Continuing Education Activity

Squamous cell carcinoma is the second most common skin malignancy in the United States, and its incidence steadily rises each year, posing a significant public health concern. Mortality rates for cutaneous squamous cell carcinoma are comparable to those of melanoma, renal carcinoma, and oropharyngeal carcinoma in the central and southern regions of the United States. Timely surveillance, early diagnosis, and prompt treatment are critical to minimize morbidity and mortality risks. Although surgical excision remains the cornerstone of treatment, ongoing research brings novel therapeutic approaches. In addition, nonsurgical options, such as radiation therapy, topical creams, cryotherapy, photodynamic therapy, and laser ablation, are available, especially for patients unsuitable for surgery. However, these nonsurgical treatments often have higher recurrence rates.

Regular skin examinations and frequent follow-ups are recommended by healthcare providers, particularly for high-risk patients, to facilitate early detection and treatment, highlighting the importance of collaborative care for optimal management. Diagnosis usually requires a skin biopsy, with advanced cases often necessitating additional imaging and sentinel lymph node biopsy. This activity covers the etiology, epidemiology, pathophysiology, histopathological subtypes, clinical features, and management options for cutaneous squamous cell carcinoma. This activity emphasizes the critical role of photoprotection in reducing the risk of developing cutaneous squamous cell carcinoma due to its strong association with UV radiation. Therefore, this activity underscores the importance of interprofessional collaboration among healthcare providers in counseling patients on preventive measures, such as practicing photoprotection through sun avoidance, using SPF 30 sunscreen, and wearing protective clothing and sunglasses.

Objectives:

• Identify the clinical features and risk factors associated with cutaneous squamous cell carcinoma.
• Implement evidence-based treatment strategies tailored to the subtype and stage of the carcinoma.
• Select appropriate imaging and biopsy techniques for advanced cases requiring further evaluation.
• Collaborate with dermatologists, oncologists, and other specialists to coordinate multidisciplinary care for comprehensive management of advanced cases and to optimize patient outcomes.

Introduction

Squamous cell carcinoma is the second most common cutaneous malignancy in the United States. Risk factors include immunosuppression, chronic wounds, fair skin, male gender, older age, several genetic syndromes, environmental exposures such as UV radiation, and a previous history of squamous cell carcinoma. Although metastasis is rare, the most common site of metastasis is the lymph nodes. As the incidence steadily increases, posing a significant public health concern, timely surveillance, early diagnosis, and prompt treatment are essential to minimize morbidity and mortality risks. Photoprotection and frequent full-body skin exams are recommended. While most cases are treated with surgical excision, novel therapeutic modalities continue to emerge. Systemic oncologic therapy and radiation therapy may be warranted for more advanced cases.[1][2][3][4]

Etiology

The development of cutaneous squamous cell carcinoma is associated with the following risk factors and etiologies: 

• UV radiation: UVA and UVB are the most significant risk factors.
• Environmental exposures other than UV radiation: This includes arsenic, polycyclic aromatic hydrocarbons, nitrosamines, alkylating agents, and ionizing radiation.
• Demographic factors: Fair skin, male, and older age.
• Immunosuppressed state: Iatrogenic, leukemia, and AIDS.
• Genetic syndromes: Huriez syndrome, xeroderma pigmentosa, oculocutaneous albinism, dyskeratosis congenita, Rothmund-Thomson syndrome, Werner syndrome, Bloom syndrome, dystrophic epidermolysis bullosa, epidermodysplasia verruciformis, Fanconi anemia, keratitis-ichthyosis-deafness syndrome, and genetic immunodeficiency syndromes.
• Preexisting lesions: Chronic wounds (Marjolin ulcer), human papillomavirus, actinic keratosis, porokeratosis, lichen sclerosus et atrophicus, hypertrophic or oral lichen planus, and discoid cutaneous lupus erythematosus.
• Medications: BRAF inhibitors, vismodegib, and voriconazole, immunosuppressive agents.[5][6][7][8][9]

Epidemiology

Squamous cell carcinoma is the second most common cutaneous malignancy in the United States. The incidence of this condition has steadily increased, with a nearly 3-fold rise reported from the 1970s to the early 2000s.[10] In 2012, the incidence of cutaneous squamous cell carcinoma was estimated at 140 per 100,000 American men and 50 per 100,000 American women. The mortality rate is approximately 1% to 2%.[11] However, in the southern and central regions of the United States, the mortality rate is similar to that of melanoma and renal and oropharyngeal carcinoma.[12] The prevalence is higher among men, fair-skinned individuals, and older age groups.

