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Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis

Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis
Authors:
Jean Lee Lim, MD
Maryam Asgari, MD, MPH
Section Editors:
Robert S Stern, MD
June K Robinson, MD
Deputy Editor:
Rosamaria Corona, MD, DSc
Literature review current through: Sep 2022. | This topic last updated: Oct 20, 2022.

INTRODUCTION — Cutaneous squamous cell carcinoma (cSCC) is a malignant tumor arising from epidermal keratinocytes [1]. In individuals with lightly pigmented skin, it typically develops in areas of photodamaged skin and presents with a wide variety of cutaneous lesions, including papules, plaques, or nodules, that can be smooth, hyperkeratotic, or ulcerated (picture 1A-B). A skin biopsy is required to confirm the diagnosis. Biopsies also provide information that is useful for staging and management.

The clinical presentation and diagnosis of cSCC will be reviewed here. The epidemiology and risk factors for the development of squamous cell carcinoma (SCC) and the treatment of cSCC are reviewed separately.

(See "Cutaneous squamous cell carcinoma: Epidemiology and risk factors".)

(See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma (cSCC)".)

(See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma".)

(See "Systemic treatment of advanced basal cell and cutaneous squamous cell carcinomas not amenable to local therapies".)

(See "Evaluation for locoregional and distant metastases in cutaneous squamous cell and basal cell carcinoma".)

CLINICAL FEATURES

Location — cSCC can develop on any cutaneous surface, including the head, neck, trunk, extremities, oral mucosa, periungual skin, and anogenital areas (picture 2A-D). In individuals with lightly pigmented skin, cSCCs most commonly arise in sites frequently exposed to the sun.

Non-sun-exposed areas represent the most common location for cSCC in individuals with darkly pigmented skin. In Black individuals, common sites for cSCC include the lower legs, anogenital region, and areas of chronic inflammation or scarring [2-6]. Lesions that develop in relation to chronic scarring processes account for 20 to 40 percent of cSCCs in Black patients [2]. (See "Cutaneous squamous cell carcinoma: Epidemiology and risk factors", section on 'Skin pigmentation and ancestry' and "Cutaneous squamous cell carcinoma: Epidemiology and risk factors", section on 'Chronic inflammation'.)

Genital and periungual cSCC lesions are less common and are usually related to infection with high-risk human papillomavirus (HPV) [7]. (See "Cutaneous squamous cell carcinoma: Epidemiology and risk factors", section on 'Human papillomavirus infection'.)

Genital lesions may also arise as a consequence of the administration of psoralen plus ultraviolet A (PUVA) phototherapy without genital shields [8]. Of note, tumors arising on the ear, preauricular surfaces, or at mucocutaneous interfaces (ie, lips, genitalia, and perianal area) tend to be more aggressive, with rates of metastasis estimated to range from 10 to 30 percent [9-11]. (See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma", section on 'Clinical features'.)

Cutaneous squamous cell carcinoma in situ (Bowen's disease) — cSCC in situ (Bowen's disease) typically presents as an erythematous, well-demarcated, scaly patch or plaque (picture 3A-B) located in sun-exposed areas, such as the head and neck and extremities. Lesions can also be skin colored or pigmented, particularly in individuals with darkly pigmented skin. Lesions of cSCC in situ tend to grow slowly, enlarging over the course of years. Unlike the inflammatory disorders that may resemble cSCC in situ, such as psoriasis or chronic eczema, cSCC in situ lesions are usually asymptomatic. (See 'Differential diagnosis' below.)

"Erythroplasia of Queyrat" is a term used to describe cSCC in situ involving the penis. This condition presents as a well-defined, velvety, red plaque (picture 2D). Patients may experience pain, bleeding, or pruritus. (See "Carcinoma of the penis: Clinical presentation, diagnosis, and staging", section on 'Premalignant lesions'.)

Invasive cutaneous squamous cell carcinoma — The clinical appearance of invasive cSCC often correlates with the level of tumor differentiation. Well-differentiated lesions usually appear as indurated or firm, hyperkeratotic papules, plaques, or nodules (picture 1A-B, 2A, 2E). Lesions are usually 0.5 to 1.5 cm in diameter but may be much larger. Ulceration may or may not be present.

In contrast, poorly differentiated lesions are usually fleshy, granulomatous papules or nodules resembling pyogenic granuloma that lack the hyperkeratosis that is often seen in well-differentiated lesions (picture 4A-B). Poorly differentiated tumors may have ulceration, hemorrhage, or areas of necrosis.

