|Year : 2014 | Volume
| Issue : 3 | Page : 686-692
Diagnostic utility of p63 and α-methyl acyl Co A racemase in resolving suspicious foci in prostatic needle biopsy and transurethral resection of prostate specimens
Vikram Singh1, V Manu1, Ajay Malik1, Vibha Dutta1, NS Mani1, Seema Patrikar2
1 Department of Pathology, Armed Forces Medical College, Pune, Maharashtra, India
2 Department of Preventive and Social Medicine, Armed Forces Medical College, Pune, Maharashtra, India
|Date of Web Publication||14-Oct-2014|
Department of Pathology, Armed Forces Medical College, Pune, Maharashtra
Source of Support: None, Conflict of Interest: None
Aim of the Study: The objective is to assess the utility of the p63 and α-methylacyl CoA racemase (AMACR) in resolving suspicious foci in prostatic needle biopsy and transurethral resection of prostate (TURP) specimens.
Materials and Methods: A total of 470 cases are selected. These included 310 TURP specimens, 157 needle biopsies and 03 radical prostatectomy specimens. All the cases are reviewed and divided into three categories. Benign (370), cases with suspicious foci (40 cases) and malignant (60 cases). Immunohistochemistry (IHC) was carried out using monoclonal AMACR and p63 antibodies in the 40 suspicious cases along with positive and negative controls.
Results: This study showed AMACR had a sensitivity of 95%, specificity of 92.5%, whereas p63 had a sensitivity of 90%, specificity of 100%. All the 40 suspicious cases were resolved using a combination of morphology and IHC expression p63 and AMACR. In 13 (32.5%), of the 40 suspicious cases there was change of diagnosis based of morphology, clinical details and staining with p63 and AMACR, In the 11 cases (11/40), diagnosis was changed from the benign to malignant. In one case benign to high grade prostatic intraepithelial neoplasia (1/40) and in one case from malignant to benign (1/40). This change was statistically significant with P value of 0.013.
Conclusions: Combination of p63 and AMACR is of great additional value in combating the morphologically suspicious cases and should be used on case to case basis especially in prostatic needle biopsies and small foci lesions.
Keywords: α-methylacyl CoA racemase, immunohistochemistry, needle biopsy, suspicious foci
|How to cite this article:|
Singh V, Manu V, Malik A, Dutta V, Mani N S, Patrikar S. Diagnostic utility of p63 and α-methyl acyl Co A racemase in resolving suspicious foci in prostatic needle biopsy and transurethral resection of prostate specimens. J Can Res Ther 2014;10:686-92
|How to cite this URL:|
Singh V, Manu V, Malik A, Dutta V, Mani N S, Patrikar S. Diagnostic utility of p63 and α-methyl acyl Co A racemase in resolving suspicious foci in prostatic needle biopsy and transurethral resection of prostate specimens. J Can Res Ther [serial online] 2014 [cited 2019 Oct 16];10:686-92. Available from: http://www.cancerjournal.net/text.asp?2014/10/3/686/138194
| > Introduction|| |
Prostate cancer accounts for 33% of all the newly diagnosed malignancies among men in the United States. , However world-wide incidence of prostate cancer is increasing and it is expected to increase by four folds between 2002 and 2050 in men ≥65 years of age. 
There is a substantial increase in number of prostate needle biopsies, due to increased awareness and the widespread use of serum prostate specific antigen (PSA) as a mass screening test along with imaging studies for prostate cancer. Accurate diagnosis on needle core biopsy or transurethral resection of prostate (TURP) specimen is of utmost importance because if diagnosed early for malignancy, patient is benefitted as a result of a lesser invasive procedure instead of more radical procedures that is associated with significant mortality and morbidity.
