Squamous-cell carcinoma

Squamous cell carcinoma, NOS
Classification and external resources
SCC of the skin tends to arise from pre-malignant lesions, actinic keratoses; surface is usually scaly and often ulcerates (as shown here).
ICD-10	C44
ICD-9	199
ICD-O:	M8070/3
MedlinePlus	000829
eMedicine	derm/401
MeSH	D002294

Squamous-cell carcinoma (SCC or SqCC) is a cancer of a kind of epithelial cell, the squamous cell. These cells are the main part of the epidermis of the skin, and this cancer is one of the major forms of skin cancer. However, squamous cells also occur in the lining of the digestive tract, lungs, and other areas of the body, and SCC occurs as a form of cancer in diverse tissues, including the lips, mouth, esophagus, urinary bladder, prostate, lung, vagina, and cervix, among others. Despite sharing the name squamous cell carcinoma, the SCCs of different body sites can show tremendous differences in their presenting symptoms, natural history, prognosis, and response to treatment.

SCC is a histologically distinct form of cancer. It arises from the uncontrolled multiplication of cells of epithelium, or cells showing particular cytological or tissue architectural characteristics of squamous cell differentiation, such as the presence of keratin, tonofilament bundles, or desmosomes, structures involved in cell-to-cell adhesion.

SCC is still sometimes referred to as "epidermoid carcinoma" and "squamous cell epithelioma", though the use of these terms has decreased.

Classification

Cancer can be considered a very large and exceptionally heterogeneous family of malignant diseases, with squamous cell carcinomas comprising one of the largest subsets.^[2][3][4] All squamous cell carcinoma lesions are thought to begin via the repeated, uncontrolled division of cancer stem cells of epithelial lineage or characteristics. Squamous-cell carcinomas arise from squamous cells, which are flat cells that line many areas of the body.^{[citation needed]} Accumulation of these cancer cells causes a microscopic focus of abnormal cells that are, at least initially, locally confined within the specific tissue in which the progenitor cell resided. This condition is called squamous cell carcinoma in situ, and it is diagnosed when the tumor has not yet penetrated the basement membrane or other delimiting structure to invade adjacent tissues. Once the lesion has grown and progressed to the point where it has breached, penetrated, and infiltrated adjacent structures, it is referred to as "invasive" squamous cell carcinoma. Once a carcinoma becomes invasive, it is able to spread to other organs and cause a metastasis, or "secondary tumor", to form.

Tissue of origin

The International Classification of Diseases for Oncology (ICD-O) system lists a number of morphological subtypes and variants of malignant squamous cell neoplasms, including:^[5]

• Papillary thyroid carcinoma (Code 8050/3)
• Verrucous squamous cell carcinoma (Code 8051/3)
• Papillary squamous cell carcinoma (Code 8052/3)
• Squamous cell carcinoma (Code 8070/3)
• Large cell keratinizing squamous cell carcinoma (Code 8071/3)
• Large cell nonkeratinizing squamous cell carcinoma (Code 8072/3)
• Small cell keratinizing squamous cell carcinoma (Code 8073/3)
• Spindle cell squamous cell carcinoma (Code 8074/3)
• Adenoid/pseudoglandular squamous cell carcinoma (Code 8075/3)
• Intraepidermal squamous cell carcinoma (Code 8081/3)
• Lymphoepithelial carcinoma (Code 8082/3)

Other variants of squamous cell carcinoma are recognized under other systems, such as:

• Keratoacanthoma

Morphology

• Basal cell carcinoma
• Bowen's disease is a sunlight-induced skin disease, and is considered to be an early form of squamous cell carcinoma.
• Erythroplasia of Queyrat
• Keratoacanthoma is a low-grade malignancy of the skin. It originates in the pilo-sebaceous glands, and is similar in clinical presentation and microscopic analysis to squamous cell carcinoma, except that it contains a central keratin plug. Statistically, it is less likely to become invasive than squamous cell carcinoma.
• Marjolin's ulcer is a type of squamous cell carcinoma that arises from a non-healing ulcer or burn wound.

