Basal Cell Carcinoma

Overview

Definition

Basal cell carcinoma is a skin cancer arising from the basal layer of epidermis and its appendages.

Epidemiology

• Most common cancer worldwide
• Most common skin malignancy
• Age-adjusted incidence in the United States is 226 per 100,000 person-years.
• > 1 million basal cell carcinomas are treated annually in the United States.
• Men > women
• Incidence increases with age.

Risk factors

• Ultraviolet (UV) light exposure:
  • Sun exposure (outdoor workers)
  • Tanning beds
  • Phototherapy for psoriasis
• Advanced age
• Arsenic exposure (e.g., contaminated drinking water, contaminated seafood)
• Ionizing radiation
• Chronic immunosuppression 
• Genetics: 
  • Fair complexion
  • Personal and family history of basal cell carcinoma
  • Genetic syndromes:
    • Gorlin syndrome (characterized by developmental anomalies and multiple basal cell carcinomas)
    • Xeroderma pigmentosum (mutation in repair of UV-induced DNA damage)
    • Bazex–Dupré–Christol syndrome (milia, hypotrichosis, multiple basal cell carcinomas)
    • Oculocutaneous albinism (disorder in melanin synthesis)

Pathophysiology and Clinical Presentation

Pathogenesis

• UV radiation:
  • Most significant factor
  • UVA and UVB light → DNA damage
  • Genes most damaged by UV light involve the hedgehog signaling pathway.
• Common mutations:
  • Patched homolog 1 (PTCH1) mutations (found in majority of basal cell carcinoma cases):
    • PTCH1 encodes a protein in the hedgehog pathway.
    • In the resting state, patched homolog 1 (PTCH1) protein normally inhibits smoothened homolog (SMO).
    • When the sonic hedgehog protein binds PTCH1 protein → PTCH1 is degraded → SMO is released
    • This process leads to a series of interacting proteins → GLI transcription factors activated → cell proliferation
    • General effect of PTCH1 gene mutations: unbound SMO allows unregulated cell growth
  • TP53 mutations also seen in 20%–60% of sporadic basal cell carcinomas:
    • TP53 normally involved in apoptosis and DNA repair
    • Mutations → cell proliferation and defective DNA
  • Other genes: SMO, SUFU

Clinical and histologic features

• Disease characteristics: 
  • Lesion can be a papule, patch, or plaque.
  • Most remain localized but can become aggressive
  • Rarely metastasize (< 0.05%)
  • Slow-growing
• Basal cell carcinoma distribution:
  • Face: 70% (nose, cheeks, forehead, nasolabial folds, and eyelids)
  • Trunk: 15%
  • Remaining body parts: 15%
• Histopathology:
  • Cells of tumor islands with palisading arrangement at the periphery
  • Cellular apoptosis
  • Scattered mitotic activity in the dermis
• Histologic types:
  • Nodular basal cell carcinoma
  • Superficial basal cell carcinoma
  • Morpheaphorm (sclerosing) basal cell carcinoma
  • Other, more rare, types:
    • Basosquamous cell carcinoma
    • Pigmented basal cell carcinoma

Diagnosis and Staging

Diagnosis

History:

• Family history of genetic diseases
• Personal history of previous skin cancers
• History of excessive sun exposure
• HIV-positive status or other forms of immunocompromise

Physical exam:

• Thorough skin examination should be performed.
• Assess for palpable lymphadenopathy.

Dermoscopy:

• Arborizing vessels
• Blue-gray ovoid nests
• Ulceration
• Lack of pigmented network (unlike melanocytic lesions)

Biopsy:

• Establishes definitive diagnosis
• Shave, punch, or excisional technique can be used.

