Basal Cell Carcinoma

Overview

Basal cell carcinoma (BCC) is a non-melanoma (keratinocyte), epithelial skin cancer arising from the basal cells (small, round cells in the lower layer of the dermis).

Is the most common malignant skin tumor in humans. More common in males (M: F ~2:1)

It typically appears on sun-exposed skin, is slow growing and rarely metastasises, with an excellent prognosis if treated early in disease course. (Accounts for <0.1% of patient deaths from cancer)

Risk Factors

• Intermittent UV exposure (as opposed to cumulative in SCC), especially in individuals with:
  • Lighter skin tone, eye colour, hair colour (blonde or red hair)
  • Inability to tan naturally/presence of freckles
  • History of sunburns
• Age >40 years
• Male sex
• Previous history of BCC (or any nonmelanoma skin cancer)
• Presence of nevus on an extremity
• Immunocompromised state, e.g., post-transplant, AIDS
• Autoimmune conditions, e.g., Rheumatoid Arthritis
• Genetic predisposition and inherited conditions
  • Albinism
  • Xeroderma pigmentosum
  • NBCC (Nevoid basal cell carcinoma) syndrome
  • Rombo syndrome
• Exposure to:
  • Ionizing radiation, especially during childhood
  • Chemicals, e.g., arsenic, tar, coal, paraffin, industrial oils
  • Some forms of phototherapy and UV light therapy

Pathophysiology

• Exact etiology is unknown; however, a well-established relationship exists between BCC and the pilosebaceous unit (most tumors occur on hair-bearing areas).
• The hedgehog intracellular pathway has been shown to play a role in both sporadic BCCs and Gorlin syndrome. This pathway is involved in the differentiation of various tissues during fetal development, and after embryogenesis continues to regulate cell growth. Loss of inhibition of this pathway may lead to malignancy, as seen in BCC.

Clinical Features

• Characteristic features of a BCC lesion
  • Well circumscribed
  • Pearly or waxy papule, nodule, or plaque (will appear as a flat/raised, pale/flesh-coloured/pink/red, shiny/ waxy/translucent area)
  • Raised/rolled borders
  • Non-healing
  • Central umbilication may be present, which is often pigmented (central erosion or ulceration in advanced disease)
  • Bleeds when traumatized
  • Gradually increasing in size (slow/indolent growth – 0.5cm in 1-2 years)
  • Is not painful, does not itch
  • May have black-blue or brown areas
  • Telangiectasia may be present over surface (one or more visible and irregular blood vessels)
  • Oozing or crusting may also be present, especially in large lesions
  • Perineural invasion may occur in high-risk BCC lesions, manifesting as neuropathy
• Location of tumors (usually areas of sun-exposure)
  • Head (scalp included)
  • Face
    • Periocular
      • Lower eyelid: 48 – 72%
      • Medial canthus: 25-30%
      • Upper eyelid: 15%
      • Lateral canthus: 5%
  • Neck
  • Hands
  • Trunk, more prevalent in younger patients (<40years)
  • Metastases: rare (<1%)
    • Lymph nodes (especially parotid, posterior auricular, suboccipital, upper cervical)
    • Soft tissue
    • Lungs
    • Bone

Clinopathologic Subtypes of BCC

Subtype	Description
Nodular BCC (Low-risk)	Second-most common. Mostly on the upper trunk/shoulders/legs. Erythematous, well-circumscribed patch or plaque, often with a whitish scale and central atrophy
Superficial BCC (Low-risk)	Tumor margins are less clinically apparent as it infiltrated the dermis in thin strands between collagen fibers, hence a high rate of recurrence. Treatment of choice: MOH’s micrographic surgery
Pigmented BCC (Low-risk)	Subtype of nodular carcinoma that contains melanin. Manifests as a blue, brown, or black lesion that can resemble melanoma
Infiltrative BCC (High-risk)	May have a seemingly well-defined border. Not prone to ulceration. Firm to touch (induration). Erythematous macule, thin papule or plaque that may appear yellow-white when stretched
Micronodular BCC (High-risk)	May have a seemingly well-defined border. Not prone to ulceration. Firm to touch (induration). Erythematous macule, thin papule, or plaque that may appear yellow-white when stretched
Morpheaform/Sclerosing BCC (High-risk)	Flat/slightly depressed, fibrotic, firm white/yellow waxy sclerotic plaque. Rarely ulcerates. Poorly defined with wide and deep subclinical extension. May infiltrate cutaneous nerves (perineural spread)

