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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 39  |  Issue : 2  |  Page : 263-269

The role and accuracy of immunohistochemistry in the preoperative staging of bladder carcinoma: a retrospective study


1 Department of Pathology, Benha University, Benha, Egypt
2 Department of Pathology, Assiut University, Assiut, Egypt

Date of Submission01-Jun-2019
Date of Acceptance15-Jun-2019
Date of Web Publication30-Sep-2020

Correspondence Address:
MD Shaimaa K Dawa
Department of Pathology, Faculty of Medicine, Benha University, Benha
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/EGJP.EGJP_34_19

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  Abstract 


Objective Our goal is to investigate the role and accuracy of the smooth muscle actin (SMA), vimentin, and smoothelin, and cluster of differentiation 10 (CD10) immunohistochemical (IHC) markers in discriminating between muscularis propria (MP), and muscularis mucosae, and myofibroblastic stromal reaction to avoid tumor overstaging or understaging bladder carcinoma (BC).
Patients and methods This retrospective study included 30 selected cases of BC diagnosed by transurethral resection as positive for MP invasion based on hematoxylin and eosin-stained sections only. After radical cystectomy, three cases of them showed no evidence of MP invasion. We applied SMA, vimentin, smoothelin, and CD10 as differentiation IHC markers hoping to clarify MP invasion from other mimickers.
Results Vimentin and smoothelin were reliable and dependable differentiation markers that could help in BC staging. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy in detecting MP invasion for the smoothelin were 94.1, 84.6, 88.8, 91.6, and 90%, respectively, and those for vimentin were 94.1, 92.3, 94.1, 92.3, and 93.3%, respectively, and were improved to 94.4, 100, 100, 92.3, and 96.7%, respectively, after combining smoothelin and vimentin results. Both SMA and CD10 could not help in differentiation between myofibroblastic and smooth muscles of both muscularis mucosae and MP.
Conclusion Morphology has certainly played a fundamental role in BC staging; however, in problematic cases, we suggest smoothelin and vimentin as IHC differentiation markers that could help in BC staging on small biopsies. We encourage our colleagues to perform larger scale prospective studies on transurethral resection specimens applying our recommended IHC panel to assess their potential role in BC staging on such small biopsies.

Keywords: bladder carcinoma, cluster of differentiation 10, smooth muscle actin, smoothelin, vimentin


How to cite this article:
Dawa SK, Elosaily GM. The role and accuracy of immunohistochemistry in the preoperative staging of bladder carcinoma: a retrospective study. Egypt J Pathol 2019;39:263-9

How to cite this URL:
Dawa SK, Elosaily GM. The role and accuracy of immunohistochemistry in the preoperative staging of bladder carcinoma: a retrospective study. Egypt J Pathol [serial online] 2019 [cited 2021 Apr 15];39:263-9. Available from: http://www.xep.eg.net/text.asp?2019/39/2/263/296055




  Introduction Top


Bladder cancer (BC) became the 10th most diagnosed type of cancer in 2018, and ∼549 000 newly diagnosed cases, with 200 000 deaths, were estimated worldwide. Among men, it occupies the sixth most prevalent cancer and the ninth cancer causing death. Male to female ratio is ∼4 : 1 globally. Incidence rates were the highest in Southern and Western Europe, followed by Northern America (Bray et al., 2018). Cigarette smoking and occupational exposures to certain chemical and water contaminants were the main risk factors concerning BC (Silverman et al., 2018). In Egypt, 8234 cases were reported in 2013 (6362 males and 1872 females). Its incidence rate in both sexes was ranked the third (6.9%) after liver (23.8%) and breast cancers (15.4%). In males, it was next to liver cancer, with an incidence rate of 10.7%. In female patients, it was next to breast cancer, with an incidence rate of 33.6%. New 28 337 cases were expected to be diagnosed cases by the year 2050 (Amal et al., 2014).

