Cutaneous Squamous Cell Carcinoma 1.
OVERVIEW
Practice Essentials Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, after basal cell carcinoma. Other significant skin lesions are actinic keratosis and melanoma. Actinic keratosis and basal cell carcinoma are easily excised and have a very good prognosis. However, SCC of the skin has a poor prognosis, especially if it invades vital structures or metastasizes to the lymph nodes. Actinic keratosis is the premalignant precursor for cSCC, and early treatment will save the patient morbidity. Extrinsic factors, such as ultraviolet light from sun exposure, are linked to cutaneous cell carcinoma, while intrinsic factors, such as the use of antioxidants, aspirin, and nonsteroidal nonsteroidal antiinflammatory drugs (NSAIDs), are reported to reduce the risk of developing cSCC. The image below depicts a large, ulcerated, invasive SCC of the left lower eyelid.
A large, ulcerated, invasive invasive squamous cell carcinoma of the left lower lower eyelid. This patient also had perineural invasion of the infraorbital nerve extending into the cranial base.
Signs and symptoms
Clinically, cSCC presents as a shallow ulcer with elevated margins, often covered by a plaque and usually located in a sun-exposed area. Typical surface changes may include scaling, deep ulceration, crusting, and cutaneous horn. A less common common presentation presentation of cSCC includes a pink cutaneous cutaneous nodule nodule without without overlying surface changes. Regional metastasis of head and neck cSCC may result in enlarged and palpable submandibular or cervical lymph nodes. If cSCC invades the adjacent peripheral nerve, it causes numbness, pain, and muscle weakness. These may be some of the clinical signs of invasion other than palpable lymph nodes. Diagnosis
Diagnostic workup of suspected cSCC will include computed tomography (CT) scanning to evaluate for soft tissue or bony invasion and lymph node metastasis. Magnetic resonance imaging (MRI) may be used to rule out invasion of neural or vital structures. Incisional or excisional biopsy are essential for definitive diagnosis. The choice of biopsy will depend on the size and location of the lesion. Management
Treatment options include the following:
Surgical excision with clear margins, as verified by frozen sections Mohs micrographic surgery for invasive cSCC in the facial region Radiation therapy as an adjuvant to surgery, to provide improved locoregional control, or as primary therapy in patients who are unable to undergo surgical excision Chemotherapy, such as treatment with oral 5-fluorouracil (5-FU) and epidermal growth factor receptor (EGFR) inhibitors, as adjuvant therapy for select highest-risk cases Systemic chemotherapy for metastatic cSCC
Background Cutaneous squamous squamous cell carcinoma (cSCC) is the second most common skin cancer and one of the most common c ommon cancers overall in the United States. An estimated 3.5 million cases of nonmelanoma skin cancers were diagnosed in the United States in 2006; of those, approximately 80% were basal cell carcinoma (BCC) and 20% were cSCC. Despite increased knowledge and public education regarding the causes of skin cancer and modes of prevention, the incidence of cSCC continues to rise worldwide. This increasing incidence is likely multifactorial; the speculated causes for the rise include an aging population, improved
detection, an increased use of tanning beds, and environmental factors, such as depletion of the ozone layer. (See the image below.)
Large, sun-induced squamous cell carcinoma (SCC) on the forehead/temple. Image courtesy of Glenn Goldman, MD.
Although cSCC is is not often often fatal, it can cause cause significant significant morbidity, morbidity, especially especially when it involves the facial skin. Most cSCCs are located in the head-and-neck region, and extensive excision required in an advanced stage of the disease can cause disfigurement. Furthermore, the cost of treatment has been shown to pose a significant public health burden. In a study of the US Medicare population, the treatment of nonmelanoma skin cancers ranked fifth among the most expensive cancers to treat in the head-and-neck region. Diagnosis of cSCC begins with a careful history and physical examination. A biopsy should be performed for any lesion suspected of being a cutaneous neoplasm to rule out basal cell carcinoma and other dermal lesions. Given the central role that ultraviolet radiation (UVR) plays in the pathogenesis of cSCC, methods aimed at decreasing UVR exposure form the cornerstone of cSCC prevention. In addition, treatment of precancerous lesions and in situ SCC may prevent the future development of invasive lesions. (See the image below.)
Squamous cell carcinoma in situ (Bowen disease). Courtesy of Hon Pak, MD.
Electrodessication and curettage is a simple technique that can be used to treat localized, superficial cSCC, while surgical excision and Mohs micrographic surgery are the two primary treatment options for invasive cSCC. Radiation therapy is typically used as an adjuvant to surgery, with primary radiation therapy typically reserved for patients who are unable to undergo surgical excision. Chemotherapy may be considered as adjuvant therapy in select highest-risk cases of cSCC. In particular, emerging evidence suggests that epidermal growth factor receptor (EGFR) inhibitors may be useful adjuncts to surgical treatment. Systemic chemotherapy may be considered for metastatic cSCC. By convention, the term head-and-neck SCC typically refers to SCC of the mucosal linings of the head and neck rather than to cSCC. Although conjunc conjunctival tival SCC SCC also involves involves mucosa mucosa rather rather than skin, skin, it is briefly considered in the Clinical Presentation and Treatment sections.
Pathophysiology Malignant transformation of normal epidermal keratinocytes is the hallmark of cSCC. One critical pathogenic event is the development of apoptotic resistance through functional loss of TP53, TP53, a a well-studied tumor suppressor gene. TP53 TP53 mutations mutations are seen in over 90% of skin cancers diagnosed in the United States, as well as in most precursor skin lesions, suggesting that loss of TP53 TP53 is is an early event in the development of [1] cSCC. UVR causes deoxyribonucleic acid (DNA) damage through the creation of pyrimidine dimers, a process known to result in the genetic mutation of TP53. TP53. Upon Upon subsequent UVR exposure, keratinocytes keratinocytes undergo clonal
expansion, acquiring further genetic defects, ultimately leading to invasive cSCC. Many other genetic abnormalities are believed to contribute to the pathogenesis of cSCC, including mutations of BCL2 and RAS. Likewise, alterations in intracellular signal transduction pathways, including the epidermal growth factor receptor (EGFR) and cyclo-oxygenase (COX), have been shown to play a role in the development of cSCC. Squamous cell carcinoma in situ (CIS), sometimes referred to as Bowen disease, is a precursor to invasive cSCC. Characteristics of this lesion include nuclear atypia, frequent mitoses, cellular pleomorphism, and dyskeratosis, parakeratosis, and hyperkeratosis. CIS is differentiated from actinic keratosis, a similar precancerous skin lesion, by the full-thickness involvement of the epidermis in CIS. Invasive cSCC is differentiated from CIS and actinic keratosis by the i nvasion of the basement membrane by malignant-appearing cells. With invasive cSCC, nests of atypical cells are found within the dermis, surrounded by an inflammatory infiltrate. Conventional cSCC can be divided into the following 3 histologic grades, based the degree of nuclear atypia and keratinization found (see the images below): Well differentiated: Characterized by more normal-appearing nuclei with abundant cytoplasm and extracellular keratin pearls Moderately differentiated: Exhibits features intermediate between well-differentiated and poorly differentiated lesions Poorly differentiated: Shows a high degree of nuclear atypia with frequent mitoses, a greater nuclear-cytoplasmic ratio, and less keratinization; it may be difficult to distinguish from mesenchymal tumors, melanoma, or lymphoma
Progressively severe atypia. The epithelium to the left is close to normal, but the epithelium to the right shows full-thickness atypia (ie, carcinoma in situ). This image illustrates carcinogenesis, the process whereby cells exposed to a carcinogen become cancerous over time.
Squamous cell carcinoma. The lesion closely approximates the specimen in the previous image. Field cancerization is illustrated; that is, if >1 cell is exposed to a carcinogen, >1 cell becomes cancerous. Note the marked inflammatory-cell response. Should limited biopsy reveal only severe atypia with a severe inflammatory response, the lesion should be investigated further, because a cancer is likely nearby.
Other histologic variants include acantholytic (adenoid) SCC, which is characterized by a pseudoglandular appearance, and spindle cell SCC, which has atypical, spindle-shaped cells. Both of these variants exhibit a more aggressive clinical course.
