Prostatic carcinoma is the most frequent malignancy and the second cause of death due to malignancy among men (Jemal et al., 2009). The diagnosis of prostate cancer is usually established by a microscopic examination of prostatic biopsy specimens performed in patients with an elevated level of prostatic-specific antigen and is based on a combination of architectural, cytological, and ancillary features rather than any single diagnostic criterion as none of them is absolutely sensitive and specific (Ryu et al., 2010). However, with the widespread use of the prostatic-specific antigen screening programs, there has been a remarkable change in prostatic carcinoma detection and staging toward an increased incidence of the low-volume, low-stage disease (Jemal et al., 2009).
A real challenge for the general pathologist is to discriminate prostatic carcinoma from its benign mimics in small prostatic biopsy specimens, especially as most mimics fit within the small gland category like basal cell hyperplasia, atrophy, postatrophic hyperplasia, atypical adenomatous hyperplasia, verumontanum mucosal glands, and mesonepheric glands (Anderco et al., 2010). This led to the newly defined entities of atypical small acinar proliferation (ASAP) suggestive but not diagnostic of malignancy and minimal/limited/minute carcinoma (Montironi et al., 2006; Anderco et al., 2010).
Not only small acinar lesions but also some metaplastic and inflammatory processes may be confused with cancer (Srigley, 2004).
The discrimination of these entities is very important because it entails different therapeutic approaches with a huge impact on patients’ lives (Jemal et al., 2009).
In these situations, an immunohistochemical study of the patient is mandatory to confirm prostatic carcinoma and/or distinguish it from its many benign mimics (Montironi et al., 2006).
Immunohistochemical stains for high-molecular-weight cytokeratins (HMWCK) such as 34 β E12, CK5/6, and more recently P63 have been used to identify basal cells that are typically present in benign glands but absent in prostatic adenocarcinoma. However, diagnostic pitfalls in the staining with basal cell-associated markers were found as Paner et al. (2008) reported false-negative staining for basal cell markers in some benign mimics and false-positive staining in some cases of prostatic carcinoma.
More recently, α-methylacyl-coenzyme A racemase (AMACR), a positive marker of prostatic adenocarcinoma, was found to be very useful to establish the malignant diagnosis (Reis Filho et al., 2003). However, diagnostic pitfalls in AMACR immunostaining were also found as Paner et al. (2008) reported positive AMACR immunostaining in some benign mimics and negative staining in some cases of prostatic carcinoma.
The aim of this study is to evaluate the role of immunohistochemical expression of P63 and AMACR (P504s) individually and in combination in improving the diagnostic accuracy (DA) of benign, atypical, and malignant prostatic lesions in order to minimize underdiagnosis or overdiagnosis of these lesions.
Materials and methods
This study comprised 48 prostatic lesions that were selected from the surgical files of the Pathology Department, Ain Shams University Hospital and Ain Shams Specialized Hospital, during the period from January 2003 to September 2010. There were 10 benign cases (eight cases of prostatic chips, one case prostatic core, and one case of simple prostatectomy), 20 malignant cases (six cases of prostatic chips, 12 cases of prostatic core, and two cases of simple prostatectomy), and 18 atypical cases (16 cases of prostatic cores and two cases of prostatic chips).
The 10 benign cases showed different benign mimics for prostatic adenocarcinoma. They comprised five cases of basal cell hyperplasia, two cases of prostatic atrophy, one case of prostatic adenosis (atypical adenomatous hyperplasia), one case of verumontanum mucosal gland hyperplasia, and one case of granulomatous prostatitis.
The 20 malignant cases were conventional prostatic adenocarcinoma (acinar) but with different Gleason patterns and scores comprising five cases of combined Gleason score 6 (3+3), eight cases of combined Gleason score 7 (3+4) in five cases and (4+3) in three cases, two cases of combined Gleason score 8 (one was 3+5 and the other 4+4), four cases of combined Gleason score 9 (4+5), and one case of combined Gleason score 10 (5+5). Two out of these 20 cases showed high-grade prostatic intraepitheal neoplasia (PIN).
