Cutaneous Squamous Cell Carcinoma

Yasmin Hadian; Jesse Howell; Michael Ramsey; Chris Buckley; Michael Ramsey

Cutaneous Squamous Cell Carcinoma

Author: Yasmin Hadian Author: Jesse Y. Howell Author: Michael L. Ramsey Author: Chris Buckley Editor: Michael L. Ramsey Updated: 7/2/2024 11:49:08 AM

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

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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] In the setting of biopsy-proven regional lymph node involvement, evaluation for distant disease is necessary, via CT or PET. NCCN guidelines recommend baseline imaging (usually MRI with contrast) for patients with very-high-risk CSCC, including tumors >4 cm, depth of invasion >6 mm, perineural invasion involving nerves ≥0.1 mm, even if unnamed, given the risk for occult perineural spread.[18]

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. For operable disease of the head and neck region, the most appropriate next step is excision of the primary tumor and ipsilateral neck dissection, as indicated.[19] 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. Sentinel lymph node biopsy should be performed concurrently with Mohs excision for high-risk lesions (recurrent, perineural invasion, desmoplastic subtype.[20][21][20] Electrodessication and curettage are alternative options for in situ cases, albeit with slightly higher recurrence rates compared to Mohs micrographic surgery and standard excision.[22] (A1)

For recurrence after resection of cutaneous squamous cell carcinoma, NCCN guidelines vary based on nodal involvement and anatomic location, and recommend multi-disciplinary evaluation and discussion. Nodal recurrence often requires salvage dissecton with radiation therapy, with possible emergeing systemic therapies in the setting of extracapsular extension. For patients with 2 or more positive nodes or 1 node larger than 3 cm without extranodular extension, the most appropriate course is radiation therapy alone. If there is evidence of extranodular extension or evidence of incompletely excised nodal disease, patients should undergo radiation therapy with systemic therapy. A recommended course might include radiation therapy with cisplatin.[23](B3)

For patients who are not suitable for surgery, options for treating cutaneous squamous cell carcinoma include superficial radiation therapy, monoclonal antibody, 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. Neoadjuvant cemiplimab is a guideline-concordant option for very-high-risk CSCC. In high-risk, unresectable SCC, using systemic immunotherapy up front may reduce tumor burden and preserve function, potentially allowing for less morbid surgery. Cemiplimab (and pembrolizumab) are FDA-approved first-line therapies for locally advanced, unresectable, or metastatic CSCC, including visceral disease. Cemiplimab showed durable response rates in prospective trials and is the preferred systemic therapy per NCCN guidelines. No prior chemotherapy is required before initiating anti–PD–1 agents in eligible patients, but this approach requires multidisciplinary planning and is supported by phase II data showing high pathologic response rates.[24][25][26] 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.[27][28](A1)

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][29][30][31]

Radiation Oncology

NCCN guidelines recommend radiation for high-risk cutaneous squamous cell carcinoma, in the adjuvant setting or as primary treatment for unresectable disease, when close surgical margins cannot be widened due to anatomic or functional constraints, particularly in the setting of very-high-risk histologic subtypes like desmoplastic SCC and/or named nerve involvement. Treatment is determined within a multidisciplinary setting, but adjuvant therapy is typically indicated for those with significant perineural invasion, positive margins, a positive node > 3 cm or multiple nodes, or extracapsular extension, and for those with a high risk for recurrence. In very-high-risk CSCC, especially with multifocal PNI and tumors >4 cm, imaging of the nodal basin or elective nodal RT should be considered, even when nodal disease is not yet apparent.[32][33]

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]

The lip, ear, central face (eyelid, nose, nasolabial fold), genitalia, hands, feet, and nail unit are designated as very-high-risk anatomic sites regardless of tumor size or histology. Even small tumors in these areas have a disproportionate risk of perineural invasion, recurrence, and metastasis. Any PNI a nerve ≥ 0.1 mm OR poor differentiation qualifies for NCCN very high-risk. Any head-and-neck tumor, regardless of size, is designated high-risk.[34]

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).

Pearls and Other Issues

Due to their immunosuppression, solid organ transplant recipients are susceptible to an increased incidence of aggressive SCC. The use of immune checkpoint inhibitors in this population may increase the risk of graft rejection. In the setting of an aggressive SCC, immunosuppression may be modified to include transition to an mTOR inhibitor that may contribute to anti-tumor activity, with the addition of PD-1 blockade. Multidisciplinary input is essential. Surveillance for this high-risk group should occur every 2-3 months for the first 2 years, then every 6-12 months.[35]

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.[36]

Media

(Click Image to Enlarge)

Cutaneous Squamous Cell Carcinoma. This type of carcinoma typically presents as a scaly, erythematous, or hyperpigmented papule or plaque on the skin.

DermNet New Zealand

(Click Image to Enlarge)

<p>Histological Slide of Cutaneous Squamous Cell Carcinoma

Histological Slide of Cutaneous Squamous Cell Carcinoma. Tumors classically consist of atypical keratinocytes with abundant eosinophilic or pink, glassy cytoplasm.

Contributed by F Farci, MD

(Click Image to Enlarge)

<p>Histological Slide of Squamous Cell Carcinoma, Acantholytic

Histological Slide of Squamous Cell Carcinoma, Acantholytic. This subtype is characterized by clefting around nests or cords of plump, polygonal tumor cells, creating a glandular appearance.