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Squamous Cell Carcinoma - Information for Medical Professionals

Definition and Description


Squamous cell carcinoma is a malignant tumor arising from the keratinocytes of the epidermis. It grows in a destructive way and metastasizes mainly via the lymphatic system. Several predisposing or pathogenetic factors for the occurrence of this tumor are known including UV-radiation, chronic inflammatory skin changes, chemical carcinogens, immunosuppression and viral infections. The tumor begins with a small, slightly raised, warty, grey or brownish hyperkeratosis and enlarges with time. The growth can progress rapidly when extensive ulcerative necrosis occurs.

Incidence and Epidemiology


Melanoma and nonmelanoma (basal and squamous cell carcinoma) skin cancer are now the most common type of cancer in the Caucasian population and the incidence of skin cancer has reached epidemic proportions. Many epidemiological studies have demonstrated that the incidence of skin cancer has been increasing rapidly over the last decades. Nonmelanoma skin cancers (NMSCs) constitute more than one-third of all cancers in the United States with an estimated incidence of over 600,000 cases per year. NMSCs are the most common malignancies occurring in the Caucasian population each year. Of these 600,000 cases approximately 500,000 are basal cell carcinomas (BCCs) and 100,000 to 150,000 are squamous cell carcinomas (SCCs). The standardized ratio of BCC to SCC is roughly 4 to 1. The incidence of NMSC (BCC and SCC) is 18 times greater than that of malignant melanoma. However, incidence data of high epidemiological quality on NMSC are sparse because traditional cancer registries often exclude NMSC or are at least incomplete. Miller & Weinstock (1994) estimated the 1994 NMSC incidence in the United States to be between 900,000 and 1,200,000. The lifetime risks were estimated to be 28% to 33% for BCC and 7% to 11% for SCC (lifetime risk of developing NMSC for a child born in 1994)

BCC represents 75% of NMSC and is, therefore, the most common malignant disease throughout the world. Silverberg et al (1990) estimated the average annual incidence of BCC in the United States to 191 new lesions per 100,000 white persons According to the estimates (lowest and highest estimated incidence rates) of Miller & Weinstock (1994) the age-adjusted incidence rates per 100,000 whites per year (1994) in the United States were as follows: BCC (men) 407485, BCC (women) 212253), SCC (men) 81-136, SCC (women) 26-59). For South Wales (United Kingdom) the age-standardized (world standard population) incidence rates per 100,000 population in 1998 were lower: BCC (men) 127.9, BCC (women) 104.8, SCC (men) 25.2, SCC (women) 8.6 (Holme et al. 2000). Although these incidence rates are high, they do not approach the rates described from Australia. The incidence is 1% to 2% per year (1000 to 2000 per 100,000 per year): Townsville, Australia (Buettner et al. 1998): BCC (male) 2058, BCC (female) 1195, SCC (male) 1332, SCC (female) 755); Nambour, Australia Green et al. 1996): BCC (male) 2074, BCC (female) 1579, SCC (male) 1035, SCC (female) 472.

There is an increased risk of NMSC in whites, especially those who have blue eyes, a fair complexion, sunburn easily, suntan poorly, freckle with sun exposure, have red, blond, or light-brown hair (Celtic ancestry). NMSC is uncommon in blacks, Asians, and Hispanics. There is a higher incidence of BCC in Albino blacks than in normally pigmented blacks. Compared with whites, blacks have a decreased risk of BCC on sun-exposed areas, but the same incidence of BCC on covered skin. In contrast to whites, sunlight does not appear to be an important etiologic factor for SCC in blacks because lesions occur on non-sun-exposed regions of the body. SCC in blacks arise most often on sites of preexisting inflammatory skin conditions, burn injuries, or trauma. SCC in blacks are often seen in scars, burns, or ulcers.

The incidence of NMSC is increasing rapidly. In white populatOnce an individual develops a NMSC, there is a 36%-52% chance that a new skin cancer will appear within 5 years.ions in Europe, the United States, Canada, and Australia the average increase of NMSC was 3-8%. Chronic sun exposure is the main cause of NMSC. Over 80% of NMSCs occur on areas of the body that are frequently exposed to sunlight, such as head, neck, and back of the hands. BCC is also most commonly found on the nose. The rising incidence rates of NMSC is probably due to a combination of increased sun exposure or exposure to ultraviolet light, increased outdoor activities, changes in clothing style, increased longevity, and ozone depletion. In incidence of NMSC in Caucasians increases proportionally with proximity to the equator, with the incidence of SCC doubling for each 8-10 degree decline in latitude. UV dosage per unit time at the equator in the Pacific is very high, about 200% that of Europe or the northern US, and 30% higher than that of the southern US. The incidence of NMSC is elevated in individuals with a high cumulative exposure to UV light, such as outdoor workers, or those with more frequent outdoor activities. The incidence is also increasing with age: According to Holme et al. (2000) in 1998 the incidence of BCC in individuals over 75 years old was approximately 5 times higher compared to individuals between 50 and 55 years old, and for SCC approximately 35 times higher. The incidence of SCC increases more rapidly with age than does BCC. The reported increases in the incidence of melanoma and NMSC have partially been attributed to a larger amount of UVB radiation reaching the surface of the earth as a result of ozone depletion in the atmosphere. The ozone layer has decreased by approximately 2% over the past 20 years. A 2% decrease in ozone concentration will increase biologically effective radiation from the sun by approximately 4%. It was estimated that this additional UV radiation will cause a 6-12% increase in NMSC in exposed populations.