In the atypical cases, the 18 cases included 14 cases of small acinar lesions and four cases of solid proliferation (two cases were initially diagnosed as prostatic carcinoma Gleason score 9, but after revision of the slides they were suspected to be inflammatory. The other two cases were initially diagnosed as benign, but after revision of the slides malignancy was suspected).
Formalin-fixed paraffin-embedded tissue sections 4–5 μm thick were prepared from the selected cases and subjected to routine hematoxylin and eosin staining (Hx and E) as well as immunohistochemical staining using both anti-P63 and anti-P504s as the primary antibodies. Histopathological examination of the Hx and E-stained sections was carried out first to label the examined focus in the benign and the suspicious cases. In malignant cases, we reevaluated the most common Gleason pattern, the highest Gleason pattern, Gleason score, PIN, and perineural invasion. Sections were prepared on positive charged slides and kept overnight at 50°C. Deparaffinization and rehydration were carried out, followed by antigen retrieval in the microwave using citrate buffer at 9.0 pH. Then peroxidase block and protein block were carried out. Incubation of the slides with the primary antibodies at 4°C overnight was carried out using anti-P63 to the human P63 antigen (a mouse monoclonal antibody, clone 4A4, 7 ml ready to use, Cat.No.CMA442R,Cell Marque, USA) and anti-P504s to the human AMACR enzyme (a rabbit monoclonal antibody, clone 13H4, 7 ml ready to use, Cat. No.CMA953R, Cell Marque, USA). This was followed by the secondary biotin-conjugated antibody for 1 h and finally peroxidase-conjugated streptavidin for another hour. Diaminbenzidine tetrachloride (freshly prepared) was added for 25 min, and then counter staining was performed in Harris hematoxylin, followed by dehydration, clearing, and mounting.
The positive control for P63 was the basal cells of the benign prostatic glands present in the slides examined (positive internal control).
The positive control for P504s included cortical renal tissue as well as prostatic adenocarcinoma.
Criteria for assessing P504s (α-methylacyl-coenzyme A racemase) immunostaining as optimal
According to Kumaresan et al. (2010), the strong coarse granular brown diffuse cytoplasmic or luminal (apical cytoplasmic) stain in the entire circumference of the gland was considered positive for AMACR, provided that the epithelial cells of the nearby hyperplastic prostatic acini as well as the prostatic stromal cells showed a negative or a weak cytoplasmic stain. They also reported that the percentage of positivity of immunohistochemical staining of AMACR was graded from 0 to +3 as follows:- 0% cells (0− negative), positive staining in 1–10% of cells (1+ mild), positive staining in 11–50% of cells (2+ moderate), and more than 51% of cells showing a positive staining pattern (3+ strong).
All our cases showed positivity in more than 51% of the cells; thus, the interpretation of the immunostaining was modified to positive or negative for statistical analysis.
Criteria for assessing P63 as optimal
A moderate-to-strong brown distinct nuclear staining of the outer basal cells of the prostatic glands (patchy or circumferential) was considered positive for P63 (Harvey et al., 2010).
Statistical analysis was performed using the SPSS (statistical program for social science) software version 15.0 (SPSS Inc., Chicago, Illinois, USA).
The diagnostic indices were calculated for each marker individually and then in combination including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and DA for AMACR as a malignant marker and P63 as a benign marker.
From this study, we found that AMACR showed a coarse granular brown cytoplasmic stain in all malignant cases (20 of 20 cases) (100%) (Figs 1a and 2a) including the PIN foci in two out of 20 malignant cases. However, it showed a negative immunostaining pattern in nearly all benign cases (nine of 10 cases) (90%), except for one positive benign case of prostatic hyperplasia with prostatic atrophy (Table 1). Thus, AMACR showed a highly significant expression in malignant cases compared with benign cases with P value less than 0.001. The diagnostic indices for AMACR (as a malignant marker) showed a sensitivity of 100%, a specificity of 90%, a PPV of 95%, a NPV of 100%, and a DA of 97% (Table 2). Thus, AMACR is a sensitive rather than a specific marker for prostatic carcinoma.