Other subtypes include:

• Metatypical/Basosquamous/Mixed basal-squamous cell carcinoma
• Infundibulocycstic
• Follicular
• Pleomorphic

Nevoid Basal-Cell Carcinoma Syndrome (Gorlin Syndrome)

• Rare, autosomal dominant inherited condition, manifesting with multiple BCC lesions during childhood or adolescence
• The gene responsible is located on chromosome 9q (long arm)
• The number of BCCs may vary from one to hundreds (up to ~500 in a lifetime)
• Multiple BCCs begin to appear before, at, or after puberty on the face, trunk, and extremities. May involve areas around the eyes and nose.
• Tumors are, in many cases, highly invasive
• Other features associated with Gorlin syndrome:
  • Malformations:
    • Macrocephaly
    • Hypertelorism
    • Shortening of the fourth and fifth metacarpals
    • Palmar and plantar pits
    • Bifid ribs
    • Pectus excavatum
  • Other tumors
    • Medulloblastoma
    • Ovarian fibroma
    • Odontogenic jaw cysts
  • Intellectual disability
  • Congenital agenesis of the corpus callosum
  • Ectopic calcification, particularly of the falx cerebri
  • Absent or undescended testes
  • Mesenteric lymphatic cysts

Diagnosis

• The patient should first undergo a full-body skin examination to identify concurrent precancerous lesions or other skin cancers
• Dermoscopy – to support visual inspection. Findings may include:
  • Ulceration without a history of trauma
  • Arborizing (branching) blood vessels
  • Features of pigmented BCC e.g., large blue-gray, ovoid nests
• Skin biopsy – for diagnostic confirmation and risk stratification
  • Possible techniques:
    • Shave biopsy – Raised lesion
    • Punch biopsy – of the most abnormal area of a large lesion. Avoid if curettage is planned for final treatment
    • Full-thickness excisional biopsy – for pigmented lesions to rule out melanoma
    • Complete excision with appropriate margins – diagnostic and therapeutic procedure for small lesions
  • Ensure adequate sample size and depth, including reticular dermis, as evidence of infiltration may only be present in the deeper layers of the tumor, leading to missed diagnoses on superficial biopsies.
  • Include in pathology report:
    • Patient demographics
    • Presence of risk factors for BCC
    • Size and morphology of the lesion
    • Indicate if the initial sample or the repeat
  • Histological findings
    • Tumor cells appear similar to basal cells of the epidermis
    • Usually well-differentiated
    • Tumor cells align in a palisading pattern
    • Each histopathologic subtype displays different distinguishing characteristics, e.g., presence of melanocytes in pigmented BCC
• Assessment of disease extent – for patients with high-risk features or regional, nodal /distant metastases
  • CT with IV contrast – suspected spread to lymph nodes or bone
  • PET-CT/ Ultrasound – suspected lymph node metastasis
  • MRI – suspected perineural or deep soft tissue involvement
• Staging and risk stratification
  • Since BCC so rarely metastasises, the AJCC TNM staging system has limited clinical utility.
  • BCC can be risk-stratified based on clinical and histopathologic features into:
    • High-risk BCC – lesions with any high-risk feature of BCC
      • High-risk features of BCC
        • Tumor characteristics
          • 2cm or more in size and located on trunk or extremities (excluding hands, feet, ankles, pretibia)
          • BCC of any size located in the following regions: head and neck, pretibial, hands, feet, anogenital region
          • Lesion with poorly defined/clinically indistinct borders
          • Recurrent or incompletely excised BCC
        • Histopathological features
          • Aggressive subtypes, e.g., morpheaform, basosquamous, infiltrating, micronodular
          • Lesions with evidence of perineural invasion
        • Patient factors
          • BCC in an immunocompromised patient
          • Tumors that develop at sites of previous radiation therapy
    • Low-risk BCC – lesions with no high-risk features of BCC
• Differential diagnoses
  • Precancerous skin lesions
    • Actinic keratosis
    • Bowen disease
    • Lentigo maligna
  • Skin and other tumors (benign and malignant)
    • Melanocytic nevi (benign)
    • Trichoepithelioma (benign)
    • Cutaneous squamous cell carcinoma
    • Melanoma
    • Cutaneous T-cell lymphoma
    • Juvenile Nasopharyngeal Angiofibroma
  • Other skin conditions
    • Psoriasis
    • Nummulite dermatitis
    • Seborrheic keratosis
    • Lichen planus
    • Molluscum contagiosum
    • Sebaceous hyperplasia

