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NON MELANOMA SKIN CANCER DIAGNOSIS AND TREATMENT

Non Melanoma skin cancers (Basal Cell and Squamous Cell Carcinoma) are the most common types of cancer in the Caucasian population and the incidence of skin cancer has reached epidemic proportions. It is difficult to determine exact incidence data because cancer registers exclude NMSCs but it is estimated that there is an increase in incidence of 3-8% per year for NMSC (and 3-7% for melanomas!). Would one include the precursor lesions like actinic keratosis then it would be realistic to assume that the morbidity in the Caucasian population at an age over 70y is close to 100%?

The rising incidence can be explained by a combination of increased sun exposure or exposure to UV light, increased outdoor activities, changes in clothing style, increased longevity and ozone depletion.

The management of damage to the skin resulting from overexposure to UV radiation and skin cancer occupies a significant proportion of any general or dermatological practice.

The increasing incidence of skin cancer and its precursor lesions such as actinic keratosis combined with an increased awareness of the problem by the public results in a rising demand for effective therapies as well as a more profound understanding of these conditions by the treating physician.

This article will go through the epidemiology, diagnosis and management of Non Melanoma skin cancers and its precursor lesions.

BASAL CELL CARCINOMA (BCC)
Definition: BCC is the most common tumour of hair bearing skin. It is slow growing and locally destructive but is often considered "semi malignant" due to the fact that it rarely ever spreads to vital organs.

It originates from undifferentiated cells of the outer root sheath and/or stem cells of the bulge region of the vellus hair follicles, which explains that it only occurs on the hair-bearing skin. It affects males and females equally and the peak incidence is between the 6-8 decade.

However, although the incidence e.g. in England is only about 110/100 000. It is 2000/100 000 in Australia (which is comparable to Southern Africa) and BCCs here are frequently diagnosed between the 3-4 decade of life.

By far the most important risk factor for the development of BCCs is UV­ radiation. UVB (290-320nm) in particular induces DNA-mutations which lead to uncontrolled growth. There are genetic factors known which influence DNA repair and therefore increase your susceptibility for development of cancer.

(i.e. PTCH-Tumour suppress organ). Mutations in the suppressor genes on one hand or an ineffective P450 gene which eliminates oxygen -radicals on the other hand contribute greatly to the chance of developing skin cancer.

A further risk factor which becomes more and more important is Immune suppression. A decreased immune surveillance by T-cells lets more damaged cells pass through and grow. This applies to iatrogenic Immune suppression (Le. after organ-transplant) as well as Le. AIDS which in our country could be a serious reason of concern!

Radiotherapy at an early age (i.e. for treatment of Hodgkins Lymphoma) is known to cause the development of multiple BCCs after a +/- 20 year delay period.

CLINICAL MANIFESTATION
Most BCCs are found on the face, 80% of which are above the outer angle of the mouth and the lower part of the earlobe. 30% of all facial BCCs occur on the nose. The rest involves the trunk in the sun exposed parts and to an even lesser degree the extremities.

Unlike the Squamous Cell Carcinoma BCCs don't have precursor lesions and arise on otherwise normal looking skin. There are many clinical manifestations which often correlate with a specific histological growth pattern:

