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  Table of Contents    
ORIGINAL ARTICLE  
Year : 2020  |  Volume : 63  |  Issue : 3  |  Page : 405-411
Diagnostic utility of amylase α-1A, MOC 31, and CD 82 in renal oncocytoma versus chromophobe renal cell carcinoma


1 Department of Pathology, Faculty of Medicine, Zagazig University, Egypt
2 Department of Urology, Faculty of Medicine, Zagazig University, Egypt
3 Department of Urology, Faculty of Medicine, Menoufia University, Egypt

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Date of Submission16-Sep-2019
Date of Decision09-Dec-2019
Date of Acceptance30-Dec-2019
Date of Web Publication7-Aug-2020
 

   Abstract 


Objective: Renal oncocytoma (RO) and chromophobe renal cell carcinoma (ChRCC) originate from the same cell origin, that is, the intercalated cells of the collecting duct.[1] In most cases, there are clear morphologic differences between RO and ChRCC; however, in some instances, overlapping features may be encountered and the differentiation between the two entities becomes difficult.[2] Several immunohistochemical markers with different expression patterns in ChRCC and RO have been described to rule out this dilemma. Materials and Methods: About 47 primary renal neoplasms that had been diagnosed as RO or ChRCC were submitted for immunohistochemical staining of amylase α-1A (AMY1A), MOC 31, and CD 82. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy have been analyzed. Results: AMY1A positivity was observed in all RO cases in our work with 91.7% sensitivity and 100% specificity in the diagnosis of RO. The PPV of its expression was (100%) and NPV (97.2%) with a diagnostic accuracy of 97.9%. A significant high expression of MOC 31 was observed in ChRCC compared to its expression in RO with a statistical significance (P < 0.001). In addition, we obtained 82.9% sensitivity and 91.7% specificity of MOC 31 expression in the diagnosis of ChRCC. The positive predictive value (PPV) was (96.7%), negative predictive value (NPV) (64.7%) with diagnostic accuracy (85.1%). In our studied cases, we detected positive immunoexpression of CD 82 in 10 cases (83.3%) of ChRCC. However, it was lost in all RO cases (100%). CD 82 sensitivity and specificity in differentiating ChRCC from RO were 100% and 83.3%, respectively. Conclusion: We propose MOC 31 and CD 82 as negative immunostains for RO, as these markers are commonly expressed in ChRCC. In conjunction with AMY1A strong immunopositivity in RO cases, we provide a triple panel of biomarkers (AMY1A, MOC 31, and CD 82) for the distinction between RO and ChRCC.

Keywords: AMY1A, CD 82, chromophobe carcinoma, MOC 31, renal oncocytoma

How to cite this article:
Abouhashem NS, Abdelbary EH, H. Abdalla MM, El-Shazly M. Diagnostic utility of amylase α-1A, MOC 31, and CD 82 in renal oncocytoma versus chromophobe renal cell carcinoma. Indian J Pathol Microbiol 2020;63:405-11

How to cite this URL:
Abouhashem NS, Abdelbary EH, H. Abdalla MM, El-Shazly M. Diagnostic utility of amylase α-1A, MOC 31, and CD 82 in renal oncocytoma versus chromophobe renal cell carcinoma. Indian J Pathol Microbiol [serial online] 2020 [cited 2020 Sep 24];63:405-11. Available from: http://www.ijpmonline.org/text.asp?2020/63/3/405/291685





   Introduction Top


Tumors of the kidney include a heterogeneous group of lesions including oncocytoma, clear cell renal cell carcinoma (RCC), papillary RCC, chromophobe RCC, collecting duct carcinoma, and others. In most cases, these variants are histologically distinguished from each other and occasionally, there are overlapping histological features between them. In such cases, there is some difficulty to make a precise diagnosis of the examined tumors.[1]

Oncocytoma comprises about 3–5% of the renal tumors. It has a typical gross appearance with a tan or mahogany-colored mass containing central scar. The microscopic features include nested growth, bland cytology, deeply eosinophilic cytoplasm, and round, regular nuclei with prominent central nucleoli.[2]