Etiology Exposure to cancer-promoting stressors and the response of the body to those exposures (host response) promote the development of cSCC. Well-known risk factors include the following: UVR exposure Immunosuppression Exposure to ionizing radiation or chemical carcinogens Human papillomavirus (HPV) infection Chronic UVR exposure, such as through tanning beds, medical UV treatments, or cumulative lifetime sun exposure, is the most important risk factor for the development of cSCC. UVR is a known mutagen capable of inducing DNA damage that can lead to keratinocyte transformation. UVR has also been shown to alter the cutaneous immune response, leaving the skin susceptible to tumor formation. [2] A number of surrogate indices of chronic UVR exposure from the sun are well known. Specifically, epidemiologic evidence suggests that geographic proximity to the equator, a history of precancerous lesions or prior skin cancers, older age, and male sex predispose an individual to the development of cSCC. Immunosuppression is also increasingly recognized as a risk factor for the development of skin cancer; this is true of iatrogenic and noniatrogenic immunosuppression (eg, in organ transplant recipients and persons with the human immunodeficiency virus (HIV), respectively). Regardless of the reason for immunosuppression, cSCC that arises in the setting of immunosuppression exhibits a more aggressive course, with a higher rate of local recurrence, metastasis, and death. Host responses that influence cSCC development include chronic inflammation, genetic predisposition to DNA damage, and, in particular, susceptibility to UVR damage. Well-known markers for UVR vulnerability include the following: Fair skin (or a history of repeated sunburns) Hazel or blue eyes Blonde or red hair Albinism The genetic influences that contribute to the development of cSCC from UVR are still poorly described. Only one such abnormality, a rare genetic defect that affects the repair mechanism for UVR-induced DNA damage, resulting in xeroderma pigmentosum, has been causally linked to UVRinduced cSCC. Xeroderma pigmentosum is characterized by severe sensitivity to UVR and premature development of cSCC.
A study by Schwaederle et al using next-generation sequencing indicated that seven genes (TP53, PIK3CA, CCND1, CDKN2A, SOX2 , NOTCH 1, FBXW7 ) are altered more frequently in various types of SCC (including cSCC) than in non-SCC, while an eighth gene, KRAS, is altered less frequently in SCC. [3] Infections that increase the risk for cSCC include the following: Acne conglobate Hidradenitis suppurativa Dissecting cellulitis of the scalp Lupus vulgaris Chronic deep fungal infection Dermatoses that influence cSCC development include the following: Xeroderma pigmentosum Dystrophic epidermolysis bullosa Epidermodysplasia verruciformis Dyskeratosis congenital Porokeratosis (Mibelli type, disseminated superficial actinic type, linear type) Nevus sebaceous KID (keratitis, ichthyosis, deafness) syndrome A cSCC may arise at a site of chronic inflammation, such as the following: Marjolin ulcer Burn scar or thermal injury Venous ulcer Lymphedema Discoid lupus erythematosus [4] Erosive oral lichen planus Lichen sclerosis et atrophicus Mutilating keratoderma Necrobiotic lipoidica A study by Mohan et al indicated that treatment of basal cell carcinoma with the smoothened inhibitor vismodegib increases the risk for the subsequent development of cSCC. The study, which included 180 patients, found no significant rise in other cancers. [5] Some of the above risk factors are discussed in more detail below. These etiologic agents, as determined on the basis of demographic and statistical data, are of limited predictive value in any given i ndividual.
UVR exposure
In most cases, the primary risk factor for cSCC is cumulative lifetime sun exposure; that is, cSCC can develop even if the associated sun exposure
occurred decades before. [6] The frequency of SCC is increased at lower latitudes, correlating with an increased intensity of ambient light. The component of sunlight believed to be most important in cutaneous carcinogenesis is UVB (290-320 nm), which is an initiator and a promoter of carcinogenesis. In animal models, UV-induced photocarcinogenesis appears to involve the UVB and UVA-2 spectral ranges. [7] UV-light treatments used for psoriasis (and other recalcitrant dermatoses) also predispose to the development of SCC. Psoralen and UVA (PUVA) therapy is particularly phototoxic, with mutations in both TP53 and the oncogene Ha -Ras being present in a large proportion of patients with PUVA-associated cSCC. [8] In addition to being mutagenic, UVA in conjunction with UVB is a potent suppressor of the cutaneous immune system, which likely contributes to its role in cutaneous carcinogenesis. Fair complexion
Persons with a fair complexion; hazel, blue, or gray eyes; and lightcolored hair (blond or red), as well as those who burn easily when exposed to the sun, are at higher risk for cSCC than are persons with other physical characteristics. Individuals with Fitzpatrick skin types I and II account for most of the patients who develop SCC. Patients with oculocutaneous albinism are also at risk; SCCs account for the most common type of cutaneous malignancy in this group. Such individuals lack natural protection from UV-induced carcinogenesis, owing to reduced levels of the photoprotective pigment, melanin. [9] DNA repair failure
Healthy human skin is constantly repairing UV-induced damage through DNA repair mechanisms. Patients with xeroderma pigmentosum have a deficiency in an enzyme essential for normal DNA repair and are thus prone to the development of innumerable SCCs and, less commonly, other cutaneous tumors. [10] Immunosuppression
The specific mechanisms by which immunosuppression leads to SCC development are poorly understood, but diminished immunosurveillance is thought to be critical. CD8 + T cells specific for the tumor suppressor gene TP53 have been observed in patients with SCC, suggesting that a functional immune system may target keratinocytes expressing mutated TP53. [11] Suppression of the immune system would presumably abrogate this response, possibly facilitating the development of SCC. Iatrogenic immunosuppression
For organ transplant recipients on long-term immunosuppressive treatment, skin cancers account for 90% of all diagnosed malignancies. [12] In this group of patients, cSCC is more common than other keratinocyte-derived neoplasms, including BCC. The use of immunosuppressive medications to prevent rejection in organ transplant recipients is associated with a 65- to 250-fold increased risk of developing SCC compared with the general population. [13] Additionally, organ transplant recipients have a high risk of developing further SCCs, with 66% developing a second SCC within 5 years of their first SCC diagnosis. [14] The degree of risk correlates with the intensity of immunosuppression (ie, number and/or dosage of medications) typically required to prevent rejection in this patient population. For example, heart transplant recipients have 3 times the risk of SCC compared with kidney transplant recipients. However, while the proportion of recipients developing new tumors is greater with heart transplants than with kidney transplants, the mean number of tumors per patient is higher in kidney transplant recipients. This may be due to a longer duration of immunosuppression in kidney transplant patients, who tend to be younger than patients who undergo heart transplantation. [14] The primary risk factor in organ transplant patients is cumulative lifetime UV exposure in combination with having Fitzpatrick skin type I or II. The risk of SCC also increases with the number of years post-transplantation, presumably because of the cumulative effects of prolonged immunosuppressive therapy. Not only is SCC a more frequent occurrence in organ transplant recipients, the tumors can be very aggressive clinically. In a study of cardiothoracic transplant recipients (heart or heart-lung transplants), 4% of patients developed aggressive cSCC within 10 years of transplantation. [15] The majority (15 of 18) of the lesions were poorly differentiated, and two thirds of the patients with aggressive lesions had distant-organ metastases or died of their disease. Pretransplantation end-organ disease may also impact the development of post-transplant SCC. For example, among renal transplant recipients, the highest prevalence of skin cancer was observed in patients with polycystic kidney disease, whereas the lowest incidence was seen in those with diabetic nephropathy. Similarly, cholestatic liver disease was associated with a greater post-transplantation risk of skin cancer compared with other causes of liver failure. Noniatrogenic immunosuppression
Patients with HIV-associated immunosuppression have a more modestly elevated risk of developing a nonmelanoma skin cancer (3-5 times that of the general population). However, they do not have the altered SCC-toBCC ratio typical of transplant recipients. [16] Defects in cell-mediated immunity related to lymphoproliferative disorders (eg, chronic lymphocytic leukemia) predispose to the development of aggressive SCC. Chronic inflammation or irritation
