Squamous Cell Carcinoma of the Skin

Are You Confident of the Diagnosis?

What you should be alert for in the history

Patients may describe a tender or scaly growth, frequently on a sun-exposed surface such as the face or dorsal hand. Lesions may be described as having been present “for years” or have rapidly increased in size over 2-3 weeks. Often the lesions may bleed following minimal trauma and do not seem to ever completely heal. The history should also include questions about abnormal nerve sensations, compromised motor nerve function, and other indicators of potential perineural involvement of tumor.

Additionally, several factors in the general medical history are important for the diagnosis and subsequent treatment planning. Prolonged immunosuppression due to medications or comorbid medical conditions significantly increases the risk for developing squamous cell carcinomas. A strong family or personal history of squamous cell carcinoma may indicate the possibility of a genetic predisposition or disorder.

Characteristic findings on physical examination

Physical examination findings vary markedly depending on the location and type of squamous cell carcinoma. While squamous cell carcinomas may develop anywhere on the skin and mucosal surfaces, they are most often found on the head, neck, and sun-exposed surfaces of the arms, hands, and legs. Lesions are typically pink to red, hyperkeratotic, and tender. They may range in size from a few millimeters to several centimeters. Double-covered areas and lesions located on mucosal surfaces may present as macerated pink erosions without any hyperkeratosis (Figure 1, Figure 2, Figure 3, Figure 4).

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Surrounding skin should also be examined and palpated. Field effects of photodamage leading to adjacent actinic keratoses, squamous cell carcinomas in situ, and even additional squamous cell carcinomas are common. Adjacent subcutaneous nodules may indicate in-transit cutaneous metastatic disease.

Dermoscopy frequently reveals surface scale, blood spots, white structureless zones, white circles, and coiled vessels.

Draining lymph node regions should be palpated.

Expected results of diagnostic studies

The gold standard for diagnosing a squamous cell carcinoma is a skin biopsy for histopathological examination. Punch biopsy, shave biopsy, or excisional biopsy are all appropriate techniques. Microscopic examination typically reveals pleomorphic atypical aggregates of keratinocytes. These often manifest nuclear atypia, hyperkeratosis, and parakeratosis (Figure 5, Figure 6).

Figure 5.

Figure 6.

By definition, invasive squamous cell carcinoma will demonstrate tumor nests invading into the dermis, frequently with associated lymphocytic inflammation. Well-differentiated squamous cell carcinoma is further characterized by large pink-staining intracytoplasmic keratin, as well as frequent extracellular keratin pearls. By contrast, poorly differentiated squamous cell carcinoma has numerous mitoses, enlarged nuclei, significant atypia, and possibly single-cell infiltration.

Immunohistochemical staining may be useful for distinguishing poorly differentiated squamous cell carcinoma (cytokeratin-positive) from atypical fibroxanthoma (CD68-positive), leiomyosarcoma (smooth muscle actin-positive), and spindle cell melanoma (S100-positive).

Lack of differentiation and single cell infiltration portend a poor prognosis. Other histological features correlated with more aggressive clinical behavior include: perineural invasion, lymphovascular invasion, arising de novo or in sites of prior injury (vs. actinic damage background), greater depth of invasion, and diameter greater than 2cm. Specifically, tumor involvement of nerves 0.1mm or greater in diameter is associated with significantly worse survival compared to tumor involvement of smaller caliber nerves.

Tumor depth of 1cm or greater as well as invasion into the subcutaneous fat is also associated with worse survival. Some data suggest epidermal growth factor receptor (EGFR) status may also influence prognosis.

All patients with clinically-suggestive or histopathologically-confirmed squamous cell carcinoma should undergo a thorough clinical assessment of regional draining lymph node basins. Cases of palpable lymphadenopathy should be further evaluated with fine needle aspiration.