The most important information is provided by the pathology report after bladder mass transurethral resection (TUR) biopsy and is crucial for further management plan, and prognosis is the staging of urothelial carcinoma, including depth of tumor invasion, as superficial tumors with involvement up to lamina propria (LP) could be treated conservatively. However, invasion of muscularis propria (MP) implies more aggressive management. Accordingly, it is essential to determine the depth of invasion in such cases. This was problematic in a significant percentage of cases and led to understaging or overstaging of cancer bladder (Cheng et al., 2000; Chang et al., 2001; Lopez-Beltran and Cheng, 2003; Humphrey, 2004). In case that the TUR biopsy is well oriented, the morphological differentiation between the MP that are thick muscle bundles from the thin smooth muscle fascicles of the muscularis mucosae (MM) that are associated with blood vessels in the LP is possible (Ro et al., 1987; Epstein et al., 2004). Unfortunately, this is not easy in every case. This is because many factors can disturb orientation, such as fragmentation of biopsy and tangential cutting. Moreover, cautery artifacts, field obscurement by inflammation, and histological structural disturbances owing to tumor desmoplasia contribute in this dilemma too (Aydin et al., 2002; Paner et al., 2007; Vakar-Lopez et al., 2007). Hyperplasia of MM can resemble the MP, especially in TUR biopsies, and this leads to a potential difficulty in tumor staging in such cases. Another probable challenge is that the accompanied reaction of the myofibroblasts of the stromal is not constantly desmoplastic one, but also other cellular patterns up to pseudosarcomatous stromal response could be found. These myofibroblasts can usually be discriminated from the MM and MP smooth muscle fibers; however, misdiagnosed invasive BC muscularis was seen now and then when the cellular myofibroblastic responses were surrounding the tumor, proved by smooth muscle actin (SMA) immunoreactivity to confirm MP invasion (Young and Wick, 1988; Abdou, 2007). This arouses several significant questions: to what degree we can depend on immunohistochemical (IHC) in distinguishing reactive myofibroblasts from smooth muscle cells of both MM and/or MP; then, can IHC reliably be used in staging BC, particularly in the such cases mentioned above? The current work selected the antibodies as follows: SMA and smoothelin for contractile cells, vimentin for mesenchymal cells, and cluster of differentiation 10 (CD10) for reactive stromal cells (Iwaya et al., 2002; Ogawa et al., 2002; Bircan et al., 2006), hoping to evaluate the difference between these possibly discriminatory markers to distinguish each of these contractile components of the bladder wall (myofibroblasts, MM, and MP smooth muscles fibers) from each other.


  Patients and methods Top


After approval by the scientific ethical committee, the current study was performed in the Pathology Department at Benha University The histopathology data at Pathology Department at Benha University and pathology department at Asute University set were looked up for cystectomy specimen diagnosed as invasive bladder carcinoma at the period between January 2013 to September 2018. We collected the available archived formalin fixed tissue blocks of the 30 cystectomy cases. The corresponding hematoxylin and eosin slides were reviewed to recognize sections demonstrating invasive tumor traversing MM, penetrating MP, and accompanied by a myofibroblastic reaction. We decisively restricted this investigation to cystectomy specimens to be sure about the depth of invasion and the type of muscle and to compare these results with the TRU biopsy results. Tumor staging was assessed according to AJCC staging manual, 8th edition (Amin et al., 2017). The selected blocks were sectioned 4 μm thick, and IHC was applied The sections were deparaffinized, and then carried to the water. After that the sections were incubated in citrate buffer (6 pH) in the microwave at 600 W for antigen retrieval for either 20 min in case of smoothelin or 30 min for the remainder antibody. The next step is the blocking of nonspecific antigen using avidin followed by incubation of primary antibody against CD10 (ab951), vimentin (ab92547), SMA (ab5694), and smoothelin (ab869) (ABCAM) (DakoCytomation, Carpentaria, California, USA) at 1 : 100 dilutions for 1 h, and then incubated for 30 min after addition of secondary antibody. To visualize the reaction, diaminobenzidine (ab143166; DakoCytomation) was applied. Hematoxylin (ab143166; DakoCytomation) was used for counterstaining of the sections, and then slides were covered. Positive and negative controls were performed with each IHC run (positive control for SMA was performed on smooth muscle of appendix, positive control for CD10 was performed on lymph node tissue, positive control for smoothelin was performed on smooth muscle of appendix, and positive control for vimentin was performed on placental tissue). IHC slides of SMA, vimentin, smoothelin, and CD10 were assessed by semiquantitative method, taking into consideration the comparison of the intensity of staining to that of vascular the stained smooth muscle (VSM) fibers (positive internal control for SMA, smoothelin, and vimentin) as follows:
  1. Absent staining considered as negative.
  2. Weaker intensity of staining than VSM (mild).
  3. Equal intensity of staining VSM (moderate).
  4. Stronger than the intensity of staining VSM (marked/strong staining).