Pathophysiology

Cutaneous squamous cell carcinoma is derived from the keratinocytes. A mutation in the tp53 tumor suppressor gene is the most common genetic abnormality observed in both squamous cell carcinoma and its precursor, actinic keratosis. Decreased immunosurveillance in immunosuppressed patients may further potentiate tumor growth. For instance, patients with solid organ transplants on immunosuppressive therapy have a 65- to 250-fold increased risk of developing squamous cell carcinoma compared to the general population.[1]

Histopathology

The histological subtypes of squamous cell carcinoma include squamous cell carcinoma in situ/Bowen disease, acantholytic/adenoid/pseudoglandular, clear cell, sarcomatoid/spindle cell, desmoplastic, keratoacanthoma, and verrucous carcinoma. Tumors classically consist of atypical keratinocytes with abundant eosinophilic or pink, glassy cytoplasm. Other common findings include parakeratosis, intercellular bridging, and keratin pearls (see Image. Histological Slide of Cutaneous Squamous Cell Carcinoma). High-risk histological subtypes include acantholytic, sarcomatoid, and desmoplastic.

Squamous Cell Carcinoma In Situ

This subtype, also known as Bowen disease, is characterized by full-thickness keratinocyte atypia that has not invaded beyond the basal layer of the epidermis. In contrast, invasive squamous cell carcinoma has penetrated beyond the basal layer (see Image. Histological Slide of Squamous Cell Carcinoma, In Situ). The basal layer is often intact, forming the "eyeliner sign." 

Acantholytic/Adenoid/Pseudoglandular

This subtype is characterized by clefting around nests or cords of plump, polygonal tumor cells, creating a glandular appearance (see Image. Histological Slide of Squamous Cell Carcinoma, Acantholytic). Clefting is due to desmosomal disruption. In contrast to tumors of true glandular origin, such as adenosquamous carcinoma, the carcinoembryonic antigen (CEA) staining is negative.

Clear Cell

This subtype is characterized by clear or pale tumor cells that may or may not demonstrate an epidermal connection (see Image. Histological Slide of Squamous Cell Carcinoma, Clear Cell). Histological differentials include clear cell acanthoma and renal cell carcinoma.

Sarcomatoid/Spindle Cell

This subtype is characterized by spindle-shaped keratinocytes with pleomorphic nuclei arranged haphazardly throughout the dermis in a typically infiltrative pattern (see Image. Histological Slide of Squamous Cell Carcinoma, Sarcomatoid). Numerous mitotic figures may be observed. Atypical fibroxanthoma is an important histological differential that typically stains negative for p63 and p40, unlike sarcomatoid or spindle squamous cell carcinoma (see Image. Histological Slide of Squamous Cell Carcinoma, Positive p40 Stain). Immunohistochemistry with p40 is more specific than p63. 

Desmoplastic 

This subtype may appear similar to the sarcomatoid or spindle cell variant of squamous cell carcinoma. However, desmoplastic carcinoma is characterized by a desmoplastic (densely collagenous) stroma in more than 30% of the tumor. Perineural invasion is frequently reported. Desmoplastic melanoma is also considered in the histological differential diagnosis. Unlike desmoplastic melanoma, desmoplastic squamous cell carcinoma typically stains positive for p63 and negative for SOX10 and S100.

Keratoacanthoma

This subtype is characterized by a crateriform invagination filled with keratin (see Image. Histological Slide of Squamous Cell Carcinoma, Keratoacanthoma). The tumor cells are typically well-differentiated.

Verrucous Carcinoma

This subtype is characterized by verruciform acanthosis with blunt, broad projections that push into, rather than infiltrate, the dermis. Human papillomavirus-related cytomorphology in verrucous carcinoma is less pronounced compared to benign warts.[2][13][14][15]

History and Physical

Cutaneous squamous cell carcinoma is typically characterized by a scaly, erythematous, or hyperpigmented papule or plaque. Some cases may exhibit ulceration, fungating features, or pain (see Image. Cutaneous Squamous Cell Carcinoma). Due to its strong association with UV radiation exposure, many cases arise in sun-damaged skin. This tumor can also develop from preexisting lesions such as actinic keratosis, chronic wounds (Marjolin ulcer), human papillomavirus infection, porokeratosis, lichen sclerosus et atrophicus, hypertrophic or oral lichen planus, and discoid cutaneous lupus erythematosus.[7][8][9][16][17]

Evaluation

A skin biopsy is necessary to confirm the diagnosis of cutaneous squamous cell carcinoma. Additionally, sentinel lymph node biopsy and/or radiological evaluation for lymph node metastasis with computed tomography or ultrasound is recommended in cases classified as stage T2B-T3 according to the Brigham and Women's Hospital (BWH) staging system or stage T4 according to the American Joint Committee on Cancer 8th ed. (AJCC-8) staging system. Case-by-case consideration is needed for AJCC-8 stage T2-3. For patients presenting with palpable lymphadenopathy, fine-needle aspiration or biopsy of the lymph node(s) is advised.[1][3]

