SQUAMOUS CELL CARCINOMA

Introduction
Background

Cutaneous squamous cell carcinoma (SCC) is the second most common form of skin cancer and accounts for 20% of cutaneous malignancies.1 Squamous cell carcinoma frequently arises on the sun-exposed skin of middle-aged and elderly individuals. Most squamous cell carcinomas 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 squamous cell carcinoma 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 squamous cell carcinoma.2,3

General risk factors associated with the development of squamous cell carcinoma are as follows4,5,6,7,8,9,10,11 :

* Age older than 50 years
* Male sex
* Light skin; blonde or light brown hair; green, blue, or gray eyes
* Skin that sunburns easily (Fitzpatrick skin types I and II)
* Geography (closer to the equator)
* History of prior nonmelanoma skin cancer
* Exposure to UV light (high cumulative dose of sunshine, tanning beds, or medical UV treatments)
* Exposure to chemical carcinogens (eg, arsenic, tar)
* Exposure to ionizing radiation (medical treatments, occupational or accidental radiation exposure)
* Chronic immunosuppression
* Chronic scarring conditions
* Certain genodermatoses
* Human papillomavirus (HPV) infection (specific subtypes)

Pathophysiology

Squamous cell carcinoma (SCC) is a malignant tumor of epidermal keratinocytes. Some cases of squamous cell carcinoma occur de novo (ie, in the absence of a precursor lesion); however, some squamous cell carcinomas arise from sun-induced precancerous lesions known as actinic keratoses. Patients with multiple actinic keratoses are at increased risk for developing squamous cell carcinoma.12 Squamous cell carcinoma is capable of locally infiltrative growth, spread to regional lymph nodes, and distant metastasis, most often to the lungs.
Frequency
United States

Determining the true incidence of squamous cell carcinoma (SCC) is difficult because health registries exclude nonmelanoma skin cancer (including squamous cell carcinoma) from their databases because of the high number of cases and limited resources to collect data and because the rate of squamous cell carcinoma varies based on geographic locale. In 1994, the annual incidence in the United States ranged from 81-136 cases per 100,000 population for men and 26-59 cases per 100,000 population for women.13

Studies also confirm a dramatic increase in the incidence of cutaneous squamous cell carcinoma over the past several decades. For example, in Rochester, Minnesota, the annual age-adjusted incidence rates of squamous cell carcinoma 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.14

One reason for the rising incidence of squamous cell carcinoma may be an increase in sun exposure in the general population. Some postulate that ozone depletion may be intensifying UV exposure. Other factors that may contribute to the increased incidence of squamous cell carcinoma include the advancing age of the US population, earlier and more frequent diagnosis of squamous cell carcinoma due to enhanced public awareness of skin cancer, and more frequent skin examinations by physicians.

Additionally, the number of patients on immunosuppressive therapy, used in solid organ transplantation and various rheumatologic and dermatologic conditions, is increasing. Squamous cell carcinoma formation has been associated with immunosuppressive drug therapy in solid organ transplantation patients, who have a markedly elevated risk of squamous cell carcinoma formation. Metastasis also may be more common in this group.15
International

Prevalence rates of squamous cell carcinoma (SCC) vary in different countries. The highest incidence occurs in Australia, where 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.16
Mortality/Morbidity

Most squamous cell carcinomas (SCCs) are readily treated and produce few sequelae. A subset of high-risk lesions causes most of the morbidity and the mortality associated with squamous cell carcinoma. Such lesions may cause extensive destruction of tissue, and their removal may entail substantial cosmetic deformity. The overall risk of metastasis for squamous cell carcinoma is in the range of 2-6%; however, rates as high as 47% have been reported for cases with extensive perineural invasion. Lymph node metastasis is associated with significant morbidity; however, 5-year survival rates as high as 73% have been achieved with the combination of surgical lymphadenectomy and radiation therapy.17 Once lung metastasis occurs, the disease is currently incurable.
Race

Squamous cell carcinoma (SCC) is the second leading cause of skin cancer in whites.1 Persons of Irish or Scottish ancestry have the highest prevalence in the United States. Squamous cell carcinoma is relatively rare in people of African and Asian descent, although it is the most common form of skin cancer in these groups. Squamous cell carcinoma in blacks 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.18
Sex

Squamous cell carcinoma (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.
Age

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

A detailed patient history often reveals the presence of one or more risk factors for squamous cell carcinoma (SCC) (see general risk factors in Background). Most squamous cell carcinomas are discovered by patients and are brought to a physician's attention by the patient or a relative. The typical squamous cell carcinoma manifests as a new or enlarging lesion that concerns the patient. Squamous cell carcinoma is typically a slow-growing malignancy, but some lesions enlarge rapidly. Although most squamous cell carcinoma patients are asymptomatic, symptoms such as bleeding, weeping, pain, or tenderness may be noted, especially with larger tumors. Numbness, tingling, or muscle weakness may reflect underlying perineural involvement, and this history finding is important to elicit because it adversely impacts prognosis.19

Actinically derived squamous cell carcinoma

The most common type of squamous cell carcinoma is the sun-induced type. As such, a history of long-term sun exposure dating back to childhood is frequently elicited. Many patients report having experienced multiple blistering sunburns during their lifetime, while others may have used indoor tanning beds or received UV light therapy (eg, psoralen plus UVA [PUVA] for psoriasis). Patients may have been treated in the past for sun-induced lesions such as actinic keratoses, basal cell carcinoma, melanoma, or squamous cell carcinoma.

Immune suppression

Patients should always be questioned about possible sources of immunosuppression. A history of solid-organ transplantation, hematologic malignancy (particularly chronic lymphocytic leukemia), HIV infection or AIDS, or long-term use of immunosuppressive medications (eg, as treatment for an autoimmune condition) may be elicited.

Marjolin ulcer

This eponym most frequently refers to a squamous cell carcinoma that arises from chronically scarred or inflamed skin; however, malignant transformation to a basal cell carcinoma, melanoma, or sarcoma may also occur.20 Patients may report a change in the skin (eg, induration, elevation, ulceration, weeping) at the site of a preexisting scar or ulcer. The average latency period is 35 years21 ; therefore, the diagnosis requires a high index of clinical suspicion. Marjolin ulcers are associated with a high rate of metastasis, estimated at 30%,22,23 and a mortality rate of 33%.24

HPV-associated squamous cell carcinoma

Virally induced squamous cell carcinoma most commonly manifests as a new or enlarging warty growth on the penis, vulva, perianal area, or periungual region. Patients often present with a history of "warts" that have been refractory to various treatment modalities in the past. A history of previously documented genital HPV infection may be elicited.
Physical

Squamous cell carcinoma (SCC) may manifest as a variety of primary morphologies, with or without associated symptoms. Note the following:

Squamous cell carcinoma in situ

Squamous cell carcinoma in situ is defined histologically by atypia involving the full thickness of the epidermis but without invasion into the dermis. Clinically, lesions of squamous cell carcinoma in situ range from a scaly pink patch to a thin keratotic papule or plaque similar to an actinic keratosis. Bowen disease is a subtype of squamous cell carcinoma in situ characterized by a sharply demarcated pink plaque arising on non–sun-exposed skin. Erythroplasia of Queyrat refers to Bowen disease of the glans penis, which manifests as one or more velvety red plaques.

Note the images below.

Sun-induced squamous cell carcinoma on the face w...
Sun-induced squamous cell carcinoma on the face with overlying hyperkeratosis, a common feature.

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Sun-induced squamous cell carcinoma on the face w...

Sun-induced squamous cell carcinoma on the face with overlying hyperkeratosis, a common feature.