The roles for diagnostic imaging (computed tomography, magnetic resonance imaging) as well as sentinel lymph node biopsy in patients with clinically node-negative but otherwise high-risk disease is less well-defined. Studies have demonstrated that sentinel lymph node biopsy for high-risk squamous cell carcinoma is both technically feasible, and may provide valuable prognostic information. A meta-analysis of sentinel lymph node biopsy of high-risk cutaneous squamous cell carcinomas located on the head and neck identified 13.5% of patients with occult metastatic disease; 4.76% of patients with negative sentinel lymph node biopsy subsequently developed regional lymphatic disease.

Newer diagnostic technologies may avoid the need for a tissue biopsy. Optical coherence tomography and reflectance confocal scanning laser microscopy may reliably confirm the diagnosis of squamous cell carcinoma, though neither is currently in widespread use in the United States.

Diagnosis confirmation

Usually physical examination reliably identifies squamous cell carcinoma however, lesions may clinically mimic: actinic keratoses, squamous cell carcinoma in situ, basal cell carcinoma, atypical fibroxanthoma, Merkel cell carcinoma, as well as nonmalignant conditions such as atopic dermatitis and psoriasis.

Who is at Risk for Developing this Disease?

Squamous cell carcinoma of the skin has been reported on all parts of the body, in all races, and throughout the world. However, fair skin, increased cumulative ultraviolet exposure, and immunosuppression significantly increase risk for developing squamous cell carcinoma.

The incidence of squamous cell carcinoma worldwide varies considerably based primarily on skin type and ultraviolet exposure. The incidence in Australia, generally a light skin type population with intense ultraviolet exposure, is reported to be 250 per 100,000. By contrast, the rate for black Americans is 3 per 100,000. Approximately 250,000 individuals in the United States are diagnosed with squamous cell carcinoma of the skin annually.

Therapeutic ultraviolet exposure and tanning booth usage also correlate with higher incidences of squamous cell carcinoma. Individuals who have ever used a tanning device have a 2.5x increased risk for developing squamous cell carcinoma. Individuals who received therapeutic ultraviolet exposure for psoriasis demonstrate a dose-related increased risk for developing squamous cell carcinoma.

In addition to correlating with cumulative ultraviolet exposure and skin type, other risk factors include: immunosuppression, older age, certain chemical exposures, ionizing radiation, viral infection, chronic scarring or inflammation, and genetic disorders.

Immunosuppression, especially in the case of solid organ transplant recipients, strongly correlates with an increased risk of developing squamous cell carcinoma. The incidence of squamous cell carcinoma in solid organ transplant recipients is 65-250 times higher than that for the general population. This incidence correlates with degree of immunosuppression and time following transplantation. Administration of voriconazole, a potent anti-fungal agent, in solid organ transplant recipients also contributes to an increased risk of developing cutaneous squamous cell carcinoma. Furthermore, squamous cell carcinomas in solid organ transplant recipients tend to develop at a younger age and behave more aggressively than those developing in age-matched controls.

Some newer immunosuppressive regimens, including mTOR inhibitors such as sirolimus, are associated with lower rates of squamous cell carcinoma.

Several recently introduced multikinase inhibitors employed in oncology, such as sorafenib and sunitinib, have been reported to induce cutaneous squamous cell carcinomas. A BRAF inhibitor FDA-approved to treat stage IV melanoma, vemurafenib, has also been associated with an increased incidence of squamous cell carcinoma.

Noniatrogenically immunosuppressed individuals, including those with chronic lymphocytic leukemia or human immunodeficiency virus, also demonstrate an increased incidence of and more aggressive behavior of squamous cell carcinoma.

Polycyclic aromatic hydrocarbons, pesticides, arsenic, and other chemical exposures are strongly associated with the development of squamous cell carcinoma. Percival Pott’s 1775 treatise Chirurgical Observations Relative to the Cancer of the Scrotum described a link between hydrocarbon (chimney soot) exposure and squamous cell carcinoma in chimney sweeps.

The dose of ionizing radiation received correlates with an increasing risk of developing squamous cell carcinoma. The latency period may, however, be as long as 20 or more years.

Human papillomavirus (HPV) infection is associated with periungual, genital, and veruccous squamous cell carcinoma. Specifically, HPV types 16, 31, 35, and 51 are associated with squamous cell carcinomas.

