Head and Neck Cutaneous Squamous Cell Carcinoma 

Cutaneous squamous cell carcinoma (SCC) is the second most common form of nonmelanoma skin cancer (basal cell carcinoma [BCC] is the most common skin cancer) and accounts for 20% of cutaneous malignancies^{[1, 2]} and 90% of all head and neck cancers. Unlike most BCCs, SCCs of the skin are associated with a risk of metastasis. A malignant tumor of epithelial origin, SCC has a regional distribution involved in the biologic activity of the neoplasm. The behavior of SCC depends on its site of origin. Each anatomic site has its own particular spread pattern and prognosis. SCC frequently arises on the sun-exposed skin of middle-aged and elderly individuals (see the image below).

Most SCCs are readily identified and removed in the physician's office as a minor surgical procedure. Larger and more invasive lesions may require aggressive surgical management, radiation therapy, or both. High-risk SCC carries a significant risk of metastasis and, as such, requires careful evaluation and treatment. An estimated 8000 cases of nodal metastasis and 3000 deaths occur in the United States annually, almost wholly attributable to aggressive or high-risk SCC.^{[3, 4]}

Historical information

Evidence of head and neck carcinomas has been found in ancient skulls. The oldest known tumor is contained in a fossil found in East Africa by Louis Leakey that dates back more than 500,000 years. Some historians speculate that a high incidence of nasopharyngeal cancer may have been present in some ancient populations because of the inhalation of wood smoke in poorly ventilated huts. In approximately 400 BC, Hippocrates described a common chronic ulcer at the edge of the tongue that he attributed to the presence of sharp teeth rubbing against the tongue.

The ancient Indian physician Sushruta described the removal of tumors and developed great skill in plastic surgery, partly from defects created by frequent amputations of the nose and ears for punishment. Modern Western medicine received its foundation from early Roman medical writings. Little medical advancement was made for head and neck cancers until the advent of anesthesia and surgical excision in the 11th century.

In 1893, President Grover Cleveland was found to have a SCC of the hard palate that required surgical excision. The operation was performed secretly on a yacht so that he could manage the "financial panic of 1893." Cleveland was known for his heavy cigar smoking and social drinking.

See the following for more information:

• Sentinel Lymph Node Biopsy for Squamous Cell Carcinoma
• Urogenital Squamous Cell Carcinoma
• Imaging of Nasopharyngeal and Laryngeal Squamous Cell Carcinoma
• Cell Biology of Head and Neck Squamous Cell Carcinoma
• Targeted Molecular Therapy in Head and Neck Squamous Cell Carcinoma.
• Mohs Micrographic Surgery
• Mohs Surgery

Squamous cell carcinoma (SCC) of the head and neck possesses unusual features not universally found in carcinomas in other anatomic sites.

SCC is a field-defect phenomenon. Although this is also true of transitional-cell carcinoma of the urinary bladder, it is not the rule for malignant degeneration in all body sites. Simply defined, field defect means that, if dysplastic changes occur in 1 location of an organ or body site, other locations in the same organ are likely to have dysplastic changes. The implications of this phenomenon can be profound. For instance, mild dysplasia in 1 region of the buccal mucosa may be associated with frankly invasive carcinoma only millimeters away.

An invasive carcinoma of the soft palate may be completely excised, in that the margins are free of morphologically recognizable neoplasm. However, the patient may present 1 year later with a carcinoma of the hard palate. This occurrence does not indicate that the margins were misread but that field-defect lesions are associated with skip lesions.

In this context, the clinician must realize that the pathologist's evaluation of the margins (eg, "free of malignancy or significant dysplasia" or "malignancy completely excised") means that the surgeon did not cut across dysplastic tissue. A premalignant lesion may be still in the patient only 2 mm away from the excisional margin. This knowledge becomes important given the complex nature of the anatomic structures in the head and neck. Wide margins are not always an option. Although a skin lesion of the shoulder may justify 2-cm margins, a "generous" margin of the maxillary sinus may lead to an orbital exenteration.

A parotid tumor may require a decision between close margins or loss of the facial nerve. Dr Charles Vaughan in Boston inculcates his otolaryngology and pathology residents with the knowledge that "SCC of the head and neck is a disease of millimeters." This statement is undeniably true, and a field-defect phenomenon that occurs where a structure must be conscientiously preserved makes oncologic therapy in this area notoriously hazardous.

Another consideration with regard to SCC of the head and neck is that this relatively small region has numerous subdivisions, which authors define in different ways. Some divide them by gross anatomic features, some by histologic barriers, and some by embryologic origins. These divisions are valid for empirical reasons.

Each area has its own peculiarities with regard to etiology, likelihood of malignancy, surgical approach, other therapeutic options, and prognosis. To consider each one individually would be exhaustive, and the literature in the general domain covers these in sufficient detail. In this article, subdivisions are considered only when the nuances of that region illustrate an important teaching point.

Mucosa

For purposes of discussing the head and neck, mucosa, a widely used term, refers to the membranous lining protecting the oral cavity, oropharynx, nasopharynx, larynx, and laryngopharynx. The lining is composed of the epithelium covering the surface and the underlying stroma, and (where appropriate), the muscularis mucosae.

The critical anatomic barrier is the basement membrane. This is the layer of collagen and glycoproteins directly beneath the inferior layer of the epithelium and the connective tissue stroma. A breach in this structure by dysplastic epithelial cells is the sine qua non for invasive carcinoma.