Chromophobe renal cell carcinoma (ChRCC) is a malignant renal neoplasm, accounting for about 5% of the renal tumors. Classic ChRCC is composed of large pale cells having a “soap bubble” cytoplasmic appearance. The eosinophilic variant, that contains >80% eosinophilic cells, has alveolar, nested, or sheet-like architecture with granular eosinophilic cytoplasm and perinuclear clearing. The latter variant may mimic RO in certain conditions.[3]

Definite histologic differentiation between RO and ChRCC is essential due to several reasons, first being the well-documented benign clinical outcome of RO. Second, though ChRCC has a favorable prognosis, variants with the aggressive clinical outcome have been encountered. Finally, some ChRCC patients either require clinical follow-up for metastases development or adjuvant chemotherapy after surgical interference.[4]

Staining with Hale's colloidal iron is considered a conventional test that is commonly used in the differentiation between RO and ChRCC. Furthermore, Electron microscopy has been utilized in the differentiation between RO and ChRCC, however, it is expensive, work-intensive, time-consuming, and not feasible to practicing pathologists.[5]

Moreover, several immunohistochemical biomarkers with different expression patterns in ChRCC and RO have been established, including caveolin-1, amylase a1A, kidney-specific cadherin, CK7, melanoma antigen family A3 and A4 (MAGE-A3/4), claudin-7 and latent membrane protein 2 (LMP2). Nevertheless, none of these markers is completely specific.[4]

ChRCC has common deletions in the 1p21.1 region that includes the amylase α-1A (AMY1A) gene, unlike oncocytoma. Human α-amylases are mainly produced in the pancreas and salivary glands. Several studies reported the production of amylase enzyme (mainly salivary type) in some malignant tumors, such as lung cancer, plasmacytoma, ovarian cancer, and thyroid tumors.[6]

MOC-31 is a glycoprotein encountered on the cell membrane that is expressed in several benign and malignant epithelial tissues such as discriminating mesothelioma from adenocarcinoma. In addition, MOC 31 differentiates hepatocellular carcinoma from metastatic adenocarcinoma or cholangiocarcinoma.[1] CD82 is considered a metastasis suppressor gene, which has the ability to block one or more steps of the metastatic pathway. In the normal kidney, CD82 expression is distributed along the cell membrane of the distal tubules. CD82 overexpression has been noted in prostatic or colorectal tumors.[7]

The aim of this study was to examine the utility of AMY1A, MOC 31, and CD 82 in distinguishing between oncocytoma and ChRCC.


   Materials and Methods Top


Tissue specimens

Forty-seven primary renal neoplasms that had been diagnosed as RO or ChRCC were submitted for this retrospective study. These specimens were received from the Pathology and Urology Departments, Faculty of Medicine, Zagazig and Menoufia Universities in the period from 2010 to 2016. Our cases were divided into two groups: 35 cases of RO and 12 cases of ChRCC. All tissue samples were formalin-fixed and paraffin-embedded. Hematoxylin and eosin (H and E) stained slides and pathology reports were reviewed to confirm the diagnosis and histologic typing. Chromophobe RCC cases were staged according to the American Joint Committee on Cancer (AJCC) (7th edition). The demographic and clinical data were collected from hospital registry files. The study complied with the guidelines of the Declaration of Helsinki and was approved by the Institution Review Board, Zagazig University (Code 5761).

Immunohistochemical staining

Paraffin sections 3–5 um thick were deparaffinized in the oven at 56°C for 30 min, and inserted in xylene for 30 min. Tissues were rehydrated in descending grades of alcohol and then rinsed with distilled water for 5 min. Antigen retrieval was performed by boiling in sodium citrate buffer (0.001M, pH 6) for 15 min in the microwave. Endogenous peroxidase activity was blocked by incubation with 3% hydrogen peroxide for 10 min. After rinsing with distilled water, the slides were incubated with primary antibody (anti-Pancreatic alpha-amylase antibody (ab21156), rabbit polyclonal antibody from Abcam, diluted 1:500), mouse anti-human KAI1/CD82 monoclonal primary antibody (l: 250; sc-17752; Santa Cruz Biotechnology, Inc., CA, USA) and mouse monoclonal MOC-31 antibody (1:50, Dako, Denmark) overnight at 4°C. After three washes with phosphate-buffered saline (PBS), sections were incubated with biotinylated secondary antibodies for 30 min at room temperature. This is followed by incubation with the streptavidin-biotin-peroxidase complex. After three rinses with (PBS), the slides were incubated with diaminobenzidine for 15 min. Further, the slides were rinsed with distilled water and counterstained with hematoxylin for 3 min. This was followed by dehydration in ascending grades of alcohol and cleared with xylene, then cover slipped and examined.