Lesions of invasive cSCC are often asymptomatic but may be painful or pruritic. Local neurologic symptoms (eg, numbness, stinging, burning, paresthesias, paralysis, or visual changes) occur in approximately one-third of patients with high-risk cSCC showing histologic perineural invasion [12]. (See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma", section on 'Clinical features'.)

CLINICAL VARIANTS

Keratoacanthoma — Keratoacanthomas are keratocytic epithelial tumors that clinically and histologically resemble squamous cell carcinoma (SCC). It is controversial whether keratoacanthomas represent a subtype of well-differentiated cSCC or a separate entity. Keratoacanthomas are usually found on actinically damaged skin. Lesions typically exhibit rapid initial growth, manifesting as dome-shaped or crateriform nodules with a central keratotic core that develop within a few weeks (picture 5). (See "Keratoacanthoma: Epidemiology, risk factors, and diagnosis".)

Verrucous carcinoma — Verrucous carcinoma is a rare variant of cSCC that presents with well-defined, exophytic, cauliflower-like growths that resemble large warts. Lesions are subclassified according to site:

Oral florid papillomatosis – Verrucous carcinoma of the oral mucosa (picture 6A-B)

Anogenital (also known as giant condyloma acuminatum of Buschke-Löwenstein) – Verrucous carcinoma involving the penis, scrotum, or perianal region (picture 7) (see "Carcinoma of the penis: Epidemiology, risk factors, and pathology", section on 'Pathology')

Epithelioma cuniculatum – Verrucous carcinoma on the plantar foot (picture 8)

Verrucous carcinoma may also occur in other locations.

Cutaneous squamous cell carcinoma of the lip — SCC of the lip primarily occurs on the lower lip. Lesions may present as nodules, ulcers, or indurated, white plaques (picture 9). (See "Oral lesions", section on 'Oral squamous cell carcinoma'.)

Oral squamous cell carcinoma — Oral SCC usually presents as an ulcer, nodule, or indurated plaque involving the oral cavity (picture 2C, 2F). The floor of the mouth and lateral or ventral tongue are the most common sites for these tumors. Lesions may arise in sites of erythroplakia (premalignant, persistent, red patches in the oral cavity) or leukoplakia (oral, persistent, white plaques) (picture 10). Oral SCC is often associated with a history of tobacco or heavy alcohol use. (See "Oral leukoplakia" and "Oral lesions", section on 'Oral squamous cell carcinoma'.)

Marjolin's ulcer — "Marjolin's ulcer" is a term used to describe a rare type of cSCC arising in sites of chronic wounds or scars [13-15]. The malignant transformation is usually slow, with an average latency time of approximately 30 years [13,16].

The tumor may initially present as an ulceration that fails to heal; nodules may develop as the lesion progresses. Other clinical signs include rolled or everted wound margins, excessive granulation tissue, rapid increase in size, and bleeding on touch.

SCCs arising in the setting of chronic wounds or scars are typically aggressive and are associated with a poor prognosis [17]. The risk of local recurrence after treatment or metastasis is approximately 20 to 30 percent [13,18-20].

Lymphoepithelioma-like carcinoma of the skin — Primary lymphoepithelioma-like carcinoma of the skin is a very rare, indolent, malignant skin tumor of epithelial origin, considered a variant of cSCC [21]. Clinically, it presents as a flesh-colored, firm nodule or plaque, most often located in the head and neck region. Histopathologically, it shows islands of poorly differentiated epithelial cells with a dense lymphoid infiltrate, resembling undifferentiated nasopharyngeal carcinoma. (See "Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma".)

DIAGNOSIS — Although clinical and dermoscopic findings may strongly suggest a diagnosis of cSCC, histopathologic examination is necessary to confirm the diagnosis. Histopathologic examination is also useful for assessment for perineural invasion, tumor differentiation, and tumor depth, factors that are important for tumor staging and prognosis. (See 'Staging' below.)

Dermoscopy — On dermoscopic examination, cSCC in situ (Bowen's disease) displays dotted and/or glomerular vessels, white to yellowish surface scales, and a red-yellowish background color (picture 11). Pigmented cSCC in situ typically shows a structureless, brown pattern with hypopigmented areas (skin colored or white) often eccentrically located and brown dots arranged as radial lines at the periphery (picture 12). Key dermoscopic features of invasive cSCC are white circles; white, structureless areas; and hairpin and linear-irregular vessels (picture 13). (See "Dermoscopic evaluation of skin lesions", section on 'Criteria for squamous cell carcinoma' and "Dermoscopy of facial lesions", section on 'Invasive squamous cell carcinoma'.)

