Squamous cell carcinoma

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Squamous cell carcinoma

Jason J. Emer and Heidi A. Waldorf

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Squamous cell carcinoma (SCC) is a malignant neoplasm arising from epithelial keratinocytes of the skin and mucous membranes that generally appears as an erythematous, keratotic papule or nodule that may become ulcerated. There may be a history of tenderness as the lesion enlarges and becomes nodular. Although it is most commonly associated with chronic sun exposure in light-skinned individuals, SCC can arise secondary to scarring processes (burns, chronic ulcers, hidradenitis suppurativa), chemical carcinogens (arsenic, tobacco tar, hydrocarbons), human papillomavirus (types 16, 18, 30, 33, 35), ionizing radiation exposure (X-rays, γ-rays, radium), and in those with a genetic predisposition (xeroderma pigmentosum). Immunosuppression due to disease or drug therapy is an instigating factor.

Management strategy

The management of SCC depends on the histopathologic classification and clinical setting. The risk of local recurrence and of metastasis is correlated with poor histologic differentiation, perineural invasion, tumor size (≥2 cm), tumor depth (≥4 mm), tumor location (lip, ear, temple, genitalia), treatment modality, history of recurrence, host immunosuppression, rate of growth, presence of neurological symptoms such as pain, paresthesias, or paralysis, and precipitating factors other than UV light (radiation, site of inflammatory process). Regional lymphadenopathy is a poor prognostic sign.

Accurate histopathologic diagnosis is the most critical investigation. The differential diagnosis may include verruca vulgaris, actinic keratosis, SCC in situ (Bowen disease), keratoacanthoma (KA), irritated seborrheic keratosis, and superficial basal cell carcinoma (BCC) (these conditions are described in separate chapters). Specimens for histopathologic diagnosis should include epidermis and deep reticular dermis. A deep curette or scoop shave biopsy is generally sufficient, but punch biopsy to subcutaneous fat, or an incisional or excisional biopsy, is useful if there is concern regarding obtaining adequate tissue.

Regional lymph node palpation is performed when an aggressive tumor is suspected, based on the criteria specified above. In the absence of palpable lymphadenopathy, additional radiologic and surgical studies are performed if deep invasion (bone, cartilage, parotid) or perineural spread is suspected.

Small superficial SCC may be effectively treated using a destructive modality. Cryosurgery destroys tumor if it is frozen to −40°C to −70°C. Cryosurgery has the advantage of being fast, simple, and inexpensive, although a serious consequence is recurrence that may become extensive due to concealment in a previous scar. Curettage and electrodesiccation involves a sequence of three curette scrapings and electrodesiccations and can be used for well-differentiated primary SCC and SCC in situ <1 cm in diameter. A margin of 3–4 mm around the tumor should be treated with cryosurgery and with curettage and desiccation. Adequately treated lesions often require several weeks to heal and may leave hypopigmented, atrophic, or hypertrophic scars. Cosmetically sensitive areas, concave surfaces, and skin prone to keloid formation or poor wound healing should be avoided. Cure rates are highly technique dependent.

Standard surgical excision, utilizing 3–4 mm margins beyond the clinically apparent tumor, is a reasonable option for a well-demarcated SCC, particularly of the trunk and extremities. Higher-risk SCC (size ≥2 cm, poor histologic differentiation, invasion to fat, high risk areas) requires at least 6 mm margins. Recent studies have suggested that light curettage of the lesion prior to excision, traditionally used to better define tumor margins, may not be efficacious. Extensive tumors of the limbs involving bone may require amputation.

The gold standard for treatment of SCC is Mohs micrographic surgery, a technique in which the surgeon also acts as pathologist. The tumor is extirpated in a series of thin layers that are precisely oriented, horizontally sectioned, and immediately processed for evaluation. The process is continued until all margins are clear to maximize tumor eradication and tissue conservation. Indications for Mohs micrographic surgery include tumor size, location (cosmetically or functionally sensitive, high recurrence rate), indistinct margins, a history of recurrence, aggressive histopathology, and young patient age. Adjuvant radiation therapy following Mohs micrographic surgery should be considered for facial SCC ≥2 cm in diameter and those with perineural spread.

Although the use of radiation therapy as a primary modality has decreased, it remains a good treatment option for selected patients, particularly those of advanced age or poor surgical risk, with uncomplicated tumors of the head and neck. A total of 4000–7000 cGy is given sequentially over several weeks. One standard schedule is administration of 500 cGy three to five times per week over 2 to 6 weeks. Complications include hypopigmentation, telangiectasia, loss of adnexae, radiation dermatitis, and late (10–20 years) tumor recurrence.

