Squamous Carcinoma of the Eyelid
Squamous Cell Carcinoma of the Eyelid
- 1 Disease Entity
- 2 Diagnosis
- 3 Management
- 4 Additional Resources
- 5 References
Diagnosis Code from ICD-10 Version 2017 : C44.329
Short Description: Squamous cell carcinoma of skin of other parts of face
Squamous cell carcinoma (pronounced: ˈskwāməs sel ˌkärsəˈnōmə and abbreviated to SCC), is a type of invasive malignancy arising from the squamous cell layer of the skin epithelium . It can be found on various organs and locations, such as : anus, cervix, head/neck, vagina, esophagus, urinary bladder, prostate, and lungs. In the eyes is it affects specially the conjunctival membrane, the cornea and the lid´s skin. It is the second most common malignant eyelid tumor and it represents around 5% of malignancies in the palpebral area. It may develop de novo but often it may arise from preexisting lesions such as actinic keratosis, xeroderma pigmentosum, carcinoma in situ (Bowen's disease), or following radiotherapy.
The SCC has multifactorial etiology among its risks factors are: ageing , chronic Ultra Violet (UV) exposure, oil derivates and arsenic exposure , cigarrette smoke exposure, Human Papilloma Virus infection (HPV), Human Immunodeficiency Virus infection (HIV), xeroderma pigmentosum, albinism, old burns, chronic ulcers and immunosupression.
Approximately 5% to 10% of all skin cancers occur in the eyelid and SCC represents 5 -10% of all types of skin cancer in the eyelids. The incidence for eyelid SCC has been reported to be between 0.09 and 2.42 cases per 100 000 population with higher prevalence in males , in the lower lid, specially at the inner canthus and in countries with high UV light exposure .
Longitudinal studies in the USA and Canada showed that the age-adjusted incidence of SCC has grown by 50% to 200% over the last decades .24The mean age of eyelid SCC diagnosis is around the 7th and 8th decade of life .
Orbital invasion has been reported to occur in up to 5.9% of all non melanoma malignant eyelid carcinomas. And, reported rates of metastasis for eyelid SCC vary from 1–21%. with the rate of 21.4% occurring in a small serie of patients, many years ago, which probably does not correspond to the true current metastasis rate. Rates for cutaneous SCC are better defined, and reported at 0.3–3.7%.
It is important to quote that cutaneous squamous cell carcinoma (cSCC) is the most common malignancy after solid organ transplantation, with a five-year incidence of 30% in lung transplant recipients and up to 26% in heart transplant recipients . The risk of developing an squamous carcinoma varies according with the type of transplant. Heart and lungs transplants have a higher risk than renal transplant , regard the drugs used to avoid cardiac and pulmonary rejection leads to a greater imunossupression. The time after the transplantation is also important. The longer the time since the transplantation, the greater the risk of developing SCC.
Clinical and pathophysiological features
SCC typically manifests as a spectrum of progressively advanced malignancies, ranging from a precursor actinic keratosis (AK) to squamous cell carcinoma (SCC) in situ (SCCIS), invasive cSCC, and finally metastatic SCC. It is classified as in situ when it is anterior to the basal membrane and it is considered invasive when it extends through the basal membrane layer of the skin. It is also possible to find in the literature others types of skin lesions classified as SCC variants, such as kerathoacantoma and cutaneous horn.
A full thickness biopsy is the gold standard to diagnose SCC as it can determine the depth of invasion and extent of invasion of the cancer. Patients with regional lymph node alterations should undergo Fine Needle Aspiration (FNA) biopsy to determine if cancer cells have spread to these nodes.
In situ carcinoma
In situ carcinoma is the term for epithelial lesions in which cells have cytological abnormalities characteristics of malignancy (hyperchromatism, pleomorphism, mitoses) and loss of the architecture, but without evidence of local invasion or distant metastases. In the skin, the squamous cell carcinoma is known as Bowen's disease. It appears as a persistent brown/red spot, which may be confused with psoriasis or eczema. There is a strong association of Bowen's disease with HPV (human papilloma virus) infection, mainly type 16.
A cutaneous horn (CH) is a lesion with a papular or nodular base and a keratotic cap of various shapes and lengths resembling an animal horn. Usually , it represents hypertrophic solar keratoses. Clinically, CHs vary in size from a few millimeters to several centimeters. The horn may be white, black, or yellowish ; straight, curved, or spiral in shape. Histologically, there is usually hypertrophic actinic keratosis, SCC in situ, or invasive SCC at the base. Because of the possibility of invasive SCC, a CH should always be excised.
