Squamous Carcinoma of the Eyelid

From EyeWiki


Squamous Cell Carcinoma of the Eyelid


Disease Entity[edit | edit source]

Diagnosis Code from ICD-10 Version 2017 : C44.329

Short Description: Squamous cell carcinoma of skin of other parts of face

Definition[edit | edit source]

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 [1]. 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.[2] 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.

Etiology[edit | edit source]

The SCC has multifactorial ethiology[3] among its risks factors are: ageing [4], chronic Ultra Violet (UV) exposure[5], oil derivates and arsenic exposure , cigarrette smoke exposure, Human Papilloma Virus infection (HPV), Human Imunodeficiency Virus infection (HIV), xeroderma pigmentosum,albinism, old burns, cronic ulcers and imunosupression.

Epidemiology[edit | edit source]

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. [6]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 .[7]

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 [8].24The mean age of eyelid SCC diagnosis is around the 7th and 8th decade of life .[9]

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%.[10] 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%.[11]

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 [12][13]. 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 [14], regard the drugs used to avoid cardiac and pulmonary rejection leads to a greater imunossupression[15][16]. The time after the transplantation is also important. The longer the time since the transplantation, the greater the risk of developing SCC.[17]


Diagnose, clinical and pathophysiological features[edit | edit source]

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
[edit | edit source]

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[18].


Cutaneus horn
[edit | edit source]

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
[edit | edit source]

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.

Figure 1. Keratoacanthoma in the right upper eyelidImage Courtesy by: Patricia Henriques Lyra Frasson M.D. , MSc - Federal University of Espirito Santo, Brazil.


Keratoacanthoma
[edit | edit source]

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[19]. 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[edit | edit source]

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[20].

Figure 2. A caucasian patient with Actinic Keratosis and an SCC suggestive lesion between the lower lid and the malar area

Courtesy by: Patricia Henriques Lyra Frasson M.D. , MSc - Federal University of Espirito Santo, Brazil.

Pathophysiology[edit | edit source]

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[21] . The mechanism of genomic instability in keratinocytes likely results from UVB-induced inactivation of p53[22]. 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, bellow,

Figure 3.A clinical, histologic, and molecular comparison of AKs, cSCC, and metastatic cSCC 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  Images kindly lent by Patricia Henriques Lyra Frasson M.D. , MSc - Federal University of Espirito Santo

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 Investigation122(2), 464–47, Courtesy by: Patricia Lyra M.D. , MSc - Federal University of Espirito Santo, Brazil.

Staging[edit | edit source]

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 : [23]


T stands for the primary tumor its size, location, and invasion level

N stands for nearby lymph nodes invasion

M is for metastasis

Figure 4. Cutaneous SCC staging according with the 7th edition of AJCC staging manual


Grade[edit | edit source]

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.

G4: undifferentiated cells.


Cancer stage grouping[edit | edit source]

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 methastasis 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 methastasis 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 methastasis 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 retucurs in the eye or another part of the body.


Treatment[edit | edit source]

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 fugures 5, 6 and 7. [24] 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. [25] Supplemental cryotherapy, topical chemotherapy and irradiation should be applied if the tumour margin is unclear or if there is residual involvement of bulbar conjunctiva .[26] Sometimes, a single or double-layered technique of suture for closure of full-thickness eyelid defects following pentagonal block excision is also need.[27]


Figure 5. An ulcerated and extense SCC in the lower lid before the surgical aproach

Courtesy by : Patricia Henriques Lyra Frasson M.D. , MSc

Figure 6.Lower eyelid SCC approached by skin autograft and conjuntival tarsal flap. 

Courtesy by : Patricia Henriques Lyra Frasson M.D. , MSc

Figure 7. Late post operative result of an skin autograft associated to a conjunctival tarsal flap on the right lower eyelid.

Courtesy by : Patricia Henriques Lyra Frasson M.D. , MSc


Cryotherapy
[edit | edit source]

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.[28]

Photodynamic therapy[edit | edit source]

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[edit | edit source]

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 treatment[edit | edit source]

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.

