with it, should be done when there is any concern for SCC.

Summary: Management of Invasive

Cutaneous SCC

•The management of cutaneous SCC is a mainstay of Mohs surgical practice. However, the treating surgeon should always consider both surgical and non-surgical treatment options.

17.4Management of Invasive Cutaneous SCC

In approaching the patient with cutaneous SCC, it is important to rule out high-risk disease (see high-risk section below). If the tumor is not high risk, surgical excision is the mainstay of care for invasive SCC. Radiation as primary therapy will also be discussed. Non-surgical modalities such as curettage, electrocautery, cryosurgery, topical creams (5-fluorouracil and imiquimod), and photodynamic therapy are generally reserved for in situ disease since cure rates are generally inferior to surgery, and non-surgical methods do not allow for evaluation of histologic margins [53]. However, non-surgical approaches play a central role in the treatment of in situ field cancerization (see below).

17.4.1 Surgical Options

Complete surgical clearance of invasive SCC is of paramount importance since negative surgical margins are critical for achieving cure. When clear histologic margins are confirmed, results are excellent (local recurrence risk 5%, lymph node metastasis 5%, distant metastasis 1%, disease-specific death 1%) [54].

Standard excision is considered appropriate for well-defined tumors in areas where tissue sparing is not critical. For well-defined tumors <2 cm, a 4-mm margin is curative 95% of the time. However, high rates of positive margins after standard excision are reported for tumors on the ear, infiltrative SCC, and recurrent or re-excised tumors [55]. Therefore, for larger tumors (>2 cm) or infiltrative growth patterns with deeper invasion, a 6-mm margin or, preferably, Mohs micrographic surgery or another method of total margin-controlled excision is generally preferred [56, 57].

Mohs micrographic surgery is the recommended therapy for high-risk cutaneous SCC (see below) and tumors located in anatomically critical or cosmetically sensitive areas. Mohs histologic sectioning allows for visualization of nearly the entire surgical margin; <1% of the margin is examined following standard excision. 5-year cure rates support the importance of meticulous margin evaluation, as traditional surgical excision cures 92% of primary tumors, while Mohs cures 97%. For recurrent disease, standard excision has a 77% cure rate, while Mohs is able to cure 90–94% [11, 58, 59].

For very large tumors which are difficult to approach with local anesthesia, a multidisciplinary surgical approach may be employed.

Controlled comparative studies of Mohs versus standard excision have not been carried out for SCC. However, given the compelling case series data, and Mohs’ ability to fully examine the marginal surface, Mohs is considered the standard of care for high-risk SCC and tumors on the head by most American dermatologists. A comparative study would be helpful in identifying a single surgical standard of care for SCC across multiple specialties, including plastic surgery, head and neck surgery, and surgical oncology specialists who routinely manage SCC with standard excision.

17.4.2Radiation Therapy as Primary Therapy

While radiation can be used as a primary treatment option for cutaneous SCCs, reported outcomes are worse than surgical therapy. In addition to the longterm cutaneous risks of radiation, tumors that do respond tend to quickly recur, and radiation is far more cumbersome for patients than surgery [60]. Its appropriate use as a primary therapy is therefore limited to a subset of patients with early disease where surgery would lead to unacceptable cosmetic or functional impairment or in patients with inoperable tumors [61]. Given the high rates of recurrence, inconvenience, and the inability to confirm clear margins with radiation, surgery remains the most effective approach for treating primary SCC.

Summary: Identification and Management

of High-Risk Squamous Cell Carcinoma

•The rare risks of metastasis and death should be considered by physicians managing invasive SCC. The precise risk of these poor outcomes for individual patients is unknown. This, coupled with a lack of clinical trials, makes decision-making regarding the need for nodal staging and adjuvant therapy difficult. This section summarizes the information currently available.

