AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Cutaneous squamous cell carcinoma (SCC) is the second most common form of skin cancer and frequently arises on the sun-exposed skin of middle-aged and elderly individuals. SCC is much more common in geographic areas where patients have a high frequency of sun exposure. 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.

General risk factors associated with the development of SCC are as follows:

• Age older than 50 years
• Male sex
• Fair skin (ie, burns easily, never or rarely tans)
• Geography (closer to the equator)
• History of prior nonmelanoma skin cancer
• Exposure to UV light (high cumulative dose)
• Exposure to chemical carcinogens (eg, arsenic, tar)
• Exposure to ionizing radiation
• Chronic immunosuppression
• Chronic scarring condition
• Genodermatoses
• Human papilloma virus (HPV) infection (specific subtypes)

Pathophysiology

SCC is a malignant tumor of epidermal keratinocytes. 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 (AKs) and patients with multiple AKs are at increased risk for developing SCC. SCC 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 SCC is difficult because health registries often exclude nonmelanoma skin cancer (including SCC) from their databases and because the rate of SCC varies based on geographic locale. Nevertheless, epidemiologic studies have estimated the annual incidence of SCC in the United States to be 107 cases per 100,000 people in the general population.

Such 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 during the period from 1984-1986 to 100 cases for the period from 1990-1992. The corresponding rates for men increased from 126 cases to 191 cases per 100,000 population.

One reason for the rising incidence of SCC is an increase in sun exposure in the general population. Other factors that may contribute to the increased incidence of SCC include the advancing age of the US population, earlier and more frequent diagnosis of SCC due to enhanced public awareness of skin cancer and more frequent skin examinations by physicians, and the rising number of immunosuppressed patients, who are at greater risk for developing SCC.

International

Incidence rates of 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 fair-skinned people in this region who have had extensive sun exposure.

Mortality/Morbidity

Most SCCs are readily treated and produce few sequelae. An identifiable subset of high-risk lesions causes most of the morbidity and the mortality associated with SCC. Such lesions may cause extensive destruction of tissue, and their removal may entail substantial cosmetic deformity. The overall risk of metastasis rate for SCC is in the range of 2-6%; however, this rate may be as high as 47% for certain high-risk tumors. Treating lymph node metastasis is much more extensive and 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. Once lung metastasis occurs, the disease is incurable.

Race

SCC is the second leading cause of skin cancer in whites. Persons of Irish or Scottish ancestry have the highest prevalence in the United States. 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 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.

Sex

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

CLINICAL

Section 3 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

History

A detailed patient history often reveals the presence of one or more risk factors for SCC (see general risk factors in Background). Most SCCs are discovered by patients and are brought to a physician's attention by the patient or a relative. The typical SCC manifests as a new or enlarging lesion that concerns the patient. SCC is typically a slow-growing malignancy, but some lesions enlarge rapidly. Although most SCC 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, especially in high-risk persons.

• Actinically derived SCC: The most common type of SCC 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 AKs, basal cell carcinoma (BCC), melanoma, or SCC.
• Immune suppression: Patients should always be questioned about possible sources of immunosuppression. A history of solid-organ transplantation, hematologic malignancy (eg, chronic lymphocytic leukemia [CLL]), 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 refers to an SCC that arises from chronically scarred or inflamed skin. Patients may report a change in the skin (eg, induration, elevation, ulceration, weeping) at the site of a preexisting scar or ulcer. The latency period is often 20-30 years; therefore, the diagnosis requires a high index of clinical suspicion.
• HPV-associated SCC: Virally induced SCC 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

SCC may manifest as a variety of primary morphologies with or without associated symptoms.