  1. Initial or early BCC. A red and flaky spot, often misdiagnosed as i.e. pressure point from glasses. It has got a tendency to bleed and one often notices the characteristic teleangiectasies along the edge of the lesion. Trauma can lead to crusting and any non healing wound on the face of the elderly should awake the suspicion of a BCC.
  1. Nodular BCC. This is the most common subtype. It looks like a waxy papule - again with characteristic peripheral teleangiectasia. Often one can see a discrete central indentation. Bleeding in response to minimal trauma is a common phenomenon. Differential diagnosis includes compound nevi, adnexal tumours or sebaceous Hyperplasias.
  1. Ulcerating BCC. Large lesions often develop a central necrosis and if untreated the course is relentless. Neglected tumours can infiltrate and destroy soft tissue, cartilage and even bone. They are usually not painful which leads to a delay in therapy. This form is also seen as a sequale from recurrences of previously unsuccessful treatments.
  1. Cystic BCC. This form shows whitish-blue glassy papules again with the characteristic teleangiectasias along the edge. It is commonly found on the eyelid or upper cheek area. Benign adnexal tumours are to be considered in the differential diagnosis. Taking into account that surgery is often the only form of treatment and the difficulty arising from this specific localisation (i.e. eyelid), one should consider histological evaluation of any suspicious lesion at any early stage.
  1. Superficial Spreading BCC. Also known as eczematoid BCC. It resembles a patch of dermatitis: red and flaky with an irregular edge. It may even itch and often gets misdiagnosed as nummular dermatitis. Its most common localisation is the upper body and extremities.
  1. Pigmented BCC. This is a variant of the nodular BCC with Melanin deposition. Due to the clumps of black pigmentation the main differential diagnosis is that of a malignant melanoma but seborrhoeic keratosis or Angiokeratomas also need to be considered.
  1. Morpheic BCC. This type can get missed easily. It has got a waxy white often flat irregular growth pattern resembling a keloid. Lack of bleeding and ulceration makes early diagnosis difficult. It often infiltrates deeper structures which need to be taken into consideration when planning the therapy. The differential diagnosis includes scars, keloids, Morphea or Dermatofibrosarcomas.

 

THERAPY
There is a variety of treatment options available and the choice of therapy will depend on the clinical subtype, its localisation, the size of the tumour as well as age and general condition of the patient. Of note is that recurrence rates with almost all forms of treatment (except Moh's Micrographic Surgery) are high (5-10%).

SURGERY
Surgical removal of the tumour can take place with curettage, simple excision or excision and repair (Le. skin graft for larger or deeply infiltrating tumours). Moh's Micorgraphic Surgery (surgery with immediate histological evaluation) is state of the art treatment for cases where tissue sparing procedures are essential (Le. eyelid, nose, recurrences, etc). It is however not commonly offered in this country.

Curretage offers good cosmetic results but should not be used in either large lesions or morpheic lesions. The disadvantage is that it is not possible to evaluate histological clearing in the specimen sent for testing.

OTHER FORMS OF TREATMENT

CRYOTHERAPY
Freezing with liquid Nitrogen is a rather non specific way of destroying cells. Except for the occasional small superficial spreading BCC it can not be recommended as treatment because:

  1. It has got high recurrence rates (16%) and
  2. Often leads to adverse cosmetic results (scarring, hypo pigmentation).

RADIOTHERAPY
Radiotherapy should never be the first choice but could be considered in the elderly or for difficult to treat areas (Le. eyelids) or as palliative treatment for tumours too large to resect. When a recurrence occurs it would be difficult to perform surgery in the irradiated area and to irradiate the same area again is also not possible.

PHOTO DYNAMIC THERAPY
This is a relatively new form of treatment. It can be used for superficial spreading BCCs, early BCCs and small nodular lesions after debulking, but not for Morpheic BCCs. It achieves excellent cosmetic results without any scarring. The lack of scarring is important if a recurrence should develop because it can then be regarded the same as a primary tumour. It is not widely used in this country yet but may well become the preferred mode of treatment in the future.

IMMUNO THERAPY
Small nodular BCCs or superficial BCCs in cosmetically important areas (nose, eye) can be treated successfully with intralesional interferon. Although effective it is a very expensive treatment and can also cause flu-like symptoms.

IMIQUIMOD (ALDARA)
Can be used for superficial spreading BCCs and achieves good results. However the duration of the treatment (up to 12 weeks) and local irritation sometimes limit compliance and therefore ultimately the outcome.

The use of topical Cytostatics (5-FU: Effudix) should be discouraged due to the extremely high recurrence rate (up to 70%).

In summary: Basal Cell Carcinomas can present in a variety of clinical manifestations and although biologically relatively indolent need to be recognised and treated early to prevent an adverse cosmetic or functional outcome.

Patients with BCCs need to be educated in the practice of sun protection and a "sun wise" behaviour. Regular skin checks must be implemented.

ACTINIC KERATOSIS AND SQUAMOUS CELL CARCINOMA

ACTINIC KERATOSIS (AK)

These extremely common red and scaly often hyperkeratotic, thick lesions occurring on the sun exposed areas of the elderly are now uniformly accepted as carcinoma in situ!