Actinic keratosis are the most common precancerous skin lesions, affecting about 60% of fair-skinned people over the 4th decade of life. Actinic keratosis (AK) appear as hyperkeratotic lesions. In general, they are round or oval, commonly present in sunlight exposed skin areas and may or may not have an erythematous base. AK is a direct precursor of invasive squamous cell carcinoma and a risk factor for other skin cancers. Although progression to invasive malignancy is rare, actinic keratoses are squamous cell carcinomas in situ. The main histological feature of actinic keratosis is dysplasia of keratinocytes , or disordered maturation of these cells.
This type of lesion, shown in the figure 1, has recently been considered as a variant of SCC, but there is still a long-standing debate as to whether those lesions are benign reactive lesions or a variant of SCC. Keratoacantoma lesion is typically a cup-shaped nodule with a central keratin crater and elevated, rolled margins. It usually develops over a short period of weeks to a few months and may regress spontaneously. Histopathologically, these dome shaped lesions have thickened epidermis containing islands of well-differentiated squamous epithelium that may be infiltrated by neutrophils surrounding a central mass of keratin. The lesion base is often well-demarcated from the adjacent dermis by inflammatory reaction.
Squamous cell carcinoma
The clinical types of carcinoma are variable and there are no pathognomonic characteristics. The tumor may be clinically indistinguishable from a basal cell carcinoma(BCC), but usually it does not have superficial vascularization, it grows more rapidly and hyperkeratosis is more frequent. The nodular SCC is characterized by a hyperkeratotic nodule that may develop with the presence of crusts and fissures. The ulcerating SCC (Figure 2) has a red base with well defined, hardened and everted edges, but the pearly margins and telagectasia are not present as in BCC. The histopathologic feature of SCC depends on the degree of differentiation of the tumor. In well-differentiated tumors, the cells are polygonal with abundant acidophilic cytoplasm and hyperchromatic nuclei with various size and staining properties, dyskeratotic cells, and intercellular bridges. Poorly differentiated SCC shows pleomorphism with anaplastic cells, abnormal mitotic figures, little or no evidence of keratinization, and loss of intercellular bridges. Variants of SCC are spindle and adenoid SCC.
Mutations induced by UVB exposure can perturb multiple cellular pathways which contributes to the formation of cSCC. This type of cancer exhibits impaired genomic maintenance leading to the acquisition of new mutations . The mechanism of genomic instability in keratinocytes likely results from UVB-induced inactivation of p53. The cronological order usully comphends the following hystological alterations: Hyperplasia/hiperkeratosis , leading to a mild to moderate dysplasia up to a severe dysplasia or in situ carcinoma, culminating with the invasive Squamous Cell Carcinoma.
A clinical, histologic, and molecular comparison of AKs, cSCC, and metastatic cSCC is shown in the figure 3, below,
Adapted from Ratushny, V., Gober, M. D., Hick, R., Ridky, T. W., & Seykora, J. T. (2012). From keratinocyte to cancer: the pathogenesis and modeling of cutaneous squamous cell carcinoma. The Journal of Clinical Investigation, 122(2), 464–47, Courtesy by: Patricia Lyra M.D. , MSc - Federal University of Espirito Santo, Brazil.
Acording with the American Joint Committee on Cancer TNM Staging 7th edition, the SCC can be staged as it is shown bellow in the figure 4 : 
T stands for the primary tumor its size, location, and invasion level
N stands for nearby lymph nodes invasion
M is for metastasis
The cancer’s grade is a predictor of cancer dissemination, the lower the tumor’s grade, the better the prognosis.
