Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Cutaneous Squamous Cell Carcinoma

  • Author: Talib Najjar, DMD, MDS, PhD; Chief Editor: Arlen D Meyers, MD, MBA  more...
 
Updated: Jun 14, 2016
 

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.

Next

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.

Previous
Next

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.

Previous
Next

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]

Previous
Next

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]

Previous
Next

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.

Previous
Next

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.

Previous
 
 
Contributor Information and Disclosures
Author

Talib Najjar, DMD, MDS, PhD Professor of Oral and Maxillofacial Surgery and Pathology, Rutgers School of Dental Medicine

Talib Najjar, DMD, MDS, PhD is a member of the following medical societies: American Society for Clinical Pathology

Disclosure: Nothing to disclose.

Chief Editor

Arlen D Meyers, MD, MBA Professor of Otolaryngology, Dentistry, and Engineering, University of Colorado School of Medicine

Arlen D Meyers, MD, MBA is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, American Head and Neck Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cerescan;RxRevu;SymbiaAllergySolutions<br/>Received income in an amount equal to or greater than $250 from: Symbia<br/>Received from Allergy Solutions, Inc for board membership; Received honoraria from RxRevu for chief medical editor; Received salary from Medvoy for founder and president; Received consulting fee from Corvectra for senior medical advisor; Received ownership interest from Cerescan for consulting; Received consulting fee from Essiahealth for advisor; Received consulting fee from Carespan for advisor; Received consulting fee from Covidien for consulting.

Additional Contributors

Marcus M Monroe, MD Attending Physician/Surgeon, Division of Otolaryngology-Head and Neck Surgery, University of Utah School of Medicine

Marcus M Monroe, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Otolaryngology-Head and Neck Surgery, American Rhinologic Society

Disclosure: Nothing to disclose.

Acknowledgements

Murad Alam, MD Associate Professor of Dermatology, Otolaryngology, and Surgery; Chief, Section of Cutaneous and Aesthetic Surgery, Department of Dermatology, Northwestern University; Director, Mohs Micrographic Surgery, Northwestern Memorial Hospital

Murad Alam, MD is a member of the following medical societies: American Academy of Dermatology, American College of Mohs Micrographic Surgery and Cutaneous Oncology, American Dermatological Association, American Medical Association, American Society for Dermatologic Surgery, American Society for Laser Medicine and Surgery, American Society of Cosmetic Dermatology and Aesthetic Surgery, American Society of Transplantation, Dermatology Foundation, Illinois Dermatological Society, Phi Beta Kappa, Society for Investigative Dermatology, and Women's Dermatologic Society

Disclosure: Nothing to disclose.

Laurence M Baibak, MD, FACS

Disclosure: Nothing to disclose.

William Joseph Campbell, MD Resident Physician, Department of Surgery, University of Florida

William Joseph Campbell, MD is a member of the following medical societies: American College of Surgeons, American Medical Association, and American Medical Student Association/Foundation

Disclosure: Nothing to disclose.

Gregory Caputy, MD, PhD, FICS Chief Surgeon, Aesthetica Plastic and Laser Surgery Center, Inc

Gregory Caputy, MD, PhD, FICS is a member of the following medical societies: American Society for Laser Medicine and Surgery, Canadian Medical Association, International College of Surgeons, International College of Surgeons US Section, Pan-Pacific Surgical Association, and Wound Healing Society

Disclosure: Syneron Corporation Salary Speaking and teaching

Jorge I de la Torre, MD, FACS Professor of Surgery and Physical Medicine and Rehabilitation, Chief, Division of Plastic Surgery, Residency Program Director, University of Alabama at Birmingham School of Medicine; Director, Center for Advanced Surgical Aesthetics

Jorge I de la Torre, MD, FACS is a member of the following medical societies: American Association of Plastic Surgeons, American Burn Association, American College of Surgeons, American Medical Association, American Society for Laser Medicine and Surgery, American Society for Reconstructive Microsurgery, American Society of Maxillofacial Surgeons, American Society of Plastic Surgeons, Association for Academic Surgery, and Medical Association of the State of Alabama

Disclosure: Nothing to disclose.

Christopher DeBacker, MD Clinical Assistant Professor of Ophthalmology, University of Texas Health Science Center at San Antonio; Clinical Assistant Professor of Ophthalmology, University of California, San Francisco Medical Center, Veterans Affairs Medical Center

Christopher DeBacker, MD is a member of the following medical societies: American Academy of Cosmetic Surgery, American Academy of Ophthalmology, and American Society of Ophthalmic Plastic and Reconstructive Surgery

Disclosure: Nothing to disclose.

