Basal Cell Carcinoma

Commonest form of skin cancer
Slow growing tumour affecting the basal cells of the skin
Can locally invade but rarely metastasises
Can sometimes be referred to by laymen as "rodent ulcer"

Epidemiology

• Accounts for 80% of non-melanoma skin cancers
• 80% of cases occur in the head and neck
• Marked geographical variation (commonest in Europe, Australia and USA)
• Much more common in fair-skinned individuals with a family history
• Up to 30% of caucasians will develop BCCs in their lifetime
• Incidence increases in those >50 years old
• Multiple BCCs in younger patients is suggestive of nevoid basal-cell carcinoma syndrome (Gorlin-Goltz Syndrome)
• ♀ > ♂

Clinical Features

• Most commonly affects sun exposed areas
• Most BCCs remain localised
• Growth rate is variable but patients tend to report slow growing lesion
  • Patients often give a history of a "spot" that occasionally bleeds
• Different clinical subtypes exist which tend to occur at different anatomical locations (see below for main types)
• Nodular and superficial BCCs can produce pigment → pigmented BCCs (~7% of cases)

Clinical subtypes

Type	Image	Clinical	Notes
Nodular		Nodular Pearly white or pink Telangiectasia Ulceration Cystic and keratotic are variants of nodular BCC Cystic → appears as a smooth, round cystic mass Keratotic → cornification in lesion	Most common form
Morphoeic (Sclerosing)		Usually found in mid-facial sites Waxy, scar-like plaque with indistinct borders Wide and deep subclinical extension May infiltrate cutaneous nerves (perineural spread)	The most important clinical subtype 5% of all BCCs More aggressive and ill-defined ∴ complete excision is more difficult Can be very large and pose reconstructive issues
Superficial		Slightly scaly, irregular plaque Thin, translucent rolled border Multiple microerosions	Most common type in younger adults Most common type on upper trunk and shoulders

Differential Diagnosis

• Squamous Cell Carcinoma
• Malignant melanoma (pigmented basal cell carcinoma)
• Melanocytic naevi (pigmented basal cell carcinoma)
• Bowen's disease (especially superficial basal cell carcinoma)
• Psoriasis (superficial)
• Eczema (superficial)
• Sebaceous hyperplasia
• Molluscum contagiosum
• Appendygeal tumours

Aetiology and Pathogenesis

Aetiology

• The exact cause of BCC is unknown
• Risk factors
  • Ultraviolet (UV) light exposure from sun/sun-beds, especially in childhood
  • Genetic predisposition/association with fair skin type (Fitzpatrick I + II)
  • Immunosuppression (post-transplant, anti-TNF drugs [infliximab], haematological malignancies)
  • Arsenic exposure
  • Previous BCC - 50% will develop second BCC within 5 years
  • Nevoid basal-cell carcinoma syndrome (Gorlin-Goltz Syndrome)
  • Xeroderma pigmentosum
  • Bazex-Dupré-Christol syndrome

Pathogenesis

• Majority of cases exhibit UV radiation-induced carcinogenesis
• 90% of cases demonstrate alterations genes causing a hyper activation of the hedgehog (HH) protein family
  • This is a pathway involved in organogenesis and tissue repair
  • Includes PTCH1 receptor, SMO signal transducer and GLI transcription factors
• TP53 mutations are the second most important gene mutation - 20-60%

Investigations

Diagnosis is usually clinical
Dermatoscope may assist in clinic diagnosis
In cases where there is uncertainty an incisional or punch biopsy may be performed

Dermatoscopy

The dermatoscopic criteria of non-pigmented BCC: (a) arborizing vessels, (b) superficial fine telangiectasia, (c) ulceration, (d) multiple small erosions, (e) shiny white-red structureless areas and (f) short white streaks. Images from Lallas et al. 2014

Pigmented BCC may display, in addition to the criteria shown in above, one or more of the following features: (a) blue-gray ovoid nests, (b) multiple blue-gray dots/globules, (c) in-focus dots, (d) maple leaf-like areas, (e) spoke wheel areas (arrow) and (f) concentric structures (arrows). Lallas et al. 2014

Histopathology

• Common histological features of BCC are:
  • Nodules and/or strands of atypical basaloid cells that show nuclear palisading, cellular apoptosis, and scattered mitotic activity in the dermis
  • Artifactual cleft formation may be seen between the tumour lobules and the surrounding stroma
  • Solar elastosis is usually present in the dermis

• Histological subtypes:

Type	Description	Aggressive
Nodular	Discrete nests of basaloid cells in the dermis. There is peripheral palisading of the malignant keratinocytes and a mucinous-surrounding tumour stroma. Between the tumor and the dermis, a separation or "cleft," is often apparent due to retraction artifact in tissue processing	No
Superficial	Foci of malignant, basaloid, palisading tumours "budding" off the epidermis	No
Pigmented	Presence of melanin and melanophages within the tumour nodules	No
Morphoeic/Infiltrative	Thin cords of basaloid tumor cells penetrating the surrounding collagen, which may appear sclerotic	Yes
Micronodular	Numerous small collections of malignant basaloid cells within the dermis and exhibit more subtle findings of peripheral palisading and retraction compared with nodular BCCs	Yes
Basosquamous	These have a component of nodular or superficial BCC overlying an invasive portion that has features of BCC and SCC	Yes

• Perivascular or perineural invasion are features associated with the most aggressive tumours

High-magnification micrograph of basal-cell carcinoma

Imaging

CT or MRI imaging may be used for extensive lesions to delineate any involvement in adjacent structures (especially if there are concerns that the tumour may have invaded major nerves, the orbit or the parotid gland)