Chemotherapy[edit | edit source]

Systemic chemotherapy is used for advance SCC that has metastasized to other sites of the body..


Follow up and prognosis[edit | edit source]

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. [29] 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


References[edit | edit source]

1. Asproudis I, Sotiropoulos G, Gartzios C, Raggos V, Papoudou-Bai A, Ntountas I, Katsanos A, Tatsioni A. Eyelid tumors at the University Eye Clinic of Ioannina, Greece: A 30-year retrospective study. Middle East Afr J Ophthalmol 2015;22:230-2

2. Font RL. Ophthalmic Pathology. An Atlas and Textbook. 3rd ed. Philadelphia: WB Saunders; 1996. Eyelids and lacrimal drainage system; pp. 2229–32. (estatistica)

3. Basti S, Macsai MS. Ocular surface squamous neoplasia: a review. Cornea. 2003;22(7): 687-704.

4. Bessa HJ, Potting MH, Bomfim MG. Neoplasias conjuntivais. Rev Bras Oftalmol. 1997; 56(10):765-7. .

5.Palazzi MA, Erwenne CM, Villa LL. Detection of human papillomavirus in epithelial lesions of the conjunctiva. São Paulo Med J. 2000;118(5):125-30

6.Treatment options and future prospects for the management of eyelid malignancies. Cook, Briggs E et al. Ophthalmology , Volume 108 , Issue 11 , 2088 - 2098

7. Cook BE, Bartley GB. Epidemiologic characteristics and clinical course of patients with malignant eyelid tumours in an incidence cohort in Olmsted County, Minnesota. Ophthalmology 1999;106:746–50.

8.Gallagher RP, Ma B, McLean DI, et al. Trends in basal cell carcinoma, squamous cell carcinoma, and melanoma of the skin from 1973 through 1987. J Am Acad Dermatol 1990;23:413–21.

9. Huang Y-Y, Liang W-Y, Tsai C-C, et al. Comparison of the Clinical Characteristics and Outcome of Benign and Malignant Eyelid Tumors: An Analysis of 4521 Eyelid Tumors in a Tertiary Medical Center. BioMed Research International. 2015;2015:453091. doi:10.1155/2015/453091.

10. Loeffler M, Hornblass A. Characteristics and behavior of eyelid carcinoma. Ophthalmic Surg 1990;21:513–18.

11.Kwa RE, Campana K, Moy RL. Biology of cutaneous squamous cell carcinoma. J Am Acad Derm 1992;26:1–26.

12.Boker A, Singer JP, Metchnikoff C, et al. High Dose Exposure to Voriconazole is Associated with Cutaneous Squamous Cell Carcinoma in Lung Transplant Recipients. J Heart Lung Transplant. 2011 In submission.

13.Alam M, Brown RN, Silber DH, et al. Increased incidence and mortality associated with skin cancers after cardiac transplant. Am J Transplant. 2011;11(7):1488–1497.

14.Brewer JD, Colegio OR, Phillips PK, et al. Incidence of and risk factors for skin cancer after heart transplant. Arch Dermatol. 2009;145(12):1391–1396

15.Penn I. Post-transplant malignancy: the role of immunosuppression. Drug Saf. 2000;23(2):101–113.

16.Stewart WB, Nicholson D, Hamilton G, et al. Eyelid tumours and renal transplantation. Arch Ophthalmol 1980;98:1771–2.

17. Rowe DE, Carroll RJ, Day CL., Jr Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection. J Am Acad Dermatol. 1992;26(6):976–990

18. Rubben, A., Baron, J., & GrussendorfConen, E. (1996). Prevalence of human papillomavirus type 16-related DNA in cutaneous Bowen's disease and squamous cell cancer. International Journal of Oncology, 9, 609-611. https://doi.org/10.3892/ijo.9.4.609

19. Leibovitch I, Huilgol SC, James CL, Hsuan JD, Davis G, Selva D. Periocular keratoacanthoma: Can we always rely on the clinical diagnosis? Br J Ophthalmol. 2005;89:1201–4.