The Marjolin ulcer variant of SCC may develop in patients with a chronic scarring condition such as dystrophic epidermolysis bullosa. In fact, the leading cause of death in patients with dystrophic epidermolysis bullosa is metastatic cSCC, [17] with an 80% mortality rate within 5 years of diagnosis of the carcinoma [18] and with two thirds of patients dying from metastatic disease. [19] Although the term Marjolin ulcer most frequently refers to an SCC that arises from chronically scarred or inflamed skin, malignant transformation to a BCC, melanoma, or sarcoma may also occur. [20] In recent years, evidence suggests that patients with junctional epidermolysis bullosa may also be at increased risk for developing SCC. [21] The underlying pathogenesis of such lesions is not understood, but mutations in the TP53 and P16 tumor suppressor genes have been described in dystrophic epidermolysis bullosa –associated SCC. Epidemiology Skin cancers are the most frequently diagnosed cancers in the United States. Determining the number of cSCCs is difficult, however, because reporting of these cases to cancer registries is not required. One report estimated that in 2006, 3.5 million cases of nonmelanoma skin cancers (ie, BCCs and SCCs) were diagnosed. In comparison, the American Cancer Society estimated that almost 1.7 million cases of most other cancers would be diagnosed in 2013. [23] Of nonmelanoma skin cancers, approximately 80% are basal cell carcinoma (BCC) and 20% are squamous cell carcinoma (SCC). Thus, cSCC is the second most common skin cancer and one of the most common cancers overall in the United States. Eyelid SCC, while not nearly as common as BCC of the eyelids, is the second or third most common eyelid malignancy, accounting for approximately 5% of all eyelid neoplasms. [24]
Rising incidence
Despite increased knowledge and public education regarding the causes of skin cancer and modes of prevention, the incidence of cSCC continues to rise worldwide. In Rochester, Minnesota, the annual age-adjusted incidence rates for SCC per 100,000 women rose from 47 cases from 1984-1986 to 100 cases from 1990-1992; the corresponding rates for men increased from 126 cases to 191 cases per 100,000 population. [25] This increasing incidence is likely multifactorial; speculated causes include an aging population, improved detection, increased use of tanning beds, and environmental factors, such as depletion of the ozone layer. Additionally, the number of patients on immunosuppressive therapy, used in solid organ transplantation and various rheumatologic and dermatologic conditions, is increasing. As noted previously, solid organ transplant recipients have a markedly elevated risk of SCC formation. Metastasis may also be more common in this group. [26] Geography-related demographics
The incidence of cSCC varies geographically, from 0.03-3.5 cases per 100,000 people per year. Patients who live close to the equator tend to present at a younger age than do patients who live more distant from it. The highest incidence of cSCC occurs in Australia, where nonmelanoma skin cancer incidences as high as 1.17 per 100, a rate 5 times greater than all other cancers combined, have been reported. [27] The high incidence is likely due to the large numbers of light-skinned people in this region who have had extensive sun exposure. [28] Race-related demographics
SCC is the second leading cause of skin cancer in white individuals. Persons of Irish or Scottish ancestry have the highest prevalence in the United States. SCC is relatively rare in people of African or Asian descent, although it is the most common form of skin cancer in these groups. SCC in black persons carries a higher mortality rate, perhaps due to delayed diagnosis, because tumors are more likely to occur in sunprotected areas, including the scalp and sites of previous injury and scarring. [29] Sex- and age-related demographics
SCC occurs in men 2-3 times more frequently than it does in women, most likely as a result of higher cumulative lifetime UV exposure in men. This increased exposure may be due to greater participation by men in
occupations that entail more significant exposure to sunlight or to other occupational hazards, such as soot, oils, or tars. The typical age at presentation for SCC is approximately 70 years. This varies widely, however, and in certain high-risk groups (eg, organ transplant recipients, patients with epidermolysis bullosa), SCC often manifests at a much younger age. In addition, a population-based study from Olmsted County, Minnesota of patients younger than 40 years with nonmelanoma skin cancer diagnosed between 1976 and 2003 demonstrated a significant increase in the incidence of SCC over the study period. [30] Prognosis Although cSCC is not often fatal, it can cause significant morbidity. Most cSCCs are located in the head and neck region, where surgery for advanced-stage disease can be disfiguring. Furthermore, the cost of treatment has been shown to pose a significant public health burden. In a study of the Medicare population, the treatment of nonmelanoma skin cancers ranked fifth among the most expensive cancers to treat. [31] Like many cancers, cSCC is classified according to the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) "tumor, node, metastasis" (TNM) staging system. [32] This anatomy-based staging system is designed to stratify patients into general prognostic cohorts based on the size and extent of disease (see Workup). Although TNM staging is useful for estimating the outcome for a group of patients with cSCC who have similar tumor characteristics, it cannot estimate the risk for an individual patient. Current methods for estimating the outcome of a patient with cSCC depend heavily on the experience of the treating physician and can vary significantly between surgeons. Despite the inherent limitations of TNM staging, the outcomes of patients with cSCC follow a predictable pattern. Most patients present with early stage tumors, and most of these patients fare well (overall 5 -yr survival rate >90%) when the tumors are adequately treated. Various mortality rates have been reported, with some rates as high as 4-8%. By adhering to a policy of complete excision of all lesions, the recurrence rate should be 10% or less. The outcome of patients with advanced-stage cSCC is considerably worse. For patients with lymph node metastases, the 5-year survival is even lower, estimated at 25-45%. Most large series in the literature have reported the risk of nodal or distant metastasis for primary tumors to be 26%.
High-risk SCC
A subset of SCCs carries an elevated risk of local recurrence, nodal or distant metastasis (usually to the lungs), and death. Tumors in this subset are termed high-risk SCCs. However, prognostic models do not exist for high-risk SCC. Because many of the risk factors discussed below occur concurrently in single tumors (intrinsic risk factors) and patients (extrinsic risk factors), determining which risk factors have the greatest prognostic significance is difficult. In the absence of prognostic models that take the presence of multiple risk factors into account, estimating risk for individual patients is based on very limited data and gestalt. Due to the lack of data, evidence-based decision making is often not possible. Consequently, current management of high-risk SCC varies widely. [33] In one case series, the 3-year disease-specific survival rate for SCC was estimated to be 85%. Survival rates approached 100% for lesions with no high-risk factors, but the disease-specific death rate was 30% for patients with at least 1 risk factor. [34] These estimates may not be reflective of the risk for SCC cases in general, possibly overestimating it, but the data highlight that a subset of SCC patients do poorly. When SCC does metastasize, metastasis usually occurs within 5 years after the time of diagnosis and involves the primary (ie, first-echelon) draining lymph nodes. Once nodal metastasis of cSCC has occurred, the overall 5-year survival rate is low. Patients with a compromised immune system, those with metastasis to multiple lymph nodes, and those with cervical lymph nodes larger than 3 cm in diameter have an extremely poor prognosis. Nevertheless, data from one study showed that the combined use of surgery and adjuvant radiotherapy for patients with nodal metastasis increased the 5-year disease-specific survival rate to 73%. [35] Metastasis to distant organs (eg, lung metastasis) remains incurable. Thus, close surveillance and early detection of nodal metastasis can be life-saving and is of paramount importance. SCC can be characterized as high-risk by virtue of tumor-related factors (intrinsic factors), patient-related factors (extrinsic factors), or a combination of both. Intrinsic factors in high-risk SCC
Tumor-related factors in aggressive SCC include the following [36, 34] : Tumor location (ie, lips, ears, anogenital region, within a scar or chronic wound) Tumor size greater than 2 cm (or 1.5 cm on ear or lip)
Invasion to subcutaneous fat (or deeper) Poorly differentiated tumor cells Recurrent tumor Perineural involvement (except, perhaps, for tumors with smallcaliber nerve invasion and no other risk factors [37] ) Detailed information on tumor-related factors such as location, diameter, depth, cellular differentiation, recurrence, and perineural invasion are reviewed below. Location Foremost among the factors influencing metastatic risk are the size and location of the tumor and, to a lesser extent, the growth rate. Rapidly growing lesions on the eyelid or ear metastasize in up to one third of cases. Unlike BCC of the eyelid, SCC of the eyelid can be an aggressive tumor that has potential to invade the orbit, metastasize to lymph nodes and distant sites, and cause death. [38, 39, 40, 41, 42] Thick cSCCs (>4-5 mm) located near a parotid gland pose a high risk. [43] Rates of metastasis are particularly high for the ear (11%) and lip (13.7%), and the 5-year survival rate after metastasis from these primary sites ranges from 25% to 40% (see the image below). [36] Other cutaneous sites, as follow, are also associated with a higher risk of metastasis: Scalp Forehead Temple Eyelid Nose Hands (dorsal surface) Penis Scrotum
Large, neglected cutaneous squamous cell carcinoma of the right ear that requires wide local excision via auriculectomy and reconstruction. The risk of lymph node metastasis with this deeply ulcerative tumor is high enough to warrant elective neck dissection.