• SCC in situ (SCCis): SCCis is defined histologically by atypia involving the full thickness of the epidermis but without invasion into the dermis. Clinically, lesions of SCCis range from a scaly pink patch to a thin keratotic papule or plaque similar to an AK. Bowen disease is a subtype of SCCis 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.
• Typical SCC: The characteristic invasive SCC is a raised, firm, pink-to-flesh–colored keratotic papule or plaque arising on sun-exposed skin. Approximately 70% of all SCCs 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, SCC may manifest as a pink cutaneous nodule without overlying surface changes. A background of severely sun-damaged skin, including solar elastosis, mottled dyspigmentation, telangiectasia, and multiple AKs, is often noted.
• Periungual SCC: Periungual SCC 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 may also be noted.
• Marjolin ulcer: This subtype of SCC appears as a new area of induration, elevation, or ulceration at the site of a preexisting scar or ulcer.
• Perioral SCC: SCC of the lip usually arises on the vermillion border of the lower lip, close to the midline. The precursor lesion is actinic cheilitis, which manifests as xerosis, fissuring, atrophy, and dyspigmentation and which is analogous to AK of the skin. SCC in this location manifests as a new papule, erosion, or focus of erythema/induration. Intraoral SCC typically manifests at 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 SCC: SCC in the anogenital region may manifests 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.
• Verrucous carcinoma (VC): VC is a subtype of SCC that can be locally destructive but rarely metastasizes. Lesions appear as exophytic, fungating, verrucous nodules or plaques, which may be described as "cauliflower-like". VC is further subdivided based on its location in the anogenital region (Buschke-Lowenstein tumor), the oral cavity (oral florid papillomatosis), and the plantar foot (epithelioma cuniculatum).
• Lymphadenopathy: With any invasive SCC, regional lymph nodes should be examined. Lymph node enlargement is an ominous sign that may indicate the presence of metastatic disease.

Causes

The primary cause of most SCC is cumulative lifetime sun exposure. The frequency of SCC is increased at lower latitudes, correlating with an increased intensity of ambient light. Other causes of SCC 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, UVB is approximately 1000-fold more potent than UVA (320-400 nm) for inducing skin cancer. The mechanism of UVB-induced photocarcinogenesis appears to be the generation of pyrimidine dimers in keratinocyte DNA, which may result in errors in DNA replication and transcription. Inactivation of the tumor suppressor gene TP53 occurs in up to 90% of all cutaneous SCC lesions. Other tumor suppressor genes found to be mutated in SCC include P16 (INK4a) and P14 (ARF). In addition to UV-induced genetic mutations, epigenetic silencing of tumor suppressor genes through aberrant DNA methylation has also been found in cutaneous SCC.
• Therapeutic UV exposure: UV light treatments used for psoriasis (and other recalcitrant dermatoses) also predispose to the development of SCC. PUVA is particularly phototoxic and mutations in both TP53 and the oncogene Ha-Ras are present in a large proportion of PUVA-associated SCC. 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 SCC; patients with oculocutaneous albinism are also at risk. Such individuals lack natural protection from UV-induced carcinogenesis, owing to reduced levels of the photoprotective pigment, melanin.
• Ionizing radiation: Therapeutic ionizing radiation can induce SCC both experimentally and clinically. Most patients with radiation-induced tumors have a remote history of x-ray therapy for acne vulgaris, although patients who develop SCC in radiation ports for Hodgkin disease or thyroid cancer are not uncommon.
• Chemical carcinogens: Exposure to arsenic is a well-established cause of cutaneous SCC and internal cancers. Today, 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.
• DNA repair failure: Normal 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, along with other cutaneous tumors.
• Iatrogenic immunosuppression: The use of immunosuppressive medications to prevent rejection in OTRs is associated with a 65- to 250-fold increased risk of developing SCC compared with the general population.
• • The primary risk factor in these patients is cumulative lifetime UV exposure in combination with skin types I and II. This risk also increases with the number of years posttransplant, 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.
  • Pretransplant end-organ disease may also impact the development of posttransplant SCC. 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 posttransplant 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 (CLL, lymphoma) 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. Suppression of the immune system would presumably abrogate this response and might be expected to facilitate the development of SCC.
• HPV: Infection with specific subtypes of HPV is believed to play a role in the development of anogenital and periungual SCC. HPV types 6 and 11 are associated with Buschke-Lowenstein tumors, whereas HPV type 16 has been frequently identified in both genital and periungual SCC, suggesting the possibility of genital-digital spread. HPV types 5 and 8 have recently been associated with cutaneous SCC in transplantation patients.
• Chronic inflammation: Chronic inflammation, irrespective of the underlying etiology, may lead to the development of SCC. Both noninfectious inflammatory diseases and chronic infections have been associated with SCC. Likewise, the Marjolin ulcer variant of SCC may develop in patients with a chronic scarring condition such as dystrophic epidermolysis bullosa (DEB). In fact, the leading cause of death in patients with DEB is metastatic cutaneous SCC. New evidence suggests that patients with junctional epidermolysis bullosa may also be at increased risk for developing SCC. The underlying pathogenesis of such lesions is not understood, but mutations in the TP53 and P16 tumor suppressor genes have been described in DEB-associated SCC.
• Some of the conditions that predispose to the development of SCC are highlighted as follows:
• • Chronic inflammatory and scarring conditions
  • • 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
  • • Osteomyelitis
    • Acne conglobata
    • Hidradenitis suppurativa
    • Dissecting cellulitis of scalp
    • Lupus vulgaris
    • Lymphogranuloma venereum
    • Granuloma inguinale
    • Chronic deep fungal infection
  • Genetic syndromes and dermatoses
  • • 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) syndrome