Scoring criteria

Immunohistochemical staining was assessed semiquantitatively according to a combined score of the staining intensity and extent. Scores of 0–3 represented the percentage of positive tumor cells (0, 0%; 1, <25%; 2, 25–50%; 3, >50%) and the staining intensity (0, 0; 1, 1+; 2, 2+; 3, 3+). We counted positive tumor cells through ten representative high-power fields. Positive immunostaining AMY1A was detected in the cytoplasm while MOC 31 and CD 82 showed positive membranous immunostaining. The two scores were multiplied to give an overall score of 0–9.[8] Distal tubular epithelial cells were used as a positive control for MOC 31[1] while human normal pancreatic tissue was used as a positive control for amylase α-1A (AMY1A) staining and human kidney sections were used as a positive control for CD 82 staining.[9]

Statistical analysis

Categorical variables were expressed as a number. The validity of AMY1A, MOC 31, and CD 82 staining was calculated using diagnostic performance depending on sample 2 × 2 contingency tables. The sensitivities, specificities, positive predictive values (PPV), negative predictive values (NPV), and accuracies with their respective 95% confidence intervals were calculated. All tests were two-sided. A P value <0.05 was considered significant. All statistics were performed using SPSS 22.0 for Windows (SPSS Inc., Chicago, IL, USA) and MedCalc 13 for windows (MedCalc Software bvba, Ostend, Belgium).


   Results Top


Clinical and histopathologic data

The present study involved 47 patients with renal tumors, 32 (68%) of them were males and 15 (32%) were females. Their age ranged from 26 to 67 years (mean age of 48.17 ± 12.61 years). The diameter of the renal masses ranged between 3.2 cm and 11.5 cm (mean = 5.8 cm). Thirty-four cases (72.3%) underwent radical nephrectomy and 13 (27.7) masses underwent partial nephrectomy. Histopathologic diagnosis of these 47 renal masses were as follows: 35 (74.5%) cases of oncocytoma and 12 (25.5%) were conventional chromophobe carcinoma. ChRCC cases were categorized as stage I (3 cases), stage II (6 cases), stage III (1 case), and stage IV (1 case) [Figure 1]a and [Figure 1]c, [Figure 2]a and [Figure 2]c, [Figure 3]a and [Figure 3]c, [Figure 4]a and [Figure 4]c.
Figure 1: (a) Renal oncocytoma composed of oncocytes that are arranged in nests separated by loose fibrous stroma. (hematoxylin and eosin, ×200). (b) Renal oncocytoma showing moderate positive cytoplasmic immunostaining of AMY1A. (AMY1A immunostaining × 400) (c) Chromophobe renal cell carcinoma composed of large polygonal cells with irregular nuclei, perinuclear clear halo, and prominent cell membrane. (hematoxylin and eosin, ×200). (d) Chromophobe renal cell carcinoma showing negative cytoplasmic immunostaining of AMY1A (AMY1A immunostaining × 400)

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Figure 2: (a) Renal oncocytoma showing tumor cells with centrally located round nuclei and strongly stained eosinophilic cytoplasm. (hematoxylin and eosin, ×200). (b) Renal oncocytoma showing diffuse strong positive cytoplasmic immunostaining of AMY1A. (AMY1A immunostaining ×400).(c) Chromophobe renal cell carcinoma showing large polygonal cells with distinct cell borders intermixed with a variable number of small eosinophilic cells. (hematoxylin and eosin, ×200). (d) Chromophobe renal cell carcinoma showing weak focal positive cytoplasmic immunostaining of AMY1A. (AMY1A immunostaining × 400)

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Figure 3: (a) Chromophobe renal cell carcinoma showing large cells with distinct cell borders and abundant translucent cytoplasm. (hematoxylin and eosin, ×200). (b) Chromophobe renal cell carcinoma showing diffuse positive membranous immunostaining of MOC 31. (MOC 31 immunostaining, ×400). (c) Renal oncocytoma showing nests of small round tumor cells with hyalinized stroma. (hematoxylin and eosin, ×200). (d) Renal oncocytoma with weak focal membranous reactivity of MOC 31. (MOC 31 immunostaining, ×400)