In one series, primary SCCs on the trunk and limbs were associated with a metastatic rate of 4.9%, but the study may have been biased toward larger lesions. SCCs that arise in injured or chronically diseased skin are associated with a risk of metastasis that approaches 40%. Numerous studies have demonstrated that the Marjolin ulcer subtype of SCC behaves aggressively, with metastasis rates of up to
35% [44] ; older studies found a mortality rate of 33%. [45] Marjolin ulcer most frequently refers to an SCC that arises from chronically scarred or inflamed skin; however, malignant transformation to a BCC, melanoma, or sarcoma may also occur. [20] The poor prognosis is likely related to delayed diagnosis. Diameter and thickness Lesions of invasive SCC measuring smaller than 2 cm in diameter have been associated with a 9.1% rate of metastasis, whereas those larger than 2 cm in diameter have a metastatic rate of up to 30.3%. A prospective study reported a 3year, disease-specific survival rate of 67% for lesions larger than 4 cm, compared with 93% for tumors smaller than 4 cm. [34] A 2008 prospective cohort study found a rate of metastasis of 4% for tumors with a thickness of 2-6 mm. [46] For tumors thicker than 6 mm, the risk increased to 16%. Depth With increasing depth of invasion of the primary SCC tumor, the risk of local recurrence and nodal metastasis increases and the rate of survival decreases. Lesions with a depth of less than 2 mm rarely metastasize; those with a depth of invasion of 2-4 mm have a historical recurrence rate of 5.3% and a metastasis rate of 6.7%. The association of tumor depth with survival rate has been reported as follows:
Less than 2 mm: 95% survival rate From 2-9 mm: 80% survival rate Larger than 9 mm: 65% survival rate
Cellular differentiation More poorly differentiated tumors have a worse prognosis in SCC, with reported recurrence rates of 33-54%. [36] The actual value of histologic grading alone, however, is less clear, because poorly differentiated tumors that metastasize or recur usually have additional primary risk factors (eg, large diameter, deep invasion). Nonetheless, poorly differentiated lesions are generally considered to behave more aggressively. Tumor recurrence Recurrence risk is increased with high-risk tumors; lesions larger than 2 cm recur at a rate of 15.7% after excision. Poorly differentiated lesions recur at a rate of 25% after excision, as opposed to well-differentiated lesions, which recur at a rate of 11.8%. Local recurrence rates following extirpation of a recurrent SCC range from 10% to 23%. Reported rates of metastasis are as high as 25-45%, but these figures may overestimate the risk in recurrences that are caught early. Perineural invasion Perineural invasion has been estimated to occur in up to 7% of persons with cutaneous SCC. The prognosis in such cases is worse, with historical rates of metastasis reported to be as high as 47%. Much lower rates of metastasis (8%) have been reported using Mohs micrographic surgery. [36] The degree of nerve involvement likely has a large impact on prognosis. Involvement of major (ie, named) nerve branches carries a very high risk of recurrence, metastasis, and death. The risks are substantially decreased when tumor-free margins are painstakingly obtained by removal of the involved nerve. However, the prognosis is still guarded.
One study showed the diameter of involved nerves to significantly impact outcomes in cSCC. No disease-specific deaths occurred in patients with involvement of nerves that were less than 0.1 mm in diameter, compared with 32% of patients dying from cSCC when nerves of 0.1 mm or larger were involved. [47] Extrinsic factors in high-risk SCC
General patient-related factors are as follows (see Etiology):
Organ transplantation Hematologic malignancy (eg, chronic lymphocytic leukemia) Long-term immunosuppressive therapy HIV infection or acquired immunodeficiency syndrome (AIDS)
A study by Manyam et al that included 38 immunocompetent individuals with cSCC and 21 immunosuppressed patients with the disease found immunosuppression to be more frequently associated with poorly differentiated tumors, lymphovascular invasion, and extracapsular extension. [48] SCC arising in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma also carries a worse prognosis. For example, one study found that in patients with chronic lymphocytic leukemia, the SCC recurrence rate in those treated with Mohs micrographic surgery was 7-fold higher at 5 years than it was in patients without the leukemia. [49] Another study found that in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma, SCCs are often multiple (67%) and high grade (56%) and have a high risk of recurrence and metastasis (25%), as well as death from disease (41%). [50] The risk of aggressive SCC in patients with bullous disease is markedly elevated. The risk of death is particularly high in those with epidermolysis bullosa, with an 80% mortality rate 5 years after diagnosis of the first primary SCC. Arsenic exposure [51] and PUVA light exposure are additional risk factors associated with aggressive disease.
Patient Education Patients should be counseled to avoid excessive UV radiation by limiting outdoor activity to early morning and late afternoon, using protective clothing, and wearing a broad-brimmed hat to shade the head and neck. Daily application of a broad-spectrum sunscreen with a sun protection factor (SPF) of at least 15 should also be encouraged. The use of artificial tanning devices should be strongly discouraged, because this has been associated with a 2.5-fold increase in the risk of developing SCC. Lesions can recur even years after excision, so patients should have routine examinations. In addition, patients should be counseled regarding treatment of areas of chronic skin inflammation or trauma to prevent the future development of SCC at those sites. Educating people who live in tropical areas and in regions with a high degree of solar exposure is particularly important.
These measures are also critically important for patients who are immunosuppressed, and they should be an integral part of the educational program for patients who have recently undergone organ transplantation. For patient education information, see the Cancer Center , as well as Skin Cancer and Skin Biopsy. For information on cancer risk, prevention, and screening in organ transplant patients, see the AT-RISC Alliance and the International Transplant Skin Cancer Collaborative. For more information about Mohs micrographic surgery, see the American College of Mohs Surgery.
2.
PRESENTATION
History The initial presentation of cutaneous squamous cell carcinoma (cSCC) typically includes a history of a nonhealing ulcer or abnormal growth in a sun-exposed area (see the image below). The clinical assessment should begin with a thorough review of the risk factors for cSCC development. An assessment of the rate of tumor growth is also important, as this often reflects the aggressiveness of the lesion. The clinician should ask about features that suggest peripheral nerve involvement by the tumor, such as local pain, numbness, twitching or muscle weakness, and, with cSCCs of the face, visual changes.
Physical Examination Approximately 70% of all cSCCs occur on the head and neck, most frequently involving the lower lip, external ear and periauricular region, or forehead and scalp. Consequently, the head and neck should be of particular interest in a comprehensive examination of a patient with suspected cSCC. The following features of the lesion should be noted (see also the images below): Location (eg, eyelid SCC is more common on the lower eyelid) Size Character (eg, smooth/nodular, vascularity, color): SCC may appear as plaques or nodules with variable degrees of scale, crust, or ulceration Presence of ulceration
A 35-year-old man with human immunodeficiency virus (HIV) infection presented with a 2-year history of a slowly enlarging, left lower eyelid lesion; incisional biopsy revealed squamous cell carcinoma.
Frequently, the presentation of cSCC is preceded by the presence of actinic keratoses. [52] These precancerous lesions appear as scaly plaques or papules, often with an erythematous base. An actinic keratosis is usually only several millimeters in size and ranges from normal skin color to pink or brown. Patients with multiple actinic keratoses have an estimated 6-10% lifetime risk of developing skin cancer. The overall appearance of any skin lesion must be detailed. The classic presentation of a cSCC is that of a shallow ulcer with heaped-up edges, often covered by a plaque. Of course, the presenting appearance of each cSCC varies according to the site and extent of disease. Tumor size and location
In addition to general appearance, the size and location of the lesion should be recorded, as both have prognostic and therapeutic importance. For instance, lesions larger than 2 cm and those located on the external ear or lip have been shown to have a higher rate of metastatic spread. Additionally, tumor size and location affect the cosmetic and functional outcome of surgical excision. Therefore, reconstructive options should be carefully considered in the assessment of every head and neck cSCC. Lesions located near critical areas, such as around the eyes, may require additional evaluation by a dedicated reconstructive surgeon before excision. Tumor characteristics
Surface changes on a typical SCC may include scaling, ulceration, crusting, or the presence of a cutaneous horn. Less commonly, the lesion may manifest as a pink cutaneous nodule without overlying surface changes. The absence of surface changes should raise suspicion of a metastatic focus from another skin or nonskin primary site or of a different and potentially more lethal tumor, such as a Merkel cell carcinoma. A background of severely sun-damaged
skin, including solar elastosis, mottled dyspigmentation, telangiectasia, and multiple actinic keratoses, is often noted. Clinically, lesions of SCC in situ (SCCIS) range from a scaly, pink patch to a thin keratotic papule or plaque similar to an actinic keratosis. Bowen disease is a subtype of SCCIS characterized by a sharply demarcated, pink plaque arising on non –sun-exposed skin (see the image below). SCC of the lip usually arises on the vermillion border of the lower lip. It is sometimes predated by a precursor lesion, actinic cheilitis, which manifests as xerosis, fissuring, atrophy, and dyspigmentation. Actinic cheilitis is analogous to actinic keratosis of the skin. Perineural invasion
Up to 14% of cSCCs exhibit perineural invasion. Evidence of cranial nerve dysfunction on examination should raise concern of significant perineural invasion. The most frequently involved cranial nerves are the facial and trigeminal nerves, [53] underscoring the importance of assessment of facial movement and sensation. Therefore, every patient with head and neck cSCC should undergo systematic evaluation of cranial nerve function. Tumor metastasis
Investigate regional spread of head and neck cSCC by palpating for enlarged preauricular, submandibular, and cervical lymph nodes. Regional metastasis occurs in 2-6% of cases of cSCC. The risk of metastasis correlates roughly with tumor size and differentiation. In general, metastasis from cSCC of the forehead, temples, eyelids, cheeks, and ears is to the parotid nodes; metastasis from cSCC of the lips and perioral region is primarily to the submental and submaxillary (upper cervical) nodes. Rarely, cSCC presents as a parotid or neck mass because of lymphatic spread from an occult cutaneous lesion or remotely treated skin cancer (see the image below). [54] The median time from initial treatment to presentation with a parotid or neck mass ranges from 10 to 13 months. Fine-needle aspiration biopsy can be of assistance in the evaluation of any mass suspected to represent occult metastasis.
