102 Abstract According to novel investigations, actinic ker- atosis (AK) is not a premalignant lesion but is a malignant lesion in the evolution to invasive squamous cell carci- noma (SCC). Thus, we analyzed p53, bcl-2 and growth hormone receptor (GHR) expression in hypertrophic-type AK (HAK) to determine the relative importance of these protooncogenes in the biological behavior of HAK. Ex- pression of p53, bcl-2 and GHR was determined by im- munohistochemistry in 33 HAK specimens and surround- ing perilesional normal skin (PNS). The relative propor- tions of immunoreactive cells were determined. Of the 33 HAK specimens, 30 (91%) showed immunopositive staining for p53, 33 (100%) for bcl-2, and 12 (36%) for GHR. Highly positive p53 expression in HAK lesions could indicate that p53 mutation is an early and crucial event in lesion development. The detected pattern of the p53/bcl-2 ratio in HAK suggests an important role for an- other gene: the proapoptotic gene bax. Our findings indi- cate that GHR expression could be a biological marker of progression of HAK to SCC. Keywords Hypertrophic actinic keratosis · P53 · Bcl-2 · Growth hormone receptor · Immunohistochemistry Introduction Actinic keratoses (AK) are extremely common epithelial precancerous lesions (Salasche 2000). AK increase in preva- lence with increasing age (Green et al. 1988), affecting nearly 100% of the elderly white population (Tindall 1976). The most important causative factor is long-term UV ex- posure, i.e. photocarcinogenesis (Moy 2000). AK are usu- ally divided into five different histological types: hyper- trophic, atrophic, bowenoid, acantholytic and pigmented (Elder et al. 1997), hypertrophic and atrophic being the most frequent (Elder et al. 1997; Pinkus 1979). AK was first identified and classified as precancerous or premalig- nant (Engman 1915). However, according to more recent investigations, AK represent an early stage in the biologi- cal continuum that leads from carcinoma in situ to inva- sive squamous cell carcinoma (SCC) (Salasche 2000; Moy 2000; Leffell 2000). There is still no general agreement about this. Techniques of molecular biology have become very im- portant in verifying the significance of various oncogenes in the pathogenesis of AK. The relationship between acti- vated protooncogenes and inactivated tumor suppressor genes plays a crucial role in the development and progres- sion of AK (Leffell 2000; Wikonkal et al. 1997; Onodera et al. 1996; Bito et al. 1995). In the majority of studies in which the expression of genes p53 and bcl-2 have been investigated in AK, immu- nohistochemical (IHC) techniques have been used (Wikon- kal et al. 1997; Onodera et al. 1996; Bito et al. 1995; Gusterson et al. 1991; Nagano et al. 1993; Taguchi et al 1993; Shimizu et al. 1999; Nakagawa et al. 1994; Morales- Ducret et al. 1995; Mills 1997; Tucci et al. 1998). How- ever, the results of these studies are controversial. The expression of p53 has been reported to be in the range 0–92% (Onodera et al. 1996; Bito et al. 1995; Gusterson et al. 1991; Nagano et al. 1993; Taguchi et al 1993; Shimizu et al. 1999) and the expression of bcl-2 in the range 0–100% (Nakagawa et al. 1994; Morales-Ducret et al. 1995; Mills 1997; Tucci et al. 1998). It has to be mentioned also that nearly all studies have been per- formed on a relatively small number of specimens. In only a few studies has p53 and bcl-2 expression been ana- lyzed strictly in hypertrophic AK (HAK) (Nagano et al. 1993; Taguchi et al. 1993; Nakagawa et al 1994). The role of growth hormone (GH) has been implicated recently in the biology of skin tumors (Lincoln et al. 1998; Andrija Stanimirović · Hrvoje Čupić · Berislav Bošnjak · Božo Krušlin · Mladen Belicza Expression of p53, bcl-2 and growth hormone receptor in actinic keratosis, hypertrophic type Arch Dermatol Res (2003) 295 : 102–108 DOI 10.1007/s00403-003-0400-0 Received: 30 October 2002 / Revised: 29 January 2003 / Accepted: 2 April 2003 / Published online: 20 May 2003 ORIGINAL PAPER A. Stanimirović · H. Čupić · B. Krušlin · M. Belicza Ljudevit Jurak University Department of Pathology, Sisters of Charity University Hospital, Zagreb, Croatia B. Bošnjak Ruđer Bošković Institute, Zagreb, Croatia A. Stanimirović (✉) Badalićeva 26/I, 10000 Zagreb, Croatia Tel.: +385-1-3821509, Fax: +385-1-3821509, e-mail: a.stanimirovic@usa.net © Springer-Verlag 2003