Biopsy and histopathology — Shave, punch, or excisional biopsies may be used for diagnosis. Regardless of the biopsy technique selected, for lesions that are papular, nodular, or otherwise suspicious for invasive cSCC, biopsies that extend at least into the mid-reticular dermis are preferred to allow for adequate evaluation of invasive disease [22]. More superficial biopsies may be performed in patients with lesions that are suggestive of in situ squamous cell carcinoma (SCC). (See "Skin biopsy techniques".)

When submitting biopsy specimens for histopathologic diagnosis, important elements that should be provided to the pathologist include anatomic location of the tumor, clinical size of the lesion, and whether the patient has additional risk factors for cSCC, such as immunosuppression, radiation therapy, or solid organ transplantation [22]. Histopathologic evaluation of skin biopsy specimens is ideally performed by a dermatologist or pathologist who is experienced in diagnosing cutaneous tumors.

Cutaneous squamous cell carcinoma in situ — cSCC in situ (Bowen's disease) is diagnosed when histopathologic examination reveals keratinocytic dysplasia involving the full thickness of the epidermis without infiltration of atypical cells into the dermis [23,24]. The keratinocytes are pleomorphic with hyperchromatic nuclei, and numerous mitoses are present. Frequently, there is associated thickening of the epidermis (acanthosis), as well as hyperkeratosis and parakeratosis of the stratum corneum. In contrast to cSCC in situ, actinic keratoses demonstrate only partial-thickness epidermal dysplasia.

Invasive cutaneous squamous cell carcinoma — Invasive cSCCs have dysplastic keratinocytes involving the full thickness of the epidermis that penetrate the epidermal basement membrane to involve the dermis or deeper tissues. Well-differentiated cSCCs contain atypical keratinocytes that are slightly enlarged with abundant amounts of cytoplasm. Keratinization is usually present. In poorly differentiated cSCC, keratinocytes are anaplastic, with little evidence for differentiation or keratinization. Multiple mitoses are often seen. Occasionally, the keratinocytic origin of the cells can only be determined by immunohistochemical stains. Perineural infiltration, a recognized risk factor for recurrence and metastasis, can be noted more frequently in poorly differentiated cSCC.

Several histopathologic variants of invasive cSCC exist, including spindle cell SCC, acantholytic (adenoid) cSCC, clear cell cSCC, adenosquamous (mucin-producing) cSCC, desmoplastic cSCC, single-cell cSCC, and others [25-27].

DIFFERENTIAL DIAGNOSIS — Multiple other skin lesions, including premalignant, malignant, and inflammatory lesions, can resemble cSCC clinically and, in some cases, histopathologically. In particular, superficial basal cell carcinoma and cSCC in situ are especially difficult to differentiate clinically and dermoscopically from each other and sometimes from a psoriasis plaque.

Premalignant lesions

Actinic keratoses — The most common clinical diagnostic dilemma involves actinic keratoses. Actinic keratoses are rough, scaly, erythematous macules that develop on sun-damaged skin and demonstrate keratinocytic atypia on histopathologic examination (picture 14). Although the rate of transformation of actinic keratoses to squamous cell carcinoma (SCC) is very low, estimated at less than 1 percent in one year, approximately 60 percent of SCCs arise from actinic keratoses [28-30].

Actinic keratoses are often found in close proximity to cSCCs and can resemble cSCC in situ or early cSCC. Tenderness, bleeding, and palpable underlying substance suggest the possibility of cSCC and indicate the need for biopsy. (See "Epidemiology, natural history, and diagnosis of actinic keratosis".)

Bowenoid papulosis — Bowenoid papulosis is a premalignant focal epidermal dysplasia characterized by multiple red- to brown-colored, small papules that primarily arise on genitals, although extragenital cases have also been reported (picture 15) [31]. The condition is classified as a transitional state between genital warts and SCC in situ.

Bowenoid papulosis is induced by human papillomavirus (HPV) infection. Although the most common inciting agent is HPV 16, other HPV types have been implicated [32]. On histopathologic examination, lesions demonstrate focal epidermal hyperplasia and partial-thickness to full-thickness epidermal dysplasia [33].