Epithelium

Epithelial cells line the surfaces of the body. Categorization is based on the number of layers and on the morphology of the most superficial cells.

Squamous epithelium usually consists of 5-7 cell layers. The basal cell layers are elongated cells arranged so that the long axis of the cell is perpendicular to the basement membrane. In normal epithelium, the basal cell layer, and perhaps the one directly above it, are the only layers engaged in active division and proliferation. For this reason, mitotic figures are the norm in the basal and parabasal layers. Mitotic figures above this level are of increasing concern given their proximity to the surface layers.

As one proceeds upward toward the surface layer, the cells take on an increasingly ovoid to round shape. By midway, the cells are approximately round. Ascending above the midway portion, one sees that the cells begin to assume an elongated shape. This time, however, the long axis of the cell is parallel to the basement membrane, which means it is also parallel to the surface. Finally, at the surface, the epithelium is completely flattened and therefore the ideal shape for complete coverage of the body.

One must understand that epithelium is avascular. Therefore, nonirritated, nontraumatized epithelium should not bleed. This is true for SCC in situ as well. By definition, carcinoma in situ (CIS) does not break through the basement membrane; therefore, blood vessels are not exposed. This being the case, a previously dysplastic lesion that begins to bleed is a cause for concern.

Stroma

The stroma underlying the squamous or respiratory epithelium of the head and neck varies by anatomic site. In some areas, voluntary (striated) muscle (eg, tongue, true vocal cord) is present. In others, no striated muscle but abundant mucous glands (eg, false cord) is present.

With some exception of the cartilaginous tissues, all locations have lymphatic channels, blood vessels, proteoglycans, and neural elements in common. The vascular channels, lymphatic and blood vessels, and nerves allow for rapid and widespread dissemination as soon as these structures are invaded. Furthermore, the stromal matrix offers little resistance to the spread of the tumor into these structures.

The stroma of the Waldeyer ring is markedly different from that of any other in the body, including stroma in other head-and-neck sites. The Waldeyer ring can be envisaged as including the base of tongue, palatine tonsils, soft palate, and pharyngeal tonsils (adenoids). Here, the epithelium does not have a clear basement membrane, and the epithelial cells intermingle with the dense lymphoid tissue in these areas. The stroma does have blood vessels, nerves, or lymphatic, but the abundance of lymphoid tissue largely obscures these structures on routine histologic examination. Invasion of these structures happens early, as no natural barrier exists between the epithelium and stroma. That is, no basement membrane is present.

See Definitions and Clinical Terminology for other specific language used in discussions of SCC.

Oral cavity

The oral cavity is defined as the area extending from the vermilion border of the lips to a plane between the junction of the hard and soft palate superiorly and the circumvallate papillae of the tongue inferiorly. This region includes the buccal mucosa, upper and lower alveolar ridges, floor of the mouth, retromolar trigone, hard palate, and anterior two thirds of the tongue.

The lips are the most common site of malignancy in the oral cavity and account for 12% of all head and neck cancers, excluding nonmelanoma skin cancers. SCC is the most common histologic type, with 98% involving the lower lip. This predilection to the lower lip has been attributed to sun exposure. Next most common sites in order of frequency are the tongue, floor of the mouth, mandibular gingiva, buccal mucosa, hard palate, and maxillary gingiva.

The tumor site and lymphatic drainage of the oral cavity are as follows:

• Anterior tongue to subdigastric, submaxillary, or midjugular nodes
• Floor of mouth to subdigastric, submaxillary, or midjugular nodes
• Gingival to jugulodigastric, submaxillary, or midjugular nodes
• Buccal mucosa to submaxillary, preparotid, or jugular nodes
• Hard palate to submaxillary or jugulodigastric nodes

The pharynx consists of the oropharynx, nasopharynx, and hypopharynx. The most common sites of cancer in the oropharynx are the tonsillar fossa, soft palate, and base of tongue, followed by the pharyngeal wall. The nasopharynx is the part of the pharynx bounded superiorly by the skull base and sphenoid bone, inferiorly by a horizontal plane at the level of the palate, laterally by the superior constrictor muscles, anteriorly by the nasal cavity through the choanae, and posteriorly bounded by the prevertebral fascia. The hypopharynx is divided into the pyriform sinus (most common site of tumor involvement), posterior pharyngeal wall, and postcricoid region.

In nasopharyngeal carcinoma, the most frequent site of origin is the fossa of Rosenmüller. This is a structure anterior and superior to the entrance of the eustachian tube. It is basically an outpouching of nasopharyngeal mucosa between the skull base and the muscular layers of the nasopharynx.

Invasion of the cartilage framework of the larynx and mobility of the vocal cords influence the treatment of primary tumors of the hypopharynx and larynx. The Ohngren line is an imaginary line drawn from the medial canthus to the angle of the mandible that divides the paranasal sinuses into an infrastructure and suprastructure. Sinus tumors that involve the infrastructure have a more favorable prognosis than tumors of the suprastructure.

Malignant transformation of normal epidermal keratinocytes is the hallmark of cutaneous squamous cell carcinoma (SCC). Some cases of SCC occur de novo (ie, in the absence of a precursor lesion); however, some SCCs arise from sun-induced precancerous lesions known as actinic keratoses, as well as leukoplakia, radiation keratosis or dermatitis, scars, chronic ulcers, or chronic sinusitis. People with actinic keratosis have atypical squamous cells in one third to one half of the epidermis, and those with multiple actinic keratoses are at increased risk for developing SCC.^[5] Those with Bowen disease (see the following image), or SCC in situ, have atypical keratinocytes in the entire epidermis. SCC is capable of locally infiltrative growth, spread to regional lymph nodes, and distant metastasis, most often to the lungs. Invasive SCC involves the epidermis and invades the dermis.