Statistical analysis

Receiver operating characteristic curve was applied to estimate the efficacy of the applied antibodies in differentiation between myofibroblasts and MM and MP smooth muscle fibers, which was assessed through calculating sensitivity, specificity, positive predictive value (PPV), as well as negative predictive value (NPV), in addition to accuracy of each IHC stain alone and in combination, considering the following formulas:



Sensitivity=[a/(a+c)]×100.

Specificity=[d/(b+d)]×100.

PPV=[a/(a+b)]×100.

NPV=[d/(c+d)]×100.

Accuracy=(true positives+true negatives)/(true positives+false positives+true negatives+false negatives)=[(a+d)/(a+b+c+d)]×100.

The collected data were statistically analyzed using Student t test, with statistically significant P value at 0.05.


  Results Top


Evaluation of routine hematoxylin and eosin-stained sections:

We found 90% agreement between preoperative and postoperative tumor staging, which revealed 27 out of 30 cases with confirmed MP invasion, whereas three (10%) cases showed disparity, as no evidence of MP involvement was detected in cystectomy specimens.

Evaluation of immunohistochemical-stained sections

  1. For the reactive myofibroblasts, it showed moderate to strong cytoplasmic vimentin expression ([Figure 1]i), moderate to strong cytoplasmic SMA staining ([Figure 1]c), and mild cytoplasmic staining of smoothelin, in all the examined cases ([Figure 1]g). However, the expression of CD10 in active myofibroblasts varied among cases, as 50% of cases showed high expression, whereas the other 50% of cases revealed mild to moderate expression ([Figure 1]e).
    Figure 1 (a) Transurethral resection (TUR) biopsy showing bladder carcinoma with query level of invasion, H&E, ×40. (b) TUR biopsy showing bladder carcinoma with myofibroblastic reaction, H&E, ×40. (c) Cystectomy specimen showing SMA expression in lamina propria stromal myofibroblastic cells, SMA, ×100. (d) Cystectomy specimen showing SMA expression in muscularis mucosa (thin arrow) and muscularis propria (arrow head), SMA, ×40. (e) Cystectomy specimen showing CD10 positivity in lymphocytic infiltrate and variable expression in vascular wall and myofibroblasts, CD10, ×200. (f) Cystectomy specimen showing CD10 negativity in both muscularis mucosa (black arrow) and muscularis propria (red arrow), CD10, ×40. (g) Cystectomy specimen showing invasive adenocarcinoma with absent smoothelin expression in muscularis mucosa and myofibroblastic with in between the muscle bundles, smoothelin. ×40. (h) Cystectomy specimen showing muscularis propria with moderate to strong smoothelin expression with invasive adenocarcinoma in between the muscle bundles, smoothelin. ×100. (i) Cystectomy specimen showing strong vimentin expression in muscularis mucosa and myofibroblasts with in between the muscle bundles, smoothelin. ×100. (j) Cystectomy specimen showing strong endomysial and endovascular vimentin expression. ×200. CD10, cluster of differentiation 10; H&E, hematoxylin and eosin; SMA, smooth muscle actin.

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  2. For smooth muscle fibers of the MM as well as MP, both displayed moderate to strong cytoplasmic SMA expression ([Figure 1]d), and both were absolutely negative for CD10 expression ([Figure 1]f). The smooth muscle fibers of the MM showed mild smoothelin cytoplasmic staining intensity in 93.3% of cases ([Figure 1]g) and moderate staining in 6.7% of cases, whereas the smooth muscle fibers of the MP showed a strong cytoplasmic smoothelin staining in all cases ([Figure 1]h, [Table 1]). In vimentin, smooth muscle fibers of the MM showed positive expression in all cases ([Figure 1]i), but detrusor smooth muscle cells rarely showed positive vimentin expression [two (6.7%) of 30 showed mild staining intensity]. In addition, a strong positive vimentin expression was observed in endomysial as well as endothelial cells between the smooth muscle fibers ([Figure 1]j).
    Table 1 The expression of the applied immunohistochemical markers in different contractile component

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We found that SMA was positive in all the contractile bladder wall component: myofibroblasts and smooth muscles of MM and MP. CD10 was negative in smooth muscles of both MP and MM in addition to its variability in staining the stromal myofibroblasts. For these aforementioned reasons, both SMA and CD10 could not be used as differentiation markers, and both were excluded from the statistical work of the current study.