Management

Patients require multidisciplinary care: oncology, surgery, and palliative care.

• Superficial therapies – for superficial low-risk BCC (higher risk of recurrence than surgery or radiation)
  • Topical pharmacotherapy – e.g., with imiquimod, 5-fluorouracil. Requires multiple sessions (imiquimod 3-5 times weekly for 6-16 weeks, 5-FU twice daily for 6-12 weeks), may result in skin irritation and inflammation, and recurrence.
  • Cryotherapy – Freezing of superficial skin lesions, usually with liquid nitrogen, resulting in a blister that crusts over and heals within weeks, leaving behind a permanent white mark. As with other superficial therapies, histological margin assessment is not feasible
  • Photodynamic therapy (PDT) – Exposure to a special light source activates the administered photosensitising chemical e.g., aminolevulinic acid lotion, methyl aminolevulinate cream, causing cellular destruction. Has good cosmetic results.
• Resection – generally preferred option as it has a lower recurrence rate
  • Mohs micrograph surgery – Recommended for high-risk BCC. Involves examination of carefully excised tissue under the microscope, layer by layer, to ensure complete excision. Preferred if minimal tissue excision is required, e.g., for lesions located on the eyelid. Lowest recurrence rate, however, limited availability.
  • Surgical excision – Performed for low-risk BCC and high-risk BCC in the absence of MMS. Margins should include 4mm of surrounding normal-appearing tissue, and depth up to mid-subcutaneous adipose tissue. Lesions with positive margins may require re-excision; hence, delayed closure should be considered until R0 resection is confirmed. Very large lesions may require a flap or skin graft for repair of the defect.
  • Curettage and electrodessiccation (C&E) – For low-risk BCC. Contraindicated on hair-bearing skin (risk of tumor extension into hair follicle), cosmetically sensitive areas, or for tumors extending beyond the dermis.
  • Shave removal – For low-risk BCC on the trunk or extremities. High risk of recurrence. Suture closure is not required. If the subcutaneous layer is breached, surgical excision should be performed.
• Radiotherapy – when resection is contraindicated/ guided by patient preference
  • Requires multiple sessions
  • Typically for adults >60 years of age due to potential adverse effects
  • Contraindicated in individuals with a genetic predisposition for skin cancers
  • Primary RT – For when resection is not feasible
  • Adjuvant RT – Consider for BCC with perineural involvement, and management of positive margins after resection.
• Systemic therapies – for locally advanced or metastatic BCC not amenable to resection or RT
  • Chemotherapy or immunotherapy – e.g cemiplimab
  • Hedgehog pathway inhibitors – e.g vismodegib, sonidegib
• Follow-up for BCC
  • Regular follow-up is crucial as patients have an increased risk of developing other skin cancers
  • 30-50% BCC patients develop another BCC within 5 years
  • Screening should occur every 6-12 months for the next 5 years, then once a year for life, except for patients with genetic predisposition (Gorlin Syndrome, xeroderma pigmentosum) who require more regular surveillance.
  • Patients should be encouraged to adhere to photoprotective measures to reduce the risk of sunburn:
    • Sun avoidance when possible
    • Use of sunscreen
    • Use of protective clothing, such as hats