Microscopic appearance

One method of classifying squamous cell carcinomas is by their appearance under microscope. Subtypes may include:

• Adenoid squamous-cell carcinoma' (also known as "Pseudoglandular squamous-cell carcinoma"), characterized by a tubular microscopic pattern and keratinocyte acantholysis.^[6]:743
• Basaloid squamous-cell carcinoma is characterized by a predilection for the tongue base.^[6]:743
• Clear-cell squamous-cell carcinoma (also known as "Clear-cell carcinoma of the skin") is characterized by keratinocytes that appear clear as a result of hydropic swelling.^[6]:743
• Signet ring cell squamous cell carcinoma (occasionally rendered as "signet-ring-cell squamous-cell carcinoma") is a histological variant characterized by concentric rings composed of keratin and large vacuoles corresponding to markedly dilated endoplasmic reticulum.^[6]:743 These vacuoles grow to such an extent that they radically displace the cell nucleus toward the cell membrane, giving the cell a distinctive superficial resemblance to a "signet ring" when viewed under a microscope.
• Spindle-cell squamous-cell carcinoma (also known as "Spindle-cell carcinoma"^[7]) is a subtype characterized by spindle-shaped atypical cells.^[6]:743

• 

  Adenoid squamous-cell carcinoma

• 

  Basaloid squamous-cell carcinoma

• 

  Clear-cell squamous-cell carcinoma

• 

  Spindle cell squamous cell carcinoma

Signs and symptoms

Symptoms are highly variable depending on the involved organs.

SCC of the skin begins as a small nodule and as it enlarges the center becomes necrotic and sloughs and the nodule turns into an ulcer.

• The lesion caused by SCC is often asymptomatic
• Ulcer or reddish skin plaque that is slow growing
• Intermittent bleeding from the tumor, especially on the lip
• The clinical appearance is highly variable
• Usually the tumor presents as an ulcerated lesion with hard, raised edges
• The tumor may be in the form of a hard plaque or a papule, often with an opalescent quality, with tiny blood vessels
• The tumor can lie below the level of the surrounding skin, and eventually ulcerates and invades the underlying tissue
• The tumor commonly presents on sun-exposed areas (e.g. back of the hand, scalp, lip, and superior surface of pinna)
• On the lip, the tumor forms a small ulcer, which fails to heal and bleeds intermittently
• Evidence of chronic skin photodamage, such as multiple actinic keratoses (solar keratoses)
• The tumor grows relatively slowly
• Unlike basal cell carcinoma (BCC), squamous cell carcinoma (SCC) has a substantial risk of metastasis
• Risk of metastasis is higher in SCC arising in scars, on the lower lips or mucosa, and occurring in immunosuppressed patients.

About one-third of lingual and mucosal tumors metastasize before diagnosis (these are often related to tobacco and alcohol use)

Causes

Human papilloma virus

Human papilloma virus (HPV) has been associated with SCC of the oropharynx, lung,^[8] fingers,^[9] and anogenital region.

By region

Skin

Squamous cell carcinoma is the second-most common cancer of the skin (after basal cell carcinoma but more common than melanoma). It usually occurs in areas exposed to the sun. Sunlight exposure and immunosuppression are risk factors for SCC of the skin, with chronic sun exposure being the strongest environmental risk factor.^[10] There is a risk of metastasis starting more than 10 years^{[citation needed]} after diagnosable appearance of squamous cell carcinoma, but the risk is low, though much higher than with basal cell carcinoma. Squamous cell cancers of the lip and ears have high rates of local recurrence and distant metastasis (20–50%).^[11] Squamous cell cancers of the skin in individuals on immunotherapy or suffering from lymphoproliferative disorders (i.e. leukemia) tend to be much more aggressive, regardless of their location.^[12]

SCCs represent about 20% of the non-melanoma skin cancers, but due to their more obvious nature and growth rates, they represent 90% of all head and neck cancers that are initially presented.^[13] The vast majority of SCCs are those of the skin, and like all skin cancers, are the result of ultraviolet exposure. SCCs usually occur on portions of the body commonly exposed to the Sun; the face, ears, neck, hands, or arm. The main symptom is a growing bump that may have a rough, scaly surface and flat reddish patches. Unlike basal cell carcinomas, SCCs carry a significant risk of metastasis, often spreading to the lymph nodes,^[14] and are thus more dangerous. During its earliest stages, it is sometimes known as Bowen's disease.

Saree cancer may occur along the waist in females wearing saree, and caused by constant irritation which can result in scaling or pigmentation. It is a rare type of cancer and generally found in the Indian subcontinent where saree is a lifetime costume worn by the female.^[15][16]

Squamous cell carcinoma are generally treated by surgical excision or Mohs surgery. Non-surgical options for the treatment of cutaneous SCC include topical chemotherapy, topical immune response modifiers, photodynamic therapy (PDT), radiotherapy, and systemic chemotherapy. The use of topical therapy, such as Imiquimod cream and PDT is generally limited to premalignant (i.e., AKs) and in situ lesions. Radiation therapy is a primary treatment option for patients in whom surgery is not feasible and is an adjuvant therapy for those with metastatic or high-risk cutaneous SCC. At this time, systemic chemotherapy is used exclusively for patients with metastatic disease.^{[citation needed]}

Head and neck cancer

Biopsy of a highly differentiated squamous cell carcinoma of the mouth. Haematoxylin & eosin stain.

