Etiology
- The pathogenesis of squamous cell carcinoma (SCC) differs at various anatomic sites based on unique oncogenetic pressures prevalent at that site.
- SCC in the eyelid seems primarily related to sun exposure, similar to neoplastic transformation in SCC of the conjunctiva.
- Ultraviolet radiation exposure might interact synergistically with cutaneous human papillomavirus (HPV) infection in basal cell carcinoma (BCC) and SCC of the skin (Iannacone 2012).
- In a case control study of 156 cutaneous SCC patients, both sensitivity to sunlight and poor tanning, and seropositivity for HPV infection, increased the risk of SCC.
- However, sun exposure is likely a more critical etiologic factor.
- Precancerous lesions include actinic keratoses, which are keratinocyte derived and found predominantly in fair skinned individuals and on-sun exposed surfaces.
- Multistep carcinogenesis is the generally accepted model for SCC, likely beginning with mutation in a tumor suppressor, leading to genetic instability and the emergence of driver oncogenes (Ratushny 2012).
- Initial genomic instability in keratinocytes likely results from ultraviolet beta ray induced inactivation of p53.
- About 58% of cutaneous SCCs harbor UVB signature mutations such as CC→TT and C→T transitions (Brash 1991).
- Activating RAS, particularly Hras (Harvey rat sarcoma virus oncogene), is among candidate oncogene mutations that promote cutaneous SCC formation (Boukamp 2005).
- Aberrant ras activation promotes mitogenesis, resistance to apoptosis and angiogenesis.
- Tumor formation by human keratinocytes transformed through retrovirally mediated expression of HRAS is inhibited with blocking antibodies to laminin 332, a component of the basement membrane, and α6β4 integrin, one of its ligation partners.
- External environment controls are important mediators of cell growth and loss of control is involved in tumor progression.
- Epidermal stem cells are the putative cells of origin of cutaneous SCC.
Epidemiology
- Prevalence varies based on factors that include relative sun exposure.
- In a 10-year review of 100 periocular malignancies at a tertiary care hospital in Tehran, Iran, BCC represented 83%, SCC 8% and sebaceous carcinoma 6% (Bagheri 2013).
- The incidence of SCC in Peshawar, Pakistan, was even higher, among 222 malignant eyelid tumors 2007–2010: BCC 59%, SCC 31%, sebaceous carcinoma 7%, melanoma and others 2% (Hussain 2013).
- In Singapore, sebaceous carcinoma was relatively more common: BCC 82%, sebaceous carcinoma 11%, SCC 4% (Lim VS 2012).
- In Hong Kong, similar incidences were reported: BCC 75%, sebaceous carcinoma 11%, SCC 5% (Mak 2011).
- In Taiwan, among 1121 eyelid malignancies reported between 1979 and 1999, the mean age at diagnosis was 62.6±14.1 years, with BCC representing 65%, SCC 12% and sebaceous carcinoma 8% (Lin 2006).
- In an Olmstead County, Minnesota, retrospective survey of 174 malignant eyelid tumors from 1976 to 1990, 91% were BCC and 8% were SCC and no cases of sebaceous carcinoma were identified (Cook 1999).
- An unusual distribution of histopathology has been reported among 178 eyelid malignancies in New Delhi, India from 1982-1992, with an almost equal incidence of sebaceous carcinoma (32%), BCC (30%) and SCC (28%) (Sihota 1996).
- In Australia, where a fair-skinned population is exposed to a relatively high degree of sun exposure, the prevalence of periocular SCC is particularly high.
- In 79 periocular SCCs recorded in the Australian Mohs Database between 1993 and 1999, 68% were lower eyelid, 24% were medial canthus and 7% were upper eyelid, as expected based on angle to the sun (Malhotra 2004).
- In that group, among 73% primary tumors and 27% recurrent tumors, 49% were well differentiated, and 35% were moderately differentiated.
- Perineural invasion was seen in only 3 cases (2 recurrent and 1 primary) suggesting that this is a relatively late event in periocular SCC tumor progression.
- In a study of 111 patients treated at MD Anderson Cancer Center from 1952 to 2000, 24% had regional nodal metastasis, and 6% had distant metastasis (Faustina 2004).
- These unusually high percentages reflect the tertiary referral patterns of a cancer center.
- In an older study of periocular eyelid malignancies, the diagnosis of SCC was changed in 18 of 49 tumors to another diagnosis, including sebaceous gland carcinoma (10), basal cell carcinoma (4), papilloma (1) and keratosis (3) (Doxanas 1987).
- Among 648 eyelid malignancies diagnosed at the Wills Eye Hospital from 1978 to 1987, 24 (3.7%) were SCC; age range was 55–96 years (median 72 years) (Dailey 1994).
History
- It is helpful to define the relative degree to which the patient was exposed to unprotected ultraviolet irradiation.
- Occupational history
- Military history
- Social history — where the patient lived, favorite recreational activities
- Medical history — is there a history of radiation for inflammatory (acne) or malignant skin conditions?
- A history of previous skin cancer might suggest recurrence and more extensive local progression.
- Current lesion — duration, change in appearance, rate of growth, prior biopsy, inflammation, bleeding
- History of pre-existing lesion such as actinic keratosis, Bowen disease, radiation dermatoses, burn scars, and inflammatory lesions
- Prior lesions removed or "burned off" without pathologic diagnosis
Clinical features (Figure 1 and Figure 2).
- Hyperkeratotic macular (flat) or nodular (elevated) skin lesion
- Can have significant inflammatory component
- Later phases can have ulceration.
- Associated sun-damaged skin
- Loss of normal eyelid architecture (i.e., loss of lashes, eyelid margin distortion)
- Regional lymphadenopathy
Testing
- Incisional or excisional biopsy depending on clinical presentation
- Computed tomography (CT) or magnetic resonance imaging (MRI) with enhancement if intraorbital or intracranial spread is suspected
Testing for staging, fundamental impairment
- The Seventh Edition AJCC definition for eyelid carcinoma:
- T1 = tumor ≤ 5 mm, not invading tarsus or lid margin
- T2a = tumor > 5 mm, < 10 mm, or any tumor invading tarsus or lid margin
- T2b = tumor > 10 mm, < 20 mm, or any tumor involving full thickness eyelid
- T3a = tumor > 20 mm, or any tumor invading adjacent ocular structure or orbit, or perineural invasion
- T3b = complete tumor resection requires enucleation, exenteration or bone removal
- T4 = tumor not resectable
- cN0 = no regional lymph nodes, based on exam and imaging
- pN0 = no regional lymph nodes, based on biopsy
- M0 = no distant metastasis
- M1 = distant metastasis
- There have been no studies of prognosis based on staging for eyelid SCC.
Figure 1. Image courtesy Navdeep Nijhawan, MD.
Figure 2. Image courtesy Mark. J. Lucarelli, MD, FACS.