Robert M Dryden, MD, FACS Clinical Professor, Department of Ophthalmology, University of Arizona School of Medicine

Robert M Dryden, MD, FACS is a member of the following medical societies: Alpha Omega Alpha, American Academy of Cosmetic Surgery, American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Ophthalmology, American College of Surgeons, American Society of Ophthalmic Plastic and Reconstructive Surgery, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Mark T Duffy, MD, PhD Consulting Staff, Division of Oculoplastic, Orbito-facial, Lacrimal and Reconstructive Surgery, Green Bay Eye Clinic, BayCare Clinic; Medical Director, Advanced Cosmetic Solutions, A BayCare Clinic

Mark T Duffy, MD, PhD is a member of the following medical societies: American Academy of Ophthalmology, American Medical Association, American Society of Ophthalmic Plastic and Reconstructive Surgery, Sigma Xi, and Society for Neuroscience

Disclosure: Allergan - Botox Cosmetic Consulting fee Consulting

Dirk M Elston, MD Director, Ackerman Academy of Dermatopathology, New York

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Jerre Freeman, MD Founder and Chairman, Memphis Eye and Cataract Associates; Clinical Professor, Department of Ophthalmology, University of Tennessee Health Science Center College of Medicine

Jerre Freeman, MD is a member of the following medical societies: American Academy of Ophthalmology, American Medical Association, American Society of Cataract and Refractive Surgery, and Tennessee Medical Association

Disclosure: Nothing to disclose.

Jaime R Garza, MD, DDS, FACS Consulting Staff, Private Practice

Jaime R Garza, MD, DDS, FACS is a member of the following medical societies: Alpha Omega Alpha, American Academy of Otolaryngology-Head and Neck Surgery, American College of Surgeons, American Society for Aesthetic Plastic Surgery, American Society of Maxillofacial Surgeons, Texas Medical Association, and Texas Society of Plastic Surgeons

Disclosure: Nothing to disclose.

Glenn Goldman, MD

Disclosure: Nothing to disclose.

Neil D Gross, MD Assistant Professor of Head and Neck Surgery and Oncology, Department of Otolaryngology – Head and Neck Surgery, Oregon Health and Science University

Neil D Gross, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Otolaryngology-Head and Neck Surgery, American Association for Cancer Research, American College of Surgeons, and American Head and Neck Society

Disclosure: Nothing to disclose.

Stephen D Hess, MD, PhD

Disclosure: Nothing to disclose.

Shahin Javaheri, MD Chief, Department of Plastic Surgery, Martinez Veterans Affairs Outpatient Clinic; Consulting Staff, Advanced Aesthetic Plastic & Reconstructive Surgery

Shahin Javaheri, MD is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery and American Society of Plastic Surgeons

Disclosure: Nothing to disclose.

Lorraine Jennings, MBBCh, MRCPI Fellow, Department of Dermatology, Mohs Micrographic Surgery Center, Brigham and Women's Hospital, Harvard Medical School

Lorraine Jennings, MBBCh, MRCPI is a member of the following medical societies: British Association of Dermatologists, International Transplant and Skin Cancer Collaborative (ITSCC), Irish Association of Dermatologists, Photomedicine Society, and Royal College of Physicians of Ireland

Disclosure: Nothing to disclose.

Lawrence Ketch, MD, FAAP, FACS Head, Program Director, Associate Professor, Department of Surgery, Division of Plastic Surgery, University of Colorado Health Sciences Center; Chief, Pediatric Plastic, The Children's Hospital of Denver

Lawrence Ketch, MD, FAAP, FACS is a member of the following medical societies: American Academy of Pediatrics, American Association for Hand Surgery, American Association of Plastic Surgeons, American Burn Association, American Cleft Palate/Craniofacial Association, American College of Surgeons, American Society for Surgery of the Hand, American Society of Maxillofacial Surgeons, American Society of Plastic Surgeons, Association for Academic Surgery, andPlastic Surgery Research Council

Disclosure: Nothing to disclose.

Simon K Law, MD, PharmD Associate Professor of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, David Geffen School of Medicine

Simon K Law, MD, PharmD is a member of the following medical societies: American Academy of Ophthalmology, American Glaucoma Society, and Association for Research in Vision and Ophthalmology

Disclosure: Nothing to disclose.