Interpretation of the small volume biopsies can be very challenging due to the presence of either a small focus of cancer or due to the presence of many benign mimickers of malignancy such as adenosis (ADEN), sclerosing ADEN, atrophy, partial atrophy, basal cell hyperplasia (BCH), clear cell cribriform hyperplasia, post atrophic hyperplasia, nephrogenic adenoma, mesonephric hyperplasia, radiation atypia and seminal vesicle tissue. ,,
Immuno-histochemically basal cells can be demonstrated using basal cell markers (p63, CK5/6 and high molecular weight cytokeratin [HMWCK] 34 βE12) while evaluation of a suspicious focus. ,,
α-methylacyl CoA racemase (AMACR), a new potential prostatic adenocarcinoma specific marker, has been reported to have sensitivity ranging from 82% to 100% respectively. ,
The present study is carried out with the aim to evaluate the utility of immunohistochemistry (IHC) in resolving morphologically suspicious foci on TURP and needle core biopsy specimens.
| > Materials and methods|| |
Selection of cases
In this study, all retrospective prostatic tru-cut biopsies, TURP and radical prostatectomy specimens received from Jun 2008 to Jun 2010 and specimens from freshly diagnosed patients with features of prostatic enlargement after Jun 2010 until Jun 2012 were studied.
All the relevant paraffin blocks and H and E stained slides of prostate needle biopsies/TURP/radical prostatectomy from Jun 2008 to Jun 2012, were retrieved from the database of the Department of Pathology, of our hospital. There were total 482 cases, out of which 12 cases were excluded due to inadequate material and biopsy being non-representative. Finally 470 cases are selected for further evaluation. These included 310 TURP specimens, 157 needle biopsies and 03 radical prostatectomy specimens. The H and E stained slides of all the cases are reviewed by two experienced pathologist and divided into three categories. Benign (370), cases with suspicious foci (40 cases) and malignant (60 cases). A total of 40 cases with suspicious foci included 28 cases of atypical small acinar proliferation (ASAP), 07 cases of atypical/distorted morphology due to dense inflammation (INFL). Five known cases of prostatic adenocarcinoma with atypical foci (ATF) with cribriform morphology were also included; with an aim to study IHC pattern of p63 and AMACR in these kinds of foci and hence that they can be differentiated from the cribriform prostatic intraepithelial neoplasia (PIN), when encountered in isolation.
The 40 cases of each category were subjected to IHC with p63 and AMACR.
IHC for p63 and AMACR
The blocks from all suspicious and control cases were cut and mounted on poly l-lysine coated glass slides. Endogenous peroxidase activity was blocked by freshly prepared 0.3% hydrogen peroxide in methanol for 20 min. Subsequently, heat-induced epitope retrieval was performed as per manufacturers' instruction. IHC was performed by using anti AMACR antibody (Dako; Monoclonal rabbit Anti Human AMACR-clone 13H4) and a monoclonal anti p63 antibody (Santa Cruz Biotechnology, Inc., Santa Cruz, CA: Monoclonal mouse antihuman p63 antibody-clone sc-8431).
Evaluation of IHC
Immunostaining for p63 was interpreted as positive/negative. Positive staining was defined as positive staining of nuclei of basal cells. Positive staining, in the foci in question, was taken as evidence of benignity and negative staining of an entire suspicious focus was taken as presumptive evidence of malignancy. The pattern of positive staining as and continuous or discontinuous was also recorded to see the difference in various non-malignant conditions.
IHC results were considered positive, in case of circumferential, dark, diffuse or granular, cytoplasmic or luminal staining. The percentage positivity was graded from 0 to 3+ as follows: −0% cells (0, negative), 1-10% cells (1+, mild), 11-50% cells (2+, moderate), ≥51% cells (3+, strong). IHC results were considered as negative; if there was an absence of staining or if only focal weak non-circumferential fine granular staining was seen with the absence of staining in the adjacent benign glands.
Statistical analysis was performed using SPSS version 17. The significance of AMACR, p63 immunostains in resolving the ATF was analyzed using Chi square test. P <0.05 was considered to be significant.
| > Results|| |
A total of 40 biopsy proven cases of prostatic adenocarcinoma (malignant controls), 40 cases of benign prostatic hyperplasia (BPH) (benign controls) and 40 cases with suspicious foci, formed part of the study group (n = 120). Out of these 40 suspicious cases, 27 cases were needle core biopsy and 13 TURP specimens.
These 40 cases with suspicious foci were further subdivided into 03 groups, based on chronology of reporting and the use of immunohistochemical stains.
