1: Basal Cell Carcinoma

Epidemiology [1]

Basal cell carcinomas are more common in fair skinned people who live in areas of the world with high sun exposure. In Queensland, an incidence of 2000 per 100,000 population has been recorded.
In general, basal cell carcinomas occur in older people, particularly men. Women dominate in younger age groups.

Aetiology and Pathogenesis

Ultraviolet ray exposure is the most common causative factor, either from sun exposure or tanning salons. Lesions generally occur in sun exposed skin. Other factors include ionising radiation or arsenic exposure. Nevoid Basal Cell Carcinoma Syndrome or Gorlin Syndrome is an inherited autosomal dominant condition caused by a mutation in the PTCH1 gene, leading to early development of multiple BCCs.

Hedgehog Pathway and Basal Cell Carcinoma [2]

The hedgehog gene was first reported in Drosophila 1980 by Nusslein-Volhard and Wieschaus. When it was knocked out, Drosophila larvae developed abnormally with a 'spiky' phenotype, hence the 'hedgehog' description. Further studies in humans identified three homologs - Sonic Hedgehog and Indian Hedgehog (reported in 1995) followed by Desert Hedgehog (in 1999). Of the three human homologs, Sonic Hedgehog has been studied the most intensively. Congenital abnormalities linked to sonic hedgehog mutations include holoprosencephaly and abnormalities in finger development. It is involved in patterning of the neural tube and somites.
The SHH gene is transcribed into sonic hedgehog protein, which undergoes cleavage in the cytoplasm and attachment of a cholesterol molecule. It is then secreted into the extracellular space, where it remains in close proximity to cells by virtue of the cholesterol molecule. Sonic hedgehog protein exerts its effect through the PTCH1 (patched-1) transmembrane receptor. PTCH1 binds SMO (smoothed), but when it interacts with sonic hedgehog SMO is released. This activates the WNT pathway, promoting cellular survival and cell cycle progression. In the classic view of oncogenes and tumour suppressor genes:

  • SHH is a potential oncogene
  • PTCH1 is a tumour suppressor gene
  • SMO is a proto-oncogene

Nevoid Basal Cell Carcinoma Syndrome or Gorlin syndrome is an autosomal dominant condition in which the person develops multiple BCCs at a young age. Other commonly seen features are odontogenic keratocysts of the mandible, other skeletal abnormalities and unusual facial features (frontal bossing, hypertelorism). Most cases are caused by a germline mutation of PTCH1, which prevents it from binding SMO. As per Knudson's two-hit hypothesis, loss of the second PTCH1 gene allows for uncontrolled activity of SMO, promoting cell survival and reducing apoptosis.
The hedgehog pathway has also been studied in non-NBCCS basal cell carcinomas. About 40% of basal cell carcinomas have mutations in PTCH1. About 40% of these mutations are due to UV mutations in the gene. This suggests than in de novo BCC, the hedgehog pathway has a significant role to play.

Targeting the Hedgehog Pathway

Agents which inhibit the function of the hedgehog pathway may be a new way to treat basal cell carcinomas, particularly those that are incurable through surgery / radiotherapy. The most popular target is SOL, which is involved in the transduction of the signal from sonic hedgehog to the nucleus. Cyclopamine, a naturally occurring substance in the corn lily plant, was found to inhibit this pathway in the 1960s after a number of lambs with holoprosencephaly were born in a farm in America.

Natural History

There are no known precursor lesions of basal cell carcinoma. Once they have developed, basal cell carcinomas are locally invasive but rarely metastatic (about 1/10,000 tumours).

Clinical Presentation

Patients may present with a pearly skin papule or nodule that may be centrally ulcerated. Alternatively the lesion may be noticed on physical examination as an incidental finding. The lesions may have surrounding telangiectasia. Some forms of basal cell carcinoma may be less distinct and instead as a pale scar-like lesion. Pigmented basal cell carcinomas can also develop and can be confused with melanoma.

Tumour Features

Regardless of their subtype, basal cell carcinomas show similar features to the stratum basalis of the skin. The majority of cells are small with minimal cytoplasm. They are usually arranged in groups, with the outer layer demonstrating peripheral palisading. The cluster of basaloid cells is surrounded by a stromal reaction. Retraction artifact is an important microscopic feature of basal cell carcinoma. The cells may appear to be separate from the stroma, unlike the basal layer of the skin which is firmly attached to its basement membrane.
Melanocytes may be present in any of the subtypes, causing them to become pigmented.
There are four major subtypes of basal cell carcinoma:

Superficial Basal Cell Carcinoma

These tumours are most frequent on the trunk and make up 10 - 30% of basal cell carcinomas.