Ninety percent ^[17] of cases of head and neck cancer (cancer of the mouth, nasal cavity, nasopharynx, throat and associated structures) are due to squamous cell carcinoma. Symptoms may include a poorly healing mouth ulcer, a hoarse voice or other persistent problems in the area. Treatment is usually with surgery (which may be extensive) and radiotherapy. Risk factors include smoking, alcohol consumption and hematopoietic stem cell transplantation.^[18] In addition, recent studies show that about 25% of mouth and 35% of throat cancers are associated with HPV. The 5 year disease free survival rate for HPV positive cancer is significantly higher when appropriately treated with surgery, radiation and chemotherapy as compared to non-HPV positive cancer, substantiated by multiple studies including research conducted by Dr. Maura Gillison, et al. of Johns Hopkins Sidney Kimmel Cancer Center.

Thyroid

Primary Squamous cell thyroid carcinoma shows an aggressive biological phenotype resulting in poor prognosis for patients.^[19]

Oesophagus

Oesophageal cancer may be due to either squamous cell carcinoma (ESCC) or adenocarcinoma (EAC). SCCs tend to occur closer to the mouth, while adenocarcinomas occur closer to the stomach. Dysphagia (difficulty swallowing, solids worse than liquids) and odynophagia are common initial symptoms. If the disease is localized, esophagectomy may offer the possibility of a cure. If the disease has spread, chemotherapy and radiotherapy are commonly used. Zinc deficiency is also implicated in the pathogenesis of ESCC in many populations,^[20] including persons with chronic alcohol consumption.^[21] Abnet et al.^[21] provided the strongest evidence of an association between dietary zinc deficiency and ESCC in a high-incidence area by establishing an inverse relationship between zinc concentration in biopsy samples and the subsequent risk of developing ESCC. In a rat model, chronic zinc deficiency induces an inflammatory gene signature that fuels ESCC development.^[22][23]

Lung

Photograph of a squamous cell carcinoma. Tumour is on the left, obstructing the bronchus (lung). Beyond the tumour, the bronchus is inflamed and contains mucus.

When associated with the lung, it is typically a centrally located large cell cancer (non-small cell lung cancer or NSCLC) that often has a paraneoplastic syndrome causing ectopic production of parathyroid hormone-related protein (PTHrP), resulting in hypercalcemia. It is primarily due to smoking.^[24]

Penile Genitalia

When squamous cell carcinoma in situ (Bowen's disease) is found on the penis, it is called erythroplasia of Queyrat.^[25] This type of cancer responds very well to imiquimod^{[citation needed]}.

Prostate

When associated with the prostate, squamous cell carcinoma is very aggressive in nature. It is difficult to detect as there is no increase in prostate specific antigen levels seen; meaning that the cancer is often diagnosed at an advanced stage.

Vagina and cervix

Vaginal squamous cell carcinoma spreads slowly and usually stays near the vagina, but may spread to the lungs and liver. This is the most common type of vaginal cancer.

Bladder

Most bladder cancer is transitional cell, but bladder cancer associated with Schistosomiasis is often squamous cell carcinoma.

Diagnosis

Diagnosis is via a biopsy. For the skin, look under skin biopsy.

The pathological appearance of a squamous cell cancer varies with the depth of the biopsy. For that reason, a biopsy including the subcutaneous tissue and basalar epithelium, to the surface is necessary for correct diagnosis. The performance of a shave biopsy (see skin biopsy) might not acquire enough information for a diagnosis. An inadequate biopsy might be read as actinic keratosis with follicular involvement. A deeper biopsy down to the dermis or subcutaneous tissue might reveal the true cancer. An excision biopsy is ideal, but not practical in most cases. An incisional or punch biopsy is preferred. A shave biopsy is least ideal, especially if only the superficial portion is acquired.

Prevention

Appropriate clothing, sunscreen with at least SPF 30, and avoidance of intense sun exposure may prevent skin cancer.^[26]

Management

Most squamous cell carcinomas are removed with surgery. A few selected cases are treated with topical medication. Surgical excision with a free margin of healthy tissue is a frequent treatment modality. Radiotherapy, given as external beam radiotherapy or as brachytherapy (internal radiotherapy), can also be used to treat squamous cell carcinomas.

