Hyperostosis frontalis interna (HFI) has been documented in the medical literature for over 300 years and was considered part of a wider phenomenon known as the Stewart-Morel-Moore Syndrome. Previous studies have identified and categorized this bony overgrowth located on the inner aspect of the frontal bone (Moore, 1955; Perou, 1964; Rudali, 1968; Verdy et al., 1978; Armelagos and Chrisman, 1988; Fulton et al., 1990; Hershkovitz et al., 1999; Ruhli and Henneberg, 2002; Talarico et al., 2008). This phenomenon commonly occurs in elderly females (Moore, 1955; Hershkovitz et al., 1999) and may be associated with a disturbance in hormonal balance due to various intrinsic and extrinsic factors (Hershkovitz et al., 1999). In males, HFI is relatively uncommon, 5%–17% (Moore, 1955; Barber et al., 1997; Hershkovitz et al., 1999). Severe cases of HFI were found only in those who suffered from hypogonadism (Moore, 1955; Perou, 1964; Hershkovitz et al., 1999; Yamakawa et al., 2006; Ramchandren and Liebeskind, 2007). Prostate cancer is one of the most common cancers occurring in males over 50 years of age (Haas and Sakr, 1997; Crawford, 2003; Wilt, 2003). An established treatment for this type of cancer is chemical castration (androgen deprivation) (Crawford, 2004; Perlmutter and Lepor, 2007). If indeed HFI development is triggered by hormonal imbalance as previously suggested, then androgen suppression (altering the androgen-estrogen ratio) should raise the prevalence of HFI in males.
The aim of the present work was to examine the hypothesis that sex hormones in males may generate the development of HFI.
MATERIAL AND METHODS
Macroscopic examination of the inner aspect of the skull was carried out in two groups of males over 60 years, at the Carmel Medical Center, Haifa, Israel between 2004 and 2007, utilizing CT scans [Brilliance 64 (Philips Medical Systems, Cleveland, Ohio): slice thickness 3 mm × 1.5 mm, 120 kV, 300–400 mAs, rotation time 0.4–0.5 sec, pitch 0.39, FOV 220 mm and Matrix 512 × 512]. The control group included 180 healthy males, 45 suffering from hypertrophy/hyperplasia of the prostate. The study group included 127 males with prostate cancer: 67 had received complete androgen block treatment for prostate cancer for 1–5 years (mean = 2.8 years, SD = 2.4). Of the remaining 60, 21 had received no treatment and 40 had received other types of treatment such as a partial androgen block, chemotherapy and/or radiotherapy between the cancer diagnosis and head CT scan. The present study was approved by the hospital's institutional review board (Helsinki committee).
HFI identification and classification was based on a modified version of Hershkovitz et al.'s (1999) method, adapted for 3D CT images (Fig. 1). The 3D reconstruction was performed on a dedicated workstation Philips EBW. A total of 90–150 slices were used per volume rendering (VR). The reconstructed skull was then sectioned on the coronal plan enabling the observer (HM) to examine the topography of the inner table of the frontal bone. Three types of HFI were identified via VR techniques: Minor HFI—a nodular bony overgrowth with a slight elevation usually occupying less than 25% of the frontal bone surface area (Hershkovitz type B); Moderate HFI—a more extensive nodular bony overgrowth, associated with irregular thickening of up to 50% of the frontal endocranial surface (Hershkovitz type C), and severe HFI—a continuous elevated bony overgrowth involving more than 50% of the frontal endocranial surface (Hershkovitz type D).
This method was adopted for three major reasons: it is the only method utilizing numerical evaluation; it considers minor occurrences of HFI, not just the severe cases; and it is the only method with known reliability and validity. It is noteworthy that all types of HFI exhibit similar typical microstructure characteristic of HFI (Hershkovitz et al., 1999; Rühli et al., 2007; Talarico et al., 2008), and should therefore be considered as a gradual expression of the same phenomenon.
Inter- and intrareliability tests were carried out on 27 individuals who had undergone a head CT at the Carmel Medical Center, Haifa, Israel [Brilliance 64 (Philips Medical Systems, Cleveland, Ohio)]. The interobserver test was performed by three independent researchers (I.H., G.D., and H.M.). The intraobserver test was performed three times by H.M at 2-week intervals between each sample ranking. Both tests produced good results (Landis and Koch, 1977), Kappa = 0.75 and Kappa = 0.793, respectively. The validation of the CT-based method was carried out by scanning 46 cadaver skull caps and rating them twice: first, from CT images only and then, by direct observation (Kappa = 0.82).