Subsequent development of squamous cell carcinoma in scars, radiation, areas of thermal injury, and chronic inflammatory processes is well-described. There is generally a latency period of several years between the initial injury and subsequent development of squamous cell carcinoma. In individuals with darker complexions, the incidence of squamous cell carcinoma secondary to scars, thermal injury, or chronic inflammation, exceeds that due to ultraviolet exposure.

Many genetic disorders are strongly linked to squamous cell carcinoma. Xeroderma pigmentosum is a group of disorders characterized by defects in DNA repair. These patients develop squamous cell carcinomas at a rate thousands of times higher than the general population.

Reduced melanin synthesis is one key feature of oculocutaneous albinism; this predisposes affected individuals to increased damage from ultraviolet radiation leading to squamous cell carcinomas. Patients with dystrophyic epidermolysis bullosa develop significant scarring and also have a higher incidence of squamous cell carcinoma.

What is the Cause of the Disease?

• Etiology

• Pathophysiology

While cumulative ultraviolet exposure and skin type are the most important etiologic factors in the development of squamous celll carcinomas, other risk factors include: immunosuppression, older age, certain chemical exposures, ionizing radiation, viral infection, chronic scarring or inflammation, and genetic disorders.

Systemic Implications and Complications

Local destruction and lymphatic metastasis are two complications associated with progressive disease.

Pain, bleeding, infection, and ulceration may characterize advanced squamous cell carcinoma. Lesions may invade and destroy fat, muscle, cartilage, and bone. Some tumors manifest perineural invasion. These lesions may cause tingling, radiating pain, or itching.

Advanced squamous cell carcinoma tends to metastasize to local draining lymphatics prior to manifesting systemic involvement. Lymph nodes may become enlarged and tender. Additionally, local symptoms such as dysphagia or otalgia (for a progressive squamous cell carcinoma on the face) are prominent.

In the United States an estimated 3932 to 8791 patients died from invasive cutaneous squamous cell carcinoma in 2012.

Treatment Options

The National Comprehensive Cancer Network (NCCN) has developed guidelines for the treatment of squamous cell carcinoma based on published evidence, as well as expert consensus opinion. These guidelines are available online at http://www.nccn.org.

MEDICAL THERAPIES

Topical Therapies

5-Fluorouracil

Imiquimod

Intralesional Treatments

5-Fluoruracil

Methotrexate

Interferon alpha-2a

Interferon alpha-2b

Bleomycin

Systemic Therapies

Acitretin

Capecitabine

Cetuximab

SURGICAL THERAPIES

Mohs micrographic surgery

Wide Local Excision

Curettage and Electrodessication

PHYSICAL MODALITIES

Photodynamic Therapy

5-aminolevulinic acid

Methyl-aminolevulinate

Radiation

Cryotherapy

Optimal Therapeutic Approach for this Disease

NCCN has developed guidelines for the treatment of squamous cell carcinoma based on published evidence as well as expert consensus opinion. These guidelines are available online at www.ncccn.org/professionals/physicians_gls/pdf/nmsc.pdf.

Important clinical considerations such as the patient’s age, comorbidities, risk factors for recurrence and metastasis, and location influence selection of the most appropriate treatment modality.

Location, history, and histopathology may characterize tumors at an elevated risk for recurrence or metastasis. Lesions located on ears, lips, or within scars behave more aggressively. Associated pain, dysesthesia, or motor defect may indicate significant perineural invasion and more aggressive bevhavior.

Additional recurrent tumor, size greater than 2cm, and systemic immunosuppression are additional poor prognostic features.

Histopathologically, perineural invasion (nerve diameter greater than 0.1mm), lymphovascular involvement, poor differentiation, and increased depth of invasion characterize high-risk tumors.

For most squamous cell carcinomas, a surgical modality is the preferred treatment approach. Biopsy of well-differentiated squamous cell carcinomas revealing negative margins may not require further treatment. Low-risk tumors located on areas with adequate redundant tissue may be treated with wide local excision. Four millimeter margins can achieve a 95% clearance rate for low-risk tumors located on the trunk and extremities.