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Figure 4: (a) Chromophobe renal cell carcinoma showing solid growth pattern with thin fibrovascular septa. (hematoxylin and eosin, ×200). (b) Chromophobe renal cell carcinoma showing diffuse positive membranous immunostaining of CD 82. (CD 82 immunostaining × 400). (c) Renal oncocytomas showing cells with abundant eosinophilic cytoplasm, indistinct cell borders and small uniform nuclei (hematoxylin and eosin, ×200). (d) Renal oncocytomas with negative membranous reactivity of CD 82. (CD 82 immunostaining × 400)

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Immunohistochemical staining results

In the current study, we evaluated the expression of AMY1A, MOC 31, and CD82 immunohistochemical markers in RO and ChRCC. The different expression patterns of the tested three markers were demonstrated in [Table 1].
Table 1: The different expression patterns of AMY1A, MOC 31, and CD 82 in RO and ChRCC

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Expression of AMY1A in RO and ChRCC

We detected higher expression of AMY1A in RO compared to its expression in ChRRC with a statistical significance (P < 0.001). AMY1A positivity was observed in all RO cases in our work [Figure 1]b and [Figure 2]b. However, it was detected in one case only of the studied ChRCC (8%) that were classified as stage II [Figure 2]d. Moderate-to-strong immunostaining for AMY1A (score 2 + and score 3+) was observed in 32 (91.4%) of the cases of RO [Table 2]. Negative AMY1A immunostaining was reported in 11 of 12 (91.7%) cases of ChRCC [Figure 1]d. Therefore, the sensitivity and specificity of AMY1A expression in the diagnosis of RO were 91.7% and 100%, respectively. The positive predictive value (PPV) was (100%), negative predictive value (NPV) (97.2%) with diagnostic accuracy (97.9%) [Table 5] and [Figure 5]a.
Table 2: AMY1A expression in renal oncocytoma and chromophobe carcinoma according to the pattern of staining

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Table 5: Diagnostic performance of AMY1A staining in the diagnosis of RO

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Figure 5: (a) ROC curve demonstrating the sensitivity and specificity of AMY1A expression in renal oncocytoma. (b) ROC curve demonstrating the sensitivity and specificity of MOC 31 expression in chromophobe renal cell carcinoma (c) ROC curve demonstrating the sensitivity and specificity of CD 82 expression in chromophobe renal cell carcinoma

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Expression of MOC 31 in RO and ChRCC

A significant high expression of MOC 31 was observed in ChRCC compared to its expression in RO with a statistical significance (P < 0.001), where only 6 cases (17%) of RO showed positive immunoreactivity for MOC 31 with about 67% of them showed weak focal expression [Figure 3]d. However, only one case (8%) of ChRCC does not react immunohistochemically with MOC 31 [Table 1] and it was categorized as stage I. Moderate-to-strong (3 + and 2+) MOC 31 positivity was observed in the remaining ChRCC cases [Table 3] and [Figure 3]b. Therefore, we obtained 82.9% sensitivity and 91.7% specificity of MOC 31 expression in the diagnosis of ChRCC [Table 6]. The positive predictive value (PPV) was (96.7%), negative predictive value (NPV) (64.7%) with diagnostic accuracy (85.1%) [Table 6] and [Figure 5]b.
Table 3: MOC 31 expression in renal oncocytoma and chromophobe carcinoma according to the pattern of staining

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Table 6: Diagnostic performance of CD 82 and MOC 31 staining in the diagnosis of chromophobe renal cell carcinoma

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Expression of CD 82 in RO and ChRCC

In our studied cases, we detected positive immunoexpression of CD 82 in 10 cases (83.3%) of ChRCC [Table 1] and [Figure 4]b. However, it was lost in all RO cases (100%) [Table 1] and [Figure 4]d. Among the positive CD 82 case s of ChRCC, more than 50% of them exhibited diffuse, strong-to-moderate immunohistochemical staining [Table 4] and [Figure 4]b. Concerning ChRCC, the negative immunoreactivity of CD 82 was observed in the high stage cases (III and IV). CD 82 sensitivity and specificity in differentiating ChRCC from RO were 100% and 83.3%, respectively. As regards, PPV, NPV diagnostic accuracy, they were 96.7%, 64.7% and 95.7%, respectively [Table 6] and [Figure 5]c.
Table 4: CD 82 expression in renal oncocytoma and chromophobe carcinoma according to the pattern of staining