Deepak Narayan, MD, FRCS Associate Professor of Surgery (Plastic), Yale University School of Medicine; Chief of Plastic Surgery, West Haven Veterans Affairs Medical Center

Deepak Narayan, MD, FRCS is a member of the following medical societies: American Association for the Advancement of Science, American College of Surgeons, American Medical Association, American Society of Maxillofacial Surgeons, American Society of Plastic Surgeons, Indian Medical Association, Plastic Surgery Research Council, Royal College of Surgeons of Edinburgh, and Royal College of Surgeons of England

Disclosure: Nothing to disclose.

Samia Nawaz, MBBS, MD Associate Professor, Department of Pathology, University of Colorado Health Science Center

Samia Nawaz, MBBS, MD is a member of the following medical societies: American Society for Clinical Pathology, American Society of Cytopathology, and International Academy of Pathology

Disclosure: Nothing to disclose.

Ron W Pelton, MD, PhD Private Practice, Colorado Springs, Colorado

Ron W Pelton, MD, PhD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, American Society of Ophthalmic Plastic and Reconstructive Surgery, AO Foundation, and Colorado Medical Society

Disclosure: Nothing to disclose.

Christopher J Rapuano, MD Professor, Department of Ophthalmology, Jefferson Medical College of Thomas Jefferson University; Director of the Cornea Service, Co-Director of Refractive Surgery Department, Wills Eye Institute

Christopher J Rapuano, MD is a member of the following medical societies: American Academy of Ophthalmology, American Society of Cataract and Refractive Surgery, Contact Lens Association of Ophthalmologists, Cornea Society, Eye Bank Association of America, International Society of Refractive Surgery, and Pan-American Association of Ophthalmology

Disclosure: Allergan Honoraria Speaking and teaching; Allergan Consulting fee Consulting; Alcon Honoraria Speaking and teaching; Inspire Honoraria Speaking and teaching; RPS Ownership interest Other; Vistakon Honoraria Speaking and teaching; EyeGate Pharma Consulting; Inspire Consulting fee Consulting; Bausch & Lomb Honoraria Speaking and teaching; Bausch & Lomb Consulting fee Consulting

Hampton Roy Sr, MD Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Hampton Roy Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, and Pan-American Association of Ophthalmology

Disclosure: Nothing to disclose.

Debjani Sahni, MBBS, MRCP Cutaneous Oncology Fellow, Brigham and Women's Hospital, Dana Farber Cancer Institute

Disclosure: Nothing to disclose.

M Sherif Said, MD, PhD, FCAP Associate Professor of Pathology, Director of Head and Neck Pathology, Department of Pathology, University of Colorado, Denver

M Sherif Said, MD, PhD, FCAP is a member of the following medical societies: American Society for Clinical Pathology and College of American Pathologists

Disclosure: Nothing to disclose.

Noah S Scheinfeld, MD, JD, FAAD Assistant Clinical Professor, Department of Dermatology, Columbia University College of Physicians and Surgeons; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, and New York Eye and Ear Infirmary; Private Practice

Noah S Scheinfeld, MD, JD, FAAD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Optigenex Consulting fee Independent contractor

Chrysalyne D Schmults, MD, MSCE Assistant Professor of Dermatology, Harvard Medical School; Director, Mohs Micrographic Surgery Center, Department of Dermatology, Brigham and Women's Hospital and Dana Farber Cancer Center

Chrysalyne D Schmults, MD, MSCE is a member of the following medical societies: American Academy of Dermatology, American College of Mohs Micrographic Surgery and Cutaneous Oncology, American Society for Dermatologic Surgery, and International Society for Dermatologic Surgery

Disclosure: Nothing to disclose.

Marvin Spann, MD Staff Physician, Department of General Surgery, New York Hospital Queens

Disclosure: Nothing to disclose.

Wayne Karl Stadelmann, MD Stadelmann Plastic Surgery, PC

Wayne Karl Stadelmann, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Surgeons, American Society of Plastic Surgeons, New Hampshire Medical Society, Northeastern Society of Plastic Surgeons, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Mia Talmor, MD Assistant Professor, Department of Surgery, Weill Medical College of Cornell University

Mia Talmor, MD is a member of the following medical societies: American College of Surgeons and American Society of Plastic Surgeons

Disclosure: Nothing to disclose.