Squamous cell carcinoma of the penis. Courtesy of...
Squamous cell carcinoma of the penis. Courtesy of Hon Pak, MD.

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Squamous cell carcinoma of the penis. Courtesy of...

Squamous cell carcinoma of the penis. Courtesy of Hon Pak, MD.

Typical squamous cell carcinoma

The characteristic invasive squamous cell carcinoma is a raised, firm, pink-to-flesh–colored keratotic papule or plaque arising on sun-exposed skin. Approximately 70% of all squamous cell carcinomas occur on the head and neck, with an additional 15% found on the upper extremities. Surface changes may include scaling, ulceration, crusting, or the presence of a cutaneous horn. Less commonly, squamous cell carcinoma may manifest as a pink cutaneous nodule without overlying surface changes. The absence of surface changes should raise suspicion of a metastatic focus from another skin or nonskin primary site or a different and potentially more lethal tumor such as Merkel cell carcinoma. A background of severely sun-damaged skin, including solar elastosis, mottled dyspigmentation, telangiectasia, and multiple actinic keratoses, is often noted.

Note the images below.

Sun-induced squamous cell carcinoma on the face w...
Sun-induced squamous cell carcinoma on the face with superficial erosion.

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Sun-induced squamous cell carcinoma on the face w...

Sun-induced squamous cell carcinoma on the face with superficial erosion.

Squamous cell carcinoma. Courtesy of Hon Pak, MD.
Squamous cell carcinoma. Courtesy of Hon Pak, MD.

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Squamous cell carcinoma. Courtesy of Hon Pak, MD.

Squamous cell carcinoma. Courtesy of Hon Pak, MD.

Periungual squamous cell carcinoma

Periungual squamous cell carcinoma typically mimics a verruca and is frequently misdiagnosed for years as a wart prior to biopsy. Less commonly, lesions may resemble chronic paronychia with swelling, erythema, and tenderness of the nail fold; onychodystrophy also may be noted. Periungual squamous cell carcinomas are frequently associated with HPV.25

Marjolin ulcer

This subtype of squamous cell carcinoma appears as a new area of induration, elevation, or ulceration at the site of a preexisting scar or ulcer. Patients with this form of squamous cell carcinoma can have a poor prognosis. The diagnosis of Marjolin ulcer should be considered in any ulcer that fails to heal with standard therapy.

Perioral squamous cell carcinoma

Squamous cell carcinoma of the lip usually arises on the vermillion border of the lower lip. It is sometimes predated by a precursor lesion, actinic cheilitis, which manifests as xerosis, fissuring, atrophy, and dyspigmentation. Actinic cheilitis is analogous to actinic keratosis of the skin. Squamous cell carcinoma on the lip manifests as a new papule, erosion, or focus of erythema/induration. Intraoral squamous cell carcinoma typically manifests as a white plaque (leukoplakia) with or without reddish reticulation (erythroplakia). Common locations include the anterior floor of the mouth, the lateral tongue, and the buccal vestibule.

Anogenital squamous cell carcinoma

Squamous cell carcinoma in the anogenital region may manifest as a moist, red plaque on the glans penis; indurated or ulcerated lesions may be seen on the vulva, external anus, or scrotum. Associated symptoms include pain, pruritus, and intermittent bleeding. These squamous cell carcinomas are also associated with HPV infection.

Verrucous carcinoma

Verrucous carcinoma is a subtype of squamous cell carcinoma that can be locally destructive but rarely metastasizes. Lesions appear as exophytic, fungating, verrucous nodules or plaques, which may be described as cauliflowerlike. Verrucous carcinoma is further subdivided based on its location in the anogenital region (Buschke-Löwenstein tumor), the oral cavity (oral florid papillomatosis), and the plantar foot (epithelioma cuniculatum).

Lymphadenopathy

With any invasive (not in situ) squamous cell carcinoma, regional lymph nodes should be examined. Lymph node enlargement must be further evaluated by fine-needle aspiration (FNA) or nodal biopsy.
Causes

The primary cause of most squamous cell carcinoma (SCC) is cumulative lifetime sun exposure. The frequency of squamous cell carcinoma is increased at lower latitudes, correlating with an increased intensity of ambient light. Other causes of squamous cell carcinoma are discussed below.

UV sunlight exposure

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.26

UVB-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.27

Inactivation of the tumor suppressor gene TP53 occurs in up to 90% of all cutaneous squamous cell carcinoma lesions.28 Other tumor suppressor genes found to be mutated in squamous cell carcinoma include P16 (INK4a) and P14 (ARF).29

Therapeutic UV exposure

UV light treatments used for psoriasis (and other recalcitrant dermatoses) also predispose to the development of squamous cell carcinoma. PUVA is particularly phototoxic and mutations in both TP53 and the oncogene Ha-Ras are present in a large proportion of PUVA-associated squamous cell carcinoma.30 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

Individuals with skin types I and II account for most of the patients who develop squamous cell carcinoma; patients with oculocutaneous albinism are also at risk, and squamous cell carcinomas 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.31

Ionizing radiation

Therapeutic ionizing radiation is typically associated with the later development of basal cell carcinomas, but the risk of developing squamous cell carcinomas is also increased.32 Most patients with radiation-induced tumors have a remote history of x-ray therapy for acne vulgaris, although patients developing squamous cell carcinoma in radiation ports for Hodgkin disease or thyroid cancer treatment is not uncommon.

Chemical carcinogens

Exposure to arsenic is a well-established cause of cutaneous squamous cell carcinoma and internal cancers.6 Today, the main source of arsenic is contaminated well water, although arsenic may also be found in traditional Chinese medicines. Other carcinogens associated with squamous cell carcinoma include polycyclic aromatic hydrocarbons such as tar, soot, and pitch.

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 squamous cell carcinomas, and, less commonly, other cutaneous tumors.33

Iatrogenic immunosuppression

The use of immunosuppressive medications to prevent rejection in organ transplant recipients is associated with a 65- to 250-fold increased risk of developing squamous cell carcinoma compared with the general population.34

The primary risk factor in these 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.

The greatest risk occurs in heart transplant patients, with diminishing risk seen in recipients of kidney and liver transplants, which correlates with the degree of immunosuppression (ie, number and/or dosage of medications) typically required to prevent rejection in these patient populations.

Pretransplantation end-organ disease may also impact the development of post-transplant squamous cell carcinoma. For example, among renal transplant recipients, the highest prevalence of skin cancer was observed in patients with polycystic kidney disease, while 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

In addition to iatrogenic immunosuppression, defects in cell-mediated immunity related to lymphoproliferative disorders (eg, chronic lymphocytic leukemia) predispose to the development of aggressive squamous cell carcinoma. The specific mechanisms by which immunosuppression leads to squamous cell carcinoma 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 squamous cell carcinoma, suggesting that a functional immune system may target keratinocytes expressing mutated TP53.35 Suppression of the immune system would presumably abrogate this response and might be expected to facilitate the development of squamous cell carcinoma.

Human papillomavirus

Infection with specific subtypes of HPV is believed to play a role in the development of anogenital and periungual squamous cell carcinoma. Attempts to definitively link squamous cell carcinoma to HPV have yielded contradictory results, as most squamous cell carcinomas tumors outside of anogenital and periungual sites do not contain HPV. The International Agency for Research on Cancer (IARC; Lyon, France) has determined that current evidence only supports HPV types 5 and 8 as possible carcinogens.36 However, HPV types 6 and 11 have been associated with Buschke-Löwenstein tumors, whereas HPV type 16 has been frequently identified in both genital and periungual squamous cell carcinoma, suggesting the possibility of genital-digital spread.37,38 HPV types 5 and 8 have been associated with cutaneous squamous cell carcinoma in the setting of epidermodysplasia verruciformis and some solid organ transplant patients.39

Chronic inflammation

Chronic inflammation, irrespective of the underlying etiology, may lead to the development of squamous cell carcinoma. Both noninfectious inflammatory diseases and chronic infections have been associated with squamous cell carcinoma.