Preauricular and helical scars (black arrows) from prior excisions are noted in a patient who presented with cervical metastases (white arrow) from an occult cutaneous squamous cell carcinoma.
Conjunctival squamous cell carcinoma
Most SCCs involving the conjunctiva manifest as chronic, unilateral, localized patches of redness or more diffuse conjunctivitis (see the image below). They can also present as a mass in the interpalpebral fissure at the nasal or temporal limbus with a gelatinous and velvety, papilliform, or leukoplakic appearance. Prominent
feeder vessels may be seen. The corneoscleral limbus is the most common location, although the palpebral conjunctiva or cornea may be involved, particularly in the interpalpebral region.
Extensive conjunctival squamous cell carcinoma of the left eye. The patient had limbal and corneal involvement temporally, as well as scleral invasion with intraocular spread. A malignant cellular reaction in the anterior chamber was present. The patient was treated with a lid-sparing exenteration.
Individuals with HIV infection and those with xeroderma pigmentosa are more likely to develop conjunctival SCC, probably because of their diminished immune status. Often, small conjunctival masses are noted on routine eye examinations. Distinguishing conjunctival SCC from conjunctival intraepithelial neoplasia is difficult on clinical examination alone. [55] Conjunctival SCC represents a type of conjunctival intraepithelial neoplasia that has either broken through the basement membrane to involve the subepithelial tissue or has metastasized. [56,57, 58] Given its variable appearance, conjunctival SCC may pose a diagnostic challenge as a masquerade syndrome. Patients with an atypical pterygium may have a conjunctival tumor and should be observed much more closely than patients with a classic pterygium. Unsuspected ocular surface neoplasia may be present within excised pterygia. For this reason, one study recommends the submission of all excised pterygia for histopathologic analysis. [59]
The examination of conjunctival SCC should determine the full extent of the lesion; rose Bengal dye is helpful for this evaluation. In addition, assess any suspicion of intraocular involvement via slit lamp examination, gonioscopy, and echography. Orbital involvement should be investigated with computed tomography (CT) scanning or magnetic resonance imaging (MRI). 3.
DDx
Diagnostic Considerations Although the typical patient with cutaneous squamous cell carcinoma (cSCC) is of northern European descent and presents with a family history of skin cancer, a personal history of previous skin cancer, and/or an extensive history of sun exposure, a detailed history and physical examination is crucial (see Presentation). In addition, the clinician should be aware of the risk factors for high-risk disease (see Prognosis). Marjolin ulcer appears as a new area of induration, elevation, or ulceration, at the site of a preexisting scar or ulcer. The diagnosis of Marjolin ulcer should be considered in any ulcer that fails to heal with standard therapy. Pseudoepitheliomatous hyperplasia (PEH) is a histologic finding in keratoacanthoma and SCC, as well as in certain other reactions, such as tattoo reactions. The clinician must determine whether the PEH is associated with cancer. In addition, with lesions containing PEH in patients with a history of lupus, the clinician must differentiate between lesions that are definitely SCC and lesions of hypertrophic lupus that are mimicking SCC or keratoacanthoma. Other conditions to be considered The following conditions should also be considered when evaluating a patient with suspected SCC:
Cancerous lesions: Sebaceous cell carcinoma and rhabdomyosarcoma Congenital tumors: Dermoids, dermolipomas, and episcleral osseous choristoma Conjunctival degeneration: Pinguecula and amyloidosis Hereditary lesions: Benign hereditary intraepithelial dyskeratosis Lymphoid tumors: Lymphoid neoplasia, benign reactive lymphoid hyperplasia, and leukemic infiltrates Neuroectodermal tumors: Nevus, primary acquired melanosis, and melanoma Papillomas: Human papillomavirus (HPV) ̶ induced papillomas Pseudocancerous lesions: Pseudoepitheliomatous hyperplasia and keratoacanthoma Vascular lesions: Angioma, lymphangioma, Kaposi sarcoma, and pyogenic granuloma Xanthomatous lesions: Juvenile xanthogranuloma and fibrous xanthoma
Differential Diagnoses
Actinic Keratosis Allergic Contact Dermatitis Atopic Dermatitis Atypical Fibroxanthoma Basal Cell Carcinoma Benign Skin Lesions Bowenoid Papulosis
Chemical Burns Limbal Dermoid Pyoderma Gangrenosum
4.
WORKUP
Approach Considerations A biopsy should be performed for any lesion suspected of being a cutaneous neoplasm. For most lesions, the biopsy can be readily accomplished in the clinic, under local anesthesia. The type of biopsy used depends on the size of the lesion. In advanced-stage cSCC, CT scanning or MRI can be helpful in defining the extent of disease. CT scanning is useful for determining the presence of bone or soft tissue invasion and for evaluating cervical lymph nodes at risk for metastasis. For evaluation of perineural invasion and orbital or intracranial extension, MRI is the preferred imaging modality (see the images below).
Contrast-enhanced, axial computed tomography (CT) scan of a patient with soft tissue invasion of the right parotid gland (arrow) by an ulcerative cutaneous squamous cell carcinoma.
Axial magnetic resonance image (MRI) of a large squamous cell carcinoma of the left lower eyelid with invasion of the anterior orbit.
Biopsy Small skin lesions in noncritical areas may be amenable to excisional biopsy, in which the entire area of concern is removed. This method has the benefit of being diagnostic as well as potentially therapeutic, without the need for a second procedure. For larger lesions or those located in cosmetic or functionally critical areas, confirming the diagnosis is often preferable before embarking on surgical excision that may be extensive and require reconstruction. In these cases, an incisional or punch biopsy should be performed initially, with further treatment based on the pathology results. Whichever biopsy method is chosen, the following principles should be observed: The biopsy should contain the full thickness of the skin in order to evaluate the depth of the lesion; therefore, a shave biopsy is generally not recommended when malignancy is suspected
The biopsy should be centered over the transition point between normal and involved skin, thereby providing a reference for comparison by the pathologist When possible, incisions should be made parallel to the natural lines of skin tension (Langer lines) for optimal cosmetic outcome For punch biopsies, stretching the skin perpendicular to the Langer lines creates an ellipse oriented in this optimal direction and facilitates closure Rarely, cutaneous squamous cell carcinoma (cSCC) presents as a parotid or neck mass, because of lymphatic spread from an occult cutaneous lesion or remotely treated skin cancer (see the image below). The median time from initial treatment to presentation with a parotid or neck mass ranges from 10 to 13 months. Fine-needle aspiration biopsy can be of assistance in the evaluation of any mass suspected to represent occult metastasis.