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   Discussion Top


Oncocytoma and chromophobe carcinoma have a common cell origin, the intercalated cells of the collecting duct.[6] Despite the clear morphologic differences between RO and ChRCC in the majority of cases, overlapping features may be encountered in some instances and the differentiation between the two entities becomes difficult.[10] Consequently, further methods are required such as Hale's colloidal iron stain and immunohistochemical markers to make such distinction.[3]

In ChRCC, the Hale's colloidal iron stain shows strong diffuse staining, whereas in oncocytoma it has weak focal positivity. Unfortunately, Hale's colloidal iron stain is an exhausting process, and its staining consistency is poor.[11] In a study conducted by Abrahams et al.[12] they detected positive staining of Hale's colloidal iron in 37% only of the included ChRCC cases. Under the electron microscope, ChRCC shows cytoplasmic microvesicles ranging from 160 to 300 nm, hyaline globules, and tubulovesicular cristae of the mitochondria, microvilli, and rare glycogen particles. In contrast to RO that is characterized by abundant mitochondria.[12] Although the detailed features observed by the electron microscopy, it is an expensive, technically difficult to perform, exhausting process, and has limitations when performed on paraffin-embedded tissues.[6]

Several renal tumors exhibited distinct cytogenetic aberrations. ChRCC is associated with multiple monosomies, including chromosomes 1, 2, 6, 10, 13, 17, and 21, the identification of which can differentiate it from RO. Despite the great value of cytogenetic data in the distinction between ChRCC and RO, FISH analyses and cytogenetic data analysis are not feasible or available in many pathological laboratories. Its high cost and time-consuming factor represent an additional obstacle.[4] Roh et al. demonstrated that FISH and/or karyotyping were technically successful in only 60% of the enrolled cases.[13] Therefore, IHC is the convenient ancillary test used to distinguish these two renal tumors.[6]

In the last decades, several immunohistochemical markers have been used in the distinction between ChRCC and RO, including kidney-specific cadherin,[14] amylase α1A,[6] melanoma antigen family A3 and A4,[15] caveolin 1,[16] latent membrane protein 2 (LMP2),[17] claudin 7 and claudin8,[18] S100 α1 (S100A1),[19] and CK7.[20] Numerous series have reported superior diagnostic value using a combination of these immunostains compared with a single marker.[21]

The amylase genes consist of 6 kinds of isogene, 3 salivary amylase isogenes (AMY1A, AMY1B, AMY1C), 2 pancreatic amylase isogenes (AMY2A and AMY2B), and a truncated pseudogene (AMYP1). AMY1A gene and its mRNA transcripts were detected in the normal lung, thyroid gland, tracheal epithelium, fallopian tube, ovary, and uterine cervix.[6]

In the present study, AMY1A has expressed in all oncocytoma 35 cases (100%) with diffuse, moderate to strong staining of the tumor cells. According to our results, AMY1A has 91.7%, 100%, 100%, 97.2%, and 97.9% for sensitivity, specificity, PPV, NPV, and diagnostic accuracy, respectively. The aforementioned findings were consistent with Ng et al.[10] in their systematic review and meta-analysis of ten immunohistochemical biomarkers including AMY1A. They recommended a panel of IHC markers for the differentiation between ChRCC and RO, AMY1A immunostain was the first one in their list. Furthermore, Jain et al.[5] reported AMY1A as a novel marker in distinguishing oncocytoma from ChRCC. They observed positive reactivity for AMY1A in all their tested RO cases, while only 13% of the included ChRCC cases showed positive staining of AMY1A with weak positivity in most of them. With regard to our enrolled ChRCC cases, we observed negative AMY1A expression in all of them except one case which showed weak, focal staining unlike the diffuse strong staining characterized most of our RO cases. Our findings supported the significant value of AMY1A in differentiating oncocytoma from ChRCC.