For patients with SCC not amenable to surgical extirpation or radiation due to advanced disease stage or large number of lesions, topical therapy with imiquimod or 5-fluorouracil (5-FU), intralesional therapy with bleomycin, 5-FU or interferon (IFN), or systemic therapy with retinoids or IFN may be effective. Photodynamic therapy (PDT), most commonly using topical porphyrins followed by selective irradiation with visible light, is another alternative. Systemic regimens, including monoclonal antibodies and protein kinase inhibitors, are also being studied for inoperable tumors. Recent studies focusing on combining more than one therapeutic modality have shown potential for increased cure rates while minimizing adverse reactions and maximizing cosmetic results.

Specific investigations

Sentinel lymph node biopsy for high risk cutaneous squamous cell carcinoma: case series and review of the literature.

Renzi C, Caggiati A, Manooranperampil TJ, Passarelli F, Tartaglione G, Pennasilico G, et al. Eur J Surg Oncol 2007; 33: 364–9.

In a consecutive series of 22 clinically node-negative high-risk cutaneous SCC patients who underwent sentinel lymph node biopsy (SLNB), 4.5% (one patient) had histologically positive nodes and developed a recurrence during follow-up. SLNB-negative patients had no metastases at a median follow-up of 17 months. Literature review revealed an incidence of positive sentinel nodes ranging from 12.5% to 44.4%. Analysis combining the results of this series and 61 patients from previous reports found in the literature supported the concept of SLNB for high-risk cutaneous SCC.

Role of neck ultrasound during follow-up care of head and neck squamous cell carcinomas.

Park JJ, Emmerling O, Westhofen M. Acta Otolaryngol 2012; 132: 218–24.

A retrospective analysis of 140 patients with primarily surgically treated head and neck SCC. Each patient received neck ultrasound during follow-up visits. Recurrence rate, survival rate, and outcome of salvage therapy were determined. Recurrences occurred in 35.0% of all studied cases. Local, regional, and distant recurrences were found in 11.4%, 7.9%, and 15.7%.

CT is the preferred imaging technique of choice during oncologic follow-up, but is limited in terms of frequency of applications because of radiation exposure. Compared with CT, neck ultrasound is an easily feasible and cost-effective examination that can be performed during any routine visit in an outpatient clinic setting.

First-line therapies

image Cryosurgery B
image Curettage and electrodesiccation B
image Standard excision B
image Mohs micrographic surgery B
image Radiation therapy B

Controversies in skin surgery: electrodessication and curettage versus excision for low-risk, small, well-differentiated squamous cell carcinomas.

Reschly MJ, Shenefelt PD. J Drugs Dermatol 2010; 9: 773–6.

Two retrospective studies investigating the efficacy of curettage and electrodesiccation in the treatment of low-risk SCC. One was a small controlled study in a Veterans Administration teaching hospital dermatology clinic that compared cure rates of low-risk SCCs at 1 year by curettage and electrodesiccation to those of surgical excision. A second study examined the cure rate of low-risk SCCs treated by curettage and electrodesiccation alone in a private practice. The first study found no significant difference in cure rates between curettage and electrodesiccation (14 of 14 cases successfully treated) and excision (15 of 16 successfully treated and one recurrence). The second study found the curettage and electrodesiccation cure rate (106 of 106 successfully treated) to be significantly greater than an arbitrary cure rate of 95%.

Recurrence after treatment of nonmelanoma skin cancer: a prospective cohort study.

Chren MM, Torres JS, Stuart SE, Bertenthal D, Labrador RJ, Boscardin WJ. Arch Dermatol 2011; 147: 540–6.

This was a prospective, long-term study (median 6.6 years after treatment) to determine tumor recurrence rates after treatment. Consecutive samples were taken from all 495 patients with 616 primary non-melanoma skin cancers diagnosed in 1999 and 2000 and treated with curettage and electrodesiccation, excision, or Mohs surgery. A total of 127 tumors were treated with curettage and electrodesiccation (20.9%), 309 with excision (50.8%), and 172 with Mohs surgery (28.3%). Over the course of the study, 21 tumors recurred (3.5%): two (two BCC) after curettage and electrodesiccation (1.6%), 13 (nine BCC, four SCC) after excision (4.2%), and six (four BCC, two SCC) after Mohs surgery (3.5%). Recurrent tumors were detected earliest after curette and electrodesiccation (1.5 years) and latest after Mohs surgery (6.0 years). Median time to detection of recurrence after excision was 3.8 years. The recurrence rate after curettage and electrodesiccation was lower than expected, and the recurrence rate after Mohs surgery was higher than expected.

