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Annals of Clinical & Laboratory Science 35:91-96 (2005)
© 2005 Association of Clinical Scientists

Immunohistochemical Expression of Bax and Bcl-2 in Penile Carcinoma

Sadia Saeed, Connie A. Keehn, Farah K Khalil and Michael B. Morgan
Department of Pathology, University of South Florida, and James A. Haley Veterans Administration Hospital, Tampa, Florida

Address correspondence to Sadia Saaed, M.D., or Michael B Morgan, M.D., Department of Pathology, University of South Florida College of Medicine, 12901 Bruce B. Downs Blvd, Tampa, FL 33612, USA; tel 813 632 9808; fax 813 971 6675; e-mail mbkmmorgan{at}aol.com.


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
There is a complex interplay between the pro-apoptotic Bax and anti-apoptotic Bcl-2 family of proteins and the tumor suppressor gene p53. The pathogenic role of Bax and Bcl-2 protein expression in penile carcinomas has not previously been investigated. We examined Bax and Bcl-2 expression in verrucous (VC) and squamous cell carcinoma (SCC) of the penis. Herein we also present a concise review of p53, Bcl-2/Bax ratios, and their relationship to apoptosis. Fourteen cases of penile carcinoma, including 7 VC and 7 well-differentiated SCC, were analyzed for Bax and Bcl-2 expression by immunohistochemical analysis of paraffin embedded archived tissues. The number of positively staining tumor cells was enumerated per 100 tumor cells within non-overlapping high power fields. The Bax immunoreactivity was similar in VC (19 ± 3%) and well-differentiated SCC (15 ± 4%) (p = 0.69). The expression of Bcl-2 protein was significantly higher in well-differentiated SCC (69 ± 12%) compared to VC (36 ± 14%) (p = 0.04). The mean Bcl-2/Bax ratio was significantly lower in VC (1.89) compared to well-differentiated SCC (4.6) (p = 0.05). These findings indicate that penile VC and SCC are immunophenotypically distinct. Bax expression is comparable in verrucous and low-grade squamous cell carcinomas, but Bcl-2 expression of Bcl-2 is significantly higher in the squamous cell carcinomas.

(received 15 September 2004; accepted 24 November 2004)

Keywords: Bax, Bcl-2, penile carcinoma, verrucous carcinoma, immunohistochemistry, apoptosis


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Penile cancer constitutes a small percentage of malignancies in Western countries, representing 0.3 to 0.5% of all cancers in men [1]. There are substantial geographically related differences in incidence, with the highest rates reported in India, China, and Puerto Rico [1–7], and with migrants to high-risk areas acquiring higher rates [6].

Squamous cell carcinoma accounts for >95% of primary penile malignancies [2], followed by the well-differentiated variant, verrucous carcinoma. Distinction of verrucous from conventional squamous cell carcinoma has prognostic and therapeutic implications. Verrucous carcinoma is a slow-growing malignancy with a locally aggressive and relapsing but non-metastasizing biologic behavior [8–10]. The incidence of verrucous carcinoma may be underestimated because of frequent confusion with low-grade squamous cell carcinoma [10]. As its name implies, verrucous carcinoma histologically mimics a verruca (ie, a wart), but in contrast to invasive squamous cell carcinoma, it possesses a "pushing" border that maintains a basement membrane [11].

Many factors have been implicated in the etiology of squamous cell carcinoma of the penis, but most attention has been focused on the human papilloma virus (HPV). The incidence of HPV positivity in penile carcinomas has a wide range, from 15 to >70% [12–15]. Several studies have suggested an association of verrucous carcinoma with HPV (particularly types 6 and 11) [16–20], but other studies have yielded conflicting results [14,21,22]. The HPV genome encodes proto-oncogenes that interfere with the functions of the retinoblastoma protein Rb and the p53 tumor suppressor protein [23]. Pro-apoptotic activity of p53 plays a key role in suppressing tumor formation [24]. The pro-apoptotic protein Bax and anti-apoptotic protein Bcl-2 are regulated by p53 [25], and strong evidence implicates p53 in the activation of Bax protein [26].

