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Skin ~ Medical student education

Skin and common skin cancers

Aim:

  • Understand the structure and function of skin
  • Understand the common tumours of the epidermis

Discussion:

Structure:

Skin is made up of three discrete layers.

Histology of normal skin

High power histology view of epidermis. The basal cells have high

The epidermis is formed by keratinocytes, which in cross section look like bricks in a brick wall (see picture below). The basal cells of this brick wall are continually dividing and mature into the more superficial keratinocytes and ultimately surface keratin.  The adnexal structures of the dermis (hair shafts, sweat ducts (eccrine and apocrine) etc) pass through this layer to open onto the skin surface. Between the keratinocytes are scattered antigen presenting cells (Langerhan’s cells) that are important components of our immune system. The base of the epidermis is the home to melanocytes, the manufacturers and distributors of our skin pigment Melanin; these cells have dendritic processes through which they pass manufactured melanosomes to surrounding basal keratinocytes. The melanin pigment then sits above the nucleus of the keratinocyte protecting it from the overlying sun, much like an umbrella.

All these cells received nutrition through diffusion from the underlying dermal blood vessels.  No blood vessels are present within the epidermis. The epidermis is glued to the underlying dermis by a thin layer of unique collagen called the basement membrane (this is the cement slab that our brick wall is built upon).

Histology of skin and underlying dermis

Low power with skin surface (upper). The underlying dermis contains the 'plumbing' (vessels) and 'wiring' (nerves) as well as all the adnexal structures (hair, sebaceous glands, eccrine and apocrine sweat glands)

The dermis is the ‘underground’ network of our skin; using our brick wall analogy, it contains all the underground plumbing (blood vessels and lymphatics) and electrical supply (nerves) to our overlying brick structure (skin). The dermis is also home to all our adnexal structures (hair follicles, sweat glands etc). All intervening tissue (ie the soil surrounding the pipes) is made up of collagen and elastic tissue and this accounts for the combined toughness and elasticity of skin; both of these components show changes with age, worsened by chronic sun exposure, accounting for the saggy, inelastic skin of the elderly. Sunscreen is important to prevent malignancy secondary to nuclear damage to epidermal cells, but it is also very important to prevent the solar damage to the collagen and elastin of the dermis. The dermis is the usual site for inflammatory cell accumulation in infection or inflammation.

The subcutaneous fat forms a variably thick protective layer. The dermis in turn is glued to this subcutaneous fat by fibrous septae.

As for all glued surfaces, the outline is often undulating, to increase the surface area between the two pieces being joined.  Hence the rete pegs seen at the epidermo-dermal junction.

Function:

Skin is much more than just the surface of the body; it serves a myriad of function and some considered it to be our largest functioning organ.

List as many functions  as you can. Here’s a list we came up with:

  • Camouflage: The world is covered in a myriad of microscopic organisms, mostly bacteria and we are no different. The bacteria growing on our skin are saprophytic and protect us from invasion by pathogenic organisms. They give us a protective bio-film.  Why do we scrub our hands so diligently before going into the operating theatre?
  • Rapid repair ability: All epithelium has the propensity to actively divide when cells have become separated, as in an ulcer (or any disruption of the epidermis for that matter).  The basal keratinocytes require cell to cell contact to stop proliferation (contact inhibition).  The keratinocyte is programmed to die slowly and becomes a flake of keratin on the surface.  This keratin layer is a semi-permeable barrier on which the bacteria grow and feed; their dinner is the dying keratinocytes and essential oils secreted by the sebaceous and eccrine glands.
  • Clotting ability.  Exposure of leaking blood to air and surrounding stroma causes rapid coagulation. You don’t want to bleed to death from a small cut.
  • Physical and chemical protection. The cells in the epidermal layer are approximately 10-15 cells thick, which, along with the surface keratin, acts as a barrier to the outside environment. The basal cells are anchored onto the basement membrane, further contributing to strength.
  • Anti-bacterial protection. The keratin, keratinocytes and secretions from the sebaceous glands and eccrine glands encourage growth of ‘good bacteria’ which is part of the defense to pathogenic bacteria.
  • Immune protection.  Patrolling through the layers of skin are Langerhan’s cells which are macrophages with antigen presenting capabilities.
  • Temperature control. The skin is our main interface with the outside world and is probably the important factor in our temperature control. The ability to control the blood flowing through dermal vessels is crucial to this role and this is regulated both centrally and by local factors; dilated vessels increase heat loss to the environment (convection cooling) while constriction of the dermal (and subcutaneous) vessels results in conservation of heat. The sweat glands also contribute to cooling by secreting fluid onto the surface to aid in cooling of the body (evaporative cooling). The subcutaneous fat acts as a thick layer of insulation. The fat controls temperature and acts as a rapid storage site for quick energy release.
  • Excretion control.  The sweat ducts are able to secrete salts, toxins and other breakdown products (garlic).
  • Hormone production.  Vitamin D and sunlight.
  • Sexual attraction. This is complicated and often initially physical; the appearance of skin (colour and quality) of skin helps in attracting a mate but the pheromones released from your apocrine glands situated in your axilla and groin also contribute to this function. The distribution and thickness of hair may also be important.