20. Pe’er J. Pathology of eyelid tumors. Indian Journal of Ophthalmology. 2016;64(3):177-190. doi:10.4103/0301-4738.181752.

21.Hoeijmakers JH. Genome maintenance mechanisms for preventing cancer. Nature. 2001;411(6835):366–374.

22. 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), 464–472. http://doi.org/10.1172/JCI57415

23. American Joint Committee on Cancer. Cutaneous squamous cell carcinoma and other cutaneous carcinomas. In: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010:301-314.

24.Calista, D., Riccioni, L., & Coccia, L. (2002). Successful treatment of squamous cell carcinoma of the lower eyelid with intralesional cidofovir. The British Journal of Ophthalmology, 86(8), 932–933.

25. Mehta, Viraj J. MD, MBA; Ling, Jeanie MD; Sobel, Rachel K. MD .Review of Targeted Therapies for Periocular Tumors

26. International Ophthalmology Clinics: Winter 2017 - Volume 57 - Issue 1 - p 153–168 doi: 10.1097/IIO.0000000000000149 26. Shields CL, Naseripour M, Shields JA, Eagle RC Jr. Topical mitomycin-C for pagetoid invasion of the conjunctiva by eyelid sebaceous gland carcinoma. Ophthalmology. 2002;109(11):2129–33.

27. Verhoekx, J. S. N., Soebhag, R. K., Weijtens, O., van den Bosch, W. A. and Paridaens, D. (2016), A single- versus double-layered closure technique for full-thickness lower eyelid defects: a comparative study. Acta Ophthalmol, 94: 257–260. doi:10.1111/aos.12927

28. Lisman RD, Jakobiec FA, Small P. Sebaceous carcinoma of the eyelids. The role of adjunctive cryotherapy in the management of conjunctival pagetoid spread. Ophthalmology. 1989;96(7):1021–26.