Once an individual develops a NMSC, there is a 36%-52% chance that a new skin cancer will appear within 5 years.

Etiology and Pathogenesis


Several factors have been implicated in the pathogenesis
of squamous cell carcinoma (SCC) including:


Ultraviolet radiation

  • Human papillomavirus infection
  • Chronic degenerative and chronic inflammatory skin changes
    (carcinoma is more common on scars following coagulation and
    burning on sclerosed lupus vulgaris scars, and on chronic
    radiodermatitis)
  • Chemical carcinogens (continuous exposure to tars, oils and arsen)
  • Long term heat exposure
  • Genetic factors (light-skin, sun-sensitive people with fair or
    red hair, people affected by xeroderma pigmentosum or albinism,
    and patients with dyskeratosis congenita show a greater susceptibility)
  • immunosuppression (immunosuppressive treatment, patients with AIDS,
    congenital immune defects)

Yet is seems that the most important factor is exposure to ultraviolet radiation.

Squamous cell carcinoma is a tumor that may arise in any epithelium, and its behavior in the skin is essentially similar to its behavior in the respiratory tract and elsewhere. Because of the accessibility of the skin, the precancerous changes that lead to the tumor are more easily observed and followed. Potentially precancerous conditions include actinic keratoses, Bowen's disease and leukoplakia.

Squamous cell carcinoma begins when atypical keratinocytes breach the dermal basement membrane and invade the dermis. The distinction is thus architectural rather than cytological, and is based on the presence of descending strands of morphologically malignant keratinocytes.

The cells of squamous cell carcinoma vary from large, well-differentiated, polygonal cells with vesicular nuclei, through to completely anaplastic cells with basophilic cytoplasm, which provide no cytological evidence of their origin.

Most tumors invade as coherent strands and column, and reproduce the same pattern in their metastases. Many of them are composed of cells uniform in type and showing only moderate mitotic activity. They excite an inflammatory reaction in the dermis. The capillary pattern is abnormal and the number of vessels considerably increased. Increasing anaplasia is associated with hyperchromatic nuclei, decreasing eosinophilia and tonofibril formation in the cytoplasm, and lessened intercellular adhesions. The cell outlines may be rounded or spindle shaped. Mitotic figures become more frequent, and abnormal mitosis can be found.

Local extension of squamous cell carcinoma may occur around nerves, sometimes for considerable distances, and may require extensive surgery. It is unusual for squamous cell carcinoma originating in a actinic keratosis of the hand or arm to show evidence of anaplasia or to metastasize until very well advanced.

Diagnosis


A first diagnosis is made by close inspection of the clinical features of the tumor. The clinical appearance of squamous cell carcinoma is highly variable, but the indurated, opaque colored, well-differentiated SCC arising in sun-damaged skin presents few problems in diagnosis. Differentiated forms of SCC have to be distinguished from keratoakanthomas. For poorly differentiated SCC the most important clinical distinctions are between poorly differentiated carcinoma arising de novo from normal skin, inflammatory ulcers, granulomas, amelanotic melanoma, or basal cell carcinoma. Any doubt in diagnosis has to be clarified by biopsy. It is important to remember that a large portion of SCC may lie below the level of the skin, where it can ulcerate and invade surrounding tissue.

Symptoms, Signs, and Course


Squamous cell carcinoma frequently begins with a small, slightly raised warty-like thikening of the top layer of the skin and is usually of grey to yellowish-brownish color.The lesion will grow from a few millimeters to a centimeter being firm in touch and painless but then it will start growing rapidly and destructively. The destruction can attack soft tissue, bones and cartilage. Sometimes, especially in an early stage, it is hard to distinguish between a rather harmless warty lesion or squamous cell carcinoma. Therefore a closer examination through taking a tissue sample (biopsy) may be appropriate. It needs to be pointed out that squamous cell carcinoma may grow like an iceberg - hiding the biggest part underneath the skin surface. Squamous cell carcinoma in an advanced stage has the tendency to spread to other parts of the body.

Prevention and Prophylaxis


In order to prevent squamous cell carcinoma, the risk factors implicated in the pathogenesis of this tumor must be avoided. Important is:

  • Protection from UV radiation
  • Avoidance of long-term heat exposure
  • Avoidance of chemical carcinogens (e.g. tars, oils, arsen)
  • Adequate treatment of chronic degenerative and chronic inflammatory skin changes

Differential Diagnosis


Complications


A squamous cell carcinoma can cause widespread soft tissue damage with substantial disfigurement. The lesion is also prone to secondary infection and ulceration. Eventually squamous cell carcinoma can metastasize over the lymphatic system resulting in infiltration of structures and organs neighboring lymph nodes. Remote metastases are uncommon.