Management

Risk Stratification

Darker shade = high risk areas on face. Image from Nasr et al. 2021

• Clinical criteria for high risk lesions:
  1. Location: Mask areas of the face (see diagram)
  2. Size: >10mm (note that for most of trunk an extremities the criteria is >20mm)
  3. Recurrent tumour
  4. Patient on immunosuppression
  5. Tumour in site of previous radiotherapy
• Pathological criteria for high risk lesions:
  1. Infiltrative growth pattern (infiltrating, morphoeic, micronodular)
  2. Basosquamous
  3. Level of invasion is beyond subcutaneous fat
  4. >6mm tumour thickness
  5. Perineural invasion (named nerve or nerve with diameter >0.1mm)
  6. pT2 >20mm / pT3 / pT4
  7. Bone invasion
  8. Involved margins (0mm) or histologically close margins (<1mm)

Patient Counselling

• Discuss different treatment options, especially in context of scars and the implication of that for the patient
• Sun protection advice (and the implication of this on vitamin D levels)
• Discuss the increased risk of developing new primary skin cancers (∴ they need to remain vigilant for early detection and treatment)

Multidisciplinary Team

• There are 2 levels of MDT for skin cancers:
  1. Local skin multidisciplinary team (LSMDT) → usually found in district general hospitals
  2. Specialised skin multidisciplinary team (SSMDT) → usually located in teaching hospitals with cancer centres
• Cases requiring discussion at LSMDT:
  1. Incompletely excised BCCs (consider referral to SSMDT where Mohs is to be offered
• Cases requiring discussion at SSMDT:
  1. Complex Mohs cases (complex reconstruction / rare tumours)
  2. Large / locally advanced BCC or BCCs requiring complex reconstruction
  3. Metastatic BCC

Surgical Treatment

• Standard surgical excision with pre-determined margins
  • Suitable for the majority of BCCs (should be offered as first line treatment for all low-risk and high-risk with well defined margins)
  • A 3mm clinical margin achieves clearance in 85% of cases whilst a 4-5mm margin achieves clearance in 95% of cases
  • In primary morphoeic BCC: 3mm margin → 66% clearance; 5mm → 82%; 13mm → 95%
  • Recommendations for surgical margins:
    • Low risk lesions → 4mm peripheral margin
    • High risk lesion → 5mm peripheral margin
    • Deep margin should be to a clear plane (including cuff of fat if present or other deep structures if needed)
    • Morphoeic BCC → 13mm peripheral margins

• Mohs micrographic surgery
  • Microscopically controlled surgery that aims to confirm removal of all tumour histologically prior to reconstruction
  • Labour intensive
  • Consider in:
    1. Recurrent tumours
    2. High risk tumours
    3. Where minimal tissue loss is essential (e.g. anatomically sensitive areas such as peri-orbital)
  • Slow Mohs = Excise → wait for H&E result → delayed reconstruction

• Destructive surgical techniques
  • Not recommended for high risk lesions
  • Curettage and cautery
  • Cryosurgery: liquid nitrogen
  • Laser therapy: CO₂ or pulse dye lasers can be used

Non-surgical Treatment

• Topical therapy
  • Imiquimod →
    • Immune modulator. 5x/week for 6 weeks. Can cause local reactions (skin discomfort) and flu-like symptoms. 84% cure rates.
  • 5-Fluorouracil cream →
    • Chemotherapeutic aged. OD or BD for 3-4 weeks. Causes local reactions as above but no flu-like symptoms. ?higher rates of wound infection

• Photodynamic therapy
  • Suitable for low risk superficial BCCs
  • Uses light and a photosensitising chemical substance (methyl aminolevulinate [MAL] or aminolevulinic acid [ALA])
  • Comparable cure rates to topical therapy

• Electrochemotherapy
  • Not currently recommended for BCCs

• Radiotherapy
  • Treatment of choice if patient refuses or is unable to tolerate surgery and treatment of the lesion is needed
  • Usually utilised superficial electrons
  • Can be single fraction (higher complications) or fractionated (usually 5 doses - less complications and higher cure rate)
  • Complications of radiotherapy:
    1. Soft tissue radionecrosis
    2. Cataracts
    3. Telangiectasia
    4. Secondary RT-induced cancers
  • Higher recurrence rates that with surgery (10%)

Prognosis and Complications

• Incomplete excision
  • Discuss at LSMDT
  • Radial margin:
    • Low risk lesions → Offer re-excision / Mohs / Observation / Other treatment options
    • High risk lesions → Offer re-excision / Mohs / Radiotherapy
  • Deep margin → Offer re-excision / Mohs / Radiotherapy

• Recurrence
  • 5-year recurrence rate is:
    • ~5% for all cases following surgical excision with predetermined margins
    • 0.5% for cases with clear margins
    • 0.3-6.5% following Mohs in the head and neck
    • Treating already recurrent tumours is associated with higher subsequent recurrent rates, ranging from 4% to 10%
    • 10% for lesions treated with radiotherapy alone

• Advanced/metastatic BCC
  • Metastatic BCC is rare
  • No standard therapy for this group; clinical trials appropriate if available
  • Use of oral/topical hedgehog pathway inhibitors (e.g. vismodegib) has been shown to be effective in patients with advanced, multiple, or metastatic BCC - funding limited in UK

Follow-up

• Completely excised BCCs / BCCs treated by Mohs do not routinely need follow up
• Patients with possibly involved / close radial margins, complex repairs, post radiotherapy, or with multiple tumours may require follow up tailored to the individuals clinical picture