DIFFERENTIALS

Section 4 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

WORKUP

Section 5 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

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. Some experts also advocate radiologic imaging for selected patients with high-risk SCC. CT scanning, MRI, ultrasonography, or positron emission tomography scanning may be used depending on the specific question being addressed, although the selection of one modality over another is often arbitrary and based on the clinician's preference. Currently, no formal guidelines regarding the use of radiologic imaging in cutaneous SCC have been developed.

Procedures

• Skin biopsy:
• • Although the diagnosis of SCC is often strongly suspected 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 SCC must reach at least the depth of the mid dermis to allow for 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.
  • Pathologic analyses may be completed by a dermatologist or a general pathologist, but they are preferably completed by a dermatopathologist with extensive experience in SCC.
  • Patients with regional lymphadenopathy identified by clinical examination or imaging studies should undergo a lymph node biopsy or fine-needle aspiration for histologic evaluation. Sentinel lymph node biopsy has been used to identify micrometastasis in a small number of patients with high-risk SCC and clinically negative nodes. While this procedure appears to detect most subclinical metastasis, it is not known whether early detection of lymph node metastasis leads to enhanced survival because no controlled studies of sentinel lymph node biopsy have been conducted for cutaneous SCC. Complete lymphadenectomy of the draining nodal basin has also been suggested for high-risk tumors with an estimated metastatic risk of 20% or greater.

Histologic Findings

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

SCCis 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, are 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 SCC from SCCis 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 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 are clinically more aggressive.)

Several variants of SCC 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 SCC, acantholytic (adenoid) SCC, and VC are highlighted in the following Table.

Histologic and Clinical Features of SCC Variants

Tumor	Histologic Characteristics	Clinical Characteristics
Keratoacanthoma	Keratin-filled crater Well-differentiated (mild atypia) Neutrophil microabscesses Eosinophils in dermal infiltrate	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 (minimal atypia) Resembles verruca Bulbous downward proliferation "Bulldozing" invasion	Oral, genital, or plantar foot Indolent growth Locally destructive Rarely metastasizes

Staging

SCC is staged according to American Joint Committee on Cancer guidelines, which use the TNM classification system. Most cutaneous SCCs are not metastatic at the time of presentation; therefore, the tumor stage in such cases is based solely on the characteristics of the primary lesion. Staging of metastatic disease takes into account the presence or absence of regional lymph node and distant metastasis. Classification of the primary tumor is described below.