One critical pathogenic event is the development of apoptotic resistance through functional loss of TP53, a well-studied tumor suppressor gene. Ultraviolet (UV) B-induced photocarcinogenesis appears to work by suppressing the immune system in several ways. The UVB spectrum inhibits antigen presentation, induces the release of immunosuppressive cytokines, and elicits DNA damage, specifically the generation of pyrimidine dimers in keratinocyte DNA that is a molecular trigger of UV-mediated immunosuppression.^[6] This process is known to result in genetic mutation of TP53. TP53 mutations are seen in over 90% of skin cancers diagnosed in the United States, as well as most precursor skin lesions, suggesting that loss of TP53 is an early event in the development of cutaneous SCC.^{[7, 8]}

Upon subsequent UV radiation exposure, keratinocytes undergo clonal expansion, acquiring further genetic defects, and ultimately leading to invasive cutaneous SCC. Other tumor suppressor genes found to be mutated in SCC include P16 (INK4a) and P14 (ARF).^[9]

Many other genetic abnormalities are believed to contribute to the pathogenesis of cutaneous SCC, including mutations of BCL2 and RAS. Likewise, alterations in intracellular signal transduction pathways, including epidermal growth factor receptor (EGFR) and cyclooxygenase (COX), have been shown to play a role in the development of cutaneous SCC.

Salehi et al noted that translational control is critical for the proper regulation of the cell cycle, tissue induction, and growth.^[2] The eukaryotic initiation factor 4E (eIF4E) is important for these processes and may play an important role in SCC.^[2] Although typically observed in elderly patients, SCC may be seen in younger patients with a history of radiotherapy or in patients with human immunodeficiency virus (HIV) infection (see the image below). Human papillomavirus (HPV) infection or TP53 overexpression may play a role in development of SCC in patients who are infected with HIV.^{[10, 11]} Multiple infectious agents likely play a role in the development of SCC of the conjunctiva via the actions of infectious oncogenes and chronic antigenic stimulation.^[12]

Occupations with considerable exposure to oils or tar may be associated with increased incidence of SCC of eyelids. In patients with xeroderma pigmentosum, defective DNA repair causes predisposition for development of malignant epithelial lesions, including SCC.

The etiology of cancer is a difficult, ill-defined, and incomplete concept. Etiology is not synonymous with cause. Cause implies a condition that is necessary and sufficient to produce a certain result, whereas etiology is literally the study of causes. As such, etiology implies a complex interaction of entities, their introduction, and their interaction with a host to produce a malignancy. This is an important point, because it underscores the reality that few etiologic agents are necessary or sufficient to produce a particular type of malignancy. Therefore, a number of etiologic agents are associated with various degrees of risk in the development of squamous cell carcinoma (SCC) of the head and neck.

Exposure to cancer-promoting stressors and the response of the body to those exposures (host response) combine to determine the risk of developing cutaneous SCC. These risk factors include exposure to ultraviolet (UV) radiation; immunosuppression; use of tobacco or alcohol; age; familial or genetic predisposition; nutritional status; chronic irritation; and exposure to industrial products or heavy metals, viruses, or ionizing radiation. Some of these 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.

UV radiation exposure

The primary risk factor of most SCC is cumulative lifetime sun exposure; that is, SCC can develop even if the history of sun exposure occurred decades before development of the skin lesion.^[13] 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 both an initiator and a promoter of carcinogenesis. In animal models, UV-induced photocarcinogenesis appears to involve the UVB and UVA-2 spectral ranges.^[14]

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 and mutations in both TP53 and the oncogene Ha-Ras are present in a large proportion of PUVA-associated SCC.^[7] 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 fair complexion, albinism, hazel or blue or gray eyes, and light-colored hair (blond or red) and those who burn easily when exposed to the sun are at higher risk for cutaneous SCC than those with other physical characteristics. Individuals with skin types I and II account for most of the patients who develop SCC; patients with oculocutaneous albinism are also at risk, and 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.^[15]

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.^[16]

Iatrogenic immunosuppression

Immunosuppression is also increasingly recognized as a risk factor for the development of skin cancer. 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.^[17] This correlates with the intensity of immunosuppression (ie, number and/or dosage of medications) typically required to prevent rejection in these patient populations, so that heart transplant recipients have 3 times the risk of SCC compared with kidney transplant recipients. Thus, although the proportion of heart transplant recipients developing new tumors is greater than in kidney transplant recipients, the mean number of tumors per patient is higher in kidney transplant recipients. This may be due to a longer duration of immunosuppression in patients who are younger at transplantation.^[18]

For organ transplant recipients on chronic immunosuppression agents, skin cancers account for 90% of all diagnosed malignancies. In this group of patients, cutaneous SCC is more common than other keratinocyte-derived neoplasms, including basal cell carcinomas (BCC). 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.^[19]

The primary risk factor in organ transplant patients is cumulative lifetime UV exposure in combination with having Fitzpatrick skin type I or II. This risk also increases with the number of years post-transplantation, presumably because of the cumulative effects of prolonged immunosuppressive therapy. In fact, 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 cutaneous SCC within 10 years of transplantation.^[20] 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.