Staging TNM staging system
Like many cancers, cSCC is classified according to the American Joint Committee on Cancer (AJCC)/International Union against Cancer (UICC) tumor-node-metastasis (TNM) staging system. This anatomy-based staging system is designed to stratify patients into general prognostic cohorts based on the size and extent of disease. The TNM staging system for nonmelanoma skin cancers, including cSCC, is as follows (see also Table 1, below) [32] : Primary tumor (T) TX: Primary tumor cannot be assessed T0: No evidence of primary tumor Tis: Carcinoma in situ T1: Tumor 2 cm or less that has fewer than 2 high-risk features T2: Tumor larger than 2 cm or tumor of any size with 2 or more highrisk features T3: Tumor with invasion of maxilla, mandible, orbit, or temporal bone T4: Tumor with invasion of axial or appendicular skeleton or perineural invasion of the skull base High-risk features include the following: Thickness >2 mm Clark level 4 or higher Perineural invasion Ear as primary site
Hair-bearing lip as primary site Poorly differentiated histology Regional lymph nodes (N) NX: Regional lymph nodes cannot be assessed N0: No regional lymph node metastasis N1: Single ipsilateral lymph node metastases ≤3 cm in greatest dimension N2a: Metastasis in a single ipsilateral lymph node and >3 cm, but ≤6 cm in greatest dimension N2b: Metastasis in multiple ipsilateral lymph nodes and ≤6 cm in greatest dimension N2c: Metastasis in bilateral or contralateral lymph nodes and ≤6 cm in greatest dimension N3: Metastasis in a lymph node and >6 cm in greatest dimension Distant metastasis (M) MX: Distant metastasis cannot be assessed M0: No distant metastasis M1: Distant metastasis
Table 1. Stage Grouping
N1S3 staging system
In early 2010, Milross et al proposed an alternative nodal staging system for metastatic cSCC of the head and neck. This system, called N1S3, stages cSCC on the basis of the number (single or multiple) and size (smaller or larger than 3 cm) of lymph nodes involved, as well as incorporating the parotid as one of the regional levels. [60] The stages of N1S3 are as follows:
Stage I - A single lymph node measuring 3 cm or less Stage II - A single lymph node greater than 3 cm, or multiple lymph nodes measuring 3 cm or less Stage III - Multiple lymph nodes greater than 3 cm
The N1S3 system was found to have a significant predictive capacity for locoregional control, disease-specific survival, and overall survival in a group of
215 patients. Testing in a different cohort of 250 patients provided validation of its predictive capacity. [60]
5.
TREATMENT
Approach Considerations Low-risk cutaneous squamous cell carcinoma (cSCC) on the trunk and extremities can be treated with electrodessication and curettage (ED&C). For invasive cSCC, surgical excision and Mohs micrographic surgery are the primary treatment options; with appropriate patient selection, these techniques have comparable cure rates. Radiation therapy is typically used as an adjuvant to surgery, to provide improved locoregional control, but it may be used as primary therapy in patients who are unable to undergo surgical excision. Chemotherapy may be considered as adjuvant therapy in select highestrisk cases of cSCC. In particular, emerging evidence suggests that epidermal growth factor receptor (EGFR) inhibitors may be useful adjuncts to surgical treatment. Systemic chemotherapy may be considered for metastatic cSCC. Prevention is an important aspect of managing cSCC. Given the central role that ultraviolet radiation (UVR) plays in the pathogenesis of cSCC, methods aimed at decreasing UVR exposure form the cornerstone of cSCC prevention. Several effective treatment modalities exist for precancerous skin lesions, including carcinoma in situ and actinic keratosis. Most of these treatments are easily performed in an outpatient setting. Electrodessication and Curettage ED&C is a simple technique that can be used to treat localized, superficial cSCC. This procedure destroys the tumor and a surrounding margin of clinically unaffected tissue via cauterization and scraping of the area with a curette. The process is repeated several times to maximize the probability of complete tumor extirpation. The technique is based on the delineation of tumor margins with a curette, because tumor tissue is generally more friable than the surrounding normal tissue. ED&C is known to be very technique dependent, and cure rates improve with a practitioner's experience. The thick scars that often occur after ED&C can delay the diagnosis of cancer recurrence. Consequently, ED&C should be used with caution in
invasive cSCC. The procedure is not appropriate for certain anatomic locations (ie, eyelids, genitalia, lips, ears). The main disadvantage of ED&C is that no specimen is available for margin evaluation, and most dermatologic surgeons believe the actual long-term cure rate for invasive SCC is much lower than that quoted in the literature. Nevertheless, the 5-year cure rates for small primary cSCC may be as high as 96%. Cure rates for high-risk tumors are much lower, although no well-controlled, prospective studies have been performed. Tumor recurrence may result from failure of ED&C treatment to eradicate atypical cells residing deep in the hair follicles or in the dermis. Nonetheless, the procedure is fast, minimally invasive, well tolerated, and effective for properly selected lesions. Surgical Excision Standard excision with conventional permanent (ie, paraffin-embedded) tissue sections is a highly effective and well-tolerated therapy for primary cSCCs that lack high-risk features and are located in areas where tissue sparing is not critical. Surgical excision offers the advantages of histologic verification of tumor margins, rapid healing, and improved cosmesis. Cure rates following simple excision of well-defined T1 lesions may be as high as 95-99%. The generally accepted 5-year cure rate for pr imary tumors treated with standard excision is 92%; this rate drops to 77% for recurrent cSCC. A 4-mm margin of healthy tissue is recommended for lower-risk lesions. [61] In this category are well-differentiated tumors smaller than 2 cm in diameter that do not occur on the scalp, ears, eyelids, lips, or nose and do not involve subcutaneous fat. Therefore, simple excision is most valuable in the treatment of small primary SCCs on the trunk, extremities, or neck, where tissue sparing is less essential. [61] Recurrence rates after the excision of low-risk lesions range from 5% to 8%. A 6-mm margin of healthy tissue is recommended for lesions that are larger than 2 cm, invasive to fat, or in high-risk locations (ie, central face, ears, scalp, genitalia, hands, feet). Given the cosmetic and functional impact of these wider margins, tumors in this latter category are often removed via Mohs surgery to achieve high cure rates while sparing normal tissue. The depth of an excision should always include a portion of the subcutaneous fat. No large randomized studies have addressed the issue of appropriate margin size in cSCC, as has been done for melanoma. The recommendations for margin size should be taken only as rough guidelines, with the understanding that large, aggressive lesions
frequently have substantial extension beyond the apparent superficial boundary. Therefore, a surgeon’s experience and judgment in planning surgical margins is paramount to the successful treatment of cSCC. Complications of excision include hematoma, seroma, infection, and wound dehiscence. Furthermore, histologic margins can be reported as negative when they are, in fact, positive (false negative), because the traditional bread-loaf method of tissue sectioning typically results in evaluation of less than 1% of the specimen’s margins. For this reason, cure rates for cSCC following excision do not significantly differ from cure rates following ED&C and may even be somewhat lower. For patients at risk for metastatic spread to lymph nodes, the standard treatment is surgical excision of the primary lesion along with the involved lymph node basins. Skin cancers located in the periauricular region, frontotemporal scalp, and mid-face often drain via lymph nodes in the parotid gland. Consequently, the parotid is the most frequently involved site of metastatic spread. In cases that involve parotid involvement, a parotidectomy with or without a simultaneous neck dissection is the procedure of choice. Mohs micrographic surgery Mohs micrographic surgery is a specialized technique for removing many forms of skin cancer, including cSCC. Because of its numerous advantages, Mohs micrographic surgery is the procedure of choice in the following situations: SCC in which tissue preservation is needed Ill-defined SCC Recurrent tumors High-risk SCC Mohs surgery, which was developed by Frederic E. Mohs in the 1930s, is a method of tumor excision in which the surgeon first excises the visible tumor with a small margin of normal tissue. Horizontal frozen sections are then prepared, and the entire margin is evaluated under the microscope. Areas that demonstrate residual microscopic tumor involvement are reexcised, and the margins are reexamined. This cycle is completed until no further tumor is visualized. [62] The main advantage of this procedure over simple excision is the ability to histologically examine nearly 100% of the surgical margins (as compared with < 1% of the margin visualized via standard histologic sectioning) and to carefully map residual foci of invasive carcinoma, making incomplete excision much less likely than with standard pathologic processing.