R Stan Taylor, MD The JB Howell Professor in Melanoma Education and Detection, Departments of Dermatology and Plastic Surgery, Director, Skin Surgery and Oncology Clinic, University of Texas Southwestern Medical Center

R Stan Taylor, MD is a member of the following medical societies: American Academy of Dermatology, American College of Mohs Surgery, American Dermatological Association, American Medical Association, American Society for Dermatologic Surgery, Christian Medical & Dental Society, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Charles W Vaughan, MD, FACS Associate Clinical Professor, Department of Otolaryngology-Head & Neck Surgery, Boston University School of Medicine

Disclosure: Nothing to disclose.

Michael J Wells, MD Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association

Disclosure: Nothing to disclose.

Michael T Yen, MD Associate Professor of Ophthalmology, Department of Ophthalmology, Division of Ophthalmic Plastic, Lacrimal, and Orbital Surgery, Cullen Eye Institute, Baylor College of Medicine

Michael T Yen, MD is a member of the following medical societies: American Academy of Ophthalmology, American Society of Ophthalmic Plastic and Reconstructive Surgery, and Association for Research in Vision and Ophthalmology

Disclosure: Nothing to disclose.

Marc S Zimbler, MD, FACS Director of Facial Plastic and Reconstructive Surgery, Director of Residency Education, Department of Otolaryngology, Head and Neck Surgery, Beth Israel Medical Center

Marc S Zimbler, MD, FACS is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery and American College of Surgeons

Disclosure: Nothing to disclose.

References
  1. Brash DE. Roles of the transcription factor p53 in keratinocyte carcinomas. Br J Dermatol. 2006 May. 154 Suppl 1:8-10. [Medline].

  2. Hanneman KK, Cooper KD, Baron ED. Ultraviolet immunosuppression: mechanisms and consequences. Dermatol Clin. 2006 Jan. 24(1):19-25. [Medline].

  3. Schwaederle M, Elkin SK, Tomson BN, Carter JL, Kurzrock R. Squamousness: Next-generation sequencing reveals shared molecular features across squamous tumor types. Cell Cycle. 2015 Jun 1. 1-7. [Medline].

  4. Harper JG, Pilcher MF, Szlam S, Lind DS. Squamous cell carcinoma in an African American with discoid lupus erythematosus: a case report and review of the literature. South Med J. 2010 Mar. 103(3):256-9. [Medline].

  5. Mohan SV, Chang J, Li S, Henry AS, Wood DJ, Chang AL. Increased Risk of Cutaneous Squamous Cell Carcinoma After Vismodegib Therapy for Basal Cell Carcinoma. JAMA Dermatol. 2016 May 1. 152 (5):527-32. [Medline].

  6. Gilberg SM, Tse DT. Malignant eyelid tumors. Ophthalmol Clin. 5:261-85.

  7. de Gruijl FR, Rebel H. Early events in UV carcinogenesis--DNA damage, target cells and mutant p53 foci. Photochem Photobiol. 2008 Mar-Apr. 84(2):382-7. [Medline].

  8. Ziegler A, Jonason AS, Leffell DJ, Simon JA, Sharma HW, Kimmelman J, et al. Sunburn and p53 in the onset of skin cancer. Nature. 1994 Dec 22-29. 372(6508):773-6. [Medline].

  9. Perry PK, Silverberg NB. Cutaneous malignancy in albinism. Cutis. 2001 May. 67(5):427-30. [Medline].

  10. Zghal M, El-Fekih N, Fazaa B, et al. [Xeroderma pigmentosum. Cutaneous, ocular, and neurologic abnormalities in 49 Tunisian cases]. Tunis Med. 2005 Dec. 83(12):760-3. [Medline].

  11. Black AP, Bailey A, Jones L, Turner RJ, Hollowood K, Ogg GS. p53-specific CD8+ T-cell responses in individuals with cutaneous squamous cell carcinoma. Br J Dermatol. 2005 Nov. 153(5):987-91. [Medline].

  12. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med. 2003 Apr 24. 348(17):1681-91. [Medline].

  13. Jensen P, Hansen S, Moller B, et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 1999 Feb. 40(2 Pt 1):177-86. [Medline].

  14. Euvrard S, Kanitakis J, Decullier E, et al. Subsequent skin cancers in kidney and heart transplant recipients after the first squamous cell carcinoma. Transplantation. 2006 Apr 27. 81(8):1093-100. [Medline].