They are caused by chronic over exposure to UV-radiation (UVB and UVA): the DNA gets damaged and failure to repair results in unrestricted, abnormal growth. AK's are defined by the border of the epidermis, however 5-10% grow into the dermis and therefore progress to a squamous cell carcinoma.

They usually occur on the forehead, scalp, ears, lips and dorsum of the hands. They can be seen in 4 subtypes:

  1. Erythematous Type. Red and flaky relatively sharply demarcated except in the severe cases where once can see "wail-to-wall" Keratosis - with small areas of normal skin dispersed among the field of abnormal cells (in particular scalp, hands).
  2. Keratocic Type. The skin is now covered with a yellow-brown scab. On removal of this crust there is often bleeding.
  3. Cutaneous Horn. Found on the forehead or ears mainly of men. Hyperkeratosis persists until it forms a small horn which is firmly adherent to the underlying skin. Removal of this would cause bleeding.

LICHENOID KERATOSIS
Usually a more elevated plaque with an inflammatory infiltrate on histology.
The differential diagnosis includes seborrhoic keratosis or psoriatic lesions.

Taking into account that AK's are carcinoma in situ and 5-10% progress to invasive SCC treatment should always be offered. A variety of treatment options exist, but still the most common form of treatment would be removal by cryotherapy.

C02 laser is a (somewhat expensive) option and topicaI5-FU(Effudix) has the same limitations as described for BCCs.

Newer therapies like Imiquimod (Aldara)-used mainly for single lesions - and photo dynamic therapy (PDT) play an important role because they offer far better cosmetic results.

PDT in particular has got the advantage that large areas can be treated at the same time (Le. whole scalp). Pain management is crucial because this would influence patients acceptance. However PDT is selective for cancerous tissue it is non invasive and non-scarring. It can be used repeatedly if necessary and cosmetic results are superior to all comparable treatments.

In summary: Actinic Keratosis need to be recognized as what they are, namely Carcinomas in situ! They need to be treated accordingly and patients need to be advised about the risk that further sun exposure can speed up the progression from AK to SCC.

SQUAMOUS CELL CARCINOMA (SCC)
The incidence of SCC's in Europe is in the region of 30/100000 and again in Australia 600/100000.60%of all SCC's occur in the mid-face. Most facial lesions occur on the lip and it is more common in males than females (40: 1) It originates from the epidermal squamous cells and develops from its precursor lesions, namely Actinic Keratosis or Bowens disease. The latter is a red and scaly lesion resembling Psoriasis. It can be pruritic and is most commonly a single lesion. 30-50% of all Bowen lesions progress to invasive SCC. The Differential diagnosis includes AK, superficial spreading BCC, Pagets disease, nummular dermatitis and Psoriasis.

Lesions should be surgically removed either by excision or Curettage. Cryotherapy, Imiquimod (Aldara) and PDT can also be used and often offer superior cosmetic results.

It is important to differentiate between the different Carcinomas in situs: While Actinic Keratosis are caused by overexposure to the sun other forms are linked to a variety of Co-Carcinogens: Risk factors include: exposure to tar products or arsenic, burn wounds, previous radiotherapy, PUVA  therapy, Human Papilloma virus (oncogenic viruses) and Immunesupression (iatrogenic or through AIDS)

Tar exposure (cigarettes, chimney-sweepers, topical creams used e.g. for Psoriasis) and Arsenic (used medically or as contaminant in borehole water) Becomes a problem in the chronically exposed.

Chronic inflammatory lesions and in particular bound down scars resulting from burns have got a +/- 1:5000 chance to develop into a SCC (Marjolin-ulcer). Previous radiotherapy can after a usually 20year delay period lead to the development of multiple SCC's in the irradiated area.

PUVA therapy given for e.g. Psoriasis increases the risk for development of SCC if a critical total accumulative Joule dose (2000J/cm) is exceeded. HPV infections (esp. with type 5,8,16 and 18) increase the risk of SCC in particular on the penis, Scrotum, Vulva, Cervix, tongue and nails.

Immunesuppression i.e. after organ-transplant or Aids can increase the risk to develop a SCC 200 fold. Of note is of course that e.g. in Aids one often sees the coexistence of Immunesuppression plus additional viral infections which means that the risk is then accumulative.