|GX||the tumor grade cannot be identified.|
|G1||well differentiated cells|
|G2||moderately differentiated cells|
|G3||poorly differentiated cells.|
Cancer stage grouping
The stage of an eyelid SCC is given by combining the T, N, M, and G classifications, as shown bellow:
|Stage 0||Carcinoma in situ (Tis, N0, M0).|
|Stage IA||The tumor is 5 mm or smaller in diameter or has not invaded the tarsal plate , there is no metastasis to regional lymph nodes or to other areas in the body (T1, N0, M0).|
|Stage IB||The tumor is larger than 5 mm but not more than 10 mm in greatest diameter, or it has invaded the tarsal plate. there is no metastasis to regional lymph nodes or to other areas in the body (T2a, N0, M0).|
|Stage IC||The tumor is between 10 mm and 20 mm in greatest diameter or has spread into the full thickness of the eyelid, but there is no metastasis to regional lymph nodes or to other areas in the body (T2b, N0, M0).|
|Stage II||The tumor is larger than 20 mm in greatest diameter or has spread to nearby parts of the eye, but it has not spread to the regional lymph nodes or to other areas of the body. (T3a, N0, M0).|
|Stage IIIA||The tumor is large enough or has spread enough so that the surgeon will need to remove the eye and nearby structures to get rid of the tumor, but it has not spread to the regional lymph nodes or to other areas of the body (T3b, N0, M0).|
|Stage IIIB||The tumor is of any size and has metastasized to the regional lymph nodes, but not to other areas of the body (any T, N1, M0).|
|Stage IIIC||The tumor has spread outside of the eye, with or without spread to the regional lymph nodes, and cannot be surgically removed due to extensive invasion in structures near the eye. The tumor has not metastasized to distant parts of the body (T4, any N, M0).|
|Stage IV||A tumor of any size has metastasized outside of the eye to distant areas of the body (any T, any N, M1).|
|Recurrent||Recurrent cancer after treatment. It may reoccur in the eye or another part of the body.|
Surgical excision is the treatment of choice for SCC, sometimes it is even necessary an extense surgical approach with autograph and flap as demonstrated in the figures 5, 6 and 7.  Published reports regarding the treatment of non melanocytic malignant eyelid tumors shows that strongest evidence favors complete surgical removal using histologic controls for verifying tumor-free margins of excision, in techniques such as Mohs’ micrographic surgery or excision with frozen-section control.  Supplemental cryotherapy, topical chemotherapy and irradiation should be applied if the tumour margin is unclear or if there is residual involvement of bulbar conjunctiva . Sometimes, a single or double-layered technique of suture for closure of full-thickness eyelid defects following pentagonal block excision is also need.
Cryotherapy uses liquid nitrogen in low temperatures to destroy the SCC tissue structure. It is only suitable for those with selected in situ squamous cell carcinomas (SCCISs) and actinic keratoses and is not suitable for invasive cancers.
It is a safe and low-cost procedure and is very useful in patients with bleeding disorders, those who refuse surgery/ poor surgical candidates, or in patients whereby surgery is contraindicated. The 5 year survival rate for superficial early stage SCC in situ can be as high as 95%. The side effects include transient localized pain, swelling, pigmentation changes, loss of hair over hair-bearing areas and blistering.
In photodynamic therapy, a photosensitizing drug, light, and oxygen are used to induce targeted cell death though apoptosis of cancerous or abnormal tissue. It is suitable for SCC in situ and actinic keratosis. There may be a higher rate of recurrence with this method as compared with surgical excision.
Radiation therapy as the only mode of therapy is only reserved for patients who have high clinical risk for surgery. Radiation therapy is usually used as an adjunct therapy for patients post-surgery who have a disease which has spread to nerves/lymph nodes or cancer with poorly defined margins. Treatment is usually given 3-5 times a week for about 1-2 months.
The side effects include localized hyperemia, erosions, alopecia , localized pain, skin atrophy, pigmentation changes and telangiectasia in the radiation site.
Topical imiquimod is an immune modulator that is approved to treat genital warts, actinic keratosis, Bowen disease and superficial SCC. It should be applied 3 times per week for 4-6 weeks. Localized side effects include increased redness, swelling, and erosions or ulcerations. If applied over large areas, it may cause flu-like symptoms. Topical chemotherapy agent like 5-fluorouracil has been used for the treatment of actinic keratosis and SCC in situ . It should be applied daily for about a month. It can cause skin irritation and hyperemia over the application area.
Systemic chemotherapy is used for advance SCC that has metastasized to other sites of the body..
Follow up and prognosis
SCC and can spread to the orbit, lymph nodes or other organs and is more aggressive than BCC. But if SCC of the eyelid is detected early and is completely removed, the prognosis is good.  If malignant orbital invasion is diagnosed, it is appropriate to collaborate with a multidisciplinary team in planning management. An oncologist should be involved and also other disciplines according to the extent and direction of tumor invasion. In general, sunscreens should be used and sun exposure should be reduced. Alcohol and tobacco use should be discouraged. Follow up appointments varies according to each case. Any recurrence should be treated aggressively
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