  15. Veness MJ, Quinn DI, Ong CS, et al. Aggressive cutaneous malignancies following cardiothoracic transplantation: the Australian experience. Cancer. 1999 Apr 15. 85(8):1758-64. [Medline].

  16. Wilkins K, Turner R, Dolev JC, LeBoit PE, Berger TG, Maurer TA. Cutaneous malignancy and human immunodeficiency virus disease. J Am Acad Dermatol. 2006 Feb. 54(2):189-206; quiz 207-10. [Medline].

  17. Mallipeddi R. Epidermolysis bullosa and cancer. Clin Exp Dermatol. 2002 Nov. 27(8):616-23. [Medline].

  18. Fine JD, Johnson LB, Weiner M, Li KP, Suchindran C. Epidermolysis bullosa and the risk of life-threatening cancers: the National EB Registry experience, 1986-2006. J Am Acad Dermatol. 2009 Feb. 60(2):203-11. [Medline].

  19. Reed WB, College J Jr, Francis MJ, et al. Epidermolysis bullosa dystrophica with epidermal neoplasms. Arch Dermatol. 1974 Dec. 110(6):894-902. [Medline].

  20. Kowal-Vern A, Criswell BK. Burn scar neoplasms: a literature review and statistical analysis. Burns. 2005 Jun. 31(4):403-13. [Medline].

  21. Mallipeddi R, Keane FM, McGrath JA, Mayou BJ, Eady RA. Increased risk of squamous cell carcinoma in junctional epidermolysis bullosa. J Eur Acad Dermatol Venereol. 2004 Sep. 18(5):521-6. [Medline].

  22. Arbiser JL, Fan CY, Su X, et al. Involvement of p53 and p16 tumor suppressor genes in recessive dystrophic epidermolysis bullosa-associated squamous cell carcinoma. J Invest Dermatol. 2004 Oct. 123(4):788-90. [Medline].

  23. American Cancer Society. Cancer facts and figures: 2013. [Full Text].

  24. Reifler DM, Hornblass A. Squamous cell carcinoma of the eyelid. Surv Ophthalmol. 1986 May-Jun. 30(6):349-65. [Medline].

  25. Gray DT, Suman VJ, Su WP, Clay RP, Harmsen WS, Roenigk RK. Trends in the population-based incidence of squamous cell carcinoma of the skin first diagnosed between 1984 and 1992. Arch Dermatol. 1997 Jun. 133(6):735-40. [Medline].

  26. Hampton T. Skin cancer's ranks rise: immunosuppression to blame. JAMA. 2005 Sep 28. 294(12):1476-80. [Medline].

  27. Staples MP, Elwood M, Burton RC, Williams JL, Marks R, Giles GG. Non-melanoma skin cancer in Australia: the 2002 national survey and trends since 1985. Med J Aust. 2006 Jan 2. 184(1):6-10. [Medline].

  28. Buettner PG, Raasch BA. Incidence rates of skin cancer in Townsville, Australia. Int J Cancer. 1998 Nov 23. 78(5):587-93. [Medline].

  29. McCall CO, Chen SC. Squamous cell carcinoma of the legs in African Americans. J Am Acad Dermatol. 2002 Oct. 47(4):524-9. [Medline].

  30. Christenson LJ, Borrowman TA, Vachon CM, et al. Incidence of basal cell and squamous cell carcinomas in a population younger than 40 years. JAMA. 2005 Aug 10. 294(6):681-90. [Medline].

  31. Housman TS, Feldman SR, Williford PM, et al. Skin cancer is among the most costly of all cancers to treat for the Medicare population. J Am Acad Dermatol. 2003 Mar. 48(3):425-9. [Medline].

  32. Edge SB, Byrd DR, Compton CC, eds. Cutaneous squamous cell carcinoma and other cutaneous carcinomas. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2009. 301-9.

  33. Jambusaria-Pahlajani A, Hess SD, Katz KA, Berg D, Schmults CD. Uncertainty in the perioperative management of high-risk cutaneous squamous cell carcinoma among Mohs surgeons. Arch Dermatol. 2010 Nov. 146(11):1225-31. [Medline].

  34. Clayman GL, Lee JJ, Holsinger FC, et al. Mortality risk from squamous cell skin cancer. J Clin Oncol. 2005 Feb 1. 23(4):759-65. [Medline].