Macroscopic Features

These tumours are typically erythematous, and may have a pearly border. They may extend over a large area of skin but show minimal invasion to deeper layers.

Microscopic Features

Superficial basal cell carcinoma demonstrates nodules extending through the epidermis into the papillary (but not rete) dermis. They are usually continuous but may show some separate nodules.

Nodular Basal Cell Carcinoma

This is the most common subtype, making up over 60% of BCC. They occur most commonly on the face and neck.

Macroscopic Features

These tumours show the classic features of basal cell carcinoma, presenting as a pearly nodule with surrounding telangiectasia. Rarely they may be flatter lesions or be pigmented.

Microscopic Features

Nodular BCC is arranged into lobules of malignant cells with peripheral palisading.

Micronodular Basal Cell Carcinoma

A more aggressive type of basal cell carcinoma. They usually occur on the back.

Macroscopic Features

These lesions have a variety of macroscopic appearances, with flat or elevated appearances with or without pigmentation.

Microscopic Features

Micronodular BCC is arranged in tiny clusters of basaloid cells which infiltrate through the dermis. Connective tissue separates the nodules. The microscopic spread of disease may be far greater than the macroscopic changes suggest.

Infiltrating Basal Cell Carcinoma

The most aggressive of the usual basal cell carcinomas, often demonstrating perineural invasion with increased risks of recurrence.

Macroscopic Features

This tumour usually appears as a poorly defined plaque.

Microscopic Features

Strands of basaloid cells may extend through the layers of the skin and into deeper tissues. The other features of basal cell carcinoma (eg. peripheral palisading) are not seen. Microscopic disease may extend far beyond the macroscopic borders of the tumour. Fibrosis and/or sclerosis are not seen (see Morpheiform below)

Less common subtypes

Fibroepithelial BCC

Strands of malignant basaloid cells form a fenestrating network beneath the epidermis. Radiotherapy seems to predispose to this variant, which is usually indolent.

Morpheiform BCC

A rare variant of BCC characterised by dense collagen formation surrounding strands and nests of basaloid cells. Margins are indistinct.

Basosquamous Carcinoma

This description is used when squamous differentiation occurs within a BCC. The tumours are generally more aggressive than normal BCC with higher rates of regional and distant metastasis.


Immunohistochemistry is typically used to exclude other malignancies that may mimic basal cell carcinoma.

  • S100 negativity excludes small cell melanoma
  • BerEP4 negativity (a keratin marker) excludes squamous cell carcinoma
  • CK20 stains for Merkel cells, which are present in other rare forms of skin malignancies

Staging [3]

Staging of skin tumours is based off the TNM guidelines released by the AJCC. The seventh edition bases the stage of the primary tumour on size as well as on high risk features.

High Risk Features

  • Depth of Invasion > 2 mm, Clark Level IV or more
  • Located on the ear or non-hair bearing lip
  • Poorly differentiated or undifferentiated

Primary Tumour (T)

  • T0 - No evidence of primary tumour
  • Tis - Carcinoma in situ
  • T1 - < 2 cm in greatest dimension with no more than 1 high risk feature
  • T2 - > 2 cm in greatest dimension, or with 2 or more high risk features
  • T3 - Tumour with invasion of the orbit, mandible, maxilla or temporal bone
  • T4 - Tumour with invasion of other bones, or perineural invasion of the skull base

Regional Nodes (N)

  • N0 - No evidence of nodal disease
  • N1 - Metastasis in a single, ipsilateral lymph node less than 3 cm in size
  • N2 - Metastasis in multiple ipsilateral or contralateral lymph nodes, not greater than 6 cm in size
    • N2a - Single metastasis, between 3 and 6 cm in size
    • N2b - Multiple ipsilateral metastases, no greater than 6 cm in size
    • N2c - Multiple ipsilateral and contralateral metastases, no greater than 6 cm in size
  • N3 - Lymph node metastasis over 6 cm in size

Distant Metastasis (M)

  • M0 - No evidence of distant metastatic disease
  • M1 - Metastatic disease

Final TNM Stage

  • Stage 0 - Tis N0 M0
  • Stage I - T1 N0 M0
  • Stage II - T2 N0 M0
  • Stage IIIA - T3 N0 M0 — T1-3 N1 M0
  • Stage IVA - T1-3 N2 M0 — T4 NANY M0 — TANY N3 M0 — TANY NANY M1

1. WHO Classification of Tumours - Pathology and Genetics of Skin Cancers
2. Iwasaki JK et al (2010) The molecular genetics underlying basal cell carcinoma pathogenesis and links to targeted therapeutics. J Am Acad Dermatol
3. AJCC 7th edition
4. Robbins and Cotran Pathologic Basis of Disease 8th Edition