Published on 18/03/2015 by admin
Filed under Dermatology
Last modified 18/03/2015
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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
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.
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.
Histopathology
Physical examination for lymphadenopathy
Radiologic examination (MRI, CT scan, ultrasound)
Sentinel lymph node biopsy
Madan V, Dawn G. J Am Acad Dermatol 2007; 56: S103–4.
Standard curette biopsy may produce fragmented tissue and hence be suboptimal for diagnosis of SCC.
Jagdeo J, Weinstock MA, Piepkorn M, Bingham S. J Am Acad Dermatol 2007; 57: 279–84.
A prospective blinded study of 3926 specimens assigned a diagnosis by local pathologists and one or both (355 slides) central dermatopathologists. Intraobserver agreement was highest for BCC and lowest in the categories of invasive SCC, SCC in situ, and actinic keratosis, suggesting that the diagnostic boundaries of these diagnoses are imprecisely defined.
Jackson JE, Kelly B, Petitt M, Uchida T, Wagner RF Jr. J Am Acad Dermatol 2012; 67: 122–7.
Retrospective study of 235 diagnostic non-melanomatous skin cancer biopsies and their corresponding excisions for margin status and the presence of residual tumor, respectively. Twelve of 148 SCCs (8.1%) had negative biopsy margins and were associated with excisional specimens free of residual tumor. The SCCs with negative biopsy margins were predominantly non-facial, superficial tumors of the well-differentiated and KA subtype. The results suggest that negative-margin diagnostic biopsies may be therapeutic for well-differentiated or KA subtypes of SCC.
Ch’ng S, Low I, Ng D, Brasch H, Sullivan M, Davis P, et al. Hum Pathol 2008; 39: 344–9.
Epidermal growth factor (EGF) receptor protein over-expression was detected in 36% of primary SCCs without metastases, 79% of primary SCCs with subsequent metastases, and 47% of SCCs with metastatic nodal disease. EGF receptor over-expression was concluded to be an independent prognostic factor for subsequent metastases and could have important prognostic and therapeutic implications for high-risk tumors.
Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, et al. N Engl J Med 2012; 366: 207–15.
Molecular analysis to identify oncogenic mutations (HRAS, KRAS, NRAS, CDKN2A, and TP53) in patients treated with the BRAF inhibitor vemurafenib was performed. Among 21 tumor samples, 13 had RAS mutations (12 in HRAS). In a validation set of 14 samples, eight had RAS mutations (four in HRAS). Thus, 60% (21 of 35) of the specimens harbored RAS mutations. Mutations in RAS, particularly HRAS, are frequent in SCC that develops in patients treated with vemurafenib.
Marinez JC, Cook JL. Dermatol Surg 2007; 33: 410–20.
A literature review suggested that patients with cutaneous SCC who underwent elective node dissection had no proven survival benefit over those who are initially staged as node negative and undergo therapeutic neck dissection after the development of apparent regional disease.
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.
Treatment of Skin Disease Comprehensive Therapeutic Strategies 4e
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