• TX - Primary tumor cannot be assessed
• T0 - No evidence of primary tumor
• Tis - Carcinoma in situ
• T1 - Tumor less than 2 cm in greatest diameter
• T2 - Tumor 2-5 cm in greatest diameter
• T3 - Tumor greater than 5 cm in greatest diameter
• T4 - Tumor with deep invasion into cartilage, muscle, or bone

TREATMENT

Section 6 of 10  

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Medical Care

Nonsurgical options for the treatment of cutaneous 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, AKs) 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 SCC. At this time, systemic chemotherapy is used exclusively for patients with metastatic disease.

• Topical chemotherapy: Topical formulations of 5-fluorouracil (5-FU) are available for the treatment of AKs and superficial BCCs. Successful treatment of Bowen disease has also been reported. Invasive SCC should not be treated with topical chemotherapy.
• Topical immune response modifier: Imiquimod is an imidazoquinoline that enhances cell-mediated immune responses via the induction of proinflammatory cytokines. It is approved by the US Food and Drug Administration for the treatment of genital warts (ie, condylomata acuminata), AKs, and superficial BCC. Imiquimod cream is effective for Bowen disease as monotherapy and in combination with topical 5-FU. Limited data suggest that imiquimod is effective even in patients on long-term immunosuppressive therapy and appears to be safe in OTRs. Imiquimod has been used to treat invasive SCC; however, it is not approved for this indication.
• 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 AKs in a single session. SCCis is also amenable to PDT, although a wide range of recurrence rates (0-52%) have been reported. At this time, PDT is not recommended for treatment of invasive SCC.
• Radiation therapy
• • Radiation therapy offers the potential advantage of avoiding the deformity and trauma of a surgical procedure. Cure rates for T1 lesions range from 85-95%.
  • 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 SCC) 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, primary radiation therapy for SCC is generally restricted to older patients who cannot tolerate or who refuse surgery.
  • In contrast, radiation of the involved nodal basins is routinely used as an adjunct to the surgical treatment of metastatic SCC and has been shown to improve outcomes. The use of adjuvant radiotherapy in high-risk cutaneous SCC in the absence of known metastasis is more controversial because no data from prospective studies support this therapy. In the setting of high-risk SCC, every attempt should be made to obtain clear surgical margins before administering adjuvant radiotherapy, which can include both the primary site and the draining nodal basins.
• Systemic chemotherapy: A variety of different chemotherapeutic agents have been used to treat metastatic cutaneous SCC. Many of the current protocols have been adapted from those used to treat metastatic head and neck SCC. Capecitabine (Xeloda), an oral formation of 5-FU, either alone or in combination with interferon alfa, has shown some efficacy in the treatment of advanced cutaneous SCC.
• Reduction in immunosuppression: In OTRs, a reduction in the magnitude of immunosuppression may be an effective adjuvant therapeutic strategy in the treatment of aggressive SCC. 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 supervision of the transplantation physician, who must carefully monitor the patient for signs and symptoms of organ rejection.

