Early onset sebaceous carcinoma
© Sung et al; licensee BioMed Central Ltd. 2011
Received: 19 March 2011
Accepted: 5 September 2011
Published: 5 September 2011
Ocular sebaceous carcinoma can masquerade as benign lesions resulting in delay of diagnosis. Early recognition is even more difficult in young patients where the disease rarely occurs. Here, we provide a clinicopathological correlation of ocular sebaceous carcinoma in a young individual lacking history of hereditary cancer or immunosuppression.
A detailed histopathological study including p53 DNA sequencing was performed on an aggressive sebaceous carcinoma presenting in a healthy 32 year-old Caucasian woman. She had no history of retinoblastoma, evidence for a hereditary cancer syndrome, or radiation therapy. However, she potentially was at risk for excessive UV light exposure. A detailed review of the literature is also provided.
A moderately well differentiated sebaceous carcinoma was established histopathologically arising from the meibomian gland of the upper eyelid. In most areas, the cytoplasm contained small but distinct Oil-red-O positive vacuoles. Direct sequencing of p53 identified a G:C→A:T mutation at a dipyrimidine site. The mutation results in substitution of arginine for the highly conserved glycine at residue 199 located at the p53 dimer-dimer interface. Energy minimization structural modeling predicts that G199R will neutralize negative charges contributed by nearby inter- and intramonomeric glutamate residues.
This study points to the importance of recognizing that sebaceous carcinoma can occur in young patients with no evidence for hereditary cancer risk or radiation therapy. The G199R substitution is anticipated to alter the stability of the p53 tetrameric complex. The role of UV light in the etiology of sebaceous carcinoma deserves further study. Our findings, taken together with those of others, suggest that different environmental factors could lead to the development of sebaceous carcinoma in different patients.
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1227870450349458.
Sebaceous carcinoma is generally considered to be a tumor of older patients (mean age, 73 years of age) . In the ocular adnexa, this highly malignant neoplasm often masquerades as common benign lesions delaying appropriate treatment [2–4]. For unknown reasons, sebaceous carcinoma is more prevalent in the ocular adnexa than elsewhere in the body. It can arise from the meibomian glands, glands of Zeis, caruncle, skin of eyelid and eyebrow, lacrimal gland, or conjunctiva [4–8]. Although its etiology is largely unknown, it has been associated with Asians [4, 9], Muir-Torre syndrome [10–14], Rb and p53 mutations [3, 15, 16], HIV , and HPV [3, 18]. The apparent increased rate of sebaceous carcinoma in Asians/Pacific Islanders is being challenged by recent studies indicating that the tumor is more common in Whites [1, 9], and showing a distribution consistent with sunlight exposure .
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 . 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 .
Here we describe a sebaceous carcinoma presenting in a 32 year-old woman. This case was previously included in a series of seven cases . Here, we revisit this case to provide further clinical, histopathological and molecular studies. The case emphasizes that this highly aggressive cancer can occur in young patients without history of retinoblastoma, radiation therapy, or hereditary cancer syndrome. Finally, the case suggests that the role of UV radiation and p53 mutations in sebaceous carcinoma deserve further study.
A healthy 32 year-old Caucasian woman was referred for a recurrent chalazion initially diagnosed 3 months prior. She had no previous ocular or medical problems. There was no significant family history of cancer (a maternal uncle had hepatocellular carcinoma; her paternal great grandmother reportedly had stomach cancer). For 14 years she was a cosmetologist, and for 9 of those years regularly used a home UV tanning bed.
Pathologic and molecular observations
Clinically, sebaceous carcinoma has a propensity to masquerade as a variety of common benign lesions. This has contributed to an extended interval between presentation and appropriate treatment. In recent years, this gap has been closing with improved awareness of its varied clinical manifestations, and histopathological features. The present case underlines that young age should not exclude consideration of sebaceous carcinoma.
Risk factors of early onset (age < 40 years) ocular sebaceous carcinoma
Number of Patients
Age Range in years
(Number of patients)
C(3), A(1), U(1)
Known p53 mutations in ocular sebaceous carcinoma
83 yrs/F 
TACt to TAGt
75 yrs/M 
GTG to ATG
36 yrs/F 
CGC to CAC
78 yrs/M 
CAT to CGT, AGT to GGT
GG A to AG A
85 yrs/M 
GG C to AG C
42 yrs/M 
cC GG to cT GG
76 yrs/F 
cC GG to cT GG
61 yrs/M 
gG TG to gA TG
61 yrs/F 
TGT to TAT
75 yrs/F 
TGT to TTT
47 yrs/F 
TGg t to TGt t
68 yrs/M 
agG T to aaG T
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 . Of those, 12 are G199R substitutions . 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 . In a study of giant cell glioblastoma multiforme, G199R was more often associated with evidence for microsatellite instability compared to other mutations . G199R, which was observed in BRCA-1 associated familial breast cancer , 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 . 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 .
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 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.
In summary, the present case emphasizes that young age should not exclude consideration of sebaceous carcinoma. Further studies are needed to determine if sebaceous carcinoma may arise through different sets of environmental factors.
Next of kin could not be reached in order to gain consent. There is no reason is suggest that consent would not be given, and all efforts have been made to maintain anonymity.
The authors would like to thank Dr. Debashis Ghosh (SUNY Syracuse) for helpful discussions and performing the energy minimization modeling. The work was supported by Merit Review Award I01BX007080 from the Biomedical Laboratory Research & Development Service of the Veterans Affairs Office of Research and Development (F.G.-F.), RO1 EY09412 (F.G.-F, D.G.), R24 EY 016662 core instrumentation grant, and an Unrestricted Grant from Research Prevent Blindness to the Department of Ophthalmology at SUNY at Buffalo. Molecular graphics images were produced using Chimera from the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIH P41 RR001081). Dr. Sung was supported in part by a research training fellowships from the Department of Biomedical Science, Medical Research Center at Kyung-Hee University, and Chong Kun Dang Kochon Foundation, Seoul; Dr. Gonzalez-Fernandez is the Ira Gile Ross & Elizabeth Pierce Olmsted Ross Endowed Chair in Ophthalmic Pathology at SUNY Buffalo.
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