  35. Veness MJ, Morgan GJ, Palme CE, Gebski V. Surgery and adjuvant radiotherapy in patients with cutaneous head and neck squamous cell carcinoma metastatic to lymph nodes: combined treatment should be considered best practice. Laryngoscope. 2005 May. 115(5):870-5. [Medline].

  36. Rowe DE, Carroll RJ, Day CL Jr. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection. J Am Acad Dermatol. 1992 Jun. 26(6):976-90. [Medline].

  37. Ross AS, Schmults CD. Sentinel lymph node biopsy in cutaneous squamous cell carcinoma: a systematic review of the English literature. Dermatol Surg. 2006 Nov. 32(11):1309-21. [Medline].

  38. Cook BE Jr, Bartley GB. Epidemiologic characteristics and clinical course of patients with malignant eyelid tumors in an incidence cohort in Olmsted County, Minnesota. Ophthalmology. 1999 Apr. 106(4):746-50. [Medline].

  39. Dailey JR, Kennedy RH, Flaharty PM, Eagle RC Jr, Flanagan JC. Squamous cell carcinoma of the eyelid. Ophthal Plast Reconstr Surg. 1994 Sep. 10(3):153-9. [Medline].

  40. Thosani MK, Schneck G, Jones EC. Periocular squamous cell carcinoma. Dermatol Surg. 2008 May. 34(5):585-99. [Medline].

  41. Bowyer JD, Sullivan TJ, Whitehead KJ, Kelly LE, Allison RW. The management of perineural spread of squamous cell carcinoma to the ocular adnexae. Ophthal Plast Reconstr Surg. 2003 Jul. 19(4):275-81. [Medline].

  42. Donaldson MJ, Sullivan TJ, Whitehead KJ, Williamson RM. Squamous cell carcinoma of the eyelids. Br J Ophthalmol. 2002 Oct. 86(10):1161-5. [Medline]. [Full Text].

  43. Veness MJ, Palme CE, Morgan GJ. High-risk cutaneous squamous cell carcinoma of the head and neck: results from 266 treated patients with metastatic lymph node disease. Cancer. 2006 Jun 1. 106(11):2389-96. [Medline].

  44. Fleming MD, Hunt JL, Purdue GF, Sandstad J. Marjolin's ulcer: a review and reevaluation of a difficult problem. J Burn Care Rehabil. 1990 Sep-Oct. 11(5):460-9. [Medline].

  45. Novick M, Gard DA, Hardy SB, Spira M. Burn scar carcinoma: a review and analysis of 46 cases. J Trauma. 1977 Oct. 17(10):809-17. [Medline].

  46. Brantsch KD, Meisner C, Schonfisch B, et al. Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study. Lancet Oncol. 2008 Aug. 9(8):713-20. [Medline].

  47. Ross AS, Whalen FM, Elenitsas R, Xu X, Troxel AB, Schmults CD. Diameter of involved nerves predicts outcomes in cutaneous squamous cell carcinoma with perineural invasion: an investigator-blinded retrospective cohort study. Dermatol Surg. 2009 Dec. 35(12):1859-66. [Medline].

  48. Manyam BV, Gastman B, Zhang AY, et al. Inferior outcomes in immunosuppressed patients with high-risk cutaneous squamous cell carcinoma of the head and neck treated with surgery and radiation therapy. J Am Acad Dermatol. 2015 May 29. [Medline].

  49. Mehrany K, Weenig RH, Pittelkow MR, Roenigk RK, Otley CC. High recurrence rates of squamous cell carcinoma after Mohs' surgery in patients with chronic lymphocytic leukemia. Dermatol Surg. 2005 Jan. 31(1):38-42; discussion 42. [Medline].

  50. Frierson HF Jr, Deutsch BD, Levine PA. Clinicopathologic features of cutaneous squamous cell carcinomas of the head and neck in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. Hum Pathol. 1988 Dec. 19(12):1397-402. [Medline].

  51. Straif K, Benbrahim-Tallaa L, Baan R, et al. A review of human carcinogens--part C: metals, arsenic, dusts, and fibres. Lancet Oncol. 2009 May. 10(5):453-4. [Medline].

  52. Salasche SJ. Epidemiology of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol. 2000 Jan. 42(1 Pt 2):4-7. [Medline].

  53. Goepfert H, Dichtel WJ, Medina JE, Lindberg RD, Luna MD. Perineural invasion in squamous cell skin carcinoma of the head and neck. Am J Surg. 1984 Oct. 148(4):542-7. [Medline].