Likewise, the Marjolin ulcer variant of squamous cell carcinoma 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 squamous cell carcinoma,10 with an 80% mortality rate within 5 years of diagnosis of squamous cell carcinoma40 and with two thirds of patients dying from metastatic disease.41 More recently, evidence suggests that patients with junctional epidermolysis bullosa may also be at increased risk for developing squamous cell carcinoma.42 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 squamous cell carcinoma.43

Conditions that predispose to the development of squamous cell carcinoma

Chronic inflammatory and scarring conditions are as follows:

* Burn scar or thermal injury
* Venous ulcer
* Lymphedema
* Discoid lupus erythematosus
* Erosive oral lichen planus
* Lichen sclerosis et atrophicus
* Mutilating keratoderma
* Necrobiotic lipoidica

Chronic infections are as follows:

* Osteomyelitis
* Acne conglobata
* Hidradenitis suppurativa
* Dissecting cellulitis of scalp
* Lupus vulgaris
* Lymphogranuloma venereum
* Granuloma inguinale
* Chronic deep fungal infection

Genetic syndromes and dermatoses are as follows:

* Dystrophic epidermolysis bullosa
* Epidermodysplasia verruciformis
* Xeroderma pigmentosum
* Oculocutaneous albinism
* Dyskeratosis congenita
* Porokeratosis (Mibelli type, disseminated superficial actinic type, linear type)
* Nevus sebaceous
* KID (keratitis, ichthyosis, deafness) syndromeDifferential Diagnoses
Actinic Keratosis
Warts, Genital
Atypical Fibroxanthoma
Warts, Nongenital
Basal Cell Carcinoma

Keratoacanthoma

Pyoderma Gangrenosum

Workup
Imaging Studies

Imaging is not routinely indicated for diagnosing cutaneous (SCC). However, radiologic imaging should be obtained in patients with regional lymphadenopathy and/or neurologic symptoms suggestive of perineural involvement, for nodal staging, and for preoperative planning in patients in whom deep or extensive tissue involvement is suspected. CT scanning, MRI, ultrasonography, or positron-emission tomography (PET) scanning may be used depending on the specific question being addressed, although the selection of one modality over another is often based on clinician and institutional preference. Currently, no formal guidelines have been developed regarding the use of radiologic imaging in cutaneous squamous cell carcinoma.

Disease staging workup in high-risk squamous cell carcinoma

Physical examination of lymph nodes

In all squamous cell carcinoma patients, the draining nodal basins should be palpated. If nodes are palpable, a biopsy should be performed using fine-needle aspiration (FNA) or excision. If lymph nodes are clinically negative but the tumor meets high-risk criteria, little data are available to guide what should be done next. Subsequently, management currently varies with regard to further staging.44 See "High-risk squamous cell carcinoma" in Prognosis.

Radiologic staging

Only a few studies have reported on the utility of radiologic imaging in cutaneous squamous cell carcinoma. One study of MRI and CT scanning in patients with histologically proven perineurally invasive squamous cell carcinoma showed that only 20% of asymptomatic patients have positive findings discovered from imaging studies. Thus, CT scanning and MRI appear to be poor in detecting asymptomatic nerve involvement. However, positive imaging findings did correlate with worse outcomes. The 5-year survival rate was 50% if CT scanning or MRI findings were positive, versus 86% if they were negative.45

Two studies reported on radiologic imaging for detecting subclinical nodal metastasis.46 The first, a study of vulvar squamous cell carcinoma, indicated that ultrasonography followed by FNA for suspicious nodes was superior to CT scanning in staging subclinical nodal metastasis, with ultrasound-guided FNA demonstrating 80% sensitivity and 100% specificity. The second is a small study of PET scanning in 9 patients with high-risk squamous cell carcinoma. PET scanning detected subclinical nodal metastasis in 3 of 9 patients.47 Thus, PET scanning and ultrasound-guided FNA may be capable of detecting many cases of subclinical nodal metastasis.

Sentinel lymph node biopsy

A review of the 85 reported cases of sentinel lymph node biopsy (SLNB) in high-risk, nonanogenital cutaneous squamous cell carcinoma showed that 21% of cases were positive based on SLNB findings. This indicates that SLNB likely can detect many cases of subclinical nodal metastasis. How the sensitivity of SLNB compares with that of PET scanning or ultrasound-guided FNA and whether detection of subclinical nodal metastasis impacts survival are unknown.48 However, because the 5-year survival rate of patients with nodal metastasis is as high as 73% with aggressive treatment,17 early detection of nodal metastasis may prove more beneficial in squamous cell carcinoma than in melanoma.

Summary

Little data are available to guide decisions about staging of nodal basins in high-risk squamous cell carcinoma. However, PET scanning, ultrasound-guided FNA, and SLNB all appear to offer a good chance of detecting subclinical nodal metastasis with low morbidity. Thus, nodal staging may be considered in patients with high-risk squamous cell carcinoma. Development of prognostic models that better predict the risk of nodal metastasis will allow for more rational decisions about which patients should undergo nodal staging.
Procedures

Skin biopsy

Although the diagnosis of squamous cell carcinoma (SCC) is often strongly suggested based on clinical findings, a skin biopsy is required for definitive diagnosis. A shave biopsy, punch biopsy, incisional biopsy, or excisional biopsy may be used. The biopsy is routinely performed in the physician's office after the patient is given a local anesthetic.

All skin biopsy samples obtained to diagnose squamous cell carcinoma must reach at least the depth of the mid dermis to allow for a determination of the presence or absence of invasive disease. For high-risk lesions, a larger sample may be helpful to assess for perineural invasion and other histologic features that confer a greater risk of metastasis. Given recent information about depth being an important prognostic factor (analogous to melanoma), a large punch biopsy through the center of the lesion or excisional biopsy may be best, particularly in high-risk lesions or immunosuppressed patients.3

Pathologic analyses may be completed by a dermatologist or a general pathologist, but they are preferably completed by a dermatopathologist with extensive experience in squamous cell carcinoma.

Patients with regional lymphadenopathy identified by clinical examination or imaging studies should undergo a lymph node biopsy or FNA for histologic evaluation. SLNB has been used to identify micrometastasis in patients with high-risk squamous cell carcinoma and clinically negative nodes, with 21% positivity.48 While SLNB appears to be able to detect most subclinical metastasis, whether early detection of lymph node metastasis leads to enhanced survival in squamous cell carcinoma is unknown, because controlled studies have not been conducted. Complete lymphadenectomy of the draining nodal basin has also been suggested for high-risk tumors with an estimated metastatic risk of 20% or greater. However, because prognostic models do not exist, knowing precisely which patients fall into this category is difficult. Thus, when it is feasible, SLNB offers a low-morbidity approach to accurately staging high-risk squamous cell carcinoma.
Histologic Findings

The biopsy report for squamous cell carcinoma (SCC) often carries prognostic implications. Recognizing the implications of the various histologic subtypes of squamous cell carcinoma is important, and the astute clinician uses his or her understanding of histopathology to advantage in planning the appropriate therapeutic intervention.