The initial diagnoses of all the 40 cases with suspicious foci that reported as, 12 cases (12/40) of BPH, 05 cases of INFL, 09 cases labeled as prostatic adeno-carcinomas (09/40). 14 cases were reported as normal prostrate tissue with no evidence of malignancy.
Group 2, cases were further subdivided into three groups
A total of 28 cases of ASAP, exhibiting small, crowded atypical glands with architectural and cytological atypia, but insufficient to be labeled as malignancy.
It consisted of 07 cases of camouflaged morphology, due to dense INFL.
Five cases of prostatic adenocarcinoma carcinoma with co-existent ATF were included in this group. It was felt that these foci needed to be resolved in regard to their malignant status as this would have a bearing on the final score, as the score would be upgrade or downgrade based on whether they were resolved as benign or malignant. In three cases, foci of high grade prostatic intraepithelial neoplasia (HGPIN) were suspected and in two cases differential diagnosis was between cribriform PIN and Cribriform carcinoma. The aim of inclusion of these cases is also to learn and have a better understanding of their morphological characteristics so that they can be evaluated more efficiently when encountered singly in TURP and needle core biopsy without coexisting carcinoma.
These were the final diagnosis considered after evaluating all the data, work-up including the IHC evaluation.
IHC expression of P63 in the benign and in the malignant controls
In all the benign control cases (40), p63 highlighted the presence of basal cells in the form of moderate to strong nuclear positivity. Out of (40) malignant control cases, in 36 cases p63 expression was absent (36/40). In 04 cases focal p63 expression was present in the malignant glands (04/40) [Figure 1]. Sensitivity and specificity was calculated comparing results of the H and E (gold standard) with p63 expression in benign and malignant controls. In our study, we have concluded that p63 has a sensitivity of 90%, specificity of 100% and accuracy of 95% as shown in [Table 1].
|Figure 1: (a and b) H and E and immunohistochemistry (IHC) photomicrograph of p63 in benign prostatic hyperplasia case showing continuous, nuclear p63 positivity (c and d) H and E and IHC photomicrograph of p63 in prostatic adenocarcinoma case showing absence of p63 nuclear positivity in smaller malignant glands and presence of p63 nuclear positivity in larger benign glands|
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Expression of AMACR in the benign controls and malignant controls
Out of all the benign control cases (40), AMACR was totally negative in 37 cases. However in 03 cases, there was focal and weak luminal staining seen in the benign glands which were interpreted as negative. Out of all the malignant cases (40), AMACR was positive in in 38 cases and negative in two cases [Figure 2]. Sensitivity and specificity was calculated comparing results of the H and E (gold standard) with AMACR expression in benign and malignant controls. In our study, we have concluded that AMACR has a sensitivity of 95%, specificity of 92.5% and accuracy of the 93.75% as shown in [Table 2].
|Figure 2: (a and b) H and E and immunohistochemistry (IHC) photomicrograph of α-methylacyl CoA racemase (AMACR) in prostatic adenocarcinoma showing strong cytoplasmic positivity in malignant glands (c and d) H and E and IHC photomicrograph of AMACR: H and E section shows focal back to back benign looking glands which show negative AMACR staining|
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IHC expression of p63 and AMACR in the suspicious cases
All the 40 cases which were labeled as suspicious by reviewing pathologists were stained with p63, AMACR. All these cases were recategorized based on IHC expression. Summary of the IHC expression of the all the markers is given in the [Table 3] and shown in [Figure 3].
|Figure 3: H and E and immunohistochemistry photomicrograph of suspicious foci|
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Change of diagnosis after IHC
In 13 (32.5%), of the 40 suspicious cases there was change of diagnosis based of morphology, clinical details and staining with p63 and AMACR. In the 11 cases (11/40), diagnosis was changed from the benign to malignant. In one case from benign to HGPIN (1/40) and in one case from malignant to benign (1/40). This change was statistically significant with P value of 0.013. Correlation of original classification (group 1), reviewed (group 2) and final diagnosis after IHC with p63 and AMACR (group 3) is shown in [Table 4].
|Table 4: Correlation of original classification (group 1), reviewed (group 2) and final diagnosis after IHC with p63 and AMACR (group 3)|
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| > Discusssion|| |
Prostate cancer causes a significant health problem, being the second most common cancer in men. In today's world, PSA is the most widely used cancer serum markers.  There is growing evidence that widespread PSA screening and early detection of cancer resulted in decreased mortality associated with the decline in metastatic rate.  However, PSA test and associated analysis have been criticized since inception and controversies are still unresolved. 