Mohs surgery is frequently utilized; considered the treatment of choice for squamous cell carcinoma of the skin, physicians have also utilized the method for the treatment of squamous cell carcinoma of the mouth, throat, and neck.^[27] An equivalent method of the CCPDMA standards can be utilized by a pathologist in the absence of a Mohs-trained physician. Radiation therapy is often used afterward in high risk cancer or patient types.

Electrodesiccation and curettage or EDC can be done on selected squamous cell carcinoma of the skin. In areas where SCC's are known to be non-aggressive, and where the patient is not immunosuppressed, EDC can be performed with good to adequate cure rate.

Nodal spread:

1) Surgical block dissection- if palpable nodes or in cases of Marjolin's ulcers but the benefit of prophylactic block lymph node dissection with Marjolin's ulcers is not proven.

2) Radiotherapy.

(Manoj Ramachandran, Marc A Gladman; Clinical cases and OSCES in Surgery- 2nd ed; churchil livingstone)

Imiquimod (Aldara) has been used with success for squamous cell carcinoma in situ of the skin and the penis, but the morbidity and discomfort of the treatment is severe. An advantage is the cosmetic result: after treatment, the skin resembles normal skin without the usual scarring and morbidity associated with standard excision. Imiquimod is not FDA-approved for any squamous cell carcinoma.

In 2007, Australian biopharmaceutical company Clinuvel Pharmaceuticals Limited began clinical trials with an experimental treatment, a melanocyte-stimulating hormone called afamelanotide (formerly CUV1647)^[28] to provide photoprotection for organ transplant patients against squamous cell carcinoma of the skin and actinic keratosis.^[29][30]

The Nigro protocol has been recommended as one approach to treatment of lesions less than 5 cm.

Prognosis

The long-term outcome of Squamous-cell carcinomas is dependent primarily upon several factors: the sub-type of the carcinoma, available treatments, location(s) and severity, and various patient health related variables (accompanying diseases, age, etc.). Generally, the long-term outcome is positive, as less than 4% of Squamous-cell carcinoma cases are at risk of metastasis (and hence life-threatening).^[31][32] Some particular forms of squamous-cell carcinomas have a higher, though still positive long-term outcome. One study found squamous-cell carcinoma of the penis had a much greater rate of mortality than some other forms of squamous-cell carcinoma, at a rate of 23%,^[33] though relatively high mortality rate may be associated with possibly latent diagnosis of the disease due to patients avoiding genital exams until the symptoms are debilitating, or a refusal on the part of the patient to submit to a possibly scarring operation upon their genitalia.

Squamous-cell carcinomas of the head and neck have been found to have a greater risk of metastatis to the lymphatic system, and hence possibly reducing treatment efficacy.^[34]

Carcinomas of the esophagus was found in one study to have a mean 58% rate of metastasis to local lymph nodes, with the number of lymph nodes compromised decreasing the survival rate.^[35] On average, the study found that in cases of lymphatic metastatis, the mean 5-year survival rate was 49.5%, with a negative decrease for every lymph node compromised.

Epidemiology

Age-standardized death from melanoma and other skin cancers per 100,000 inhabitants in 2004.^[1]

  no data

  less than 0.7

  0.7–1.4

  1.4–2.1

  2.1–2.8

  2.8–3.5

  3.5–4.2

  4.2–4.9

  4.9–5.6

  5.6–6.3

  6.3–7

  7–7.7

  more than 7.7

Incidence of squamous cell carcinoma varies with age, gender, race, geography, and genetics. The incidence of SCC increases with age and the peak incidence is usually around 66 years old. Males are affected with SCC at a ratio of 2:1 in comparison to females. Caucasians are more likely to be affected, especially those with fair Celtic skin, if chronically exposed to UV radiation. There are also a few rare congenital diseases predisposed to cutaneous malignancy. In certain geographic locations, exposure to arsenic in well water or from industrial sources may significantly increase the risk of SCC.^[10]

See also

• List of cutaneous conditions associated with increased risk of nonmelanoma skin cancer

References

External links

Wikimedia Commons has media related to Squamous-cell carcinoma.

• Information on Squamous Cell Carcinoma from The Skin Cancer Foundation
• DermNet NZ: Squamous cell carcinoma
• Squamous cell carcinoma in transplant recipients
• Including TCC, CIS and papillary tumour SCC
• Cancer Management Handbook: Head and Neck Tumors