Treatment


There are several effective approaches to cure SCC: surgery and cryosurgery, curettage, electrodessication and radiation therapy. Each method may be more or less useful for specific clinical situations. In deciding what is best for the patient, the first goal is complete eradication of the carcinoma, and the next is preservation of form and function; the cost of treatment is a subsidiary, but not insignificant, factor. Of all treatment methods available, Mohs micrographic surgery has the highest 5-year cure rate for both primary and recurrent tumors.

Surgery
This is the treatment of choice for tumors when primary closure, a simple graft or a flap can make good the defect. The palpable margin of the tumor should be outlined before any local anaesthetic is injected, and at least 3-5 mm clearance allowed beyond it. Surgical removal is quick and the wound heals in 2 weeks. The specimen provides better material for the pathologist than a biopsy or curettings. Mohs micrographic surgery has the highest cure rate of all surgical treatments. This method uses microscopic control to evaluate the extent of tumor invasion. Surgery is also the best treatment for lesions that have invaded bone or cartilage or when lymphnode metastases have developed. It is usually employed on cases that have recurred after other treatment has been given or on sclerosing tumors with ill-defined margins.

Cryosurgery
Cryosurgery is used for clinically well defined in situ tumors and in patients with medical conditions that preclude other types of surgery. Liquid nitrogen is used to either chill a cryoprobe continuously or to spray on a surface. It allows the local destruction of tissue to quite a considerable and calculable depth. The technique is simple, it requires no local anaesthetic and complications are rare. However, the successful treatment of malignant tumors requires adequate freezing of the tumor and the margin all round it, which is not always accomplished. The cytotoxic effect of freezing and thawing can be enhanced if the tumor is refrozen once or twice. Collagen, cartilage and bone are less sensitive than dermal cells to injury by freezing.

Curettage and electrodessication
Treatment by curettage and cauterization or diathermy is a quick method for destroying the tumor, but the adequacy of treatment cannot be assessed immediately since the surgeon cannot visually detect the depth of microscopic tumor invasion. These methods should be reserved for very small primary tumors.

Radiotherapy
Radiotherapy is particularly indicated for poorly differentiated squamous cell carcinoma that has not spread to bone or cartilage, nor metastasized. Its main use is in tumors of the head and neck.This treatment leaves rather fragile scars on the hand and forearm, and it may be followed by radionecrosis on the trunk. It is usually preferred by very elderly patients (who form a considerable proportion of cases). The quality of the scar following superficial X-ray therapy depends, to a considerable extent, upon the number of doses into which the total treatment dose is divided and the time taken to complete the treatment. In many centres, a total dose of 5000cGy is given in 10 doses over a period of 2 weeks. Large lesions, especially when situated on the trunk, require more protracted treatment, lasting for tip to 6 weeks. In a number of situations, especially where a curved area has to be treated, radium or radioactive cobalt applied as a surface mould gives excellent results. Interstitial radiation from radium needles, gold grain or iridium wire is a convenient and effective way of treating mobile areas, such as the lip and tongue, or curved surfaces. Electron-beam therapy can be used in areas, such as over nasal cartilage, where conventional radiation might result in radionecrosis. The planning of radiotherapy requires cooperation between the clinician and the physicist.

Carbon dioxide laser
This method may be helpful in the management of selected squamous cell carcinoma in situ. It may be considered when a bleeding diathesis is present, since bleeding is unusual when this laser is used.

Interferon alfa
Clinical trials are ongoing regarding the curative effects of intralesionally applied interferon alfa in squamous cell carcinoma. The results should be available in several years.

Treatment of lesions at special sites
The dorsum of the hand should not be treated by radiotherapy. Most tumors in this area are quite small, and curettage or excision gives good results.

The lip may be treated by any of the methods. Extensive superficial lesions are suitable for lipshave or curettage and cautery; radiotherapy of a large area leaves considerable scarring, and surgical excision calls for plastic repair. Smaller tumors may be excised by wedge excision, which is a relatively simple operation but leaves the lip shorter and thus changes the shape of the mouth. Poorly differentiated and invasive tumors of the lip should be irradiated unless they invade the mandible, when an extensive surgical removal is required.

The face can be treated by any of the methods according to the general considerations already mentioned.

Small tumors of the ear not involving the cartilage can be treated by any of the techniques. Involvement of cartilage is an indication for surgery, and lesions on the helix can be excised with a wedge of cartilage. If it is important to preserve the symmetry of the ears, a wedge from the other ear of up to 1cm in length at the helix can be used as a free graft.

Prognosis


The prognosis of squamous cell carcinoma depends on the localization, size, the degree of differentiation of the tumor and other risk factors such as immunosuppression. The risk of metastasis varies from less than 1% to up to almost 50%. High-risk sites are any chronic wound (leg ulcers etc.), lip, ear, palm/sole, and perineum. Lesions on chronically sun-exposed skin have lower risk. Carcinomas of the skin up to a size of 2 - 3 cm can be cured in about 90% of cases, but the prognosis becomes poorer with increasing size. More differentiated tumors display less tendency to metastasis.



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