Squamous cell carcinoma in situ is characterized by an intraepidermal proliferation of atypical keratinocytes. Hyperkeratosis, acanthosis, and confluent parakeratosis are seen within the epidermis, and the keratinocytes lie in complete disorder, resulting in the classic "windblown" appearance. Cellular atypia, including pleomorphism, hyperchromatic nuclei, and mitoses, is prominent. Atypical keratinocytes may be found in the basal layer and often extend deeply down hair follicles, but they do not invade the dermis.

The main feature that distinguishes invasive squamous cell carcinoma from squamous cell carcinoma in situ is invasion of malignant keratinocytes through the basement membrane and into the dermis. Keratinization results in the production of squamous eddies or keratin pearls. The neoplastic cells may demonstrate varying degrees of squamous differentiation and atypia. If the tumor is poorly differentiated, this fact is typically reported by the dermatopathologist because the degree of differentiation has prognostic implications (ie, poorly differentiated tumors have been associated with a higher risk of metastasis).

Several variants of squamous cell carcinoma can be distinguished by clinical and/or histologic criteria. In some cases, these tumors may be difficult to distinguish from other malignancies based on routine histology findings alone. Therefore, immunohistochemical staining with antibodies to cytokeratins and epithelial membrane antigen is often used to confirm the epithelial (ie, keratinocyte) origin of the tumor. The salient features of keratoacanthoma, spindle cell squamous cell carcinoma, acantholytic (adenoid) squamous cell carcinoma, and verrucous carcinoma are highlighted in the following table.

Histologic and Clinical Features of Squamous Cell Carcinoma Variants

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Table
Tumor
Histologic Characteristics
Clinical Characteristics
Keratoacanthoma
Keratin-filled crater
Well-differentiated (mild atypia)
Neutrophil microabscesses
Eosinophils in dermal infiltrate
Elastic tissue trapping
Lack of acantholysis
Solitary nodule
Central craterlike depression
Rapid growth
May spontaneously involute
Spindle cell SCC
Atypical spindle cells
Foci of squamous differentiation
May resemble other spindle cell tumors (eg, atypical fibroxanthoma)
Resembles typical SCC
May be clinically aggressive

Acantholytic (adenoid) SCC
Glandlike differentiation
Acantholysis
May resemble adenocarcinoma or sweat gland carcinoma
Arises on sun-damaged skin
Elderly patients
Resembles typical SCC
Clinically aggressive
Verrucous carcinoma
Well-differentiated (glassy atypia)
Surface resembles verruca
Bulbous downward proliferation
"Bulldozing" invasion
Oral, genital, or plantar foot
Indolent growth
Locally destructive
Rarely metastasizes
Sarcomatoid SCC
Poorly differentiated cells resembling sarcoma
Clinical appearance may be that of typical SCC or may have more nodular appearance with less surface change
Elevated risk of local recurrence and metastasis
Tumor
Histologic Characteristics
Clinical Characteristics
Keratoacanthoma
Keratin-filled crater
Well-differentiated (mild atypia)
Neutrophil microabscesses
Eosinophils in dermal infiltrate
Elastic tissue trapping
Lack of acantholysis
Solitary nodule
Central craterlike depression
Rapid growth
May spontaneously involute
Spindle cell SCC
Atypical spindle cells
Foci of squamous differentiation
May resemble other spindle cell tumors (eg, atypical fibroxanthoma)
Resembles typical SCC
May be clinically aggressive

Acantholytic (adenoid) SCC
Glandlike differentiation
Acantholysis
May resemble adenocarcinoma or sweat gland carcinoma
Arises on sun-damaged skin
Elderly patients
Resembles typical SCC
Clinically aggressive
Verrucous carcinoma
Well-differentiated (glassy atypia)
Surface resembles verruca
Bulbous downward proliferation
"Bulldozing" invasion
Oral, genital, or plantar foot
Indolent growth
Locally destructive
Rarely metastasizes
Sarcomatoid SCC
Poorly differentiated cells resembling sarcoma
Clinical appearance may be that of typical SCC or may have more nodular appearance with less surface change
Elevated risk of local recurrence and metastasis
Staging

Squamous cell carcinoma (SCC) is staged according to American Joint Committee on Cancer (AJCC) guidelines, which use the tumor, node, metastasis (TNM) classification system.49 This staging system has been updated to incorporate information about tumor factors that impact prognosis. Cutaneous squamous cell carcinoma of the eyelid is excluded from the updated system.

The previous staging system had classified tumor stage based solely on tumor diameter and invasion of deep structures (cartilage, muscle, or bone). Along with tumor diameter, the new system incorporates the following high-risk features:

* Greater than 2 mm thickness or Clark level greater than or equal to IV
* Perineural invasion
* Primary anatomic location on the ear or non–hair-bearing lip
* Poorly differentiated or undifferentiated cellular histology

T1 tumors are those 2 cm or less in diameter and with 0 or 1 high-risk features. T2 tumors are those with diameters exceeding 2 cm or with 2 or more high-risk features. T3 tumors are those involving facial bones (maxilla, mandible, orbit, or temporal). T4 tumors are those with other bone involvement or with perineural invasion involving the skull base.

The new TNM staging system has also revised nodal staging. Previously, the system had only had a single N1 level to signify nodal involvement. The new system has 5 levels. The decision to stage patients according to extent of nodal disease was based on significant findings of several studies, both prospective and retrospective, showing that the number and size of lymph node involvement correlated with patient prognosis.50,51,52,53,54

In the new staging system, N1 disease involves a single ipsilateral node 3 cm or smaller in its largest dimension. N2a disease includes cases with a single ipsilateral node greater than 3 cm but less than or equal to 6 cm. N2b refers to those with multiple ipsilateral nodes smaller than or equal to 6 cm. N2c includes cases of bilateral or contralateral involvement less than or equal to 6 cm. N3 disease is reserved for cases with any involved node greater than 6 cm.