17.5Identification and Management of High-Risk Squamous Cell Carcinoma

The evaluation of a patient with invasive cutaneous SCC is incomplete without considering the risk for recurrence or metastasis. Although for the vast majority of patients this risk is minute, for a subset of patients, the risk appears to be substantial. Tumors with features that have been associated with metastasis and death have been termed high-risk cutaneous SCC (HRSCC). To date, there is no consensus for defining HRSCC. The potential for aggressive disease can be attributed to both tumor and host factors. As there is no prognostic model available, it is unknown how various risk factors combine and lead to recurrence or metastasis. Therefore, estimating these risks for an individual patient remains challenging. Current recommendations are summarized in the table below and indicate that there are significant areas of ambiguity of opinion regarding management of high-risk tumors. This uncertainty has been further demonstrated in a recent survey study of Mohs surgeons which indicated that there is only agreement at the far ends of the high-risk spectrum. Opinion regarding nodal staging and adjuvant radiation varies widely for most HRSCC cases (Table 17.1) [12, 62–67].

17.5.1Tumor Factors Associated with High-Risk SCC

Location: Cutaneous SCC arising in skin that has been previously injured, such as a scar, chronic wound, ulcer, or burn site, has a higher risk of recurrence and metastasis [11, 68–70]. Recurrence rates have been reported as high as 58% and 5-year survival only 52% [71]. Tumor location appears to impact prognosis. The largest review of available data suggests that location on the lip and ear have higher rates of metastases (14% and 9%, respectively) than other sun-exposed sites [11]. A three-fold higher risk of metastasis from lesions on the ear has been shown in a prospective study [10]. Anogenital SCC has shown high metastatic rates, ranging from 15% to 74% [72–75]. However, studies to evaluate the prognostic importance of anatomic location relative to other risk factors have been underpowered. Thus, the question of the impact of location on outcomes remains open.

Table 17.1 Expert consensus recommendations for the management of high-risk SCC

196

.al et LeBoeuf .R.N

NR no recommendations made, PNI perineural involvement, NMSC non-melanoma skin cancer, OTR organ transplant recipient, mTOR mammalian target of rapamycin

aAny high-risk feature places tumor in the high-risk category: >2.0 cm on trunk and extremities, >1.0 cm on cheeks, forehead, scalp, and neck, >0.6 cm on remaining “mask” area of face; poorly defined borders, recurrent tumor, moderately or poorly differentiated, adenoid/acantholytic adenosquamous or desmoplastic subtypes, Clark level IV,V or depth >0.4 cm, rapid growth, neurologic symptoms, occurring in a site of prior RT or chronic inflammation and occurring in the setting of immunosuppression

bGuidelines for treatment of cutaneous SCC, specifically in organ transplant recipients

cSize >0.6 cm on “mask” areas of the face, >1.0 cm on cheeks, forehead, neck, and scalp, >2.0 cm on trunk and extremities, location on scalp, ear, lip, midface, genitalia, or nail unit, rapid growth, poorly defined margins, ulceration, poorly differentiated histology, perineural involvement, and invasion to subcutaneous fat

dA multidisciplinary cutaneous oncology team has the following available: A dermatologist, pathologist, Mohs surgeon, surgical oncologist, medical oncologist, and a clinical nurse

eSize >1 cm, rapid growth, ulceration, immunocompromised host, recurrent tumors, location on mucous membranes, ear, temple, scalp, or eyelid, undifferentiated histology, depth into and beyond the subcutaneous fat, perineural invasion, lymphatic invasion

Carcinoma Cell Squamous 17

197

Diameter: Tumor diameter correlates with risk of metastasis with most series reporting tumors greater than 2 cm as higher risk [11, 69, 76]. Smaller tumors of the lip and ear can metastasize, and cut points of 1.0 or 1.5 cm have sometimes been used to connote higher risk in these locations [77].

History of recurrence after surgical excision: Local recurrence has been associated with distant metastatic disease; 30–50% of metastatic tumors occur in patients with a prior local recurrence [11, 78].

Histologic characteristics: Histologic features associated with increased rates of recurrence, metastasis, and death, assessed via case series and small prospective studies, include tumor depth, perineural involvement (PNI) and poorly differentiated histology [11, 79].

