Early recognition of sebaceous carcinoma is often challenging, requiring close collaboration between ophthalmologist and pathologist. Early stages of the disease can consist of only Pagetoid extension without tumefaction [3]. This in situ stage can be mistaken for blepharoconjunctivitis. Sebaceous carcinoma is often clinically misdiagnosed as chalazion, a common lipogranulomatous lesion of the eyelid. Furthermore, it is important to recognize that Merkel and basal cell carcinomas can mimic sebaceous carcinoma microscopically. Therefore, early diagnosis of sebaceous carcinoma requires appreciation of its varied clinical presentation, and recognition of entities that can mimic it histopathologically [4].

When ocular sebaceous carcinoma occurs at a young age, it is generally associated with a predisposing factor (Table ​(Table1).1). The youngest cases are from children with bilateral retinoblastoma (8 and 12 years). Older patients (17 and 28 years) had unilateral retinoblastoma. Although radiation therapy may have played a role, it may not be necessary as sebaceous carcinoma has occurred outside the radiation field, and in a patient who never received radiation or chemotherapy [22]. Muir-Torre syndrome, which is due to inactivation of MSH2 or MLH1, predisposes to sebaceous tumors and other neoplasms [23]. Genomic instability may provide a mechanism for the occurrence of sebaceous carcinoma in a 31 year-old man with Muir-Torre syndrome [24]. Early onset disease in the setting of HIV and steroid treatment suggests a role for immunosuppression [17,25]. In the present case, there was no history of retinoblastoma, radiation therapy or immunosuppression. Furthermore, there was no clinical or family history suggesting Muir-Torre syndrome, or another hereditary cancer syndrome. Potential risk factors for this patient were her 14-year employment as a cosmetologist, and regular home-tanning bed use for 9 of those years. Although this is speculative, a cancer risk has been associated with hair dye exposure [26], and tanning bed use [27].

Epidemiological studies suggest a role of sunlight and radiation in sebaceous carcinoma. A recent retrospective study of 1,349 cases, showed that Caucasians are more frequently affected with sebaceous carcinoma compared to Asian/Pacific Islanders and Blacks [1]. Furthermore, Rao et al. (1982) found only four Blacks among 75 patients with sebaceous carcinoma [28], and Zürcher et al. (1998) noted no black patients in their series of 43 cases (42, Caucasian; one, Chinese) [8]. Finally, sebaceous carcinoma has occurred at nonocular sites in the setting of radiation exposure [29,30] and sunlight [19]. Interestingly, the G199R substitution detected in our patient was due to a G:C→A:T mutation at a dipyrimidine site (GGA to AGA, sense strand; TCC to TCT, antisense strand). UV light is known to cause C→T substitutions at dipyrimidines, or CC→TT substitutions in the p53 gene [31]. Although this class of mutation is typical of UV light induced mutations, it does not prove that the mutation was caused by UV exposure. Among 11 cases of sebaceous carcinoma with documented p53 mutations, 5 showed C→T mutations at dipyrimidine sites [15]. An additional reported case from a 75 year-old woman showed a G:C→T:A typical of bulky carcinogens [3]. The diversity of mutations suggests that different mechanisms may play a role in different cases (Table ​(Table22).

Clinical data and molecular studies suggest that G199R likely interferes with p53 function. Early X-ray structures of p53 showed that the known "hot-spot" mutations are often involved in DNA binding. However, codon 199 lies outside of the direct DNA-protein binding site. Nevertheless, missense mutations of this codon are listed in 48 tumors in the International Agency for Research on Cancer database [32]. Of those, 12 are G199R substitutions [32]. In many of these cases, a link between G199R and p53 function can be made. Cyclophosphamide induced bladder cancer is more commonly associated with G199R compared to sporadic, smoking-related, and schistosomiasis-linked tumors [33]. In a study of giant cell glioblastoma multiforme, G199R was more often associated with evidence for microsatellite instability compared to other mutations [34]. G199R, which was observed in BRCA-1 associated familial breast cancer [35], shows reduced activity in yeast transactivation capacity assays. Thus, although not directly involved in DNA-protein binding, G199 appears to have a critical role in p53 function.

X-ray crystallography is providing key insights into the structure-function significance of p53 mutations [36]. An emerging picture is that p53 functions as homotetrameric complexes interacting with the DNA helix, and a multitude of regulatory proteins. DNA-p53 and p53-p53 monomer contacts are important in stabilizing the tetrameric complex. The tetramer is composed of two p53 dimers each straddling the DNA helix. The dimers come together through binding closely spaced DNA decameric half-sites [37,38]. The resulting dimer-dimer is further stabilized by specific p53-p53 interaction sites. G199, which is located in such a key interface termed "patch I", makes critical contacts with residues of the adjacent p53 monomer [39].

To evaluate the effect of the arginine substitution, in silico energy minimization within a 10Å sphere surrounding G199R was performed using the Molecular Operating Environment (Figure ​(Figure4B).4B). Although the analysis anticipates only a subtle conformational change in the interface site, the electrostatic environment is significantly altered. The arginine residue affects interactions with other amino acids much more than the neutral glycine residue originally did. The modeling predicts that the substitution of arginine for glycine at position 199 will neutralize negative charges contributed by nearby inter- and intramonomeric glutamate residues (E171 and E198, respectively). It is therefore likely that G199R would destabilize the tetramer, acting in a dominant negative manner reducing its DNA affinity, and disrupting cooperative interactions between its subunits, and perhaps regulatory proteins. Taken together, the above observations suggest that G199R probably contributed to the molecular events leading to the development of sebaceous carcinoma in this patient.