In early 2010, Milross et al proposed an alternative nodal staging system (the N1S3), which also stages cutaneous squamous cell carcinoma patients based on the number (single or multiple) and size (< or > 3 cm) of lymph nodes involved, but also incorporates the parotid as one of the regional levels. Stage I disease refers to those with a single lymph node measuring less than or equal to 3 cm. Stage II includes cases with a single lymph node greater than 3 cm or multiple lymph nodes less than or equal to 3 cm, while stage III is any patient with multiple lymph nodes greater than 3 cm.55 This system was found to have a significant predictive capacity for locoregional control (P <.0001), disease-specific survival (P <.0001), and overall survival (P <.0001) in a group of 215 patients and was reproduced on external validation in a cohort of 250 patients. Distant metastases are staged according to the presence (M1) or absence (M0) of metastases in distant organs or sites outside of regional lymph nodes. This remains unchanged from the previous TNM staging system Stage 0 is equivalent with in situ disease. Disease stages I and II include patients with T1 and T2 tumors, respectively who have no nodal or distant metastasis (N0, M0). Stage III disease includes T3 cases without nodal involvement (N0) or cases with N1 involvement. Stage IV includes those with T4 disease, or N2 or N3 disease, or distant metastasis (M1).Treatment Medical Care Nonsurgical options for the treatment of cutaneous squamous cell carcinoma (SCC) include topical chemotherapy, topical immune response modifiers, photodynamic therapy (PDT), radiotherapy, and systemic chemotherapy. The use of topical therapy and PDT is generally limited to premalignant (ie, actinic keratoses) and in situ lesions. Radiation therapy is a primary treatment option for patients in whom surgery is not feasible and is an adjuvant therapy for those with metastatic or high-risk cutaneous squamous cell carcinoma. In current practice, systemic chemotherapy is used exclusively for patients with metastatic disease. However, newer, more targeted drugs, such as epidermal growth factor receptor (EGFR) antagonists (eg, cetuximab), have favorable adverse effect profiles and await trails to determine if they are beneficial in high-risk squamous cell carcinoma. Topical chemotherapy Topical formulations of 5-fluorouracil (5-FU) are available for the treatment of actinic keratoses and superficial basal cell carcinomas. Successful treatment of in situ squamous cell carcinoma has also been reported.56 Invasive squamous cell carcinoma should not be treated with topical chemotherapy. An oral form of a 5-FU prodrug (capecitabine), which is approved by the US Food and Drug Administration (FDA) for other forms of cancer, may be considered in patients with diffuse in situ squamous cell carcinoma over large skin areas, on which topical 5-FU is difficult to apply. However, studies of efficacy have not yet been performed. Topical immune response modifiers Imiquimod is an imidazoquinoline that enhances cell-mediated immune responses via the induction of proinflammatory cytokines. It is approved by the FDA for the treatment of genital warts (ie, condylomata acuminata), actinic keratoses, and superficial basal cell carcinoma. Imiquimod cream has also shown effectiveness in the treatment of Bowen disease as monotherapy and in combination with topical 5-FU. However, systemic flulike symptoms and other adverse effects can occur when applied to large surface areas; therefore, using this agent in patients with diffuse in situ squamous cell carcinoma is difficult.57,58 Photodynamic therapy Treatment with PDT involves the application of a photosensitizer (given topically or systemically) followed by exposure to a light source. The resulting photochemical reaction causes inflammation and destruction of the targeted lesion(s). PDT is used primarily to treat large numbers of actinic keratoses in a single session. Squamous cell carcinoma in situ is also amenable to PDT, although a wide range of recurrence rates (0-52%) have been reported. A study of organ transplant recipients with multiple actinic keratoses and field actinic damage showed PDT to be superior to topical 5-FU.59 A 2009 noncomparative study showed repeated cycles of PDT to be associated with significant reduction in squamous cell carcinoma formation in organ transplant recipients.60 At this time, PDT is not recommended for treatment of invasive squamous cell carcinoma due to poor long-term cure rates.61 Radiation therapy Primary radiation therapy as a treatment option for squamous cell carcinoma offers the potential advantage of avoiding the deformity and trauma of a surgical procedure. Cure rates for T1 lesions range from 85-95%. However, a number of disadvantages are associated with radiation therapy. For example, radiation therapy is expensive and requires a significant time commitment because treatments are usually given 3-5 times per week for 4-8 weeks. Most patients experience significant irritation at the radiation site, and they frequently develop erythema, erosions, alopecia, and pain, which may require narcotic-level analgesia. Although the initial cosmetic result following radiation is usually good, the long-term outcome is often poor, owing to the development of cutaneous atrophy, dyspigmentation, and telangiectasia in the radiation field. Patients treated with radiation also have a slightly increased risk of developing cutaneous carcinoma (most commonly squamous cell carcinoma) or sarcoma later in life. Radiation therapy does not involve histologic margin control and has a lower cure rate compared with surgery. For these reasons, as well as those discussed in the preceding paragraph, radiation as a primary therapy is usually confined to a small subset of tumors in which the cosmetic or functional outcome would be superior to that of surgery62 or in elderly patients with inoperable squamous cell carcinoma. In contrast, radiation is routinely used as an adjunct to surgical treatment in cases of nodal metastasis, and the reported 5-year cure rate is 73% for combined surgical and radiation therapy to involved nodal basins.17 Squamous cell carcinomas with advanced perineural invasion have an elevated risk of recurrence, even when surgical margins are thought to be clear.44,48,63 Thus, adjuvant radiation may be considered, particularly in cases involving larger nerves, although its utility has yet to be proven. A systematic review analyzing all reports related to outcomes of high-risk squamous cell carcinoma treated with surgical monotherapy compared with those treated with surgery plus adjuvant radiation64 was unable to show an advantage of adjuvant radiation in the treatment of squamous cell carcinoma with perineural invasion. However, the available studies were uncontrolled for tumor stage and more advanced tumors with a worse baseline prognosis likely received radiation. In summary, the additional benefit of adjuvant radiotherapy is uncertain, especially when clear surgical margins are obtained. However, it may be considered in patients with multiple high-risk factors, those with significant nerve involvement (particularly named nerves or nerves >0.1 mm in diameter), those with uncertain surgical margins (eg, poorly differentiated, infiltrative, or multiply-recurrent tumors), or as salvage therapy for in-transit metastasis or other tumors which cannot be cleared surgically. A lower threshold for adjuvant radiation should be used in immunocompromised patients with high-risk squamous cell carcinoma.64

Systemic chemotherapy

A variety of different chemotherapeutic agents have been used to treat metastatic cutaneous squamous cell carcinoma. Many of the current protocols have been adapted from those used to treat metastatic head and neck squamous cell carcinoma.

Cisplatin-based combination chemotherapy with 5-FU, methotrexate, bleomycin, and doxorubicin have all been used to treat advanced squamous cell carcinoma with variable outcomes.

The oral 5-FU prodrug, capecitabine (Xeloda), has been designed to be metabolized to 5-FU selectively within tumor tissues, thus producing less systemic toxicity. Either used alone, or in combination with interferon alfa, it has shown some efficacy in the treatment of advanced cutaneous squamous cell carcinoma.65

More recently, cetuximab, an EGFR inhibitor, has had reported as successful in several case reports.66,67,68 In the head and neck literature, phase I and II trials of capecitabine, used with cisplatin or paclitaxel69,70 or in combination with radiation therapy71 also showed favorable outcomes. EGFR inhibitors are well tolerated with relatively low risks, so they may be considered in cases not amenable to surgery or radiation or as an adjuvant in cases considered to have a high risk of death.

Reduction in immunosuppression

In organ transplant recipients, a reduction in the magnitude of immunosuppression may be an effective adjuvant therapeutic strategy in the treatment of aggressive squamous cell carcinoma. Because a decrease in immunosuppression may increase the risk for rejection of the transplanted organ, this strategy should only be considered in selected high-risk patients and under the careful management of the transplantation physician, who must closely monitor the patient for signs and symptoms of organ rejection.72

Newer immunosuppressive agents (eg, sirolimus) are associated with a lower incidence of squamous cell carcinoma when compared with more traditional agents (eg, calcineurin inhibitors), without compromise in graft function.73,74 Patients on sirolimus also produce thinner, less vascularized tumors,75 likely due to the drug’s antiangiogenic and antitumor properties. In a study of 182 organ transplant recipients, the mean cumulative doses of prednisone, cyclosporine, azathioprine, and mycophenolate were significantly higher in those with skin cancer. Conversely, the cumulative doses of sirolimus and tacrolimus were significantly lower in those with skin cancer, suggesting that these drugs may be protective.
Surgical Care

Most squamous cell carcinomas (SCCs) are readily treated in the physician's office by surgical or destructive methods, with a high expectation of cure. The treatment of squamous cell carcinoma must take into account multiple patient- and lesion-specific factors. The standard modalities available for the treatment of localized (primary) invasive squamous cell carcinoma are described below. Because squamous cell carcinoma is a lesion that can recur, metastasize, and cause death, and, because recurrent squamous cell carcinoma carries a worse prognosis, every opportunity should be taken to effect complete tumor extirpation at first presentation.

