Year : 2008 | Volume
: 51 | Issue : 2 | Page : 167--171
Useful markers for differential diagnosis of oncocytoma, chromophobe renal cell carcinoma and conventional renal cell carcinoma
Bita Geramizadeh, Mahmoud Ravanshad, Marjan Rahsaz
Department of Pathology, Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Transplant Research Center, Pathology Department, Shiraz University of Medical Sciences, Shiraz
Renal oncocytoma, conventional RCC (granular cell type) and chromophobe RCC have different prognosis. Sometimes differentiation between them is difficult in HandE slides. In a 5-year study of 128 renal tumors, we selected 76 cases [30 conventional RCC (CRCC), 16 papillary RCC, 21 chromophobe RCC (ChRCC), 8 oncocytoma, 1 collecting duct carcinoma (cdc)] and staining with Hale俟Q製 colloidal iron, CK7, CK8, CK18, CK19, CK20, Vimentin, EMA, CD10 and RCC marker were done. No significant difference was seen between renal tumor subtypes with CK8, CK18, CK19, CK20 and EMA. The most useful markers were Vimentin, CK7, CD10, RCC marker and Hale俟Q製 colloidal iron. Hale俟Q製 colloidal iron staining with diffuse reticular fine cytoplasmic pattern was present in ChRCCs, but was absent in other subtypes and oncocytomas. Vimentin, CK7, CD10, RCC marker and Hale俟Q製 colloidal iron can be used for the differential diagnosis of problematic epithelial tumors of kidney (CRCC, ChRCC and oncocytoma) - i.e. ChRCC: Vimentin, CD10 and RCC marker - negative, CK7 - positive and positive diffuse fine reticular cytoplasmic pattern of Hale俟Q製 colloidal iron; oncocytoma: Vimentin, CK7, RCC marker and CD10 - negative and Hale俟Q製 colloidal iron - negative; CRCC: CK7 - negative, Vimentin, CD10 and RCC marker - positive and Hale俟Q製 colloidal iron - negative.
|How to cite this article:|
Geramizadeh B, Ravanshad M, Rahsaz M. Useful markers for differential diagnosis of oncocytoma, chromophobe renal cell carcinoma and conventional renal cell carcinoma.Indian J Pathol Microbiol 2008;51:167-171
|How to cite this URL:|
Geramizadeh B, Ravanshad M, Rahsaz M. Useful markers for differential diagnosis of oncocytoma, chromophobe renal cell carcinoma and conventional renal cell carcinoma. Indian J Pathol Microbiol [serial online] 2008 [cited 2019 May 21 ];51:167-171
Available from: http://www.ijpmonline.org/text.asp?2008/51/2/167/41641
Renal cell carcinoma (RCC) is a malignant renal tumor of adults.  RCC is categorized as clear cell/conventional, papillary, chromophobe and cdc, renal medullary carcinoma, tubulocystic carcinoma, mucinous tubular and spindle cell carcinoma, oncocytoma and metanephric adenoma.  They have different prognosis. ,,
Oncocytoma is also a benign renal neoplasm that makes up approximately 7% of primary non-urothelial epithelial renal neoplasms. 
In most instances, oncocytoma and different histologic subtypes of RCC can be differentiated by gross and H and E stained microscopic slides, but sometimes differentiation between them is difficult, especially between eosinophilic variant of chromophobe RCC, granular variant of conventional RCC and oncocytoma. ,,
Several immunohistochemical and histochemical stainings are used to differentiate these tumors. ,,,,,,,,,,,,,,
In this study, we tried to combine H and E, IHC and histochemistry for the diagnosis of these tumors. For IHC, we used CK7, CK20, CK18, CK19, CK8, EMA, Vimentin, CD10 and RCC marker.
Materials And Methods
In this study, 128 cases of adult renal tumors were retrieved from the pathology archive (1998-2006). Patient's sex, age and gross features of tumors (necrosis, central scar, site and size) were collected from the pathologic reports. The age of patients was between 27 and 83 years. Fifty-eight percent of patients were males and 42% were females. All H and E slides of these 128 cases were reviewed, examined and recorded for necrosis, microscopic scar, papilla, inflammation, perinuclear clearing, oncocytic changes, hyperchromasia, nuclear wrinkling, nuclear pleomorphism, mitosis, nucleolus and multinucleation.
Out of 128 renal tumors in this period, we selected 76 cases [conventional RCC [grade I to IV] 30 cases; papillary RCC 16 cases; chromophobe RCC 21 cases; oncocytoma 8 cases; and cdc 1 case. Indeed, we reviewed all the cases but selected 30 out of 82 conventional clear-cell RCCs that had exactly the same characteristics.
The diagnosis of different types of RCCs was made according to the published criteria. ,
We selected the best representative slide and paraffin block for Hale's colloidal iron and IHC staining.
Monoclonal antibodies, which we used in this study by their dilutions, are listed in [Table 1].
Colloidal iron staining was performed using Muller-Mowry staining method. 
Normal renal tubular epithelium was present in most cases and provided good internal control for each antibody.
For each case and each antibody, a negative control with appropriate normal serum substituted for the primary antibody was performed simultaneously.
A case with more than 10% positive cells of different intensities was considered positive. Slides with less than 10% positive tumor cells were regarded as negative.