In addition, the excised specimens are managed in a way that maintains orientation relative to the operative site. Consequently, Mohs surgery offers tissue sparing, which facilitates small, minimally disfiguring reconstructions of the resulting defects. Thus, it is considered ideal for removing small lesions on the face. However, Mohs surgery is time consuming and highly dependent on technique. Moreover, it is ill suited for large, aggressive, or recurrent cSCC, in which the risk of recurrence or regional metastasis is high. In those cases, en bloc surgical excision is the standard method of treatment. Radiation Therapy Radiation therapy as primary treatment for cSCC is typically reserved for patients who are unable to undergo surgical excision. More frequently, radiation therapy is used as an adjuvant to surgery for improved locoregional control. Postoperative radiotherapy is considered for tumors that exhibit perineural invasion or other high-risk features and for those that involve regional metastasis. [63] No comparative studies of surgery versus surgery plus adjuvant radiotherapy for high-risk SCC have been performed. With no clear evidence of benefit and the potential of significant morbidity, clinical judgment is required in deciding which patients should receive adjuvant radiation. One systematic review suggests that adjuvant radiation be considered in patients with uncertain or positive surgical margins or advanced nerve involvement. [64] Chemotherapy
Adjuvant chemotherapy Adjuvant medication may be considered in select highest-risk cases of cSCC. Options include oral 5-fluorouracil (5-FU) and epidermal growth factor receptor (EGFR) inhibitors. Treatment should be administered through oncology treatment centers. Although survival data are lacking, these medications are generally well tolerated, with few adverse effects. One study found that the use of topical 5-FU 1% is effective as an adjuvant to surgical excision in treating patients with localized ocular surface squamous neoplasia. Although frequent short-term complications were noted, a low rate of local recurrence was found; a full course is usually tolerated, and serious complications in the study were uncommon. [64] Systemic chemotherapy
A variety of different chemotherapeutic agents have been used to treat metastatic cSCC. Although many of these agents have an established role in chemotherapy for mucosal head and neck squamous cell carcinoma, high-quality data is frequently lacking for their use in cSCC. Among the most common nontargeted agents used in cSCC are cisplatin and carboplatin, 5-FU, and taxanes. Cetuximab, a chimeric immunoglobulin G1 monoclonal antibody that inhibits EGFR, has been reported as successful in multiple case reports [65, 66, 67, 68]High-quality studies examining these agents in high-risk cSCC are needed. Treatment of Conjunctival Squamous Cell Carcinoma Excisional biopsy is the treatment of choice for conjunctival SCC. For extremely large lesions, incisional biopsy may be performed. However, strict notation of the biopsy site and minimal handling of the surrounding tissues are imperative to prevent seeding of the tumor. Surgical excision is best performed under the operating microscope. Removal of a cuff of normal conjunctival tissue surrounding the lesion is prudent, and an episclerectomy at the base of the lesion is also advisable if it is adherent to the sclera, in order to remove any superficial cells infiltrating the sclera. Involved corneal tissues may be best removed following treatment with 100% ethanol. The tissues superficial to the Bowman layer are removed easily in a single sheet, which is sent to the laboratory for analysis. Care should be taken not to incise into the Bowman membrane. Cryotherapy is performed, in a double freeze-thaw manner, to the edges of the uninvolved conjunctiva and Tenon capsule. It also can be applied to the involved limbal area. The exposed sclera occasionally is treated with 100% ethanol to devitalize any remaining tumor cells. All excised tissues are submitted for histopathologic analysis. Reconstruction is performed with direct closure, local flaps, or free conjunctival grafts. Extensive lesions with orbital involvement require exenteration. Radiation therapy may be used as adjunctive therapy in cases of extensive lesions with poorly defined margins and as palliative therapy in cases in which the patient cannot tolerate extensive surgery. Conjunctival intraepithelial neoplasia
Topical cytotoxic therapy (ie, 5-FU, mitomycin C [MMC]) has been used to treat conjunctival intraepithelial neoplasia and to debulk large carcinomas before surgical excision. Orbital invasion may be observed despite topical therapy, however, and careful monitoring of patients on these agents is warranted. [69, 70] Despite its significant potential for deleterious effects on limbal stem cells, mitomycin C 0.04% is effective as a neoadjuvant or postoperative agent in the treatment of conjunctival intraepithelial neoplasia and primary acquired melanosis.
Its utility is less well proven for truly invasive tumors, such as melanoma and carcinoma. [71]
Prevention Given the central role that UVR plays in the pathogenesis of cSCC, methods aimed at decreasing UVR exposure form the cornerstone of cSCC prevention. The evidence behind other measures to prevent cSCC is lacking; eg, large, well-controlled studies have failed to show a beneficial role for dietary supplements, including selenium, beta-carotene, retinol, and isotretinoin, in the prevention of skin cancers. [72, 73, 74, 75] Reduction of UV exposure
Reduction of UVR exposure can be accomplished as follows: Avoiding excessive sun exposure Avoiding artificial sources of UV light (eg, tanning beds) Using sunscreen Wearing protective clothing Limiting outdoor activities (especially between 10 am and 4 pm) should be recommended to all patients, particularly fair-skinned, elderly patients. Even young patients should be advised to take precautions against excessive sun exposure, to reduce the risk of developing cutaneous malignancies in future. Sunscreens Patients who are at risk for cSCC but are not able to avoid sun exposure should use sunscreen scrupulously when outdoors. Sunscreen should be reapplied every 30 minutes during acute sun exposure. Several randomized, controlled clinical trials have shown a protective role for the daily application of a broad-spectrum sunscreen in the prevention of new actinic keratoses and new cSCC. [74, 76, 77] The efficacy of UV protection is measured by its sun protection factor (SPF), which is the ratio of the least amount of UVB radiation that will induce erythema on covered skin to the amount of UVB required to generate the same amount of erythema on uncovered skin. It is often described as the amount of additional time a person can spend in the sun with protection versus without protection. For patients at risk for cSCC, the minimum recommended SPF is 30 or higher. All patients should be advised to protect their eyelids from sun exposure. Physical sunblocks with the active ingredients of zinc oxide or titanium oxide provide the most complete protection from UVA and UVB rays. [78] Alternatively, a combination chemical sunblock of octocrylene,
ecamsule, and avobenzone also provides excellent broad-spectrum UV protection. [79] Clothing Clothing is the simplest method of protection; however, it is often inadequate. For example, a cotton T-shirt has an SPF of less than 10, which decreases sharply when the cloth is wet. Hats with a wide brim or extra-long bill may offer additional protection. Clothing with a high SPF rating is available, but these are often expensive and restrictive. Skin cancer screening
Current recommendations from the American Cancer Society for skin screening call for a skin examination every 3 years for persons aged 2039 years and annually after age 40 years. The American Academy of Dermatology recommends annual screening for all patients. However, the US Preventive Services Task Force found insufficient evidence to issue a recommendation either for or against skin examination by a primary care clinician or patient skin self-examination, for the early detection of skin cancer in the adult general population. [80] Treatment of Precancerous Lesions Several effective treatment modalities exist for precancerous skin lesions, including squamous cell carcinoma in situ (SCCIS) and actinic keratosis. Most of these treatments are easily performed in an outpatient setting. Topical application of 5-FU or imiquimod is effective in treating precancerous skin lesions. Similarly, liquid nitrogen cryotherapy or electrocautery and curettage may be used, with cure rates reported at greater than 95%. The risks associated with cryotherapy include transient pain, edema, and blistering. Hypopigmentation and alopecia are also common and may be permanent, so treatment of hair-bearing areas and in darkly pigmented individuals is generally not recommended. [81] Many patients with light skin and a history of extensive sun exposure develop epidermal atypia in the form of actinic keratosis and SCCIS over large areas of their skin. Most of these patients also develop multiple invasive cSCCs. The management of such patients is highly labor intensive and involves the following steps: Surgically remove all tumors that clinically appear to have to have an invasive (dermal) component and confirm clearance of histologic margins Evaluate for underlying immunosuppression, such as from chronic lymphocytic leukemia or from overimpairment of the immune system by immunosuppressive or immunomodulatory therapy; if this last is
suspected, discuss with the patient’s other doctors wheth er the immunosuppression can be safely remedied or lessened Perform field treatment of the areas of epidermal atypia Follow the patient closely for recurrence of actinic keratosis/SCCIS and for new invasive SCCs; field treatment may need to be repeated every 6-12 months to keep precursor actinic keratosis and SCCIS lesions to a minimum Options for field treatment include topical chemotherapy with 5-FU or photodynamic therapy. Imiquimod has limited utility in diffuse disease because adverse effects increase when this agent is applied to large surface areas. If 5-FU therapy is planned, remove any hyperkeratotic lesions with a curette just before beginning therapy, to enhance penetration of the medication to the basal layer.
5-florouracil, capecitabine, and diclofenac sodium
A full course of 5-FU therapy is twice-daily administration for 4 weeks. However, even if the newer, low-concentration 5-FU cream is used (0.5% vs previously available 5% concentration), significant discomfort and irritation are inevitable, and residual erythema at the site of application may persist for months. Patients who cannot tolerate this duration may try shorter courses and then resume treatment after a healing phase. Subsequent treatments become more tolerable as the epidermal damage is corrected. An oral form of a 5-FU prodrug (capecitabine), which is approved by the US Food and Drug Administration (FDA) for other forms of cancer, may be considered in patients with diffuse SCCIS over large skin areas on which topical 5-FU is difficult to apply. However, studies of efficacy have not yet been performed. Topical diclofenac sodium gel has been approved for the treatment of actinic keratoses. Twice-daily applications for 60-90 days may similarly clear actinic damage, with the longer course potentially offset by a lesser degree of cutaneous irritation. Photodynamic therapy
Actinic keratosis can also be treated with photodynamic therapy, which uses light, a photosensitizing drug, and oxygen to induce targeted cell death of neoplastic or abnormal tissue. In this treatment, sensitization of the target tissue is selective and occurs through the topically or systemically administered photosensitizing agent. The resulting photochemical reaction causes inflammation and destruction of the targeted lesion(s) via highly reactive oxygen intermediates and free radicals.