However, P63 was not expressed in any malignant case (zero of 20 cases) (Figs 1b and 2b), except the glands of a PIN lesion that showed a patchy expression of P63. P63 showed a positive expression in nearly all benign cases (nine of 10 cases) (90%) (Figs 3 and 4), except in one case of solid proliferation (granulomatous prostatitis) (Table 1). Thus, P63 showed a highly significant expression in benign cases compared with malignant cases with P value less than 0.001. The diagnostic indices for P63 (as a benign marker) showed a sensitivity of 90%, a specificity of 100%, a PPV of 100%, an NPV of 95%, and a DA of 97% (Table 2). Thus, P63 is specific rather than a sensitive marker for benign prostatic glands.
With the combined use of AMACR and P63, the sensitivity, the specificity, PPV, NPV, and DA became 100% for the malignant immunostaining expression pattern (+AMACR/−P63) with an increase in the specificity of AMACR for malignant cases (Table 2).
The application of AMACR (as a malignant marker) and P63 (as a benign marker) immunostaining on the suspicious (atypical) cases was carried out for their further reevaluation (Table 3).
After interpretation of the immunohistochemical results for the atypical group (18 cases), in strict correlation with the morphology of the Hx and E-stained sections, the cases were reevaluated as follows: seven cases of small acinar lesions (initially diagnosed as suspicious) were (AMACR+ve/P63−ve) (Fig. 5a and b) and thus, reevaluated as malignant. Seven cases of the small acinar lesions (initially diagnosed as suspicious) were reevaluated as benign; six of these were (AMACR−ve/P63+ve) (Fig. 6a and b) and one case was diagnosed only by negative AMACR. Two cases of solid proliferations (initially diagnosed as benign prostatic hyperplasia) were (AMACR +ve/P63−ve) (Fig. 7a and b) and thus, reclassified as malignant. Two cases of solid proliferations (initially diagnosed as prostatic adenocarcinoma Gleason score 9) were (AMACR −ve/P63−ve) and were reclassified as benign inflammatory lesions. (Table 4). Therefore, the final diagnoses of our studied cases were 29 malignant cases and 19 benign cases, with no remaining atypical cases (Table 5).
Underdiagnosis of a small focus of prostatic adenocarcinoma or the overdiagnosis of a benign lesion mimicking cancer is not uncommon. It represents a potential liability for pathologists that may have unfortunate consequences for patients and so differentiation of these entities is very important (Jiang et al., 2004).
The immunohistochemical diagnosis of prostatic carcinoma largely depends on a panel of markers because no absolutely specific and sensitive marker for prostate cancer has been discovered as yet (Wang et al., 2008). Negative staining for basal cells in a few suspicious glands is not a definitive proof of malignancy, as benign conditions can have a patchy or a discontinuous distribution of basal cells. Rarely, prostatic adenocarcinoma may also contain cells positive for basal cell markers. Therefore, AMACR, a sensitive and specific positive marker of prostatic adenocarcinoma, would be very useful in raising the confidence level in the diagnosis on limited specimens for prostatic needle cores (Reis Filho et al., 2003).
The most commonly used basal cell-specific marker was HMWCK but more recently (P63) has been used to highlight the basal cells (Oliai et al., 2002).