Staging

• Basal cell carcinoma metastasis is rare and is thus not usually staged.
• Often, the cancer is treated before it spreads.
• Sites of metastasis:
  • Regional lymph nodes
  • Lungs
  • Bones
  • Liver
  • Skin
• Imaging: CT or MRI used for evaluation of metastasis
• Staging follows that for cutaneous squamous cell carcinoma but is applicable only to head and neck lesions (American Joint Committee on Cancer, 8th edition).
• Stages:
  • Stage 0: cancer involves only the epidermis (in situ)
  • Stage I: 
    • Cancer is not large (≤ 2 cm).
    • No spread to the lymph nodes or other organs
  • Stage II: 
    • Cancer is large (>2 cm but ≤ 4 cm). 
    • No spread to lymph nodes or other organs
  • Stage III: 
    • Cancer > 4 cm or cancer of any size with deep, perineural or minor bone invasion and/or spread to 1 ipsilateral lymph node (no extranodal extension)
    • No spread to other organs
  • Stage IV: lesions of any size; spread to other organs (distant metastasis)

Management and Prognosis

Treatment approach

Assess risk of recurrence:

• Helps determine treatment of choice
• Inadequate treatment of high-risk lesions can result in recurrence and complications (e.g., deformities).
• High-risk features:
  • Location: face, ears, hands, and feet
  • Size:
    • ≥ 10 mm on head, neck, and pretibia
    • ≥ 20 mm in other areas
  • Aggressive variants: morpheaform, basosquamous, micronodular
  • Recurrent lesions
  • Perineural invasion
  • Poorly defined borders
  • Basal cell carcinomas in previous radiation sites
  • Immunocompromised patient

Surgery:

• Standard surgical excision: 
  • 1st-line treatment for low-risk lesions
  • Margins: 4–5 mm
• Mohs micrographic surgery:
  • 1st-line treatment for high-risk lesions
  • For facial lesions/cosmetically sensitive areas (less normal tissue resected)

Alternative therapies: 

• Options for patients who are poor surgical candidates or who prefer not to have surgery:
  • Topical chemotherapy (e.g., imiquimod or fluorouracil):
    • Low-risk sites
    • 6-week treatment
    • Skin irritation is a side effect.
  • Electrodesiccation and curettage:
    • Can be used for small low-risk basal cell carcinomas
    • Risk of incomplete tumor removal
  • Cryosurgery:
    • Not for high-risk lesions
    • Can result in scarring and hypopigmentation
  • Radiotherapy: for high-risk lesions in poor surgical candidates

Therapy for advanced disease: 

• For metastasis or locally advanced basal cell carcinoma that is not amenable to radiotherapy or surgery
• Inhibitor of sonic hedgehog pathway: vismodegib, sonidegib

Prognosis

• Overall prognosis is excellent.
• Metastatic potential: 0.05%–0.1%.
• Population-based case mortality: 0.05%.

Differential Diagnosis

• Squamous cell carcinoma: second most common skin cancer: Squamous cell carcinoma usually presents as a firm, erythematous, keratotic plaque or papule. Diagnosis is through biopsy. Histopathologic examination confirms the diagnosis by showing findings such as atypical keratinocytes infiltrating into the dermis.
• Dermatofibroma: a common mesenchymal growth of the skin where skin fibroblasts are the major constituents: Dermatofibroma usually presents as a firm, indurated, mobile nodule measuring about 0.5–1 cm. Upon lateral compression, a dimple-like depression in the overlying skin appears (“buttonhole” sign). 
• Melanoma: skin malignancy arising from melanocytes: Melanoma presents as irregular pigmented lesions and can resemble pigmented variants of basal cell carcinoma. Diagnosis is confirmed by biopsy. This condition carries a significantly worse prognosis than basal cell carcinoma.
• Actinic keratosis: benign keratinocytic lesion considered a precursor to squamous cell carcinoma: Lesions of actinic keratosis present as scaly erythematous macules. Diagnosis is established by biopsy.
• Inflammatory skin conditions: Psoriasis and eczema can present with erythematous papules and plaques and clinically resemble superficial basal cell carcinoma. Diagnosis is made with a thorough exam, dermoscopy, and biopsy.