SEBACEOUS CARCINOMA - TUMOR PROGRESSION THROUGH MUTATIONAL INACTIVATION OF P53

Background: Sebaceous carcinoma may masquerade for years as an inflamm atory condition, In many cases, this may be because of the presence of longstanding intraepithelial disease (e.g., dysplasia or carcinoma in situ), which eventually progresses to invasive carcinoma recognized t hrough tumefaction and a worsening clinical presentation, The mechanis m for this tumor progression is unknown, In the Far East, human papill oma virus (HPV) has been suggested to play a role in the development o f sebaceous carcinoma by inactivating tumor suppressor gene p53, Here, the authors explore the molecular basis of the progression of ocular sebaceous carcinoma. Methods: Cases of sebaceous carcinoma seen at the University of Virginia, Department of Ophthalmology, during the perio d from 1989 to 1996 were analyzed for HPV infection by in situ hybridi zation and polymerase chain reaction, The expression of p53, p21(WAF-1 ), Bcl-2, and epithelial membrane antigen was examined by immunohistoc hemistry, In one of the cases, frozen tumor was available, allowing ex ons 5 through 9 of the p53 gene to be sequenced. Results: Seven cases were identified, all of which were from women. All were negative for H PV, In cases in which disease was restricted to dysplasia (carcinoma i n situ), p53 but not p21(WAF-1) was negative, In contrast, cases that contained a component of invasive or metastatic carcinoma showed strik ing hyperexpression of nuclear p53 in all of the malignant cells, In o ne of these cases, a G:C --> T:A transversion was found in the p53 gen e, This mutation, characteristic of bulky carcinogens, substituted phe nylalanine for cysteine 277, a residue that participates in hydrogen b onding to the p53 DNA binding consensus sequence. Conclusions: Mutatio nal inactivation of p53 may be involved in the progression of sebaceou s carcinoma.