Weinstein et al. (2002) found less false-negative results for P63 compared with HMWCK. This is concomitant with the results of Shah et al. (2002), who found a higher sensitivity for P63 over CK 903, as it was expressed in all the benign cases studied with 100% sensitivity compared with lower sensitivity for CK 903 as it was affected by extended formalin fixation. They concluded that P63 is sensitive and specific for the identification of basal cells in diagnostic prostatic specimens. This is parallel to our result, which demonstrated that P63 is a specific benign marker as it was not expressed in any malignant case (100% specificity). However, our results showed lower sensitivity for P63 (90%) as there was one negative benign case with granulomatous prostatitis. Logically, P63 positivity was not expected in this case as it is composed of inflammatory cells with no basal cells. If this case were to be excluded from our statistical analysis, the sensitivity of P63 would increase to (100%). This is in agreement with Molinié et al. (2004), who found a sensitivity of (98%) for P63. However, the patchy distribution of P63 in some benign glands in most of our benign cases should merit a meticulous examination of any suspicious gland. This finding is supported by Hameed and Humphrey, (2005) as they found weak reactivity to basal cell markers in a percentage of benign cases. Moreover, Paner et al. (2008) reported some benign glandular lesions that were P63 negative for the mesonepheric gland, Cowper’s gland, and nephrogenic adenoma because they do not have basal cells. Therefore, these lesions represent potential diagnostic pitfalls for P63 immunostaining. Unfortunately, our results cannot confirm this finding as such cases were not encountered in our studied cases.
In this study, the two cases of PIN showed a definite focal staining for P63 and this was comparable with the results of Herawi et al. (2006), who reported disruption of basal cells in high-grade PIN glands. Moreover, several studies supported the focal reactivity to P63 (or any other basal cell marker) in PIN glands as well as some benign glands (Epstein, 2004; Paner et al., 2008; Hong-Fai et al., 2009). Thus, negative staining for basal cells in a few suspicious glands could not help establish a definite diagnosis of malignancy. Consequently, there was a real need for a sensitive and specific prostatic malignant marker.
Since the discovery of AMACR, several studies have been carried out and have shown significant expression of AMACR in malignant cases compared with benign cases, with some variation in sensitivity and specificity (Jiang et al., 2001; Jiang et al., 2002; Luo et al., 2002; Luo et al., 2002; Rubin et al., 2002).
Jiang et al. (2001) reported 100% sensitivity for malignancy regardless of Gleason grades. Rubin et al. (2002) reported 97% sensitivity and 100% specificity. Jiang et al. (2002) reported 95% sensitivity and 100% specificity. Finally, Luo et al. (2002) as well as Luo et al. (2002) reported 95% sensitivity and 96% specificity.
In this study, we found strong granular cytoplasmic staining for AMACR in all the malignant cases studied with (100%) sensitivity and minimal expression in benign cases with (90%) specificity. In agreement with our results, Suzue et al. (2005) found strong cytoplasmic granular staining of AMACR in all prostatic carcinoma cases with 100% sensitivity and no staining in most of the benign prostatic cases with 88% specificity. More recently, Jiang et al. (2004) reported strong AMACR immunostaining in almost all prostate cancers with little or no immunoreactivity in benign glands. Harvey et al. (2010) reported higher specificity than that recorded in our study as no immunostaining for AMACR was found in all their studied benign cases (100% specificity for malignancy). In contrast, Kumaresan et al. (2010) reported lower sensitivity for AMACR than that found in our study with 94% sensitivity.
However, Beach et al. (2002); Zhou et al. (2004); and Paner et al. (2008) reported much lower sensitivity and specificity for AMACR that ranged from 75 to 82%.
With the difference in the sensitivity and specificity of AMACR immunostaining, Magi-Galluzzi et al. (2003) studied AMACR in prostatic specimens from different institutions and they concluded that the sensitivity and specificity for AMACR may vary in specimens from different pathology laboratories, possibly because of differences in fixation and processing. They emphasized the importance of optimizing the staining technique for each laboratory.
In the present study, we showed strong AMACR expression in two cases of premalignant lesions (PIN) but the number of cases was insufficient for a statistical analysis. Epstein, (2004) reported that AMACR labeled almost all cases of high-grade PIN, and this was in agreement with Paner et al. (2008) and Hong-Fai et al. (2009), who reported positive AMACR immunostaining in PIN cases.