Second-line therapies

image Topical imiquimod A
image Topical 5-fluorouracil B
image Intralesional 5-fluorouracil B
image Intralesional bleomycin E
image Electrochemotherapy with bleomycin B
image Intralesional interferon-α B
image Intralesional methotrexate D

Electrochemotherapy in primary and metastatic skin tumors: phase II trial using intralesional bleomycin.

Rodríguez-Cuevas S, Barroso-Bravo S, Almanza-Estrada J, Cristóbal-Martínez L, González-Rodríguez E. Arch Med Res 2001; 32: 273–6.

Fifteen patients with 38 skin lesions participated in a phase II prospective clinical trial, using intralesional bleomycin plus electric pulses delivered 10 minutes after bleomycin injection, which lasted 100 ms each at field strength of 1300 V/cm and a frequency of 1 Hz. There were BCC (n=9), in-transit metastasis of melanoma (n=2; total 13 nodules), SCC of the upper aerodigestive tract metastatic to the skin (n=2; total two nodules), and skin metastases from breast cancer (n=2; total 14 nodules). Overall objective responses were 98%, with complete responses achieved in 49%, partial responses in 49% (100% of SCCs), and no responses in 2%. The authors concluded that electrochemotherapy treatment represents an alternative to standard surgery or radiotherapy, with an outpatient-based treatment applied in one to three sessions.

Intralesional methotrexate treatment for keratoacanthoma tumors: a retrospective study and review of the literature.

Annest NM, VanBeek MJ, Arpey CJ, Whitaker DC. J Am Acad Dermatol 2007; 56: 989–93.

Thirty-eight cases of KA treated with intralesional methotrexate (MTX) were identified from the author’s institution (n=18) and literature search (n=20). Intralesional MTX achieved resolution in 92%, requiring an average of 2.1 injections an average of 18 days apart. Adverse events were rare, with two reports of pancytopenia in patients with chronic renal failure. The authors concluded that intralesional MTX is a useful non-surgical therapy for the treatment of KA, that histologic diagnosis before initiation of treatment is preferred, and a complete blood cell count at baseline and during treatment should be considered.

Third-line therapies

image Amputation D
image Photodynamic therapy B
image Systemic retinoids B
image Protein kinase inhibitors B
image Chemoradiation E

Oral retinoid use reduces cutaneous squamous cell carcinoma risk in patients with psoriasis treated with psoralen-UVA: a nested cohort study.

Nijsten TEC, Stern RS. J Am Acad Dermatol 2003; 49: 644–50.

To assess whether oral retinoids reduce the risk of developing cutaneous SCC a nested cohort of 135 patients participating in the PUVA follow-up study with at least 1 year of substantial retinoid use was identified. Each patient’s tumor incidence during retinoid therapy was compared to the incidence of SCC development in periods of no use. Overall, a 30% reduction in SCC incidence was noted when patients were on oral retinoid therapy.

Retinoids (isotretinoin, acitretin) may play a role in the treatment of patients with SCC not amenable to surgical extirpation owing to advanced stage of disease or large number of lesions. Several studies have shown an overall response rate of about 70%.

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Squamous cell carcinoma

Jason J. Emer and Heidi A. Waldorf

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Squamous cell carcinoma (SCC) is a malignant neoplasm arising from epithelial keratinocytes of the skin and mucous membranes that generally appears as an erythematous, keratotic papule or nodule that may become ulcerated. There may be a history of tenderness as the lesion enlarges and becomes nodular. Although it is most commonly associated with chronic sun exposure in light-skinned individuals, SCC can arise secondary to scarring processes (burns, chronic ulcers, hidradenitis suppurativa), chemical carcinogens (arsenic, tobacco tar, hydrocarbons), human papillomavirus (types 16, 18, 30, 33, 35), ionizing radiation exposure (X-rays, γ-rays, radium), and in those with a genetic predisposition (xeroderma pigmentosum). Immunosuppression due to disease or drug therapy is an instigating factor.

Management strategy

The management of SCC depends on the histopathologic classification and clinical setting. The risk of local recurrence and of metastasis is correlated with poor histologic differentiation, perineural invasion, tumor size (≥2 cm), tumor depth (≥4 mm), tumor location (lip, ear, temple, genitalia), treatment modality, history of recurrence, host immunosuppression, rate of growth, presence of neurological symptoms such as pain, paresthesias, or paralysis, and precipitating factors other than UV light (radiation, site of inflammatory process). Regional lymphadenopathy is a poor prognostic sign.