A review of the literature failed to disclose any previous studies of the differential expression of Bcl-2 and Bax in verrucous vs conventional squamous cell carcinomas of the penis. In this study, we examine the immunohistochemical expression of Bcl-2 and Bax in penile verrucous and squamous cell carcinoma, in order to shed light on their possible pathogenic significance in penile cancer.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Archived paraffin blocks and corresponding medical records were selected from the files of the James A. Haley Veterans Hospital, Tampa, Florida. The diagnoses were confirmed by a dermatopathologist (MBM). Cases (n = 14) of penile carcinoma were selected, including 7 cases of verrucous carcinoma and 7 cases of squamous cell carcinoma. Formalin-fixed paraffin sections were cut at 3 µm. Slides were immunostained with the Dako Autostainer using the Dako LSAB peroxidase detection kit (Dako Corp., Carpinteria, CA). Monoclonal mouse anti-Bax antibody (#18-0218, Zymed Laboratories, South San Francisco, CA) was used at 1:200 dilution following microwave antigen retrieval or heat induced epitope retrieval. Pre-diluted (ready to use) monoclonal mouse anti-Bcl-2 antibody (#N1587, Dako) was used without retrieval. Tissue blocks of Hodgkin’s lymphoma were used as the positive control for Bax. Tonsil was used as the positive control for Bcl-2. Mouse IgG was used as the negative control reagent.

In each case of penile carcinoma, the number of immunohistochemically positive-staining tumor cells was enumerated within non-overlapping high power fields (40x). Approximately 20 cells were enumerated per high power field, with 5 high power fields examined for a total of 100 cells enumerated per case, reported as a percentage of positively staining cells (mean labeling index). The immunohistochemical intensity was assessed by a single dermatopathologist (MBM). The assessment was as objective as possible, but a potential for bias could not be eliminated, since the diagnoses were evident on the immunostained sections and thus could not be blinded. Statistical analysis of the mean labeling index (MLI) of both proteins was performed by Student’s t-test, comparing the mean expression of Bax and Bcl-2 in VC and well-differentiated SCC. Results were reported as mean ± SE.


   Results
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 Results
Discussion
 References
 
Immunohistochemical analysis for Bax protein showed diffuse cell membrane and cytoplasmic staining, randomly distributed in tumor cells of both verrucous (VC) and well-differentiated squamous cell carcinoma (SCC). Bax staining was absent in normal, non-malignant cells, including the epidermis. The mean labeling index for Bax in cases of VC and well-differentiated SCC was similar (19 ± 3% in VC, vs 15 ± 4% in well-differentiated SCC, p = 0.69) (Fig. 1Go).



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  		Fig. 1. Immunostaining for Bcl-2 protein shows cytoplasmic and nuclear membrane staining with significantly higher expression in squamous cell carcinoma (upper right) compared to verrucous carcinoma (upper left). Immunostaining for Bax protein shows diffuse cell membrane and cytoplasmic staining in both verrucous carcinoma (lower left) and squamous cell carcinoma (lower right) (400x).

 
Immunohistochemical analysis for Bcl-2 protein showed uniform staining of the cytoplasm and nuclear membrane of malignant cells. In benign epithelium, Bcl-2 expression was confined to the basal cells. Within the tumors, expression of Bcl-2 protein was higher in well-differentiated SCC (69 ± 12%) compared to VC (36 ± 14%) (p = 0.04) (Fig. 1Go). The mean Bcl-2/Bax ratio was significantly lower in VC (1.89), compared to well-differentiated SCC (4.6) (p = 0.05).


   Discussion
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References
 
Although immunoreactivity of Bax protein was similar in verrucous and squamous cell carcinomas, the immunoreactivity of Bcl-2 protein was significantly higher in squamous cell carcinoma. This has interesting pathogenic implications.

Apoptosis is an important mechanism of growth regulation that influences the biologic behavior of tumors. Apoptosis involves a complicated cascade of events that may be divided into overlapping stages that are not mutually exclusive [27–30]. The Bcl-2 family of proteins is comprised of inhibitors (Bcl-2, Bl-xL, Bcl-w, and Mcl-1) and promoters (Bax, Bik, Bok, Bak, Blk, Bid, Bad, Bim, and Hrk) of apoptosis [31], which share structural domains, including BH1, BH2, and BH3. The C termini of the Bcl-2 and Bax proteins contain a domain that is necessary for mitochondrial insertion; its deletion blocks Bax-induced apoptosis [32].