In the present study, we had only two cases of prostatic atrophy: one was positive to AMACR, whereas the other was negative to AMACR. Unfortunately, the number of cases was insufficient for the statistical analysis of this result. On the contrary, the results of Molinié et al. (2004) confirmed the absence of AMACR expression in cases of prostatic atrophy but they observed granular cytoplasmic expression of AMACR in normal prostatic cells in 2% (four cases out of 260 cases) of their studied cases. In contrast, Herawi et al. (2006) reported that 15 out of 19 cases of prostatic atrophy were positive for AMACR. The increased AMACR expression by some normal prostatic glands may be attributed to upregulation of the metabolic pathways of prostate glands during carcinogenic processes that precede any malignant morphological changes in the cells.
Molinie et al. (2004) studied the sensitivity using both P63 and AMACR in making a decision in the evaluation of atypical prostatic cases. They reported that both the sensitivity and the specificity of using both markers was 95%, which was lower than our results (100% sensitivity, specificity, PPV, NPV, and DA) for the malignant immunostaining expression pattern (+veAMACR/−veP63). Iczkowski, (2006) and Paner et al. (2008) reported that the combined use of a basal cell-associated marker such as (P63) and a prostatic carcinoma marker (AMACR) can provide the best solution for ASAP, as benign prostatic glands are never simultaneously positive for AMACR and negative for basal cell markers (100% specificity). This is in accordance with our results, which showed 100% specificity for the benign immunostaining expression pattern (−veAMACR/+veP63).
In this study, foci of PIN were present in two cases of adenocarcinoma and they showed positive immunostaining for AMACR and P63. This expression was expected for the premalignant lesion as the metabolic pathways during carcinogenesis become activated, whereas basal cells are not yet lost. This is in agreement with the previous study of Browne et al. (2004), who reported positive staining for both markers in nine of their studied cases and evaluated them as PIN.
In the present study, all four cases of suspicious solid proliferation were negative for P63 and this was expected as P63 labels the basal cells of the benign acini and would never stain a solid proliferation unless it was comprised of basal cells (solid basal cell hyperplasia). Thus, in solid proliferations (such as poorly differentiated prostatic carcinoma, inflammatory cores, tangential cut in transitional epithelium, squamous metaplasia, and malakoplakia), it is recommended to use AMACR first to confirm or exclude malignancy. In this study, two out of the four cases (initially diagnosed as benign prostatic hyperplasia) were positive for AMACR and were reclassified as malignant. The other two cases (initially diagnosed as prostatic carcinoma) were negative for AMACR and, in combination with Hx and E morphology, they were reclassified as inflammatory lesions. This study points to a diagnostic pitfall where pathologists pay more attention to the small acinar lesions than to the solid proliferations, consequently missing the diagnosis of solid proliferations.
Anderco et al. (2010) reported that out of 17 equivocal cases they studied, six cases were positive for AMACR and negative for P63 and were reclassified as malignant, whereas 11 cases showed benign features (negative AMACR/ positive P63). In agreement, our study demonstrated the utility of AMACR/P63 in reducing the incidence of equivocal diagnoses in favor of diagnostic certainty as the 18 suspicious cases were reevaluated as nine benign cases and nine malignant cases.
Our study concluded on the following interpretation of AMACR/P63 immunostaining: Positive AMACR/negative P63; the case diagnosed as prostatic adenocarcinoma, negative AMACR/positive P63; the case diagnosed as benign mimics, positive AMACR/positive P63; the case diagnosed as prostatic intraepithelial neoplasia (prostatic premalignant lesion), negative AMACR/negative P63; and the ASAP is retained and further immunostaining may solve the case as prostatic-specific antigen. The same interpretation has been reported by Molinie et al. (2004) and Paner et al. (2008).
In conclusion, this study highlighted the value of the combined use of both AMACR as a marker for prostatic carcinoma and P63 as a marker for benign prostatic glands. This can improve the DA and reduce the use of a nonspecific diagnosis such as an ‘atypical or a suspicious lesion’. However, the diagnostic pitfalls and the limitations due to tissue loss in deeper sections must be kept in mind.
Conflicts of interest
There are no conflicts of interest.
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