The rate of malignant transformation of bowenoid papulosis to SCC is low (estimated to be 1 to 2.6 percent), and the majority of lesions can be treated successfully with simple, local destruction or topical immunomodulators [34,35]. Because bowenoid papulosis has the potential to undergo malignant transformation, follow-up evaluation is warranted if the lesions recur or undergo rapid enlargement. (See "Carcinoma of the penis: Clinical presentation, diagnosis, and staging".)

Inflammatory skin disorders — The well-demarcated, scaling, pink plaques of cSCC in situ can resemble inflammatory skin disorders, including:

Nummular eczema (picture 16) (see "Nummular eczema")

Psoriasis (picture 17) (see "Psoriasis: Epidemiology, clinical manifestations, and diagnosis")

Inflamed seborrheic keratosis (picture 18) (see "Overview of benign lesions of the skin", section on 'Seborrheic keratosis')

Prurigo nodularis (picture 19A-B) (see "Prurigo nodularis")

Pyoderma gangrenosum (picture 20A-B) (see "Pyoderma gangrenosum: Pathogenesis, clinical features, and diagnosis")

Venous stasis ulcers (picture 21) (see "Clinical assessment of chronic wounds", section on 'Venous ulcers')

Other malignant skin tumors — A number of malignant skin tumors may share clinical features with cSCC:

Merkel cell carcinoma (picture 22A-B) (see "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma")

Basal cell carcinoma (picture 23A-C) (see "Epidemiology, pathogenesis, clinical features, and diagnosis of basal cell carcinoma")

Atypical fibroxanthoma (picture 24) (see "Atypical fibroxanthoma")

Amelanotic melanoma (picture 25A-B) (see "Melanoma: Clinical features and diagnosis")

STAGING — At the time of diagnosis, patients with invasive cSCC should be given a full body skin examination that includes palpation of regional lymph nodes to evaluate for additional cSCCs and clinical signs of metastatic disease. The staging of cSCC is discussed separately. (See "Evaluation for locoregional and distant metastases in cutaneous squamous cell and basal cell carcinoma", section on 'Squamous cell carcinoma' and "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma", section on 'Staging'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cutaneous squamous cell carcinoma".)

SUMMARY

Clinical presentation Cutaneous squamous cell carcinoma (cSCC) can develop on any surface of the skin, but sun-exposed sites are the most common locations in individuals with lightly pigmented skin. Involvement of other areas, in particular the lower legs and anogenital region, is more common in people with darkly pigmented skin (see 'Location' above):

Cutaneous squamous cell carcinoma in situ – cSCC in situ (Bowen's disease) typically presents as an erythematous, well-demarcated, scaly patch or plaque (picture 3A-B) located in sun-exposed areas. cSCC in situ involving the penis (erythroplasia of Queyrat) presents as a well-defined, velvety, red plaque (picture 2D). (See 'Cutaneous squamous cell carcinoma in situ (Bowen's disease)' above.)

Invasive cutaneous squamous cell carcinoma – Invasive cSCC often correlates with the level of tumor differentiation. Well-differentiated lesions usually appear as indurated or firm, hyperkeratotic papules, plaques, or nodules of 0.5 to 1.5 cm (picture 1A-B, 2A, 2E), although some lesions may be much larger. (See 'Invasive cutaneous squamous cell carcinoma' above.)

Clinical variants – Clinical variants of cSCC include keratoacanthoma (picture 5), verrucous carcinoma (picture 7), squamous cell carcinoma (SCC) of the lip (picture 9), oral SCC (picture 2F), cSCC arising at sites of chronic inflammation and scarring (Marjolin's ulcer), and primary lymphoepithelioma-like carcinoma of the skin. (See 'Clinical variants' above.)

Diagnosis – Biopsy is necessary to confirm the diagnosis of SCC. For lesions clinically suspected to be invasive, a shave, punch, or excisional biopsy that extends at least into the mid-reticular dermis is preferred. (See 'Biopsy and histopathology' above.)

Staging – Patients with a confirmed diagnosis of invasive cSCC should be given a full body skin examination that includes palpation of regional lymph nodes to evaluate for additional cSCCs and clinical signs of metastatic disease. The staging of cSCC is discussed separately. (See "Evaluation for locoregional and distant metastases in cutaneous squamous cell and basal cell carcinoma", section on 'Locoregional evaluation' and "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma", section on 'Staging'.)

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