Treatment / Management

The preferred therapeutic intervention for cutaneous squamous cell carcinoma is surgical excision. Mohs micrographic surgery is preferred in cases that meet appropriate use criteria (AUC). Factors listed in the AUC include, but are not limited to, clinical diameter of the apparent lesion greater than 2 cm, high-risk histological features, recurrent versus primary lesions, cosmetically sensitive and/or high-risk anatomical locations such as the ears, lips, nose, and periocular regions, as well as immunosuppression.[18] The reported 5-year recurrence rate for Mohs micrographic surgery is approximately 3.1%, whereas standard excision with 4 to 6 mm margins has a reported recurrence rate of approximately 8.1%. Mohs micrographic surgery offers a significantly greater risk reduction compared to standard excision, particularly in cases with high-risk features. For example, locally recurrent (previously treated) lesions showed a 10% recurrence rate with Mohs micrographic surgery and a 23.3% recurrence rate with standard excision.[19] Electrodessication and curettage are alternative options for in situ cases, albeit with slightly higher recurrence rates compared to Mohs micrographic surgery and standard excision.[20] 

For patients who are not suitable for surgery, options for treating cutaneous squamous cell carcinoma include superficial radiation therapy, 5-fluorouracil cream, imiquimod cream, cryotherapy, photodynamic therapy, and/or ablative laser. However, these treatments often result in higher recurrence rates and lack histologically confirmed clearance.[21][22] Lymphadenectomy of the associated nodal basin is recommended for cases with positive lymph nodes. Radiation therapy is typically used for cases involving large-caliber nerve invasion, lymphovascular invasion, multiple lymph nodes, or extracapsular extension. Adjuvant systemic oncologic therapy for advanced cases may include chemotherapy, epidermal growth factor inhibitors, or immunotherapy.[3] Recently, novel immunotherapeutic agents have emerged, showing superior clinical outcomes compared to traditional systemic therapies.[23][24]

Differential Diagnosis

Differential diagnoses include but are not limited to:

• Basal cell carcinoma
• Melanoma
• Extramammary Paget disease
• Actinic keratosis
• Seborrheic keratosis
• Porokeratosis
• Lichen planus-like keratosis
• Verruca
• Psoriasis
• Nummular dermatitis
• Lichen planus
• Lichen sclerosus et atrophicus
• Discoid cutaneous lupus erythematosus [16][17][25][26][27]

Staging

The staging categories for cutaneous squamous cell carcinoma as per BWH and AJCC-8 are listed below.

BWH Staging System 

• Stage T1: 0 high-risk features
• Stage T2A: 1 high-risk feature
• Stage T2B: 2 to 3 high-risk features
• Stage T3: 4 or more high-risk features or bone invasion
• High-risk features, as defined by BWH, include:

  • Tumor diameter of at least 2 cm
  • Histologically poor differentiation
  • Perineural invasion of at least 0.1 mm
  • Invasion beyond subcutaneous tissue

AJCC-8 Staging System

• Stage Ti: In situ
• Stage T1: Tumor diameter less than 2 cm
• Stage T2: tumor diameter 2 to 3.9 cm
• Stage T3:

  • Tumor diameter of at least 4 cm
  • Minor bone erosion
  • Perineural invasion at least 0.1 mm or invading a nerve located deeper than the dermis
  • Invasion beyond subcutaneous tissue
  • Invasion greater than 6 mm depth
• Stage T4A: Gross cortical bone or marrow invasion
• Stage T4B: Skull invasion or skull base foramen involvement [1]

Prognosis

The prognosis for localized disease is generally excellent. The overall mortality rate for cutaneous squamous cell carcinoma is approximately 1% to 2%,[11] with approximately 3% of cases metastasizing.[12] The lymph nodes are the most common site of metastasis.[2] Cases involving single node metastasis up to 3 cm are associated with a 90% disease-specific 5-year survival.[1] 

Complications

Complications of cutaneous squamous cell carcinoma include:

• Metastases
• Local invasion
• Pain
• Loss of function
• Poor cosmesis
• Death

Deterrence and Patient Education

The American Academy of Dermatology (AAD) recommends the following preventative measures for patients:

• Individuals should limit sun exposure during peak UV index hours.
• Sunscreen with at least SPF 30 should be regularly used and reapplied every 2 hours and even after swimming or excessive sweating.
• Protective clothing and sunglasses should always be worn when exposed to sunlight.
• Annual full-body skin exams are recommended for the general adult population, with more frequent exams suggested for patients with significant risk factors (AAD, Shade, Clothing, and Sunscreen).

Enhancing Healthcare Team Outcomes

Due to the strong association with UV radiation, photoprotection is crucial in reducing the risk of developing cutaneous squamous cell carcinoma. Healthcare professionals should advise patients on photoprotective measures. Annual full-body skin exams are recommended, with more frequent exams advised for patients with significant risk factors. Referral to radiation or surgical oncology, urology, gynecology, or otolaryngology may be necessary for comprehensive management in advanced cases.[28]

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Disclosure: Yasmin Hadian declares no relevant financial relationships with ineligible companies.

Disclosure: Jesse Howell declares no relevant financial relationships with ineligible companies.

Disclosure: Michael Ramsey declares no relevant financial relationships with ineligible companies.

Disclosure: Chris Buckley declares no relevant financial relationships with ineligible companies.