The association between prostate cancer and HFI was examined using the Chi-square test. The Mann-Whitney test was conducted to study the differences in HFI type distribution between the two groups (using SPSS 15.0 software).
The mean age of the prostate cancer group was 78.54 (6.76) and the control group, 77.82 (9.54). In the nonprostate cancer group, no significant difference in HFI prevalence was found between males who manifested hypertrophy/hyperplasia of the prostate and those who did not, 37.0% versus 28.9%, respectively (x2 = 0.985, df = 1, P = 0.321). In the prostate cancer group, the difference in prevalence of HFI between males with prostate cancer who received a complete androgen block and those who received other types of treatment or no treatment at all was 58.2% versus 41.7% (x2 = 3.465, df = 1, P = 0.063; Fig. 2). The prevalence of HFI among males who received a complete androgen block to suppress the cancer (58.2%) was significantly higher compared to males without prostate cancer (35%; x2 = 10.849, df = 1, P = 0.001). No significant difference was found between healthy males and males with prostate cancer who had not received a complete androgen block, 35% and 41.7%, respectively (x2 = 0.861, df = 1, P = 0.353).
No significant difference in HFI type distribution between the study and control groups was observed (P = 0.559). The relative proportion of each type was similar in both groups, however, there was a significant difference (P < 0.05) in the prevalence of minor HFI between the groups (28% vs. 49%, respectively).
Because of the limited sample of individuals who received a complete androgen block over a 3-year period, no significant association between duration of hormonal treatment and manifestation of HFI was found. Nevertheless, the data distribution presents a positive association between the two (Fig. 3). Males with prostate cancer who did not receive a complete androgen block manifested the lowest frequency of HFI (42%). Among males who received hormonal treatment, an increment in HFI prevalence with an increase in duration of treatment was found, appearing in 63% of all individuals who had undergone hormonal treatment for 5 years or more. A further study with an increased number of individuals, who received a complete androgen block for more than 5 years, should be performed.
The notion that HFI is hormonal imbalance-related, for both females and males, is well rooted in the medical literature, [e.g., (Richter, 1939; Henschen, 1949; Perou, 1964; Hershkovitz et al., 1999; Yamakawa et al., 2006)], albeit other factors have also been proposed (Ruhli and Henneberg, 2002; Glab et al., 2006; Mulhern et al., 2006; Talarico et al., 2008). In the current study, the hypothesis that one of the possible causes of HFI in males was due to a hormonal disturbance was examined. Both prostate cancer and hypertrophy/hyperplasia of the prostate are fed by androgens (Bostwick et al., 1992; Meikle et al., 1997), however, the treatment is different; only males with prostate cancer receive a complete androgen block. The fact that HFI is not associated with the benign growth of the prostate but is associated with androgen deprivation, strengthens the hypothesis that this treatment has more unidentified side effects. Furthermore, the difference in HFI prevalence between patients who received the luteinizing hormone-releasing hormone (LHRH) agonist and patients who received other types of treatment, lends further support to the hypothesis of this study. It should be emphasized that the androgen itself does not produce the HFI phenomenon but rather the changes in the estrogen/androgen ratio, namely a surplus of estrogen.
The finding that males who received a complete androgen block manifested significantly higher prevalence only for minor HFI compared to the controls, may be due to the short-term hormonal treatment prior to their head scans, not sufficient enough for HFI to develop beyond minor HFI. This view again supports the fact that HFI manifestation is associated with the duration of LHRH agonist treatment.
Finally, observing that between 35% and 41% of individuals without androgen suppression treatment developed HFI, may indicate that other unknown factors are involved in HFI development. However, the increase in the appearance of HFI when androgen suppression is involved (∼20%) strengthens the hypothesis that hormonal imbalance is a factor contributing to HFI formation.
Limitations of the study include: a) the absence of data relating to androgen levels of the three groups studied, and b) the inability to conduct direct observations on the inner aspect of the skulls. It may well be that one of the reasons for the high prevalence of HFI in this study compared to previous studies carried out on skeletal, cadaveric and plain radiograph materials [e.g., (Moore, 1955)] is due not only to the high resolution used in the current study, i.e., minor changes on the inner plate of the frontal bone were recorded as positive HFI, but also to the limitations of the VR method (false positive). These limitations did not affect the major conclusion of the study (the significant differences in HFI prevalence between the study and control groups) since both groups were similarly examined.
This study suggests that BPH does not promote development of HFI and that males who are hormonally treated for prostate cancer (androgen suppression) are at a higher risk of developing HFI compared to healthy males. In addition, the longer the duration of hormonal treatment, the higher the risk of developing HFI.
The authors thank Mrs. Phyllis Curchack Kornspan for her editorial services.