Patients immunosuppressed secondary to human immunodeficiency virus (HIV) infection have a more modestly elevated risk of developing a nonmelanoma skin cancer, 3-5 times that of the general population, but do not have the altered SCC-to-BCC ratio typical of transplant recipients. Regardless of etiology, cutaneous SCC that arises in the setting of immunosuppression exhibits a more aggressive course, with a higher rate of local recurrence, metastasis, and death.

Noniatrogenic immunosuppression

In addition to iatrogenic immunosuppression, defects in cell-mediated immunity related to lymphoproliferative disorders (eg, chronic lymphocytic leukemia) predispose to the development of aggressive SCC. 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.^[21] Suppression of the immune system would presumably abrogate this response and might be expected to facilitate the development of SCC.

Tobacco use

The medical and epidemiologic literature contains numerous reports of the association between carcinomas of the head and neck and use of tobacco, including tobacco inhaled as smoke and the smokeless products, such as snuff and chewing tobacco. Although the association is strong and dose related, the issue is more complex than is usually assumed.

Factors that make assessing the role of tobacco in cancer causation difficult are problems with self-reporting, variations in responses to tobacco and tobacco products among individuals, the complex chemical nature of tobacco and its products, and the presence of confounding risk factors or causes.

Self-reporting is notoriously unreliable; therefore, dose dependency is not as reliable as it may seem at first. Moreover, the fact that some individuals have an impressive tobacco exposure history but never develop malignancy highlights the complex relationship of putative etiologic agents. Conversely, some people develop head and neck cancers but have relatively limited tobacco exposure or none at all.

Both smoked and smokeless forms of tobacco contain considerable numbers of putative carcinogens. Therefore, pinpointing the mechanism of tobacco-induced carcinogenesis is exceedingly difficult and largely speculative.

Finally, smokers are likely to have other risk factors or etiologic agents in addition to their tobacco use. Factors such as poor dentition, ethanol use, and poor nutrition are associated with tobacco use. Even more difficult to remove from consideration is the person's age, which is inextricably linked with the years of tobacco use. Age may be one of the most important risk factors for many malignancies.

Alcohol use

An association between alcohol use and human cancer has been observed since 1910, when it was noted in Paris that 80% of patients with esophageal carcinomas were heavy drinkers. Even then, confounders were similar to those noted for tobacco. The fact that absinthe, a fermentation product of wormwood (Artemisia absinthium) accounted for much of the alcohol consumed at that time in Paris suggests a possibility that other substances may have contributed to this association.

Nevertheless, the incidence of head and neck carcinoma is undoubtedly associated with the use of ethanol. In 1998, the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO) concluded that the evidence was sufficient to show that alcoholic beverages are carcinogenic in humans.

SCC of the head and neck is most commonly associated with the use of alcohol and tobacco. Both case-control and cohort studies have shown an association between alcohol and carcinomas of the oral cavity, oropharynx, and larynx. The risk for oral cancer is additive and is up to 40 times greater than in those who neither smoke nor drink. In some studies, the use of both ethanol and tobacco increased the risk of head and neck cancer 100-fold. In SCC, mutations in the TP53 gene correlate with drinking and smoking habits.

The results of one study confirmed that tobacco and alcohol use are the main risk factors for the development of head and neck SCC and affect overall patient survival. However, comparable disease outcomes were found in patients who either did or did not use these substances.^[22]

Age

Head and neck cancers have age-related patterns similar to those of many epithelial malignancies, with rising rates of occurrence closely linked to increasing age. In the United States, the median age at which patients present with oral cancers is 63 years.

Although data show that men and women as young as 25 years can die from oral and/or pharyngeal cancer, the mortality rate steadily increases in subsequent decades.

Familial and genetic predisposition

Genetic profiles are associated with an increased, albeit slight susceptibility for oral carcinoma. Patients with xeroderma pigmentosum, polydysplastic epidermolysis bullosa, or Bloom syndrome are certainly at increased risk for oral cancer. These conditions are fairly uncommon and not major public health issues; however, to the individual and family, they are rightfully of paramount concern.

Familial associations of head and neck cancers have been investigated. Studies have demonstrated many cases of head and neck cancers, and a case report describes identical twins with oral carcinoma. However, the familial cases highlight the problem of assigning a role to genetics versus environmental factors to the development of SCC.

The genetics of nasopharyngeal carcinoma have been studied in some detail. The histocompatibility locus human leukocyte antigen (HLA)-A2 may be a marker for susceptibility to this tumor. Other loci also being considered include HLA-B17 and HLA-Bw46.

Nutritional status

The role of a single factor such as nutritional status is difficult to ascribe with certainty. Diet is often associated with numerous confounders, such as tobacco exposure, lifestyle-related viral exposure, alcohol use, and oral hygiene. However, despite this difficulty, some conclusions are fairly cogent. For example, vitamin A deficiency and iron deficiency associated with Plummer-Vinson syndrome have been linked to oral and pharyngeal cancers.

Nitrosamine-rich fish is a large part of the diet in many regions where nasopharyngeal carcinoma is prevalent. This diet is by no means universal, it does not seem to explain the sexual distribution of the disease, and it is not as compelling as the association of Epstein-Barr virus (EBV) with this malignancy. Malignant epithelial cells harboring EBV have been demonstrated on in situ hybridization (ISH), polymerase chain reaction (PCR) tests, immunohistochemical analysis, and ultrastructural studies.