Surgical Care

Most SCCs are readily treated in the physician's office by surgical or destructive methods, with a high expectation of cure. The treatment of SCC must take into account multiple patient- and lesion-specific factors. The standard modalities available for the treatment of localized (primary) invasive SCC are described below. Because SCC is a lesion that can recur, metastasize, and cause death, and because recurrent SCC carries a relatively poor 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 SCCs. The 5-year cure rate for SCC can be 95% or higher with proper tumor selection and technique. In the United States, cryosurgery is routinely used for in situ disease and AKs. It is not often used for invasive SCC 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 may be permanent so treatment of hair-bearing areas and darkly pigmented individuals is generally not recommended.
• Electrodesiccation and curettage
• • Electrodesiccation and curettage (ED&C) is a simple technique that can be used to treat low-risk SCC on the trunk and extremities. The tumor indications are similar to those for cryotherapy. In addition, ED&C may be used to treat superficially invasive SCCs without high-risk characteristics, but 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. With careful patient selection, cure rates of 96-99% have been quoted in the literature.
  • The main disadvantage of ED&C is a lack of histologic margin control, and most dermatologic surgeons believe that the actual long-term cure rate for invasive SCC is much lower than that quoted in the literature. Tumor recurrence may result from failure of ED&C to eradicate atypical cells residing deep in the hair follicles. Nonetheless, the procedure is fast, minimally invasive, well tolerated, and effective for properly selected in situ and superficially invasive lesions.
• Excision with conventional margins
• • Standard excision with conventional permanent (ie, fixed) tissue sections is an excellent, highly effective, and well-tolerated therapy for many primary SCCs. 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 SCC treated with standard excision is 92%; this rate drops to 77% for recurrent SCC.
  • A 4-mm margin of normal 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 normal tissue is recommended. The depth of the 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 tumor margins. More commonly, a greater amount of normal tissue is removed than is necessary for complete tumor extirpation. Therefore, simple excision is most valuable in the treatment of small primary SCCs on the trunk, extremities, or neck, where tissue sparing is less essential.
• Mohs micrographic surgery:
  • Dermatologic surgeons can offer the specialized modality of Mohs micrographic surgery (MMS). Because of its many advantages, MMS is the procedure of choice for SCC in which tissue preservation is needed, for ill-defined SCC, and for high-risk SCC. The main advantage of MMS over simple excision is the ability to examine nearly 100% of the surgical margins 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 SCC and has been of particular value in curing SCC associated with perineural invasion. In a comprehensive historical review, Rowe et al noted that local recurrences are less frequent when SCC is treated by MMS compared with all non-Mohs modalities. This local recurrence rate differential in favor of MMS was observed in primary SCC of the skin and lip (3.1% vs 10.9%), for locally recurrent SCC (10% vs 23.3%), for poorly differentiated SCC (32.6% vs 53.6%), and for SCC with perineural involvement (0% vs 47%). MMS offers the added benefit of preserving normal tissue and facilitating reconstruction.
  • MMS is routinely performed in an outpatient setting with the patient under local anesthesia and, therefore, is safe and cost effective. As a result of the fellowship training programs in dermatologic surgery, MMS is now widely available throughout the United States.

Consultations

Physicians responsible for treating primary SCC must be cognizant of the urgency of treating metastatic SCC in a timely fashion, and colleagues in surgery and oncology with experience in treating metastatic SCC must be available. Head and neck surgeons are uniquely qualified to treat metastases from SCC of the skin, and, depending on the case, they may use wide excision and parotidectomy (superficial or total) with or without neck dissection and with or without adjunctive radiation therapy.

• MMS may be an integral component in the management of certain high-risk SCCs that would otherwise be beyond the realm of a cutaneous surgeon. A multidisciplinary approach using MMS and performed in conjunction with an otolaryngologist and/or a plastic surgeon may aid in completely removing deeply invasive SCC, preserving a vital structure (eg, facial nerve), and facilitating the reconstruction of a large operative defect.
• 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

Section 7 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

• Low-risk tumors are usually cured with appropriate surgical therapy; however, patients who develop one SCC have a 40% risk of developing additional SCCs within the next 2 years. This risk is likely even greater as more time elapses. Thus, patients with a history of SCC should be evaluated with a complete skin examination every 6-12 months.
• Patients with high-risk tumors require skin and lymph node examinations at 3- to 6-month intervals for at least 2 years after diagnosis. In very high-risk cases, surveillance with CT scanning or MRI may be considered.

Deterrence/Prevention

• General preventive measures
• • Prevention of SCC is best accomplished by limiting exposure to UV radiation, including both natural sunlight and artificial sources of UV light such as tanning devices.
  • Wearing protective clothing, limiting outdoor activities (especially between 10:00 AM and 4:00 PM), and using daily applications of a broad-spectrum sunscreen (ie, blocks UVA and UVB light) with an sun protection factor of at least 15 all help reduce UV exposure.
  • Treatment of precancerous AKs and Bowen disease may prevent the future development of invasive SCC.
  • 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 SCCs 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 SCC or at reducing the risk of recurrence after treatment.
  • The mechanisms by which retinoids protect against the development of SCC have not been fully elucidated. Recent 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.
  • Many patients are unable to tolerate the adverse effects associated with systemic retinoid therapy, although lower doses are better tolerated than higher doses. OTRs appear to be more sensitive to the adverse effects of systemic retinoids compared with other patients. Adverse effects of systemic retinoids include mucocutaneous xerosis, dyslipidemia, liver function abnormalities, and teratogenicity.
  • Emerging evidence from animal and human studies suggests that regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) may protect against the development of both AKs and SCC. In a recent case-control study conducted in Australia, patients with SCC were significantly less likely than control subjects to have routinely used NSAIDs. Among participants without SCC, regular users of NSAIDs had fewer AKs. The chemopreventive effects of NSAIDs may due to the inhibition cyclooxygenase, because the cyclooxygenase 2 isoform of this enzyme has been shown to be frequently overexpressed in SCC. Use of NSAIDs for chemoprophylaxis of SCC is not currently recommended because data from human studies are limited.