The advent of the PSA screening also caused a significant increase in number of needle core biopsies. The diagnosis of prostate cancer in needle biopsy is based on the constellation of morphological features and frequently can be challenging, if only a small focus of atypical glands suggestive of adenocarcinoma is noted in the biopsy. 
Whenever we encounter smaller biopsies, tissue diagnosis of prostate cancer can be difficult due to the presence of either a small focus of cancer or due to the many benign mimickers of malignancy. ADEN, atrophy, partial atrophy, BCH, clear cell hyperplasia, post atrophic hyperplasia, nephrogenic adenoma, mesonephric hyperplasia, seminal vesicle all can mimic the malignancy. ,,
Proliferative foci of small atypical acini on prostatic biopsy that show some but not all features diagnostic of adenocarcinoma, have been described by a wide variety of terms which are synonymous such as suspicious, atypical focus and ASAP, suspicious and highly suggestive of but not diagnostic of malignancy. The most accepted terminology however is ASAP. The likelihood of prostate cancer on subsequent biopsy in men with a diagnosis of ASAP on initial biopsy is 21-49%. , Amongst the mimickers, atrophy and partial atrophy  are commonly misdiagnosed as prostate carcinoma (PCa). Low power maintenance of lobular architecture at least in part, uniform cytology, absence of prominent nucleoli and presence of a basal cell layer are the helpful features to distinguish it from prostatic adenocarcinoma. ADEN is defined as a focus of very crowded small glands suspicious for cancer, admixed with more recognizably benign glands. Glands have pale to clear cytoplasm with nuclei showing a lack of a very prominent nucleoli , and possess a fragmented or continuous basal cell layer.
In recent years, IHC using monoclonal antibodies against basal cell markers like p63, HMWCK (34 βE12) and CK 5/6 and prostatic adenocarcinoma specific biomarker AMACR have been used as adjuvant to morphology in diagnostically challenging cases with a very high sensitivity and specificity. This has increased the diagnostic accuracy of prostate cancer world-wide. Basal cell markers such as HMWCK (34 βE12) and CK 5/6 and p63 are very useful for demonstration of basal cells as their presence hints against a diagnosis of invasive prostatic adenocarcinoma. 
There are several limitation associated with the use of basal cell markers for the diagnosis of PC. The first is that relying on a negative finding, i.e. lack of basal cell staining to make a positive diagnosis of carcinoma. The second limitation is that some benign atypical lesions such as Atypical adenomatous hyperplasia (AAH), HGPIN, post atrophic hyperplasia (PAH) may show discontinuous or patchy staining, causing diagnostic confusion. , Seminal vesicle and ejaculatory duct epithelium is usually positive for basal cell markers, however results in Cowper's glands are controversial. 
Hence, one must be cautious in interpreting negative basal immunostains as they are supportive of a diagnosis of PCa in the appropriate H and E findings. The final limitation is the fact that there are reports of PCa positive for basal cell markers. 
Most of these positive cases are high grade PCa and are usually readily diagnosed based on H and E appearance. However there are reports of gland forming invasive acinar adenocarcinomas reported to harbor basal cells in 1% of cases. 
Thus, although basal cell markers are an extremely useful adjunct, it is important to recognize that the diagnosis of cancer is based on the absence of a detectable positive basal cell layer. Therefore, a sensitive and specific additional positive adenocarcinoma specific marker is required for confirmation of the diagnosis.
AMACR also known as CoA racemase or p504 S is a well-characterized enzyme that plays a key role in peroxisomal β oxidation of dietary branched-chain fatty acids and C27-bile acid intermediates. It is a sensitive and specific IHC marker found to be consistently up regulated in PCa. 