Vitamins A, D, and E have all been suggested for the prevention or treatment of carcinomas. In addition, increased fruit consumption has shown an effect in preventing malignancy. The role of fruits in the diet may be related to more than simply their vitamin content.

To date no significant, prospective, and comprehensive study has been conducted to evaluate the combined and perhaps synergistic effects of diet, tobacco use, and ethanol consumption.

Concern over the use of alcohol-containing mouthwash in recent years should be addressed. This is a fascinating issue, and some reports suggest that the frequency and duration of the use of such mouthwash may be associated with an increased risk of oral SCC. This finding certainly deserves further study.

Exposure to industrial products and heavy metals

Numerous studies have been undertaken to ascertain the risks of head and neck cancer associated with various occupations and exposures. Studies have demonstrated that individuals working in the heavy-metal, textile, or electronic industry or those exposed to paint fumes, plastic byproducts, asbestos, wood dusts, and gasoline fumes have increased cancer risks. However, these studies were often small surveys, and, in some cases, subsequent studies did not show increased risks.

Exposure to arsenic is a well-established cause of cutaneous SCC and internal cancers.^[23] In the present day, the main source of arsenic is contaminated well water, although arsenic may also be found in traditional Chinese medicines. Other carcinogens associated with SCC include polycyclic aromatic hydrocarbons such as tar, soot, and pitch.

Chronic inflammation or irritation

Likewise, 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 cutaneous SCC,^[24] with an 80% mortality rate within 5 years of diagnosis of SCC^[25] and with two thirds of patients dying from metastatic disease.^[26] In recent years, evidence suggests that patients with junctional epidermolysis bullosa may also be at increased risk for developing SCC.^[27] 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.^[28]

Precisely defining the role of poor oral hygiene in SCC of the oral cavity is difficult; however, they are associated. Poor dentition increases the risk of oral carcinoma, with the use of tobacco and ethanol. Some studies have demonstrated an association with ill-fitting dentures with oral cancer. However, other investigations have not revealed a similar association. Overall, the consensus among oral-cancer investigators is that poor dentition and poor oral hygiene appear to increase the risk of oral SCC.

Gastroesophageal reflux disease is now thought to be a significant risk factor for cancer of the larynx and especially the anterior two thirds of the vocal cords.

Viruses

One of the most exciting developments in oncology within the last 20 years is the investigation of viral oncogenesis. The explosion of research into this topic was the result of 3 major events occurring in a short span: (1) the invention of the PCR in 1983, followed by tens of thousands of reports of this technology used in its first 20 years; (2) the observation of unusual tumor types in association with newly identified and unusual viruses (eg, Kaposi sarcoma and HIV, nasopharyngeal carcinoma, and EBV, and hepatitis virus and hepatocellular carcinoma [HCC]); and (3) improved better understanding of the molecular biology of cancer.

Some 15% of patients with SCC have a viral etiology. In the arena of head and neck cancer, EBV and human papilloma virus (HPV) are both prominent. EBV is a DNA-containing herpes virus that has been implicated in at least 5 distinct malignancies: endemic Burkitt lymphoma, NPC, Hodgkin disease, T-cell lymphoma, and immunoblastic lymphoma. High antibody titers to EBV capsid antigen are observed in more than 80% of patients with nasopharyngeal carcinoma. The geographic distribution of EBV and nasopharyngeal carcinoma in those regions impressively overlap with a high prevalence of EBV infection that corresponds to high incidence of nasopharyngeal carcinoma.

HPV has been demonstrated to be a cause of uterine cervical SCC. Increasing evidence suggests a similar role for HPV in the development of head and neck SCC,^[29] as well as in the carcinogenesis of upper aerodigestive tract tumors. In particular, HPV-16 can be isolated in up to 72% of oropharyngeal cancers. In recent years, the increase in cancer of the tongue and tonsils in developed countries, particularly in patients younger than 45 years, has been linked to HPV infection.^[30] Studies of patients without the commonly assumed risk factors for lung SCC (ie, tobacco use, radiation or asbestos exposure) have revealed a previous history of laryngeal papillomatosis and the same type of HPV present in both the laryngeal papillomata and the lung malignancy.

PCR and ISH have been used to ascertain the role of the various types of HPV in development of SCC of the head and neck. Nearly 100 types of HPV have been identified, and these have been classified as high or low risk with respect to their potential to cause malignancy. Original investigations of this DNA virus and cancer focused on uterine cervical cancer and, to a lesser degree, cutaneous and genital carcinomas.

The International Agency for Research on Cancer (IARC) determined that current evidence only supports HPV types 5 and 8 as possible carcinogens^[31] ; these have been associated with cutaneous SCC in the setting of epidermodysplasia verruciformis and some solid organ transplant patients.^[32] However, HPV-6 and -11 have been associated with Buschke-Lowenstein tumors, whereas HPV-16 has been frequently identified in both genital and periungual SCC, suggesting the possibility of genital-digital spread.^{[33, 34]}

Evidence now suggests that high- or low-risk HPV in 1 anatomic location may not neatly fit the same category in other anatomic locations. As an example, verrucous carcinomas are associated with HPVs in 30-60% of cases examined, depending on the study. When these are found in the larynx, HPV-6 and -11 are frequently identified, whereas in the uterine cervix, these viruses are infrequently found and classified as low risk.