Tumor thickness and the tissue level of invasion (e.g., fat, fascia, muscle, or bone) may predict metastatic disease. The millimeter depth that defines a high-risk tumor and the magnitude of that risk are not well defined. Reported rates of metastasis correlating with depths of 4–6 mm are 16–46% depending on the series [10, 11, 80]. The wide range may be due to small numbers of subjects and the biases of case-series, single-center data. Patients with tumors <2 mm thick appear to have a very low risk of metastasis [10]. Tumors infiltrating through subcutaneous fat are associated with disease-specific death [79].

Histologic grade appears to be a very important prognostic factor. The estimated cure rate for poorly differentiated tumors is 37%. In contrast, it reaches 88% for well-differentiated disease and 59% in moderately differentiated cases [69]. A 33% risk of metastasis has also been reported in patients with poorly differentiated tumors [11]. Desmoplastic or infiltrative SCCs have a tendency toward local recurrence and regional metastasis; this risk increases with increasing tumor thickness. Infiltrative cutaneous SCCs have been reported to have six times the rate of lymph node metastases and ten times the rate of local recurrence compared to non-infiltrative tumors [80].

Perineural invasion (PNI) is associated with a high incidence of recurrence, metastasis, and death [11, 79, 81]. However, the spectrum of PNI is vast varying from involvement of tiny dermal nerve twigs to cranial nerve extension inside the skull. Patients may have evidence of cranial nerve involvement on physical exam, most commonly in fifth and seventh nerves [82], or they may be asymptomatic. Patients with symptomatic involvement of named nerves have a particularly poor prognosis. The risk of death from SCC in patients

with involvement of nerves 0.1 mm or greater was reported to be 32% in a small cohort study. Conversely, those with involvement of smaller nerve twigs less than 0.1 mm had a good prognosis with only rare local recurrence and no metastasis or death [83].

17.5.2Host Factors Associated with High-Risk SCC

Immunosuppressed patients are at substantially greater risk of developing SCC than the immunocompetent, and they have a higher risk of poor outcomes. The rate of metastasis is twice as high in the immunocompromised, with rates of 13% described [11]. The type of immunodeficiency correlates with varying degrees of increased risk.

Organ transplant recipients (OTRs) have a 65-fold increased incidence of cutaneous SCCs when compared to the general population [84]. The ratio of SCCs to basal cell carcinomas (BCCs) is 3:1, which is reversed compared to the general population [85, 86]. Degree of immunosuppression may impact risk. For example, there is a nearly three times greater incidence of SCCs in heart transplant recipients when compared to kidney transplants [84], presumably because heart transplant patients need to receive higher doses of immunosuppression to avoid rejection. When additional risk factors are added to a history of organ transplantation, such as fair skin and extensive sun exposure, incidence rates approach 70% [53]. Additionally, the cumulative incidence of developing skin cancer increases with longer duration of immunosuppression; in one Australian study rates were 7% after 1 year, 45% after 11 years, and 70% after 20 years [53]. A history of one cutaneous SCC in OTRs has been shown to correlate with a 66% chance of developing a second primary tumor within 5 years [87]. Unfortunately, OTRs present more commonly with high-risk cutaneous SCCs with a greater tendency toward metastasis; since tumors are more often deep and poorly differentiated [88]. Heart transplant patients have been shown to have a 4% incidence of aggressive and poorly differentiated cutaneous SCC within 10 years of transplant. The risk of death from high-risk SCC 20 years after heart transplantation has been shown to be extraordinarily high at 66% in one small study [89]. The occurrence of in-transit cutaneous metastases which carry a high (65%) associated mortality is also higher in OTRs [90].

