Cutaneous Squamous Cell Carcinoma

Updated: Jun 14, 2016
  • Author: Talib Najjar, DMD, MDS, PhD; Chief Editor: Arlen D Meyers, MD, MBA  more...
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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 anti-inflammatory 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 squamous cell carcino A large, ulcerated, invasive squamous cell carcinoma of the left 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 presentation of cSCC includes a pink cutaneous nodule 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

See Treatment and Medication for more detail.

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Background

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and one of the most common 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) o Large, sun-induced squamous cell carcinoma (SCC) on the forehead/temple. Image courtesy of Glenn Goldman, MD.

Although cSCC is not often fatal, it can cause significant morbidity, 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). C 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 conjunctival SCC also involves mucosa rather than skin, it is briefly considered in the Clinical Presentation and Treatment sections.

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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, a well-studied tumor suppressor gene. TP53 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 is an early event in the development of cSCC. [1]

UVR causes deoxyribonucleic acid (DNA) damage through the creation of pyrimidine dimers, a process known to result in the genetic mutation of TP53. Upon subsequent UVR exposure, 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 invasion 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 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 approx 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.

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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 UVR-induced 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 individual.

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 light-colored 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-to-BCC 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. [22]

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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 sun-protected 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]

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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 2-6%.

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 small-caliber 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 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 3-year, 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.

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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.

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