HIV infection and acquired immunodeficiency syndrome (AIDS) are not definitively associated with high-risk SCC; however, an increased incidence of anal and penile SCC associated with HPV has been reported in HIV patients. A high risk of recurrence has been reported after desiccation and curettage in HIV patients,^[35] and a small series reported cases of aggressive cutaneous a 50% mortality rate at 7 years in these patients.^[36]

Exposure to ionizing radiation

External-beam radiation has been used to treat a variety of diseases, such as tonsillar hypertrophy, acne, thyroid disease, and laryngeal papillomatosis. Laryngeal cancers have been statistically associated with previous radiation. Patients treated with radiation for laryngeal carcinoma are well known to develop metachronous carcinomas years later. Therapeutic ionizing radiation is typically associated with the later development of BCCs, but the risk of developing SCCs is also increased.^[37] Most patients with radiation-induced tumors have a remote history of x-ray therapy for acne vulgaris, although patients developing SCC in radiation ports for Hodgkin disease or thyroid cancer treatment is not uncommon.

The incidence of metastasis from cutaneous SCC has been found to be 0.23-2.4% of cases; however, tumors arising from areas of previous radiation therapy may have an incidence of metastasis as high as 20%.^{[38, 39]}

Summary of risk factors that predispose to SCC development

General risk factors associated with the development of SCC are as follows^{[40, 41, 23, 42, 43, 36, 24, 44]} :

• Age older than 50 years
• Male sex
• Tobacco and/or alcohol use
• Geography (closer to the equator)
• History of previous nonmelanoma skin cancer

The following are exposure-related risk factors in the development of cutaneous SCC:

• UV radiation exposure (high cumulative dose of sunshine, tanning beds, or medical UV treatments)
• Immunosuppression (eg, HIV), including iatrogenic immunosuppression (eg, transplant recipients)
• Ionizing radiation (eg, medical treatments, occupational or accidental radiation exposure)
• Infections (eg, HPV, osteomyelitis, acne conglobata, hidradenitis suppurativa, dissecting cellulitis of scalp, lupus vulgaris, lymphogranuloma venereum, granuloma inguinale, and chronic deep fungal infection)
• Chemical carcinogens (eg, arsenic, tar, polyaromatic hydrocarbons)

Host responses that influence cutaneous SCC development include the following:

• Genetic susceptibility and dermatoses (eg, xeroderma pigmentosum, dystrophic epidermolysis bullosa, epidermodysplasia verruciformis, xeroderma pigmentosum, oculocutaneous albinism, dyskeratosis congenita, porokeratosis [Mibelli type, disseminated superficial actinic type, linear type], nevus sebaceous, and KID syndrome [keratitis, ichthyosis, deafness])
• Susceptibility to UV radiation (eg, fair skin [Fitzpatrick skin types I and II], blond or red hair, light-colored eyes)
• Chronic inflammation, such as nonhealing burns or scars (eg, Marjolin ulcer, burn scar or thermal injury, venous ulcer, lymphedema, discoid lupus erythematosus,^[45] erosive oral lichen planus, lichen sclerosis et atrophicus, mutilating keratoderma, and necrobiotic lipoidica)

Skin cancers are the most frequently diagnosed cancers in the United States. More than 1 million estimated new nonmelanoma skin cancers were diagnosed in the United States in 2005, a number that was nearly equivalent to the number of all other cancers diagnosed in the US the same year. Of these cases, approximately 80% are basal cell carcinoma (BCC) and 20% are squamous cell carcinoma (SCC), making cutaneous SCC the second most common skin cancer and one of the most common cancers overall in the US.

On initial presentation, more than 90% of cancers of the head and neck are SCCs. In the US, head and neck carcinomas account for approximately 5% of all malignancies in adults. The percentage is slightly lower than this in women and slightly higher in men. Nevertheless, the low percentage belies the fact that SCC is a major public health problem. The 2004 report by the American Cancer Society illustrates this point dramatically, as shown in Table 1 below.

Table 1. Estimated Number of New Cancer Cases and Deaths in Both Sexes in the United States in 2004 (Open Table in a new window)

Despite increased knowledge and public education regarding the causes of skin cancer and modes of prevention, the incidence of cutaneous SCC continues to rise worldwide. This increasing incidence is likely multifactorial. Speculated causes for the increased incidence of skin cancer include an aging population, improved detection, an 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, SCC formation has been associated with immunosuppressive drug therapy in solid organ transplantation patients, who have a markedly elevated risk of SCC formation. Metastasis may also be more common in this group.^[47]

Patients who live close to the equator tend to present at a younger age than patients who live more distant from the equator. The incidence of the disease varies geographically, 0.03-3.5 cases per 100,000 people per year.

United States statistics

Determining the true incidence of SCC is difficult, because health registries exclude nonmelanoma skin cancer (including SCC) from their databases owing to the high number of cases and limited resources to collect data and due to the varying rate of SCC based on geographic locale.

SCC of the head and neck comprises about 4% of all malignancies. This corresponds to an estimated 17 per 100,000 persons with newly diagnosed SCC of the head and neck per year. Male-to-female incidence rates are greater than 3:1; this discrepancy in the male-to-female ratio is even more pronounced in laryngeal tumors, in which carcinoma is 4-5 times more common in men. This ratio has declined in the last 20 years, possibly reflecting the increased number of women using tobacco products during this period.^[48]

Nasopharyngeal carcinoma most frequently affects individuals aged 40-60 years. In black individuals, the disease peaks in those aged 10-20 years.