Cryotherapy

Cryotherapy with liquid nitrogen is a safe and low-cost procedure for the ablation of selected in situ squamous cell carcinomas. The 5-year cure rate for squamous cell carcinoma can be 95% or greater with proper tumor selection and technique. In the United States, cryosurgery is routinely used for in situ disease and actinic keratoses. It is not often used for invasive squamous cell carcinoma because deeper portions of the tumor may not be eradicated by this technique and because the development of scar tissue at the site of cryotherapy might obscure a recurrence. The risks associated with cryotherapy include transient pain, edema, and blistering. Hypopigmentation and alopecia are also common and may be permanent, so treatment of hair-bearing areas and in darkly pigmented individuals is generally not recommended.76

Electrodesiccation and curettage

Electrodesiccation and curettage (ED&C) is a simple technique that can be used to treat low-risk squamous cell carcinoma on the trunk and extremities. The tumor indications are similar to those of cryotherapy. In addition, ED&C can be used to treat superficially invasive squamous cell carcinomas without high-risk characteristics. However, the thick scars that often occur after ED&C can delay the diagnosis of cancer recurrence. Subsequently, ED&C should be used with caution in invasive squamous cell carcinoma. It is not appropriate for certain anatomic locations (ie, eyelids, genitalia, lips, ears).

The technique is based on the delineation of tumor margins with a curette because tumor tissue is generally more friable than the surrounding normal tissue. ED&C is known to be very technique dependent, and cure rates improve with a practitioner's experience. The main disadvantage of ED&C is a lack of histologic margin control, and most dermatologic surgeons believe the actual long-term cure rate for invasive squamous cell carcinoma is much lower than that quoted in the literature. Tumor recurrence may result from failure of ED&C treatment to eradicate atypical cells residing deep in the hair follicles or in the dermis. Nonetheless, the procedure is fast, minimally invasive, well tolerated, and effective for properly selected lesions.

Excision with conventional margins

Standard excision with conventional permanent (ie, paraffin-embedded) tissue sections is an excellent, highly effective, and well-tolerated therapy for primary squamous cell carcinomas that lack high-risk features and are located in areas where tissue sparing is not critical. Cure rates following simple excision of well-defined T1 lesions may be as high as 95-99%. The generally accepted 5-year cure rate for primary squamous cell carcinoma treated with standard excision is 92%; this rate drops to 77% for recurrent squamous cell carcinoma.

A 4-mm margin of healthy tissue is recommended for lower-risk lesions (<2 cm, well-differentiated, without subcutaneous fat invasion) on the trunk and extremities. For lesions larger than 2 cm, invasive to fat, and in high-risk locations (ie, central face, ears, scalp, genitalia, hands, feet), a 6-mm margin of healthy tissue is recommended. Given the cosmetic and functional impact of these wider margins, tumors in this latter category are often removed via Mohs surgery (see below) to achieve high cure rates while sparing normal tissue. The depth of an excision should always include a portion of the subcutaneous fat.

One pitfall of standard excision is that histologic margins can be reported to be negative when they are, in fact, positive (false negative) because the traditional bread-loaf method of tissue sectioning typically results in evaluation of less than 1% of the specimen’s margins. More commonly, a greater amount of healthy tissue is removed than is necessary for complete tumor extirpation. Therefore, simple excision is most valuable in the treatment of small primary squamous cell carcinomas on the trunk, extremities, or neck, where tissue sparing is less essential.77

Mohs micrographic surgery

Mohs micrographic surgery (MMS) is a specialized technique for removing many forms of skin cancer, including squamous cell carcinoma. Because of its many advantages, MMS is the procedure of choice for squamous cell carcinoma in which tissue preservation is needed, for ill-defined squamous cell carcinoma, recurrent tumors, and for high-risk squamous cell carcinoma. The main advantage of MMS over simple excision is the ability to histologically examine nearly 100% of the surgical margins (as compared with <1% of the margin visualized via standard histologic sectioning) and to carefully map residual foci of invasive carcinoma. This residual tumor is removed in a step-wise fashion until clear margins are obtained.

MMS provides the best available cure rates (94-99%) for squamous cell carcinoma and has been of particular value in curing squamous cell carcinoma associated with perineural invasion. In a comprehensive historical review, Rowe et al78 noted that local recurrences are less frequent when squamous cell carcinoma is treated with MMS compared with all non-Mohs modalities. This local recurrence rate differential in favor of MMS was observed in primary squamous cell carcinoma of the skin and lip (3.1% vs 10.9%), for locally recurrent squamous cell carcinoma (10% vs 23.3%), for poorly differentiated squamous cell carcinoma (32.6% vs 53.6%), and for squamous cell carcinoma with perineural involvement (0% vs 47%).

MMS offers the added benefit of preserving healthy tissue, thus facilitating reconstruction and optimizing cosmetic and functional outcomes. It is performed in an outpatient setting with local anesthesia and is therefore a safe and cost-effective procedure79,80 , and MMS is less expensive than surgical excision with anesthesia in a hospital setting.79,80

As a result of the fellowship training programs in Mohs surgery overseen by the American College of Mohs Surgery and the new Accreditation Council for Graduate Medical Education (ACGME)–accredited Procedural Dermatology Fellowship programs, MMS has become widely available throughout the United States.81,82

Care of patients with diffuse actinic keratosis and in situ squamous cell carcinoma

Many patients with a history of extensive sun exposure and light skin develop epidermal atypia in the form of actinic keratosis and in situ squamous cell carcinoma over large areas of their skin. Most of these patients also develop multiple invasive squamous cell carcinomas. The management of such patients is highly labor intensive and involves the following steps:

* Surgically remove all tumors that clinically appear to have to have an invasive (dermal) component and confirm clearance of histologic margins.
* Evaluate for underlying immunosuppression, such as from chronic lymphocytic leukemia or an overly impaired immune system from immunosuppressive or immunomodulatory therapy. If this is suspected, discuss with the patient’s other doctors whether the immunosuppression can be safely remedied or lessened.
* Perform field treatment of the areas of epidermal atypia. Treatment options include topical chemotherapy with 5-FU or PDT. Imiquimod has limited utility in diffuse disease because adverse effects increase when applied to large surface areas. If 5-FU therapy is planned, remove any hyperkeratotic lesions with a curette just prior to beginning therapy to enhance penetration of the medication to the basal layer. A full course of 5-FU therapy is twice-daily administration for 4 weeks. Patients who cannot tolerate this duration may try shorter courses and then resume treatment after a healing phase. Subsequent treatments become more tolerable as the epidermal damage is corrected.
* Follow the patient closely for recurrence of actinic keratosis/squamous cell carcinoma in situ and for new invasive squamous cell carcinomas. Field treatment may need to be repeated every 6-12 months to keep precursor actinic keratosis and squamous cell carcinoma in situ lesions to a minimum.
* Oral retinoids in the form of low-dose acitretin can decrease new cancer formation, although they do not generally alter the course of existing tumors.83 Although most patients do not require retinoids if the above measures are taken, patients who are still developing multiple cancers 6-12 months after beginning an intensive program to clear disease may benefit from retinoid therapy. Once the desired effect is achieved, considering a dose reduction of long-term maintenance therapy rather than discontinuing therapy is better because the latter typically leads to a rebound of multiple squamous cell carcinoma formation.

Treatment of patients with high-risk tumors

Management of primary tumors

See "High-risk squamous cell carcinoma" in Prognosis. The use of ED&C in the treatment of high-risk squamous cell carcinoma, particularly in immunocompromised individuals, is best avoided, because histologic margin status cannot be evaluated. Clear margins must be obtained for optimal outcomes.