Multiple studies have now evaluated the utility of AMACR immunostain in the diagnosis of PCa. However there are varied reports regarding the expression of AMACR in prostate cancer which ranges from 62% to 100% respectively. ,,
In addition to prostate cancer, AMACR positivity has been demonstrated in 90% cases of HGPIN suggesting that the possibility of HGPIN must be carefully excluded by morphology and the use of basal cell markers, before AMACR positivity is used to establish the diagnosis of adenocarcinoma. AMACR positivity in HGPIN has been found to vary from weak to strong. AMACR expression is also identified in 4-21% of benign prostatic glands , and up to 18-27% of cases of ADEN. 
Although AMACR is a useful immunohistochemical marker for prostate cancer, it has also got significant limitations. In our view, AMACR should also be interpreted in the appropriate H and E findings and in conjunction with basal cell markers.
In the previous studies based on morphology, clinical details and the interpretation of the two markers Jiang et al.  found that the AMACR and HMWCK (34 βE12) IHC in the work-up of 41 foci of so-called ASAP led to a 76% agreement rate between the 3 pathologists participating in the study. Zhou et al.  demonstrated that, of 115 prostate biopsies diagnosed as atypical by an expert pathologist, 34 (30%) were changed to a final diagnosis of cancer based on a positive AMACR immunostain. A study done by Browne et al.  also found that the use of a cocktail of both a basal cell antibody and an AMACR immunostain helped resolve the diagnosis in 70% (86/123) of "challenging" prostate needle biopsies. Kunju et al.  were able to resolve 27 (93%) of 29 atypical biopsies after immunostaining with AMACR and basal cell markers. In one Indian study by Kumaresan et al.  showed that they could resolve 49 of the 50 atypical cases (98%), using HMWCK and AMACR.
In our study, we utilized the AMACR and p63 monoclonal antibodies and found AMACR has a sensitivity of 95%, specificity of 92.5% whereas p63 has a sensitivity of 90%, specificity of 100%. We have utilized these two monoclonal antibodies in combination (on different sections) to solve cases with atypical/suspicious foci. In the present study, we had 40 cases (40/470) equivalent to (8.5%) cases with suspicious foci, In various studies in literature the incidence of atypical biopsies ranged from 0.4% to 23% with a mean of 5.5%. 
We have also included five known cases of prostatic adenocarcinoma with ATF with cribriform morphology; with an aim to study IHC pattern of p63 and AMACR in these kinds of foci so that they can be differentiated from the cribriform PIN, when encountered in isolation. It is important because in modified Gleason score (GS) cribriform pattern is considered grade 4 when compare to grade 3 in classical GS. Since cribriform PIN can mimic cribriform pattern of prostatic adenocarcinoma, it can upgrade the tumor to intermediate grade (GS-7), in otherwise low grade (GS- ≤6) tumor and can potentially cause overtreatment of the patient because of difference in the treatment between these two grades. 
In this study, in 84.61% (11/13) cases there was change of diagnosis from benign to malignant, in 7.77% (1/13) cases from malignant to benign and in 7.77% (1/13) cases from benign to premalignant (HGPIN). These two cases were being under diagnosed on routine H and E due to the presence of limited adenocarcinoma. It would be better if the diagnosis of suspicious but not diagnostic of malignancy is given to such cases and IHC should be utilized as an adjunct to morphology. The other reasons for the error were INFL, missing out on HGPIN (not looking at high power judiciously) and diagnostic errors with benign mimics of carcinoma.
Rarely high grade PCa can express p63 and this is usually not a diagnostic problem, as AMACR is positive in the malignant cells (as was in our cases) and morphology is diagnostic of malignancy. In this study we have used p63 instead of 34betaE12, because 34betaE12 is highly susceptible to effect of formalin fixation and IHC procedures such as antigen retrieval pre-treatment, resulting in variable staining. It results in loss of staining in the benign glands and can cause misdiagnosis of prostatic adenocarcinoma. 
Hence, we conclude that though histopathological exanimation is the gold standard, a combination of p63 and AMACR is of great additional value in combating the morphologically suspicious cases and should be used on case to case basis especially in needle biopsies and small foci lesions.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]