The positivity of vimentin, along with negativity to smoothelin, was characteristic for reactive myofibroblasts. The combination of positive vimentin, along with negative to weak smoothelin staining, was found to demonstrate the MM smooth muscle cells. Positive strong smoothelin expression, and strong endomysial and endothelial vimentin expression were found to highlight detrusor smooth muscle fibers.

The observed IHC results of vimentin and smoothelin were subjected to statistical analysis using receiver operating characteristic curve to find out the accuracy, specificity, and sensitivity of each marker alone and in combination.

Smoothelin and vimentin were helpful in discriminating the three contractile components of the bladder wall (myofibroblasts and smooth muscles of both MM and MP). Smoothelin had 94.1% sensitivity, and 84.6% specificity, 88.8% PPV, 91.6% NPV, and 90% accuracy, with area under the curve (AUC) of 0.971. Vimentin had 94.1% sensitivity, 92.3% specificity, 94.1% PPV, 92.3% NPV, 93.3% accuracy, with AUC of 0.932. After combination of both smoothelin and Vimentin expression results, the statistical results were improved to be 94.4% sensitivity, 100% specificity, 100% PPV, 92.3% NPV, 96.7% accuracy, with AUC=0.995 (Graph 1).




  Discussion Top


The assessment of bladder lesions usually requires histopathological examination of small biopsies such as polypectomy or TUR biopsy. If carcinoma is detected, then an adequate pathological staging evaluation of such small specimens depends on the level of tumor invasion, which may be restricted to the epithelium only (noninvasive papillary carcinoma, or carcinoma in situ, invade into the subepithelial but not reach to detrusor muscle, extend to the detrusor muscle/MP, or invading the perivesical tissues) (Amin et al., 2017). Unless, this seemed to be quite straightforward, in BC staging at the pathological level, several pitfalls can occur (Lapetino et al., 2008) that every pathologist should take care to evade understaging or overstaging in such cases, as both of them are reviewed in a substantial percentage of cases in several studies (Cheng et al., 2000; Chang et al., 2001; Lopez-Beltran and Cheng, 2003). For example, a case was staged as pT2 BC after misinterpretation of smooth muscle fibers of the MM as MP; this case was directed for radical surgical excision (cystectomy) of such tumor, which would have the chance of conservative management (intravesical BCG therapy). This is a well-known problem particularly in the assessment of small bladder biopsies and TUR specimens (Ro et al., 1987; Aydin et al., 2002; Epstein et al., 2004; Paner et al., 2007; Vakar-Lopez et al., 2007). An infrequent difficulty emerged when myofibroblasts exhibited the sarcomatoid desmoplastic reaction associated with invasive BC, which deceptively gave the impression of MP invasion especially after confirmation by a positive SMA expression in such spindle cells that led to diagnosis of invasive tumor rather than tumor limited to LP (Young and Wick, 1988; Eyden, 2008). IHC characterization of each myofibroblasts versus MM versus MM smooth muscle cells is significantly crucial to explore the possible role of IHC in differentiating these cell types. Our result showed that SMA was highly sensitive in highlighting smooth muscle cells (100%, all smooth muscles were positive) but not specific in discriminating smooth muscle cells from myofibroblasts (the later were positive for SMA too). This was expected as earlier studies detected that myofibroblasts expressed smooth muscle-specific immunostains (Skalli et al., 1989; Ceballos et al., 2000). Accordingly, after assessment of SMA immunostained slides, we do not endorse using SMA to judge histologically questionable muscle-invasive BC. On the contrary, the current study found that absence of cytoplasmic vimentin expression in MP with endomysial and endothelial immunoreactivity pattern was diagnostically useful in discriminating the MP smooth muscles from that of the MM (the latter has strong cytoplasmic vimentin expression) with high sensitivity, specificity, and accuracy, as vimentin had 94.1% sensitivity, 92.3% specificity, 94.1% PPV, 92.3% NPV, and 93.3% accuracy, with AUC of 0.932. This finding confirmed a previous immunofluorescence study results, which noticed that the smooth muscle fibers of MP did not express vimentin in 8/8 cystectomy specimens assessed (Maake et al., 2006). Additionally, Kuijpers et al. (2007) detected ‘vimentin-positive cells in between smooth muscle bundles, and in the microseptae encircling their fascicles, but not in smooth muscle cells.’ This agreed with our finding of strong vimentin expression in the endomysial and endothelial cells in between the smooth muscle, which showed an exuberantly different expression of vimentin discriminating MP from MM smooth muscle fibers. In addition, the current study validated smoothelin as a highly sensitive and specific differential marker for smooth muscle fibers that could differentiate between smooth muscle fibers of MM (week staining intensity) and that of MP (strong staining intensity) beside the absence of smoothelin immunoreactivity in myofibroblasts. These results actually help along with routine stained sections in problematic diagnostic setting. These high specificity, sensitivity, and accuracy (smoothelin had 94.1% sensitivity, and 84.6% specificity, 88.8% PPV, 91.6% NPV, and 90% accuracy, with AUC=0.971) go hand in hand with earlier reports (Council and Hameed, 2009). Maake et al. (2006) was the first study to identify the smoothelin gene (by RT-PCR) and protein (by and immunofluorescence) in which they found that smoothelin was expressed by the bladder MP smooth muscle cells. Afterward, Kuijpers et al. (2007) detected smoothelin expressed only by the MP and did not stain the MM. The study by Lapetino et al. (2008) showed moderate to strong smoothelin expression in MP smooth muscle cells in 100% (32/32) of cases, whereas none (0/32) of the hyperplastic MM expressed moderate staining. These previous findings are comparable to our results in spite of minor differences, which may be owing to variations in antibody concentrations and methodologies used in these studies. Some authors hypothesized that the smoothelin expression on the muscularis propria an differs from its expression on muscularis mucosae because it is expressed at later stages of smooth muscle cell differentiation (Ratajska et al., 2001; Eyden et al., 2009) with more development of the contractile phenotype (van der Loop et al., 1997; Johansson et al., 1999). It might also be claimed that comparable developmental or functional suppositions may explain the different vimentin immunostaining patterns between MM and MP, which needs to be investigated in a future study.We investigated the sensitivity, specificity, PPV, NPV, and accuracy of a combination of vimentin and smoothelin, and we got better values than when each immunostaining was judged separately (94.4% sensitivity, 100% specificity, 100% PPV, 92.3% NPV, and 96.7% accuracy, with AUC=0.995). As in the current work, smoothelin and vimentin were very sensitive and specific in differentiating the smooth muscle cells of MM and MP as well as discriminating them from myofibroblasts, addition of mesenchymal markers like CD10 was no more needed to explore this issue. Furthermore, CD10 showed a wide difference in the myofibroblast staining intensity, and the absence of a dependable internal control diminished its diagnostic role too.

Study limitation

Although the current results acclaimed a possible role for immunostaining in staging of debated BC TUR biopsy specimens, some limitations that may decrease reproducibility of this study are the dependency of the results on the degree of immunostaining intensities in discriminating the MP from MM. To overcome these disparities in intensity that may occur due to, for example, different fixation methods or antibody dilutions, we recommended to custom the vascular smooth muscles an internal control to minimize these disparities and increase study reproducibility.

Another limitation of the current work is the limited sample number; this is because our study was planned to explore the potentiality of different IHC antibodies in nonequivocal cases (concerning the depth of BC invasion) to explore their potential role in BC staging.


  Conclusions Top


We investigated some immunostains that helped to discriminate myofibroblasts from urinary bladder smooth muscles as well as between MM and MP. Our results recommend an IHC stain panel composed of smoothelin, and vimentin to be the most useful in this regard. Positive vimentin expression along with negativity to smoothelin was an accurate marker that can distinguish myofibroblasts from smooth muscle fibers, whereas moderate to strong smoothelin expression and endomysial staining of vimentin discriminated MP.

Recommendations for future work

We advocate our colleagues to investigate more cases to perform further confirmatory research works on TUR specimens to explore the potential utility of our recommended IHC panel in BC staging of TUR specimens, as still the current results should be confirmed through gathering more cases having justified staging data, after which, a definitive conclusion may be made.[29]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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