Bcl-2, the prototypic anti-apoptotic protein, was originally discovered in relation to chromosomal translocations in follicular B cell lymphomas. It is located in the mitochondria, endoplasmic reticulum, and nuclear membrane [33]. Bcl-2 modulates its anti-apoptotic property by forming heterodimers with the pro-apoptotic members of its family, predominantly Bax, blocking their key functions. Through this mechanism, Bcl-2 protein is suspected to impart resistance to the apoptosis induced by radiation and chemotherapeutic agents [25]. Unlike other proto-oncogenes, Bcl-2 exerts its influence by blocking programmed cell death and thereby enhancing cell survival, rather than by stimulating cell division [33].

The Bax molecule resides in the cytoplasm and migrates to mitochondria upon activation [34], where it modulates the release of cytochrome C [35], thereby activating the apoptotic cascade. Bax is activated by p53 in cells with irreversibly damaged DNA. The mechanism whereby Bax antagonizes the action of Bcl-2 is unclear. Hypothetical mechanisms include the dimerization of Bax with domains BH1, BH2, and BH3 of bcl-2, and Bax inhibition of Bcl-2 activity [31,35]. It appears that with over-expression of Bcl-2, Bax is unable to be inserted into the mitochondrial membrane, suggesting the number of binding sites may be limited [34]. There is also evidence that Bax and Bcl-2 can function independently of each other [31].

In our investigation, Bax expression was not significantly different in verrucous and squamous cell penile carcinomas, whereas Bcl-2 was expressed to a much greater degree in squamous cell carcinoma (SCC). The higher Bcl-2 expression in SCC is intuitive, as it is the more aggressive of the 2 tumors. Bcl-2 immunoreactivity has been correlated with tumor grade in similar tumors, such as laryngeal SCC [36]. The substantial increase of Bcl-2 expression relative to Bax in penile SCC in our investigation confirms the importance of the ratio of these proteins in determining the biologic character of lesions.

As listed in Table 1Go, previous studies have reported increased Bcl-2/Bax ratios in oral [37] and head and neck [38] SCC, compared to normal epithelium. The Bcl-2/Bax ratio is considered to be one of the strongest independent predictors of disease progression and prognosis [39,40]. Higher ratios are seen in poorly differentiated squamous tumors [37]. Increased Bcl-2/Bax ratios are linked to poor outcomes in other tumor types, including resistance to chemotherapy in multiple cancers [41], transitional cell carcinomas [42,43,] and a diverse group of hematologic malignancies [44–47]. A high Bcl-2/Bax ratio is coupled with increased resistance to adjuvant radiotherapy (as in prostatic [48] and rectal [49] adenocarcinoma).


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  		Table 1. Adverse effect of increased Bcl-2/Bax ratio in various malignancies
 
A study of Bcl-2 expression in radio-resistant tumors (metastatic transitional cell carcinoma), compared to more curable cancers (metastatic testicular cancer), yielded similar results [50]. These findings seem counter-intuitive to our study, since penile verrucous carcinoma generally has a distinctly poor response to radiation therapy. However this may be reconciled by the recognition that apoptosis, and therefore response to radiation therapy, involves numerous other factors that were not measured and could be operative. These include other anti- and pro- apoptotic members of the bcl-2 family, along with p-ras [51], c-myc [52], p53 [53], and Rb [23].

The relationship of various HPV proteins to p53 and Rb was noted in the introduction to this paper. Furthermore, apoptosis is only one of many mechanisms involved in tumorigenesis and dedifferentiation, including factors that govern cell cycling. These includes pro-proliferative proteins (eg, p-ras, c-myc, cyclin D [23], and erb B1). The latter 2 proteins have been directly linked with SCC in various organs [23].

Attention is also directed to mutational inactivation of tumor suppressor genes like p16 (an inhibitor of Cyclin D-cdk 4/6 complex), which have been implicated in numerous human cancers, including SCC [54]. It may be hypothesized that loss of a downstream negative regulator of Bcl-2, or upregulation of an upstream Bcl-2 agonist, might lead to the higher expression of Bcl-2 in squamous cell carcinoma.


   References
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 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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