Prognosis

• Most SCCs are readily treated with an expectation of cure. The 3-year disease-specific survival rate has recently been estimated to be 85%; this rate approaches 100% for lesions with no high-risk factors, but it decreases to 70% for patients with at least 1 risk factor. See Tumor- and patient-related risk factors, below.
• Local recurrence following definitive treatment is not uncommon, and metastasis and death may ensue. Most representative series in the literature have quoted an across-the-board prevalence rate of metastasis for primary cutaneous SCC of 2-6%.
• • When SCC does metastasize, it is usually occurs within several years from the time of diagnosis and involves the primary (ie, first echelon) draining lymph nodes. In general, metastasis from SCC of the forehead, the temples, the eyelids, the cheeks, and the ears is to the parotid nodes; metastasis from SCC of the lips and the 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 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, recently published data show that the combined use of surgery and adjuvant radiotherapy for patients with nodal metastasis increased the 5-year disease-specific survival to 73%. Metastasis to distant organs remains incurable. Thus, close surveillance and early detection of nodal metastasis can be life saving and is of paramount importance.
• A subset of SCC is considered high risk because of its aggressive behavior. Such tumors have a tendency for rapid local growth, higher rates of recurrence and regional metastasis, and a poor prognosis. 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- and patient-related risk factors associated with higher rates of recurrence and metastasis are as follows:
• • Tumor-related factors in high-risk SCC
  • • Tumor location (ie, lips, ears, scar)
    • Tumor size greater than 2 cm
    • Invasion to subcutaneous fat (or deeper)
    • Poorly differentiated tumor
    • Recurrent tumor
    • Perineural involvement
  • Patient-related factors in high-risk SCC
  • • Organ transplant recipient
    • Hematologic malignancy (eg, CLL)
    • Chronic immunosuppressive therapy
    • HIV infection or AIDS
• The lips and the ears have a much higher rate of recurrent and metastatic disease than SCC at other sites. The historical rates of metastases for SCC of the external ear and the lip are approximately 11% and 10-14%, respectively. Numerous studies have demonstrated that the Marjolin ulcer subtype of SCC behaves aggressively, with a metastatic rate of approximately 18-38%. 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.
• Lesions of invasive SCC measuring less than 2 cm in diameter have been associated with a risk of metastasis of 9.1%, whereas those greater than 2 cm in diameter have a metastatic rate of up to 30.3%. A recent prospective study reported a 3-year disease-specific survival rate of 67% for lesions greater than 4 cm, compared with 93% for tumors less than 4 cm.
• Increased depth of invasion of SCC is strongly associated with local recurrence, metastasis, and death. SCC with a depth of less than 2 mm rarely metastasizes. SCC with a depth of invasion less than 4 mm has a historical recurrence rate of 5.3% and a metastasis rate of 6.7%; these rates increase to 17.2% and 45.7%, respectively, for tumors invading greater than 4 mm.
• An inverse correlation exists between the degree of cellular differentiation and the prognosis in cutaneous SCC. The actual value of histologic grading alone, however, is less clear because poorly differentiated tumors that do metastasize or recur may do so because of other primary risk factors (eg, large size, deep invasion). Additionally, most metastases from SCC are well differentiated. Nonetheless, poorly differentiated SCCs are generally accepted to behave more aggressively.
• The local recurrence rate following extirpation of a recurrent SCC ranges from 10-23%; recurrent SCC has a site-dependent rate of metastasis of 25-45%.
• Perineural invasion has been estimated to occur in 2.4-14% of persons with cutaneous SCC, most commonly in elderly men with tumors of the head and neck. The prognosis in such cases is extremely poor, with historical rates of local recurrence and metastasis reported to be as high as 47%.
• • Perineural involvement is often identified on the initial biopsy specimen or on frozen sections prepared during the course of MMS. Furthermore, in most cases of perineural involvement, MMS allows for the precise mapping needed to effect complete tumor extirpation. Using MMS, several authors have recently reported much lower rates of recurrence and metastasis.
  • The degree of nerve involvement likely also affects the 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. The prognostic significance of small dermal nerve twig involvement and neurotropism (ie, cells abutting the perineurium but not invading the perineural space) remains less clear and awaits further study.
• The prognosis related to various immunosuppressive states is discussed as follows:
• • SCC in OTRs occurs more frequently, appears at an earlier age, is often multicentric, and may be clinically aggressive. The rate of local recurrence has been reported to be as high as 13.4%, while metastasis occurs in 5-8% of patients. Metastatic SCC in OTRs has a dismal prognosis, with a 3-year disease-specific survival of only 56%.
  • SCC arising in patients with CLL also carries a worse prognosis. For example, in patients with CLL, the recurrence rate of SCC treated with MMS was 7-fold higher at 5 years compared with patients without CLL. In addition, a small case-control study found the 5-year cumulative incidence of SCC metastasis to be 17.7% for patients with CLL.
  • HIV infection and AIDS may also be associated with aggressive SCC. In one small case series, 5 of 10 patients with HIV and aggressive SCC died of metastasis within 7 years of the initial diagnosis.