Disease

There are many types of skin diseases. As with any organ, the disease processes can be broken down into non-neoplastic and neoplastic conditions. Within the neoplastic group, lesions can be divided into benign and malignant. The following discussion concentrates on malignant tumours.

The simplest way to create a list of tumours that arise in an organ is to think about all the different tissue types that are found in that organ and then create a benign and malignant category for each tissue type. To use the epidermis as an example;

Cell type Malignant tumour name
Keratinocyte – superficial Squamous cell carcinoma
Keratinocyte – basal Basal cell carcinoma
Melanocyte Melanoma
Langerhan’s cells Langerhan’s cell histiocytosis

Obviously other tumours involve the epidermis, some almost exclusively, but this should be considered secondary involvement, eg lymphoma – the epidermis is involved but the malignancy originally arose outside the epidermis.

Keratinocytes

Low power of a squamous cell carcinoma

Low power of a squamous cell carcinoma

The commonest human malignancies are the skin cancers arising from the keratinocytes; these are referred to as squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). These are both related to chronic UV light exposure and are the result of cumulative DNA damage (the sun exposure both causes the damage and also creates the conditions for increased replication) Australians have one of the highest incidences of these carcinoma, due in part to non-pigmented Caucasian skin meeting the Australian sun.

Both tumour types arise from keratinocytes but they are recognised as different tumour categories based on their different microscopic appearances (morphology); the cells of basal cell carcinomas show features most in keeping with basal keratinocytes with closely packed cells showing high nuclear to cytoplasmic ratios (see picture). Squamous cell carcinomas on the other hand usually show differentiation towards surface keratinocytes with evidence of ‘keratinisation’ (see picture). Some epidermal tumours of the skin show differentiation towards both cell types (basi-squamous carcinoma) while a small group show no differentiation (poorly or undifferentiated carcinoma).

Basal cell carcinoma with nests of 'basaloid' cells.

Squamous cell carcinoma are thought to develop from pre-cancerous lesions; in early stages the keratinocyte dysplasia (non-invasive malignant change in cells) is limited to the base of the epidermis and is referred to as solar keratosis. When the dysplasia involves the full thickness of the epidermis it is referred to as Bowen’s disease or Bowenoid keratosis, a form of ‘carcinoma in-situ’.

These carcinomas rarely metastasize (especially basal cell carcinoma) but if left untreated they can burrow deeply into underlying structures; in this situation they are sometimes referred to as ‘rodent ulcer’ and show little respect for tissue boundaries (in the head and neck these can even extending through bone into underlying central nervous system). Searching Google for rodent ulcer will give you some pretty gory pictures. Treatment of these epidermal tumours is usually limited to surgical excision (preferably before development of a rodent ulcer!)

 

Melanocytes

Malignant melanoma, is also common in Australia and again related to sun exposure however, in contrast to BCC and SCC, melanoma risk is thought to be increased by severe, sporadic UV exposure.

Epidermis with single and nested atypical melanocytes

This is related to melanocytes being permanent cells that stay with us from birth to death; an initial ‘hit’ to a melanocyte caused by severe UV exposure is carried forward in time. Any subsequent ‘hits’ then have an increased chance of causing a critical mutation. Unlike the very well studied adenoma-carcinoma pathway in colorectal carcinoma, the pathway for melanoma development is not entirely known.

Histology of nodular melanoma

Low power view of nodular melanoma

Pathologists are important in the management of melanoma because many of the features we see under the microscope have been found to have prognostic significance. A good pathology report therefore becomes crucial to the subsequent treatment and management of these patients. Some of these features include;

  • Type – Including superficial spreading, lentigo maligna (Hutchinson’s melanotic freckle), nodular and acral lentigenous melanoma.
  • Depth of invasion – This is described as Clark’s level (anatomical level of involvement) and as Breslow thickness (physical measurement in mm). Both measurements are important as the thickness of skin varies throughout the body. The deeper the level, the worse the prognosis. It is important to note that Clark’s Level 1 relates to epidermal involvement and infers an in-situ lesion; there is no evidence of dermal invasion, and therefore it should not have a risk of metastasis.
  • Mitotic activity
  • Vascular or perineural invasion
  • Regression – This is described when part of the lesion, usually the superficial dermal aspect, is replaced by fibrous scar and chronic inflammation; it is thought this is a form of immune response to the tumour and probably infers that tumour cells have been processed by the immune system outside the lesion (ie metastasis).
  • Ulceration

The treatment involves surgical excision with a clear margin. The excision of the lesion reduces the risks of local recurrence but has no influence on the outcome of metastasis.

Clinically, any changing pigmented lesion should be carefully examined and probably removed for histological assessment

A/Prof John Pedersen and Dr Andrew Ryan


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