Sutured wounds generally provide good cosmesis. Additionally, standard excision provides tissue to confirm negative margins as well as the initial biopsy diagnosis. Risks include bleeding and infection. For primary squamous cell carcinoma, cure rates are 92%, while they fall to 77% for recurrent tumors.

In areas of the body where tissue conservation is of concern or the tumor manifests high-risk features, Mohs micrographic surgery is the standard of care. A consensus conference statement published in 2012 identified appropriate use criteria for Mohs surgery. Mohs involves narrow excision, followed by histopathological examination of 100% of the excised specimen margin. This process is repeated until clear tissue margins are achieved. The two primary advantages to Mohs micrographic surgery are reduced excision of uninvolved skin and improved cure rates.

Compared to excision, electrodessication and curettage, and radiation, Mohs provides the highest 5-year cure rate for primary squamous cell carcinoma (97%). This technique, however, is expensive and may require several hours for treatment. Standard surgical risks of bleeding and infection also apply.

In patients unable to tolerate a surgical excision, or those with small, low-risk tumors located in non-cosmetically-sensitive areas, electrodessication and curettage may be an appropriate alternative.

Cure rates are highly operator-dependent, but have been reported to be as high as 98% for appropriately selected lesions treated by experienced physicians. This treatment is rapid, inexpensive, and has a low risk of complications. Drawbacks include the fact that healing may require weeks to months, depending on the treated location, there is no tissue available for histopathological confirmation of the diagnosis or adequacy of treatment, and scarring may be suboptimal.

Some patients either cannot tolerate or refuse to pursue a surgical treatment modality. For many of these patients, radiation therapy offers an excellent alternative, providing cure rates comparable to surgical excision as well as excellent short-term cosmesis. There are some data, however, to suggest that these patients may have an increased risk of secondary skin malignancies in treated fields 15-20 years later. Additionally, treatment is usually fractionated over 20-30 days.

The remaining treatment options generally involve case reports or small case series only.

Photodynamic therapy involves application of a photosensitizer—either 5-aminolevulinic acid or methyl aminolevulinate—to the skin, followed by subsequent stimulation by a light source. While this approach may effectively treat actinic keratoses and some in situ disease, it is not effective for invasive squamous cell carcinoma. Recurrence rates are up to 69%.

One study demonstrated a 71% clearance rate of seven tumors following treatment 5 days/ week for 12 weeks with imiquimod cream. 5-Fluoruracil has been reportedly used topically to treat squamous cell carcinoma.

Intralesional injections of 5-fluoruracil, interferon-alpha, methotrexate, and bleomycin have all reportedly been employed to treat squamous cell carcinoma. Case reports and small series demonstrate high response rates. These treatments often require a series of multiple treatments. They frequently involve significant local site irritation as well as limited systemic toxicity.

Patient Management

Patients and families need to be told that squamous cell carcinoma is an extremely common type of cancer that, when caught early and treated effectively, has a limited chance of metastasis and significant morbidity (or mortality).

Once a patient has been diagnosed with a primary squamous cell carcinoma of the skin, however, there is a 30% chance that a second primary squamous cell carcinoma of the skin will develop within 5 years. Accordingly, patients should undergo a professional full skin examination every 3-6 months. Ninety percent of reccurrences and metastases will develop in the first 5 years following treatment.

Patients should be taught early signs and symptoms of skin cancer, as well as how to perform a thorough self-exam. They should also be encouraged to practice sun protective behavior (hat, sunscreen, limit exposure, sunglasses) daily.

Unusual Clinical Scenarios to Consider in Patient Management

There is a subset of patients who develop multiple (more than six) squamous cell carcinomas each year. Many of these patients additionally manifest extensive actinic damage with innumerable actinic keratoses, as well as squamous cell carcinomas in situ. The most common etiologies include extensive sun exposure, fair skin type, and immunosuppression. For these patients, field treatment of actinically damaged skin as well as potential chemopreventive strategies are essential.