Chronic lymphocytic leukemia (CLL) and smallcell lymphocytic lymphoma (SLL) are well known to be associated with cutaneous malignancy. SCC is reported most frequently [91] and is commonly aggressive with high rates of recurrence and metastasis [20]. The cumulative 5-year recurrence rate for cutaneous SCC in patients with CLL/SLL has been reported at 19%, seven times higher than controls [20]. While the number of patients with CLL/SLL developing SCC is less than 5%, tumors in these patients tend to be more aggressive, with more than half in patients with CLL/ SLL meeting high-risk criteria [91]. One quarter of the tumors in these patients recur or metastasize despite standard therapy, and 41% of cutaneous SCC patients with CLL/SLL have been reported to die from their skin cancer [91]. The behavior of the tumors may correlate with the status of their underlying lymphoproliferative disorder; if neoplasms suddenly become more aggressive, their CLL/SLL very well may be progressing, and the treating oncologist should be notified.

While there is a well-documented increase in anogenital cutaneous SCC in association with HPV in HIV patients, a definitive association with high-risk cutaneous SCC has not been made. Small case series have described patients with HIV who developed aggressive SCC, with 50% mortality at 7 years [21]. It is reasonable to conclude that caution should be used when managing patients with poorly controlled HIV or AIDS who develop cutaneous SCC, particularly high-risk tumors.

Other host conditions have been associated with highrisk cutaneous SCC and worse outcomes. These include iatrogenic psoralen-ultraviolet-A (PUVA) or ionizing radiation exposure, environmental arsenic exposure, and chronic inflammatory states. In patients with recessive dystrophic epidermolysis bullosa (RDEB), cutaneous SCC is the leading cause of death, with an 80% mortality rate within 5 years of diagnosis of the neoplasm [92]. Other chronic autoimmune diseases, treated with immunosuppression, may also be associated with a higher risk of developing cutaneous SCC [93]; this may be related to both therapy and the disease itself.

17.5.3Work-Up (Staging of Primary Tumor and Nodal Basins)

Examination of draining lymph node basins is important in evaluating a patient with high-risk SCC. If nodes are palpable on exam, a fine-needle aspiration (FNA)

or excisional biopsy should be performed. Different from its counterpart melanoma, most patients with lymph node metastasis from cutaneous SCC are curable if the tumors are operable, and therefore evaluation of the nodal basin and early identification of disease are critical.

Radiologic imaging is the most common approach used to detect subclinical tumor extension and nodal disease. The gold standard imaging modality of choice, as well as which patients require imaging, has not been established in cutaneous SCC. However, there is data evaluating imaging for oronasopharyngeal SCC. This data suggests that CT, MRI, PET, and ultrasound all have variable specificity and sensitivity and commonly result in false positives and negatives. The addition of PET to CT improves sensitivity; however, because it has not yet shown an impact on outcomes, justifying its cost can be difficult for routine cases. For detecting nodal necrosis, extracapsular spread, and bone or cartilage involvement, CT is generally most useful. MRI is the better choice if the goal is to evaluate tissue plains, distinguish soft tissues, or gauge extent of large-nerve invasion [94, 95]. Given their different strengths, both MRI and CT may be helpful in planning a surgery. They may be of particular use in SCC thought to be involving LNs or deeper bone, glands, or major nerves. CT scanning and MRI appear to have little utility in detecting asymptomatic perineural invasion (PNI). However, when PNI is visible on imaging, outcomes are often poor; the 5-year survival with positive imaging is reported at 50% versus 86% with negative imaging [46]. PET scanning and ultrasound-guided FNA may be useful screening tools in detecting subclinical nodal metastases, but their utility and likelihood of altering management have been minimally studied [96, 97]. The use of 18F-fluoro- deoxyglucose positron emission tomography (FDGPET) to detect nodal metastasis may be a useful staging tool, but there is very limited data on its effectiveness in cutaneous SCC. Its utility lies in its ability to detect metastasis where radiotherapy has resulted in necrosis, fibrosis, and dense scarring [98].

While radiologic imaging in cutaneous SCC requires further study to determine which patients are likely to benefit from which study, imaging is safe. Given its low risk, it should be considered in those with high-risk neoplasms to evaluate the draining nodes and when deeper tissue involvement is suspected, for surgical planning.

Sentinel lymph node (SLN) biopsy is another method of evaluating clinically negative nodal basins. Again,