  54. Hong TS, Kriesel KJ, Hartig GK, Harari PM. Parotid area lymph node metastases from cutaneous squamous cell carcinoma: implications for diagnosis, treatment, and prognosis. Head Neck. 2005 Oct. 27(10):851-6. [Medline].

  55. Barros JN, Lowen MS, Ballalai PL, Mascaro VL, Gomes JA, Martins MC. Predictive index to differentiate invasive squamous cell carcinoma from preinvasive ocular surface lesions by impression cytology. Br J Ophthalmol. 2009 Feb. 93(2):209-14. [Medline].

  56. Pe'er J. Ocular surface squamous neoplasia. Ophthalmol Clin North Am. 2005 Mar. 18(1):1-13, vii. [Medline].

  57. Papaioannou IT, Melachrinou MP, Drimtzias EG, Gartaganis SP. Corneal-conjunctival squamous cell carcinoma. Cornea. 2008 Sep. 27(8):957-8. [Medline].

  58. Gokmen Soysal H, Ardic F. Malignant conjunctival tumors invading the orbit. Ophthalmologica. 2008. 222(5):338-43. [Medline].

  59. Hirst LW, Axelsen RA, Schwab I. Pterygium and associated ocular surface squamous neoplasia. Arch Ophthalmol. 2009 Jan. 127(1):31-2. [Medline].

  60. Forest VI, Clark JJ, Veness MJ, Milross C. N1S3: a revised staging system for head and neck cutaneous squamous cell carcinoma with lymph node metastases: results of 2 Australian Cancer Centers. Cancer. 2010 Mar 1. 116(5):1298-304. [Medline].

  61. Brodland DG, Zitelli JA. Surgical margins for excision of primary cutaneous squamous cell carcinoma. J Am Acad Dermatol. 1992 Aug. 27(2 Pt 1):241-8. [Medline].

  62. Nelson BR, Railan D, Cohen S. Mohs' micrographic surgery for nonmelanoma skin cancers. Clin Plast Surg. 1997 Oct. 24(4):705-18. [Medline].

  63. Veness MJ, Morgan GJ, Palme CE, Gebski V. Surgery and adjuvant radiotherapy in patients with cutaneous head and neck squamous cell carcinoma metastatic to lymph nodes: combined treatment should be considered best practice. Laryngoscope. 2005 May. 115(5):870-5. [Medline].

  64. Rudkin AK, Muecke JS. Adjuvant 5-fluorouracil in the treatment of localised ocular surface squamous neoplasia. Br J Ophthalmol. 2011 Jul. 95(7):947-50. [Medline].

  65. Bauman JE, Eaton KD, Martins RG. Treatment of recurrent squamous cell carcinoma of the skin with cetuximab. Arch Dermatol. 2007 Jul. 143(7):889-92. [Medline].

  66. Suen JK, Bressler L, Shord SS, Warso M, Villano JL. Cutaneous squamous cell carcinoma responding serially to single-agent cetuximab. Anticancer Drugs. 2007 Aug. 18(7):827-9. [Medline].

  67. Arnold AW, Bruckner-Tuderman L, Zuger C, Itin PH. Cetuximab therapy of metastasizing cutaneous squamous cell carcinoma in a patient with severe recessive dystrophic epidermolysis bullosa. Dermatology. 2009. 219(1):80-3. [Medline].

  68. Reeves TD, Hill EG, Armeson KE, Gillespie MB. Cetuximab therapy for head and neck squamous cell carcinoma: a systematic review of the data. Otolaryngol Head Neck Surg. 2011 May. 144(5):676-84. [Medline].

  69. Char DH, Crawford JB. Orbital invasion despite topical anti-metabolite therapy for conjunctival carcinoma. Graefes Arch Clin Exp Ophthalmol. 2008 Mar. 246(3):459-61. [Medline].

  70. Shields CL, Demirci H, Marr BP, Masheyekhi A, Materin M, Shields JA. Chemoreduction with topical mitomycin C prior to resection of extensive squamous cell carcinoma of the conjunctiva. Arch Ophthalmol. 2005 Jan. 123(1):109-13. [Medline].

  71. Russell HC, Chadha V, Lockington D, Kemp EG. Topical mitomycin C chemotherapy in the management of ocular surface neoplasia: a 10-year review of treatment outcomes and complications. Br J Ophthalmol. 2010 Oct. 94(10):1316-21. [Medline].