Ensuring clear surgical margins wherever possible is highly recommended. A systematic review of available data for high-risk squamous cell carcinoma compared cases with clear surgical margins (n = 943) versus those in which margins were not specified (n = 1506) and demonstrated statistically better outcomes in cases in which clear margins were documented, with risks of local recurrence, regional metastasis, distant metastasis, and disease-specific death of 5%, 5%, 1%, and 1%, respectively, in clear-margin cases, versus 8%, 14%, 7%, and 7% in cases with undocumented margins.64

A prospective study identified several risk factors for incomplete excision of squamous cell carcinomas, namely, ear lesions, invasive lesions, and previously incompletely excised lesions referred for reexcision. The study also recommended more care with tumor markings, taking margins of at least 5 mm, deeper margins, and referring such lesions to centers with personnel who have more experience.84

No controlled comparative studies of Mohs versus excision in high-risk squamous cell carcinoma have been performed, but case series data suggest that Mohs is superior to excision for high-risk squamous cell carcinoma patients.81

Adjuvant therapy

No comparative studies of surgery versus surgery plus adjuvant radiotherapy for high-risk squamous cell carcinoma have been performed. With no clear evidence of benefit and the potential of significant morbidity, clinical judgment is required in deciding which patients should receive adjuvant radiation. One systematic review of available outcome data suggests that adjuvant radiation be considered in patients with uncertain or positive surgical margins or advanced nerve involvement (eg, involvement of named nerves, nerves ≥0.1 mm in diameter, or with clinical or radiologic evidence of nerve invasion).64 Adjuvant medication may also be considered in select highest-risk cases. Options include oral 5-FU (Xeloda) and EGFR inhibitors via oncology treatment centers. Although survival data are lacking, these medications are generally well tolerated with few adverse effects.
Consultations

Most cases of squamous cell carcinoma (SCC) are easily and successfully treated by dermatologists or Mohs surgeons. However, in certain cases, a multidisciplinary approach may be needed (see "High-risk squamous cell carcinoma" in Prognosis). Such cases include the following:

* Large or deep tumors in which excision and reconstruction under local anesthesia is not feasible
* When clear surgical margins are not achieved or are in doubt
* Cases of nodal or distant metastasis

A multidisciplinary approach using MMS performed in conjunction with an otolaryngologist and/or a plastic surgeon may aid in completely removing deeply invasive squamous cell carcinoma, preserving a vital structure (eg, facial nerve), and facilitating the reconstruction of a large operative defect. For example, MMS may be used in cases of squamous cell carcinoma of the scalp involving bone to establish peripheral margins to the level of the galea. MMS is then followed by resection of the deep margin, including bone, with the patient under general anesthesia, performed by a head and neck or plastic surgeon. Because the peripheral margins are established in advance, the head and neck or plastic surgeon can then focus on the deep margin and reconstruction. The patient is often spared hours of anesthesia time, lowering surgical morbidity.

Metastatic disease also requires aggressive management by a multidisciplinary team. Surgical treatment of metastatic disease may require the expertise of an otolaryngologist, a general surgeon, or a surgical oncologist. Adjuvant or palliative radiotherapy may be administered by a radiation oncologist. A medical oncologist should be consulted if systemic chemotherapy is considered for metastatic disease.Follow-up
Further Outpatient Care

Low-risk tumors are usually cured with appropriate surgical therapy; however, patients who develop one squamous cell carcinoma (SCC) have a 40% risk of developing additional squamous cell carcinomas within the next 2 years. This risk is likely even greater as more time elapses. Thus, patients with a history of squamous cell carcinoma should be evaluated with a complete skin examination every 6-12 months.

Patients with high-risk tumors require skin and lymph node examinations at 3- to 6-month intervals for at least 2 years after diagnosis. In very high-risk cases, surveillance with CT scanning or MRI may be considered.
Deterrence/Prevention

General preventive measures

Prevention of squamous cell carcinoma (SCC) is best accomplished by limiting exposure to UV radiation, including both natural sunlight and artificial sources of UV light such as tanning beds. Wearing protective clothing, limiting outdoor activities (especially between 10:00 am and 4:00 pm), and applying a broad-spectrum sunscreen (ie, one that blocks UVA and UVB light) with a sun protection factor of at least 15 every day all help reduce UV exposure.

Treatment of precancerous actinic keratoses and in situ squamous cell carcinoma may prevent the future development of invasive squamous cell carcinoma. Additionally, patient education regarding skin cancer warning signs and periodic self-directed and physician-directed complete skin examinations are recommended.

Chemoprevention

Chemoprevention with systemic retinoids is effective for reducing the number of new squamous cell carcinomas in both immunocompetent and immunosuppressed patients. Most recent studies have focused on the prophylactic use of oral acitretin, which has a relatively long half-life compared with isotretinoin. Low doses are often sufficient for prophylaxis. However, treatment must be continued indefinitely because a relapse in tumor development occurs following discontinuation of oral retinoids. Furthermore, systemic retinoids have not been shown to be beneficial in treating existing squamous cell carcinoma or at reducing the risk of recurrence after treatment.85

The mechanisms by which retinoids protect against the development of squamous cell carcinoma have not been fully elucidated. Data suggest that retinoids induce the expression of proapoptotic and antiproliferative genes, including TP53, caspases, and P73, in keratinocytes. The increase in epidermal Langerhans cells noted in one study suggests that retinoids may also enhance cutaneous immunosurveillance.86,87

Many patients are unable to tolerate the adverse effects associated with systemic retinoid therapy, although lower doses are better tolerated than higher doses. Organ transplant recipients appear to be more sensitive to the adverse effects of systemic retinoids than other patients. Adverse effects of systemic retinoids include mucocutaneous xerosis, dyslipidemia, liver function abnormalities, and teratogenicity.
Prognosis

Most squamous cell carcinomas (SCCs) are readily treated with an expectation of cure. Most large series in the literature have reported the risk of nodal or distant metastasis for primary tumors to be 2-6%.

A subset of squamous cell carcinoma 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 squamous cell carcinoma (see below). However, prognostic models do not exist for squamous cell carcinoma. Because many of the risk factors 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 squamous cell carcinoma varies widely.44

In one case series, the 3-year disease-specific survival rate for squamous cell carcinoma 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.88 These estimates derived from a case series may not be reflective of the risk for squamous cell carcinoma in general and may overestimate risk. However, the data highlight that a subset of squamous cell carcinomas do poorly (see below).

When squamous cell carcinoma 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 squamous cell carcinoma of the forehead, temples, eyelids, cheeks, and ears is to the parotid nodes; metastasis from squamous cell carcinoma of the lips and perioral region is primarily to the submental and submaxillary (upper cervical) nodes.

Once nodal metastasis of cutaneous squamous cell carcinoma has occurred, the overall 5-year survival rate has historically been in the range of 25-35%. Prognosis is extremely poor for patients with a compromised immune system, with metastasis to multiple lymph nodes, or with cervical lymph nodes greater than 3 cm in diameter. Nevertheless, data published in 2005 show that the combined use of surgery and adjuvant radiotherapy for patients with nodal metastasis increased the 5-year disease-specific survival rate to 73%.17 Metastasis to distant organs remains incurable. Thus, close surveillance and early detection of nodal metastasis can be life saving and is of paramount importance.