Studies also confirm a dramatic increase in the incidence of cutaneous SCC over the past several decades. For example, in Rochester, Minnesota, the annual age-adjusted incidence rates of SCC per 100,000 women rose from 47 cases from 1984-1986 to 100 cases from 1990-1992.^[49] The corresponding rates for men increased from 126 cases to 191 cases per 100,000 population.^[49]

SCC is the most common conjunctival malignancy in the United States and accounts for 4-29% of all oculo-orbital tumors.^[50] Although eyelid SCC is not nearly as common as BCC of the eyelids, previous studies have found this condition to be the second or third most common eyelid malignancy, accounting for approximately 5% of all eyelid neoplasms.^[51] Certain benign and malignant epithelial tumors may simulate SCC both clinically and histopathologically^{[52, 53]} ; earlier studies may have overestimated the frequency of SCC.^[54] Kwitko found that of 115 tumors originally diagnosed as SCC at the Armed Forces Institute of Pathology, only 12 were diagnosed correctly after reevaluation.^{[51, 52]}

International statistics

Prevalence rates of SCC vary in different countries. The highest incidence occurs in Australia, where nonmelanoma skin cancer incidences as high as 1.17 per 100 have been reported, a rate 5 times greater than all other cancers combined. The age-adjusted incidence has been calculated to be 1332 cases per 100,000 population for men and 755 cases per 100,000 population for women. Again, this is likely due to large numbers of light-skinned people in this region who have had extensive sun exposure.^[55]

Laryngeal cancer generally is a disease of the elderly, with a peak incidence in the 50s and 60s. In certain parts of India and Southeast Asia, the practice of mixing cured tobacco with betel nuts has been associated with head and neck cancers. More than 200 million persons are thought to engage in this practice worldwide. A resultant 2.8 times higher relative risk of cancer exists for these individuals, and this increases to more than 10 times when smoking is also practiced. In these areas, the incidence of oral cancer alone is greater than 25 cases per 100,000 persons.^[56]

In some African populations, nasopharyngeal carcinoma is responsible for approximately 15% of childhood malignancies. In fact, in Sudan, nasopharyngeal carcinoma is the most common malignancy of children, and it affects males more frequently than females at a ratio of roughly 3:1.

Racial differences in incidence

SCC is the second leading cause of skin cancer in white individuals.^[1] Persons of Irish or Scottish ancestry have the highest prevalence in the US. SCC is relatively rare in people of African and 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.^[57]

SCC of the conjunctiva is most common in white individuals. The incidence of nasopharyngeal is increased in China, especially Southeast China (about 30 per 200,000 population), as well as in Taiwan, Hong Kong, and Singapore. Northern Canadian and Greenland indigenous peoples also have an incidence of nasopharyngeal carcinoma that is higher than that of the general population. The incidence of this carcinoma among Western people of Caucasian descent is approximately 1 per 200,000 population; the incidence is also higher in parts of Central Africa than in areas of Europe, South America, North America, and Australia. These areas in Africa correspond to areas where the prevalence of EBV infection is high.

Sex- and age-related differences in incidence

SCC occurs in men 2-3 times more frequently than it does in women, most likely as a result of greater cumulative lifetime UV exposure, which may be due to certain occupations that entail more significant exposure to sunlight or other occupational hazards such as soot, oils, or tars.

The typical age at presentation for SCC is approximately 70 years; however, this varies widely, and, in certain high-risk groups (eg, organ transplant recipients, patients with epidermolysis bullosa), SCC often manifests at a much younger age.

Patients with SCC of the conjunctiva tend to be elderly, with an average age of 60 years, whereas immunocompromised individuals develop SCC at a younger age. In a study of cutaneous SCC, the mean age of patients infected with HIV was 49 years, whereas the mean age of patients who were not immunocompromised was 75 years.^{[10, 11]} In addition, Patients with acquired immunodeficiency syndrome (AIDS) have a 13-fold increased risk of developing conjunctival epithelial malignancies; these patients also present at a younger age.

Although patients infrequently die from cutaneous squamous cell carcinoma (SCC), these tumors can cause significant morbidity. Most cutaneous SCCs are located in the head and neck region, where surgery for advance 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. Like many cancers, cutaneous SCC is classified according to the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) "tumor, node, metastasis" (TNM) staging system.^[58] This anatomy-based staging system is designed to stratify patients into general prognostic cohorts based on the size and extent of disease (see SCC Staging and Classification).

Although TNM staging is useful for estimating the outcome for a group of patients with cutaneous SCC who have similar tumor characteristics, it cannot estimate the risk for an individual patient. Palme et al have argued that the staging system for SCC of the head and neck is too simple and should account for the many variables involved in a metastatic SCC of the head and neck to be useful in informing treatment.^[59] It does not take into consideration other tumor and patient factors, such as ultraviolet (UV) radiation exposure, age, and comorbidity, that may also affect prognosis. Therefore, current methods for estimating the outcome of a patient with head and neck cutaneous SCC 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 head and neck cutaneous SCC follow a predictable pattern. In general, most patients with early-stage tumors fare well (overall 5-yr survival rate >90%) when the tumors are adequately treated. Most patients present with early-stage tumors, and the prognosis is reasonably good for completely excised lesions. 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 cutaneous SCC 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 SCC 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 SCC. However, prognostic models do not exist for SCC. Because many of the risk factors discussed below occur concurrently in single tumors and patients, 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. Subsequently, current management of high-risk SCC varies widely.^[60]

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.^[61] These estimates derived from a case series may not be reflective of the risk for SCC in general and may overestimate risk. However, the data highlight that a subset of SCC do poorly.