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 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 are to undergo organ transplantation.
• Counseling patients regarding treatment of areas of chronic skin inflammation or trauma is important in preventing the future development of SCC at those sites.
• For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education articles Skin Cancer and Skin Biopsy.

MISCELLANEOUS

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Malpractice suits are uncommon following the diagnosis and treatment of SCC because, in most cases, both are straightforward and readily accomplished. Nonetheless, SCC is a lesion with the potential to cause substantial morbidity and even mortality, and physicians who diagnose and treat SCC are held legally accountable for actions that are taken (or not taken) that fall outside the standard of care.
• Failure to diagnose SCC may lead to substantial morbidity and occasionally mortality. Large court awards have been set for cases in which failure to diagnose SCC has led to death.
• Failure to treat and perceived inadequate treatment of SCC are common causes of malpractice claims against physicians. These cases occur most frequently when physicians either fail to use an adequately aggressive primary treatment or fail to recognize a high-risk lesion. Recognizing that high-risk SCC may metastasize and lead to death is important. Therefore, appropriately aggressive and prompt treatment is indicated in such cases.
• Failure to provide appropriate follow-up is a pitfall. The courts hold the physician, not the patient, responsible for appropriate follow-up. Because primary treatment of SCC is not a guarantee of cure, ensuring adequate patient follow-up is essential. Failure to inform patients of the potential morbidity associated with SCC may lead to the lesion being regarded as trivial and not requiring follow-up. Missed appointments following surgery may also indicate the patient is worried or angry; the patient should be contacted by phone to reschedule the appointments and, when necessary, with a certified letter.
• Failure to explain all possible risks and complications of surgery is a pitfall. Surgery for SCC may cause bleeding, infection, scar formation, 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. Also, 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.

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Large sun-induced squamous cell carcinoma on the forehead/temple.
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Media file 2:  Squamous cell carcinoma in situ, Bowen disease. Courtesy of Hon Pak, MD.
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Media file 3:  Squamous cell carcinoma. Courtesy of Hon Pak, MD.
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Media file 4:  Squamous cell carcinoma. Courtesy of Hon Pak, MD.
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REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

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