Photodynamic therapy is used primarily to treat large numbers of actinic keratoses in a single session. SCCIS is also amenable to photodynamic therapy, although a wide range of recurrence rates (0-52%) have been reported. The efficacy of topical medications for the treatment of actinic damage is difficult to measure because biopsies are rarely performed before and after treatment (to compare results). Instead, improved skin appearance is used as a gauge for apparent resolution of early SCCIS lesions. For a full discussion of treatment of these lesions, see Actinic Keratosis . Consultations Most cases of cSCC are easily and successfully treated by dermatologists or Mohs surgeons. In certain cases, however, such as the following, a multidisciplinary approach may be needed: Large or deep tumors in which excision and reconstruction under local anesthesia is not feasible Surgical margins that are not clear or are in doubt Nodal or distant metastasis A multidisciplinary approach using Mohs micrographic surgery performed in conjunction with an otolaryngologist, a plastic surgeon, or both may aid in completely removing deeply invasive SCC, preserving a vital structure (eg, the facial nerve), and facilitating the reconstruction of a large operative defect. For example, Mohs micrographic surgery may be used in cases of SCC of the scalp that involve bone, to establish peripheral margins to the level of the galea. This would be followed by resection of the deep margin, including bone, with the patient under general anesthesia, performed by a head and neck or plastic surgeon. A surgical focus on the deep margin and reconstruction often spares the patient hours of anesthesia time, lowering surgical morbidity. Metastatic disease also requires aggressive management by a multidisciplinary team. Surgical treatment of metastatic disorder may require the expertise of an otolaryngologist, a general surgeon, or a surgical oncologist. Adjuvant or palliative radiotherapy may be administered by a radiation oncologist. A medical oncologist should be consulted if systemic chemotherapy is considered for metastatic disease.
Long-Term Monitoring With exposure to risk factors, patients require vigilant follow-up care even after successful treatment, because they continue to be at risk for
development of additional cutaneous skin malignancies (eg, basal cell carcinoma and SCC of the eyelid). The incidence of multiple primaries is 40% in long-term survivors. Therefore, minimization of modifiable risk factors and early detection of new skin cancers are essential to improve prognosis. Low-risk tumors are usually cured with appropriate surgical therapy; however, patients who develop 1 SCC have a 40% risk of developing additional SCCs within the next 2 years. This risk likely becomes even greater as more time elapses. Thus, patients with a history of SCC should be evaluated with a complete skin examination every 6-12 months. Patients with high-risk tumors require skin and lymph node examinations at 3- to 6-month intervals for at least 2 years after diagnosis. In very ̶ highrisk cases, surveillance with CT scanning or MRI may be considered. Recurrent lesions should be treated aggressively. Success in treating recurrences with topical mitomycin C has been reported. In areas of bare sclera, however, pyogenic granulomas occasionally occur soon after tumor excision. These lesions typically respond quickly to topical steroid treatment and must be differentiated from recurrent tumor. 6.
MEDICATION
Medication Summary Nonsurgical management for cutaneous squamous cell carcinoma (SCC) includes the use of systemic and topical chemotherapy. Various topical agents are used to treat patients with a history of extensive sun exposure or actinic keratosis and SCC in situ. The addition of chemotherapy to radiotherapy may also be beneficial in improving survival in squamous cell carcinoma of the head and neck but it is associated with adverse effects. Antineoplastics, Topical Class Summary
Nonsurgical options for the treatment of cSCC include topical chemotherapy and topical immune response modifiers. The use of topical therapy and photodynamic therapies is generally limited to actinic keratoses and in situ lesions. Fluorouracil topical (Efudex, Carac, Fluoroplex)
View full drug information
5-Fluorouracil (5-FU) is a classic antimetabolite anticancer drug with a chemical structure similar to endogenous intermediates or building blocks of DNA or RNA synthesis. This agent inhibits tumor cell growth through at least 3 different mechanisms that ultimately disrupt DNA synthesis or cellular viability. Topical 5-FU is approved for the treatment of multiple actinic or solar keratoses. Antineoplastics, EGFR Inhibitor Class Summary
Multiple chemotherapeutic agents have been used to treat metastatic cSCC. Adaptation of traditional chemotherapeutics to local and regional administration techniques in treating head and neck cancers is being actively pursued to provide higher local concentrations of otherwise systemically toxic drugs. Cetuximab (Erbitux)
View full drug information Cetuximab is approved for the initial treatment of locally or regionally advanced SCC of the head and neck. Cetuximab when used alone is indicated for the treatment of recurrent or metastatic cases for which prior platinum-based therapy has failed. It is a chimeric immunoglobulin G1 monoclonal antibody that inhibits EGFRs and has been reported as successful in several case reports. EGFR inhibitors are well tolerated, with relatively low r isks, so they may be considered in cases not amenable to surgery or radiation or as an adjuvant in cases that pose a high risk of death. Current recommendations are to use cetuximab as an alternative to chemotherapy in patients who cannot tolerate chemotherapy.
Topical Skin Products Class Summary
The use of topical and photodynamic therapies is generally limited to actinic keratoses and in situ lesions. Imiquimod (Aldara, Zyclara)
View full drug information Imiquimod is approved by the FDA for the treatment of genital warts, actinic keratoses, and superficial basal cell carcinoma (BCC). This agent is an imidazoquinoline that enhances cell-mediated immune responses
via the induction of proinflammatory cytokines; that is, it up-regulates interferon and other cytokines. Diclofenac topical (Solaraze)
View full drug information Diclofenac gel is approved by the FDA for the treatment of actinic keratoses. It is applied to lesion areas twice a day for 60-90 days.
Antineoplastics, Alkylating Class Summary
Cisplatin is another chemotherapeutic drug of choice for metastatic cSCC. Although this agent is one of the most successful in the treatment of cancer, it produces major toxicities to normal cells and organs at the concentrations necessary for effective treatment of malignancies. Cisplatin (Platinol, Platinol AQ, CDDP)
View full drug information Cisplatin is a platinum coordination compound that inhibits DNA synthesis, cross-links and denatures strands of DNA, and disrupts DNA function by covalently binding to DNA bases. It can also produce DNA intrastrand cross-linking and breakage. It has been used in the treatment of SCC of the head and neck. Combination chemoradiotherapy using cisplatin and concurrent radiation treatment has improved locoregional control in locally advanced SCC. Chemoradiotherapy is now considered the standard of care in locally advanced disease following surgical resection, as well as in unresectable disease. Cisplatin-based combination chemotherapy with 5-FU, methotrexate, bleomycin, and doxorubicin all have been used to treat advanced SCC, with variable outcomes.
Carboplatin (Paraplatin)
View full drug information Carboplatin is an analogue of cisplatin. This is a heavy-metal coordination complex that exerts its cytotoxic effect by platination of DNA, a mechanism analogous to alkylation, leading to interstrand and intrastrand DNA cross-links and inhibition of DNA replication. Carboplatin binds to protein and other compounds containing the SH group. It has been used in the treatment of advanced and recurrent head and neck SCC.
Antineoplastics, Antimicrotubular Class Summary
Antimicrotubular therapy may be used as part of combination therapy in patients with SCC. Docetaxel (Taxotere)
View full drug information Docetaxel is a semisynthetic taxane, a class of drugs that inhibits cancer cell growth by promoting assembly and blocking the disassembly of microtubules, thereby preventing cancer cell division and causing cell death. It is indicated in combination with cisplatin and 5-FU for induction therapy of locally advanced SCC of the head and neck before patients undergo chemoradiotherapy and surgery.
Paclitaxel
View full drug information Paclitaxel is an antimicrotubule agent. Its mechanism of action includes tubulin polymerization and microtubule stabilization, which, in turn, inhibit mitosis and may result in breakage of chromosomes. It is used off-label in SCC of the head and neck.
Antineoplastics, Antimetabolite Class Summary
Antimetabolite therapy may be used as part of combination therapy in patients with SCC. Methotrexate (Trexall)
View full drug information Methotrexate is an antimetabolite that inhibits dihydrofolate reductase, thereby hindering DNA synthesis and cell reproduction in malignant cells. It has been used in combination with other chemotherapeutic agents for the treatment of cancers of the head and neck.
Antineoplastics, Antibiotic Class Summary
Bleomycin is used as palliative treatment of head and neck SCC.