  72. Duffield-Lillico AJ, Slate EH, Reid ME, et al. Selenium supplementation and secondary prevention of nonmelanoma skin cancer in a randomized trial. J Natl Cancer Inst. 2003 Oct 1. 95(19):1477-81. [Medline].

  73. Frieling UM, Schaumberg DA, Kupper TS, Muntwyler J, Hennekens CH. A randomized, 12-year primary-prevention trial of beta carotene supplementation for nonmelanoma skin cancer in the physician's health study. Arch Dermatol. 2000 Feb. 136(2):179-84. [Medline].

  74. Green A, Williams G, Neale R, et al. Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial. Lancet. 1999 Aug 28. 354(9180):723-9. [Medline].

  75. Levine N, Moon TE, Cartmel B, et al. Trial of retinol and isotretinoin in skin cancer prevention: a randomized, double-blind, controlled trial. Southwest Skin Cancer Prevention Study Group. Cancer Epidemiol Biomarkers Prev. 1997 Nov. 6(11):957-61. [Medline].

  76. Naylor MF, Boyd A, Smith DW, Cameron GS, Hubbard D, Neldner KH. High sun protection factor sunscreens in the suppression of actinic neoplasia. Arch Dermatol. 1995 Feb. 131(2):170-5. [Medline].

  77. Thompson SC, Jolley D, Marks R. Reduction of solar keratoses by regular sunscreen use. N Engl J Med. 1993 Oct 14. 329(16):1147-51. [Medline].

  78. Seite S, Colige A, Piquemal-Vivenot P, et al. A full-UV spectrum absorbing daily use cream protects human skin against biological changes occurring in photoaging. Photodermatol Photoimmunol Photomed. 2000 Aug. 16(4):147-55. [Medline].

  79. Seite S, Moyal D, Richard S, et al. Mexoryl SX: a broad absorption UVA filter protects human skin from the effects of repeated suberythemal doses of UVA. J Photochem Photobiol B. 1998 Jun 15. 44(1):69-76. [Medline].

  80. U.S. Preventive Services Task Force. Screening for Skin Cancer: Recommendation Statement. AHRQ Publication No. 09-05128-EF-2, Feb 2009. Available at http://www.uspreventiveservicestaskforce.org/uspstf09/skincancer/skincanrs.htm. Accessed: Nov 7, 2013.

  81. Kuflik EG, Gage AA. The five-year cure rate achieved by cryosurgery for skin cancer. J Am Acad Dermatol. 1991 Jun. 24(6 Pt 1):1002-4. [Medline].

  82. Lewis R. NSAIDs May Protect Against Common Skin Cancer. Medscape Medical News. Available at http://www.medscape.com/viewarticle/836938. Accessed: December 20, 2014.

  83. Muranushi C, Olsen CM, Pandeya N, Green AC. Aspirin and nonsteroidal anti-inflammatory drugs can prevent cutaneous squamous cell carcinoma: a systematic review and meta-analysis. J Invest Dermatol. 2015 Apr. 135(4):975-83. [Medline].

  84. Gloster HM Jr, Brodland DG. The epidemiology of skin cancer. Dermatol Surg. 1996 Mar. 22(3):217-26. [Medline].

  85. Beadle BM, Liao KP, Elting LS, et al. Improved survival using intensity-modulated radiation therapy in head and neck cancers: a SEER-Medicare analysis. Cancer. 2014 Mar 1. 120(5):702-10. [Medline].

  86. Boggs W. Intensity-Modulated Radiotherapy Improves Head and Neck Cancer Survival. Medscape [serial online]. Available at http://www.medscape.com/viewarticle/819080. Accessed: Jan 28 2014.

 
Previous
Next
 
Large, sun-induced squamous cell carcinoma (SCC) on the forehead/temple. Image courtesy of Glenn Goldman, MD.
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.
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.
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.
Squamous cell carcinoma in situ (Bowen disease). Courtesy of Hon Pak, MD.
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.
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.
Axial magnetic resonance image (MRI) of a large squamous cell carcinoma of the left lower eyelid with invasion of the anterior orbit.
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.
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.
Table 1. Stage Grouping
Stage Primary Tumor Regional Lymph Nodes Distant Metastasis
Stage 0 Tis N0 M0
Stage I T1 N0 M0
Stage II T2 N0 M0
Stage III T3 N0 M0
T1-3 N1 M0
Stage IV T4 N0 M0
Any T N2-3 M0
Any T Any N M1
Previous
Next
 
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.