Solid organ transplant recipients will often develop fewer skin cancers (and may demonstrate spontaneous tumor regression) with a lessening of the degree of immunosuppression. Utilization of mTOR-inhibtors to prevent rejection rather than more traditional agents is also helpful.

EGFR inhibitors may effectively treat advanced and metastatic squamous cell carcinomas. Proliferating undifferentiated keratinocytes in the basal layer normally express EGFR, and immunohistochemical studies suggest significant overexpression in metastatic squamous cell carcinomas. One small clinical trial (n=37) as well as case reports of cetuximab (human-murine anti-EGFR monoclonal antibody) suggest efficacy in treating advanced and metastatic squamous cell carcinoma.

Oral retinoids are the most extensively documented modestly effective agent for squamous cell carcinoma chemoprevention. Few patients are able to tolerate prolonged treatment with these agents, however, due to adverse effects, including hypertriglyceridemia, alopecia, dry and “sticky” skin, and poor night vision. Furthermore, patients appear to demonstrate a rebound in the number of squamous cell carcinomas developing once the retinoid is discontinued.

A study employing topical retinoids for chemoprevention was discontinued early because of excess mortality in the treatment group.

A case series has demonstrated dramatic improvement in solid organ transplant recipients treated with capecitabine (Xeloda). Capecitabine is an oral 5-flurouracil pro-drug FDA-approved to treat colorectal and breast cancers. In lower doses, the drug may dramatically decrease the development of new squamous cell carcinomas with a tolerable side effect profile.

Some data suggest that photodynamic therapy may be a well-tolerated effective field treatment with chemopreventive benefits. Destructive field treatments, including chemical peels and ablative (or fractional) laser resurfacing, may also be effective.

In this author’s experience, treatment with topical 5-fluoruracil, imiquimod cream, urea cream, and retinoids irritates the skin and provides little lasting benefit.

What is the Evidence?

Alam, M, Ratner, D. “Cutaneous squamous cell carcinoma”. N Engl J Med. vol. 344. 2001. pp. 975-83. (Although this is over 10-years-old, it is a clearly written introduction to squamous cell carcinoma. Clinical and histopathological descriptions, the epidemiology, and even major treatment modalities have not changed significantly.)

Berg, D, Otley, CC. “Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management”. J Am Acad Dermatol. vol. 47. 2002. pp. 1-17. (This presents a thorough discussion of basic features of squamous cell carcinoma in solid organ transplant recipients.)

Madan, V, Lear, JT, Szeimies, RM. “Non-melanoma skin cancer”. Lancet. vol. 375. 2010. pp. 673-85. (This review provides current insights into the pathogenesis, risk factors, and prevention strategies for squamous cell carcinoma as well as basal cell carcinomas.)

Schmults, CD, Karia, PS, Carter, JB, Han, J, Qureshi, AA. “Factors predictive of recurrence and death from cutaneous squamous cell carcinoma: a 10-year, single-institution cohort study”. JAMA Dermatol. vol. 149. 2013. pp. 541-7. (This study identifies characteristics of high risk cutaneous squamous cell carcinomas.)

Ahmed, MM, Moore, BA, Schmalbach, CE. “Utility of Head and Neck Cutaneous Squamous Cell Carcinoma Sentinel Node Biopsy: A Systematic Review”. Otolaryngology-Head and Neck Surgery. vol. 150. 2014. pp. 180-7. (This review describes the published experience of utilizing sentinel lymph node biopsies for high risk cutaneous squamous cell carcinomas.)

O’Bryan, K, Sherman, W, Niedt, GW, Taback, B. “An evolving paradigm for the workshop and management of high-risk cutaneous squamous cell carcinoma”. J Am Acad Dermatol. vol. 69. 2013. pp. 595-602. (Based on a limited case series, the authors propose an approach to managing high risk cutaneous squamous cell carcinomas.)

Foote, MC, McGrath, M, Guminski, A, Hughes, BG, Meakin, J, Thomson, D, Zarate, D, Simpson, F, Porceddu, SV. “Phase II study of single agent panitumumab in patients with incurable cutaneous squamous cell carcinoma”. Ann Oncol. vol. 25. 2014. pp. 2047-2052.

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