High-risk squamous cell carcinoma

A subset of squamous cell carcinoma is considered high risk because it has been associated with higher rates of recurrence, metastasis, and death in case series data. Squamous cell carcinoma 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 squamous cell carcinoma78

Tumor-related factors are (1) tumor location (ie, lips, ears, anogenital, within a scar or chronic wound), (2) tumor size greater than 2 cm (or 1.5 cm on ear or lip), (3), invasion to subcutaneous fat (or deeper), (4) poorly differentiated tumor cells, (5) recurrent tumor, and (6) perineural involvement (except perhaps for tumors with small-caliber nerve invasion and no other risk factors.48

Additionally, a prospective study of 210 patients with a diverse range of squamous cell carcinomas showed tumor-related factors were associated with adverse disease-specific survival using univariate analyses.88 Specifically, these factors were (1) local recurrence at presentation (P = .05), (2) invasion beyond subcutaneous tissue (P = .009), (3) depth in general (P = .05), (4) perineural invasion (P = .002), and (5) size greater than or equal to 4 cm (P = .0003).

Detailed information on tumor-related factors is as follows:

* Location: The lips and the ears may have a higher rate of recurrent and metastatic disease than squamous cell carcinoma at other sites. The historical rates of metastases for squamous cell carcinoma of the external ear and the lip are approximately 11% and 10-14%, respectively.78 Numerous studies have demonstrated that the Marjolin ulcer subtype of squamous cell carcinoma behaves aggressively, with metastatic rates of up to 35%. Similarly, invasive squamous cell carcinoma 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 squamous cell carcinoma measuring less than 2 cm in diameter have been associated with a rate of metastasis of 9.1%, whereas those greater than 2 cm in diameter have a metastatic rate of up to 30.3%. A 2005 prospective study reported a 3-year disease-specific survival rate of 67% for lesions greater than 4 cm, compared with 93% for tumors smaller than 4 cm.88
* Depth: Increased depth of invasion of squamous cell carcinoma is strongly associated with local recurrence, metastasis, and death. Squamous cell carcinoma with a depth of less than 2 mm rarely metastasizes. Squamous cell carcinoma with a depth of invasion of 2-4 mm has 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 thick. For tumors thicker than 6 mm, the risk increased to 16%.3
* Cellular differentiation: More poorly differentiated tumors have a worse prognosis in cutaneous squamous cell carcinoma, with recurrence rates reported to be from 33-54%.78 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 squamous cell carcinomas are generally considered to behave more aggressively.
* Recurrent tumors: Local recurrence rates following extirpation of a recurrent squamous cell carcinoma range from 10-23%. 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 squamous cell carcinoma. 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 (MMS).78 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 to 32% of patients dying from disease when nerves 0.1 mm or larger were involved.63

Patient-related factors in high-risk squamous cell carcinoma

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

Detailed information on patient-related factors is as follows:

* Organ transplant recipients are discussed as follows:
o A 65-fold increased risk of squamous cell carcinoma exists in organ transplant recipients. This correlates with the intensity of immunosuppression, so that heart transplant recipients have 3 times the risk of squamous cell carcinoma compared with kidney transplant recipients.89 However, 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 could be explained by a longer duration of immunosuppression in patients who are younger at transplantation.
o Additionally, organ transplant recipients have a high risk of developing further squamous cell carcinomas, with 66% developing a second squamous cell carcinoma within 5 years of their first squamous cell carcinoma diagnosis.90
o In addition to squamous cell carcinomas being a more frequent occurrence in organ transplant recipients, the tumors can be clinically very aggressive. In one study of cardiothoracic transplant recipients (heart or heart-lung transplants), 4% of patients developed aggressive cutaneous squamous cell carcinoma within 10 years of transplantation. The majority (15 of 18) were poorly differentiated, and two thirds of the patients with aggressive squamous cell carcinoma had distant-organ metastases or died of their disease.91
* Chronic lymphocytic leukemia: Squamous cell carcinoma arising in patients with chronic lymphocytic leukemia and small lymphocytic lymphoma also carries a worse prognosis. For example, in patients with chronic lymphocytic leukemia, the recurrence rate of squamous cell carcinoma treated with MMS was 7-fold higher at 5 years compared with patients without chronic lymphocytic leukemia.92 One study found that squamous cell carcinomas in chronic lymphocytic leukemia and small lymphocytic lymphoma patients are often multiple (67%), high grade (56%), and with a high risk of recurrence and metastasis (25%) and death from disease (41%).93
* HIV infection: HIV infection and AIDS are not definitively associated with high-risk squamous cell carcinoma. An increased incidence of anal and penile squamous cell carcinoma associated with human papillomavirus (HPV) has been reported in HIV patients. A high risk of recurrence has been reported after desiccation and curettage.94 A small series reported cases of aggressive cutaneous squamous cell carcinoma in HIV patients, with a 50% mortality rate at 7 years.9

Other reported conditions associated with aggressive squamous cell carcinoma

The risk of squamous cell carcinoma 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 first primary squamous cell carcinoma.

Other reported conditions include arsenic exposure95 and psoralen plus UVA (PUVA) light exposure.
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 the neck area. 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 of at least 15 should also be encouraged. 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.

Counseling patients regarding treatment of areas of chronic skin inflammation or trauma is important in preventing the future development of squamous cell carcinoma at those sites.

For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Additionally, see eMedicine's patient education articles 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.
Miscellaneous
Medicolegal Pitfalls

Malpractice suits are uncommon following the diagnosis and treatment of squamous cell carcinoma (SCC) because, in most cases, both are straightforward and readily accomplished. Nonetheless, squamous cell carcinoma is a lesion with the potential to cause substantial morbidity and even mortality, and physicians who diagnose and treat squamous cell carcinoma are held legally accountable for actions that are taken (or not taken) that fall outside the standard of care.

Failure to diagnose squamous cell carcinoma may lead to substantial morbidity and occasionally mortality. Large court awards have been set for cases in which failure to diagnose squamous cell carcinoma has led to death.

Failure to treat and perceived inadequate treatment are common causes of malpractice claims against physicians. These cases occur most frequently when physicians fail to use an adequately aggressive primary treatment or fail to recognize a high-risk lesion. Recognizing that high-risk squamous cell carcinoma may metastasize and lead to death is important. Therefore, appropriately aggressive and prompt treatment is indicated in such cases. However, because defined prognostic criteria and models have not been developed, little information is available to guide clinicians in the most appropriate staging and treatment for individuals with high-risk squamous cell carcinoma. Because of a lack of data, care standards regarding nodal staging, radiologic imaging, and postsurgical adjuvant therapy have not been developed. Subsequently, a lack of uniformity exists among experienced physicians in the treatment of high-risk squamous cell carcinoma.44

Failure to provide appropriate follow-up is a potential pitfall. The courts hold the physician, not the patient, responsible for appropriate follow-up. Because primary treatment of squamous cell carcinoma is not a guarantee of cure, ensuring adequate patient follow-up is essential. Failure to inform patients of the potential morbidity associated with squamous cell carcinoma may lead to the lesion being regarded as trivial and not requiring follow-up. Missed appointments may indicate the patient is worried or angry. Thus, patients with a history of squamous cell carcinoma who miss follow-up appointments should be contacted by phone (or when necessary, with a certified letter) to reschedule. All medical staff are advised to document phone calls in writing and to save certified letter documentation.

Failure to explain all possible risks and complications of surgery is another legal pitfall. Surgery for squamous cell carcinoma may cause bleeding, infection, scar formation, physical deformity, and nerve damage. The removal of deeply invasive lesions may lead to substantial morbidity, including paralysis and pain syndromes. Explaining all possible risks prior to surgery is essential. Such explanations should ideally be documented in written consent forms signed by the treating physician and the patient. Additionally, the physician should not treat lesions outside the realm of his or her comfort zone. If a surgical complication develops, the physician who performed the primary procedure is held legally responsible, regardless of who handles the complication.