29. Balasubramanian A, Kannan NS. Eyelid Malignancies- Always Quite Challenging. Journal of Clinical and Diagnostic Research : JCDR. 2017;11(3):XR01-XR04. doi:10.7860/JCDR/2017/23695.9582
  1. Asproudis I, Sotiropoulos G, Gartzios C, Raggos V, Papoudou-Bai A, Ntountas I, Katsanos A, Tatsioni A. Eyelid tumors at the University Eye Clinic of Ioannina, Greece: A 30-year retrospective study. Middle East Afr J Ophthalmol 2015;22:230
  2. Font RL. Ophthalmic Pathology. An Atlas and Textbook. 3rd ed. Philadelphia: WB Saunders; 1996. Eyelids and lacrimal drainage system; pp. 2229–32. 
  3. Basti S, Macsai MS. Ocular surface squamous neoplasia: a review. Cornea. 2003;22(7): 687-704.
  4. Bessa HJ, Potting MH, Bomfim MG. Neoplasias conjuntivais. Rev Bras Oftalmol. 1997; 56(10):765-7.  .
  5. Palazzi MA, Erwenne CM, Villa LL. Detection of human papillomavirus in epithelial lesions of the conjunctiva. São Paulo Med J. 2000;118(5):125-30
  6. Treatment options and future prospects for the management of eyelid malignancies. Cook, Briggs E et al. Ophthalmology , Volume 108 , Issue 11 , 2088 - 2098
  7. CookBE, Bartley GB. Epidemiologic characteristics and clinical course of patients with malignant eyelid tumours in an incidence cohort in Olmsted County, Minnesota. Ophthalmology 1999;106:746–50.
  8. Gallagher RP, Ma B, McLean DI, et al. Trends in basal cell carcinoma, squamous cell carcinoma, and melanoma of the skin from 1973 through 1987. J Am Acad Dermatol 1990;23:413–21.
  9. http://www.meajo.org/article.asp?issn=0974-9233;year=2015;volume=22;issue=2;spage=230;epage=232;aulast=Asproudis
  10. Loeffler M, Hornblass A. Characteristics and behavior of eyelid carcinoma. Ophthalmic Surg 1990;21:513–18.
  11. Kwa RE, Campana K, Moy RL. Biology of cutaneous squamous cell carcinoma. J Am Acad Derm 1992;26:1–26.
  12. Boker A, Singer JP, Metchnikoff C, et al. High Dose Exposure to Voriconazole is Associated with Cutaneous Squamous Cell Carcinoma in Lung Transplant Recipients. J Heart Lung Transplant. 2011 In submission. 
  13. Alam M, Brown RN, Silber DH, et al. Increased incidence and mortality associated with skin cancers after cardiac transplant. Am J Transplant. 2011;11(7):1488–1497. 
  14. Brewer JD, Colegio OR, Phillips PK, et al. Incidence of and risk factors for skin cancer after heart transplant. Arch Dermatol. 2009;145(12):1391–1396
  15. Penn I. Post-transplant malignancy: the role of immunosuppression. Drug Saf. 2000;23(2):101–113.
  16. Stewart WB, Nicholson D, Hamilton G, et al. Eyelid tumours and renal transplantation. Arch Ophthalmol 1980;98:1771–2.  
  17. Rowe DE, Carroll RJ, Day CL., Jr Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell
  18. Rubben, A., Baron, J., & GrussendorfConen, E. (1996). Prevalence of human papillomavirus type 16-related DNA in cutaneous Bowen's disease and squamous cell cancer. International Journal of Oncology, 9, 609-611. https://doi.org/10.3892/ijo.9.4.609
  19. Leibovitch I, Huilgol SC, James CL, Hsuan JD, Davis G, Selva D. Periocular keratoacanthoma: Can we always rely on the clinical diagnosis? Br J Ophthalmol. 2005;89:1201–4.
  20. Pe’er J. Pathology of eyelid tumors. Indian Journal of Ophthalmology. 2016;64(3):177-190. doi:10.4103/0301-4738.181752.
  21. Hoeijmakers JH. Genome maintenance mechanisms for preventing cancer. Nature. 2001;411(6835):366–374.
  22. [1] 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 Investigation122(2), 464–472. http://doi.org/10.1172/JCI57415
  23. American Joint Committee on Cancer. Cutaneous squamous cell carcinoma and other cutaneous carcinomas. In: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010:301-314.
  24. Calista, D., Riccioni, L., & Coccia, L. (2002). Successful treatment of squamous cell carcinoma of the lower eyelid with intralesional cidofovir. The British Journal of Ophthalmology, 86(8), 932–933.
  25. Mehta, Viraj J. MD, MBA; Ling, Jeanie MD; Sobel, Rachel K. MD  Review of Targeted Therapies for Periocular Tumors International Ophthalmology Clinics: Winter 2017 - Volume 57 - Issue 1 - p 153–168 doi: 10.1097/IIO.0000000000000149
  26. Shields CL, Naseripour M, Shields JA, Eagle RC Jr. Topical mitomycin-C for pagetoid invasion of the conjunctiva by eyelid sebaceous gland carcinoma. Ophthalmology. 2002;109(11):2129–33.
  27. Verhoekx, J. S. N., Soebhag, R. K., Weijtens, O., van den Bosch, W. A. and Paridaens, D. (2016), A single- versus double-layered closure technique for full-thickness lower eyelid defects: a comparative study. Acta Ophthalmol, 94: 257–260. doi:10.1111/aos.12927
  28. Lisman RD, Jakobiec FA, Small P. Sebaceous carcinoma of the eyelids. The role of adjunctive cryotherapy in the management of conjunctival pagetoid spread. Ophthalmology. 1989;96(7):1021–26.
  29. Balasubramanian A, Kannan NS. Eyelid Malignancies- Always Quite Challenging. Journal of Clinical and Diagnostic Research : JCDR. 2017;11(3):XR01-XR04. doi:10.7860/JCDR/2017/23695.9582.