When SCC does metastasize, it is usually occurs within 5 years from the time of diagnosis and involves the primary (ie, first echelon) draining lymph nodes. In general, metastasis from SCC of the forehead, temples, eyelids, cheeks, and ears is to the parotid nodes; metastasis from SCC of the lips and perioral region is primarily to the submental and submaxillary (upper cervical) nodes.

Once nodal metastasis of cutaneous SCC has occurred, the overall 5-year survival rate is low, as discussed earlier. Patients with a compromised immune system, those with metastasis to multiple lymph nodes, or 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%.^[62] Metastasis to distant organs remains incurable (eg, lung metastasis). 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.

Tumor-related factors in high-risk SCC

Tumor-related factors include the following^[3] :

• 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^[63] )

Additionally, a prospective study of 210 patients with a diverse range of SCCs showed tumor-related factors were associated with adverse disease-specific survival using univariate analyses.^[61] Specifically, these factors were:

• Local recurrence at presentation
• Invasion beyond subcutaneous tissue
• Depth in general
• Perineural invasion
• Size of 4 cm or larger

Detailed information on tumor-related factors such as location, diameter, depth, cellular differentiation, recurrent tumors, 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, a rapid growth rate.

Rapidly growing lesions on the eyelid or ear metastasize in up to one third of cases. Unlike basal cell carcinoma (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.^{[64, 65, 66, 54, 67, 68]}

The morbidity from conjunctival SCC relates to the ocular side effects of the disease and its treatment, as well as regional orbital sequelae, periorbital spread, periorbital sinus involvement, and intracranial involvement (see the following image). Rarely ocular penetration can occur, particularly with the mucoepidermoid type. Death may result from distant or regional metastases, as well as intracranial spread.

Metastatic rates 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%.^[3] Other sites associated with a higher risk of metastasis are the scalp, forehead, temple, eyelid, nose, mucous membranes, hands (dorsal surface), penis, scrotum, and anus.

Primary SCCs on the trunk and limbs have been associated with a metastatic rate of 4.9% in a series that may be 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 metastatic rates of up to 35%,^{[69, 70]} and a mortality rate of 33%.^[71] 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.^[72] Similarly, invasive SCC of the anogenital region carries a greater risk of metastasis. The poor prognosis of both the Marjolin ulcer and anogenital subtypes is likely related to delayed diagnosis.

Diameter

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%, which is 3 times that of smaller lesions. Lesions deeper than 4 mm behave similarly. 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.^[61]

Depth

Depth of infiltration is predictive of prognosis. Increased depth of invasion of SCC is strongly associated with local recurrence, metastasis, and death. That is, with increasing depth of invasion of the primary tumor, the risk of nodal metastasis increases and 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%. A 2008 prospective cohort study found a rate of metastasis of 4% for tumors of 2-6 mm thickness.^[4] For tumors thicker than 6 mm, the risk increased to 16%.

The depth of the lesion associated with the percentage 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%.^[3] The actual value of histologic grading alone, however, is less clear, because poorly differentiated tumors that metastasize or recur also usually have other primary risk factors (eg, large diameter, deep invasion). Nonetheless, poorly differentiated lesions are generally considered to behave more aggressively.

Recurrent tumors

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.^[3] 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, with no disease-specific deaths occurring in those with involvement of nerves less than 0.1 mm in diameter, compared with 32% of patients dying from disease when nerves 0.1 mm or larger were involved.^[73]

Patient-related factors and conditions associated with aggressive SCC

General patient-related factors are (1) organ transplant recipient, (2) hematologic malignancy (eg, chronic lymphocytic leukemia), (3) long-term immunosuppressive therapy, and (4) human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) (see Etiology).

SCC arising in patients with chronic lymphocytic leukemia and small lymphocytic lymphoma carries a worse prognosis. For example, in patients with chronic lymphocytic leukemia, the SCC recurrence rate in those treated with Mohs micrographic surgery was 7-fold higher at 5 years compared with patients without chronic lymphocytic leukemia.^[43] Another study found that SCC in chronic lymphocytic leukemia and small lymphocytic lymphoma patients are often multiple (67%), high grade (56%), and have a high risk of recurrence and metastasis (25%) and death from disease (41%).^[74]

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. In addition, arsenic exposure^[75] and psoralen plus UVA (PUVA) light exposure are associated with aggressive disease.

Patients should be counseled to avoid excessive ultraviolet (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 the neck area. Patients should seek prompt evaluation of suspicious eye lesions, even chronic red eyes, to rule out early ocular surface malignancies. Educating people who live in tropical areas and in regions with a high degree of solar exposure is particularly important. 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 squamous cell carcinoma (SCC). Daily application of a broad-spectrum sunscreen with a sun protection factor (SPF) of at least 15 should also be encouraged.

Recurrences of lesions are possible even years after excision, so patients should have routine examinations. In addition, counsel patients regarding treatment of areas of chronic skin inflammation or trauma to prevent the future development of SCC at those sites.

These measures are 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 and Tumors 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 MMS, see the American College of Mohs Surgery.