SCC can metastasise into regional lymph nodes and later other organs. The prognosis like with other malignancies depends on depth of invasion and tumour-size. A SCC of 2mm invasion is restricted to the dermis and basically never metastasises while a 6mm tumour can metastasise in 25-40%!

A complete workup with e.g. CT scan or MRI is recommended for tumours exceeding 5mm depth of invasion. Other prognostic factors include tumour size and localisation and the histological differentiation. The poorer the differentiation, the worse the prognosis. Immunesupressed patients - as can be expected of course- have got a worse prognosis than the immunocompetent patient.

The Differential diagnosis includes a variety of lesions: Verruca vulgaris, seborrhoic Keratosis Keratoacanthoma, amelanotic Melanoma, adnexal tumours and of course Actinic keratosis, BCCs and Bowen’s disease. Histological evaluation is indicated in all suspicious lesions.

THERAPY
The Standard treatment is surgical excision with histological evaluation.
In large lesions and in cosmetically important areas a biopsy is indicated to plan the complete removal depending on depth of invasion and histological type. Mohs Micrographic surgery with immediate intraoperative evaluation would be an excellent alternative.

Cryotherapy (the physical destruction of cells with liquid nitrogen at a temperature of -196 degrees Celsius) is only indicated in the elderly or for small and superficial tumours.
Radiotherapy can be used for tumours too large to be excised, in the elderly or in areas where surgery would compromise function like i.e. the eyelid. Metastasis can be treated successfully with a combination Chemotherapy ­however this is always only palliative because recurrence rates in the first 4 years are as high as 80%.

SPECIFIC SUBTYPES

LIP CARCINOMA

By far the most common precursor is the solar Cheilitis. It is therefore mainly involving the lower lip. To a lesser degree Leucoplakia caused by nicotine in smokers also plays a role. The earliest sign is a variegated colour: whitish, yellowish brown or red. There is often peeling and sometimes painless erosion. Differential diagnosis includes actinic Cheilitis chronic HSV 1 infection (recurrent fever blisters although those are usually painful) and to a lesser degree secondary syphilis.

Any indurated or ulcerated plaque on the background of a leucoplakia ­especially if painless - should be biopsied or primarily excised if small.

GENITAL SCC
Penis carcinoma is often correlated to chronic infections as seen in patients with Phimosis or in co-existing Lichen sclerosus et atrophicus and HPV infections (HPV 16 and 18).Bowen’s disease and Erythroplasia Queyrat are the corresponding Carcinomas in situ.

In situ Carcinomas can be treated with PDT; all invasive carcinomas must be treated surgically usually requiring partial amputation

Non Melanoma skin cancers pose an ever increasing challenge for the treating physician in our country. There is a low level of suspicion as far as the patient is concerned because precursor lesions such as Actinic Keratosis occur so frequently in the elderly that it is presumed "normal". Their real biological behaviour needs to be understood the necessity of their treatment must be emphasized. The principles for treating cancer don't differ from those of skin cancer just because it is more common: The earlier any given lesion is diagnosed and treated the better the prognosis and final outcome!

REFERENCES
Diepgen TL, Mahler V (2002) The epidemiology of skin cancer. Br J Dermatol 146 (SuppI61): 1-6

Reinfenberger J, Sch6n MP (2003) Molekulare Grundlagen und pathogeneseorientierte Therapie epithelialer Tumoren der Haut. Hautarzt 54: 1164-1170

Wennberg AM (2000) Basal cell carcinoma - new aspects of diagnosis and treatment. Acta Dermato Venereol (Stockh) (Suppl) 209: Z·25

Schmook T, Stockfleth E (2003) Current treatment patterns in non-melanoma skin cancer across Europe. J Dermatol Treat 14: S3-S10

Babilas P, Landthaler M, Szeimies RM (2003) Die aktinische Keratose. Hautarzt 54: 551-562

Heaphy MR Jr, Ackerman AB (2000) The nature of solar keratosis: a critical review in historical perspective. JAm Acad Dermatol43: 138-150

Moy RL (2000) Clinical presentation of actinic keratoses and squamous cell carcinoma. JAm Acad Dermatol42: 8-10

Thompson SC, Jolley D, Marks R (1993) Reduction of solar keratoses by regular sunscreen use. N Engl J Med 329: 1147-1151

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