In the present work, we detected the diffuse membranous expression of MOC-31 in most cases of chromophobe carcinoma (91.7%) unlike oncocytoma with a significant statistical difference (P < 0.001). Pan et al.[21] observed positive reactivity of MOC 31 in 23 (82%) of 28 chromophobe RCCs, whereas complete negativity was detected in all oncocytoma cases of their study. Furthermore, In Lee et al.[1] study, MOC-31 showed strong, diffuse membranous staining in 22 (96%) of 23 chromophobe RCCs and diffuse cytoplasmic staining in only 2 (25%) of 8 oncocytomas. Regarding the diagnostic utility of MOC 31 in the diagnosis of ChRCC, we obtained 82.9%, 91.7%, 96.7%, 64.7%, and 85.1% for sensitivity, specificity, PPV, NPV, and diagnostic accuracy, respectively.

In general, most oncocytomas do not react positively to MOC-31, but in some cases, MOC-31 positive staining may be noticed especially in oncocytomas with tubular differentiation. Further molecular analysis is needed to reveal the precise role of MOC-31 in tubular differentiation and tumorigenesis.[1]

Recently, CD 82, which is a metastasis suppressor gene, was found to be useful in the diagnosis of ChRCC.[9] In this study, we detected the positive expression of CD 82 in 10 cases (83.3%) of ChRCC. However, it was lost in all RO cases (100%) with 100% sensitivity and 83% specificity in differentiating ChRRC from RO. As regards, PPV, NPV and diagnostic accuracy, they were 96.7%, 64.7% and 95.7%, respectively.

Many authors have suggested the intercalated cells of the collecting ducts as the origin of RO and ChRCC tumor cells. With regards to the CD 82 expression in the normal collecting ducts, it is logic to observe positive staining of it in most ChRCC cases. However, CD 82 staining loss in RO could be related to the decrease of cell-cell interactions that occurred through the tumorigenesis.[9]

Kauffman et al.[22] have demonstrated that ChRCC stained diffusely with CD 82, where 87% (27/31) of their ChRCC tumors were stained positive with CD 82. Moreover, Yusenko et al.[9] demonstrated that CD 82 is an excellent marker in differentiating ChRCC from RO, using molecular methods such as reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. Furthermore, in Ohe et al.[8] immunohistochemical study on CD 82, 90% (18/20) of their ChRCC cases stained positive for CD 82 whereas 90% (9/10) of RO was negative. Therefore, our results coincided with the previous studies.

Taking into account the immunostaining profile of the evaluated 3 markers between indolent and aggressive ChRCC cases, there was no difference in the immunostaining of AMY1A as the only positive case was among the stage II group with the remaining 5 cases of the same group and other different stages showed negative results. To our knowledge, no previous reports support or contradict this finding. In relation to MOC 31 immunoreactivity, which was diffusely distributed among (91.7%) of ChRCC cases regardless the corresponding stage, the only negative case was categorized as stage I. The latter observation is in agreement with Lee et al.[1] Moreover, CD 82 staining was detected in (83.3%) of ChRCC cases that were classified as indolent chromophobe carcinoma (stage I and II). The loss of CD 82 expression was noted in two cases, one of them was stage III and the other case was reported as stage IV. The present result was consistent with Ohe et al.[8] who suggested that high CD 82 expression in ChRCC may denote a favorable prognosis based on the consideration of CD 82 as a metastasis suppressor gene. However, further studies with large-scale cases of aggressive ChRCC will be needed to prove this hypothesis.

Although the total number of the enrolled cases in this study is relatively small (this is related mainly to the rarity of the studied tumors), our results support the combined use of MOC 31 and CD 82 in excluding the diagnosis of oncocytoma, because no cases of RO were positive for both markers. Despite the observation of immunostaining in few cases of RO for MOC 31 marker, they did not react positively for CD 82.

In conclusion, we have demonstrated the utility of AMY1A, MOC 31 and CD 82 markers for the differential diagnosis of RO and ChRCC. We propose MOC 31 and CD 82 as negative immunostains for RO, as these markers are commonly expressed in ChRCC. In conjunction with AMY1A strong immunopositivity in RO cases, we provide a triple panel of biomarkers (AMY1A, MOC 31 and CD 82) for the distinction between RO and ChRCC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Correspondence Address:
Nehal S Abouhashem
Faculty of Medicine, Zagazig University
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJPM.IJPM_719_19

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