Accurate histopathologic diagnosis is the most critical investigation. The differential diagnosis may include verruca vulgaris, actinic keratosis, SCC in situ (Bowen disease), keratoacanthoma (KA), irritated seborrheic keratosis, and superficial basal cell carcinoma (BCC) (these conditions are described in separate chapters). Specimens for histopathologic diagnosis should include epidermis and deep reticular dermis. A deep curette or scoop shave biopsy is generally sufficient, but punch biopsy to subcutaneous fat, or an incisional or excisional biopsy, is useful if there is concern regarding obtaining adequate tissue.

Regional lymph node palpation is performed when an aggressive tumor is suspected, based on the criteria specified above. In the absence of palpable lymphadenopathy, additional radiologic and surgical studies are performed if deep invasion (bone, cartilage, parotid) or perineural spread is suspected.

Small superficial SCC may be effectively treated using a destructive modality. Cryosurgery destroys tumor if it is frozen to −40°C to −70°C. Cryosurgery has the advantage of being fast, simple, and inexpensive, although a serious consequence is recurrence that may become extensive due to concealment in a previous scar. Curettage and electrodesiccation involves a sequence of three curette scrapings and electrodesiccations and can be used for well-differentiated primary SCC and SCC in situ <1 cm in diameter. A margin of 3–4 mm around the tumor should be treated with cryosurgery and with curettage and desiccation. Adequately treated lesions often require several weeks to heal and may leave hypopigmented, atrophic, or hypertrophic scars. Cosmetically sensitive areas, concave surfaces, and skin prone to keloid formation or poor wound healing should be avoided. Cure rates are highly technique dependent.

Standard surgical excision, utilizing 3–4 mm margins beyond the clinically apparent tumor, is a reasonable option for a well-demarcated SCC, particularly of the trunk and extremities. Higher-risk SCC (size ≥2 cm, poor histologic differentiation, invasion to fat, high risk areas) requires at least 6 mm margins. Recent studies have suggested that light curettage of the lesion prior to excision, traditionally used to better define tumor margins, may not be efficacious. Extensive tumors of the limbs involving bone may require amputation.

The gold standard for treatment of SCC is Mohs micrographic surgery, a technique in which the surgeon also acts as pathologist. The tumor is extirpated in a series of thin layers that are precisely oriented, horizontally sectioned, and immediately processed for evaluation. The process is continued until all margins are clear to maximize tumor eradication and tissue conservation. Indications for Mohs micrographic surgery include tumor size, location (cosmetically or functionally sensitive, high recurrence rate), indistinct margins, a history of recurrence, aggressive histopathology, and young patient age. Adjuvant radiation therapy following Mohs micrographic surgery should be considered for facial SCC ≥2 cm in diameter and those with perineural spread.

Although the use of radiation therapy as a primary modality has decreased, it remains a good treatment option for selected patients, particularly those of advanced age or poor surgical risk, with uncomplicated tumors of the head and neck. A total of 4000–7000 cGy is given sequentially over several weeks. One standard schedule is administration of 500 cGy three to five times per week over 2 to 6 weeks. Complications include hypopigmentation, telangiectasia, loss of adnexae, radiation dermatitis, and late (10–20 years) tumor recurrence.

For patients with SCC not amenable to surgical extirpation or radiation due to advanced disease stage or large number of lesions, topical therapy with imiquimod or 5-fluorouracil (5-FU), intralesional therapy with bleomycin, 5-FU or interferon (IFN), or systemic therapy with retinoids or IFN may be effective. Photodynamic therapy (PDT), most commonly using topical porphyrins followed by selective irradiation with visible light, is another alternative. Systemic regimens, including monoclonal antibodies and protein kinase inhibitors, are also being studied for inoperable tumors. Recent studies focusing on combining more than one therapeutic modality have shown potential for increased cure rates while minimizing adverse reactions and maximizing cosmetic results.

Specific investigations

Sentinel lymph node biopsy for high risk cutaneous squamous cell carcinoma: case series and review of the literature.

Renzi C, Caggiati A, Manooranperampil TJ, Passarelli F, Tartaglione G, Pennasilico G, et al. Eur J Surg Oncol 2007; 33: 364–9.

In a consecutive series of 22 clinically node-negative high-risk cutaneous SCC patients who underwent sentinel lymph node biopsy (SLNB), 4.5% (one patient) had histologically positive nodes and developed a recurrence during follow-up. SLNB-negative patients had no metastases at a median follow-up of 17 months. Literature review revealed an incidence of positive sentinel nodes ranging from 12.5% to 44.4%. Analysis combining the results of this series and 61 patients from previous reports found in the literature supported the concept of SLNB for high-risk cutaneous SCC.

Role of neck ultrasound during follow-up care of head and neck squamous cell carcinomas.
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