There was no significant difference between age and sex across different renal tumors.
The mean tumor greatest diameter in oncocytomas (5.8 cm) was less than ChRCCs (8.3 cm), PRCC (7.2 cm) and CRCCs (7.1 cm).
Microscopic central scars were seen in 5% (1) of CRCCs, 18% (4) of ChRCC, 87.5% (7) of oncocytoma and not seen in other subtypes.
Macroscopic central scars were seen in 50% of oncocytomas, 5% (1) of CRCCs, 12% (2) of ChRCCs and was absent in other subtypes.
Necrosis (microscopic or macroscopic) was seen in 72% (22) of CRCCs, 75% (12) of PRCCs, 50% (10) of ChRCCs and was absent in all oncocytomas.
Nuclear pleomorphism was seen in 12.5% (1) of oncocytomas and in 18.8% (4) of ChRCCs. Nuclear wrinkling was seen in 43.8% (9) of ChRCCs but not seen in oncocytomas.
Bi- and mutinucleation was seen in 50% (10) of ChRCCs and in only one oncocytoma. In other subtypes, multinucleation was more commonly present in higher grade tumors.
In addition to oncocytomas, focal oncocytic change was present in 6% (2) of CRCCs and 18.8% (4) of ChRCCs.
Mitosis was rare (or absent) in all cases and only one case had more than 1 mitosis per 20 HPF, which was considered grade IV CRCC.
CK8 was positive in 70% (21) of CRCCs, 87% (14) of PRCCs, 93% (20) of ChRCCs, 87.5% (7) of oncocytomas and 100% of cdc.
CK18 was positive in 87% (26) of CRCCs, 93% (15) of PRCCs, 100% of ChRCC, 87.5% (7) of oncocytomas and 100% of cdc.
CK19 was positive in 41% (12) of CRCCs, 75% (12) of PRCCs, 37.5% (8) of ChRCCs, 62.5% (5) of oncocytomas and 100% of cdc.
CK20 was positive in only 8% (2) of CRCCs, 6% (1) of PRCCs and 12.5% of ChRCCs, but was negative in all oncocytomas and one cdc.
CK7 was positive in 100% of ChRCCs, 8% (2) of CRCC and was negative in all oncocytoma.
EMA was positive in 75% (22) of CRCCs, 93% (15) of PRCCs, 100% of ChRCCs, 100% of oncocytomas and 100% of cdc.
Vimentin was positive in 95% (29) of CRCCs, 100% of PRCCs, 6.3% (1) of ChRCCs, 12.5% (1) of oncocytomas and 100% of cdc.
CD10 was positive in 79% (24) of CRCCs, 50% (8) of PRCCs and 6.3% (1) of ChRCCs. CD10 was negative in all oncocytomas and cdc.
RCC marker was positive in 62.5% (18) of CRCCs, 68% (10) of PRCCs and 100% of cdc. RCC marker was negative in all ChRCCs and was positive in only one case of oncocytomas (12.5%).
Hale's colloidal iron staining with chromophobe pattern (diffuse fine cytoplasmic) was present in 87.5% (18) of ChRCCs, but was negative in CRCC and oncocytomas. Four cases of PRCCs and one oncocytoma were also stained by Hale's colloidal iron, but staining was focal, coarse and without perinuclear halo pattern.
We had four cases with foci of sarcomatoid pattern in this study: two cases accompanied with chromophobe component and two cases accompanied with clear cell component. The spindle cell part of these tumors showed immunoreactivity for CD8 (50%), CD18 (50%), Vimentin (100%), EMA (50%), CD10 (100%), RCC marker (25%) and negative for CK19, CK20 and Hale's colloidal iron. The epithelial component of these four tumors showed same immunoreactivity of clear and chromophobe RCC.
There were no significant difference across different grades of RCCs regarding tumor size, age, site, presence of central scar, percentage of clear cell, expression of CK7, CK8, CD10, CK19, CK18, CK20, Vimentin, EMA and Hale's colloidal iron, but necrosis, hemorrhage, inflammation, papilla formation and nuclear atypia were more common with rising tumor grade. RCC marker was higher in low-grade tumor, i.e. 25% in grade IV and 75% in grade I.
The results of the most useful markers are summarized in [Table 2].
Renal epithelial neoplasms have different subtypes with different prognosis. ,,,, In most instances, differentiation between them is possible by careful examination of hematoxylin and eosin-stained slides and gross features of tumors. However, some renal tumors may show overlapping morphologic features, requiring the use of ancillary methods to reach a definitive diagnosis.
Pervious studies and the current study showed that, in addition to different gross and microscopic features, different renal epithelial neoplasms demonstrate distinctive Hale's colloidal iron and immunohistochemical staining patterns. ,,,,,,,,,,,,,,
Different expression patterns of cytokeratins (CK7, CK8, CK18, CK19 and CK20), Vimentin, EMA, CD10 and RCC marker may be potentially useful in differential diagnosis of renal epithelial neoplasm. ,,,,,,,,,,,,,,
Necrosis: In this study, necrosis was absent in all oncocytomas but present in other renal neoplasms (45-100%). So, the presence of necrosis is highly against the diagnosis of oncocytoma. This has also been appreciated in previous studies.
Stellate scar (macroscopy): In this study, scar was seen in 50% of oncocytomas but only seen in 5% of CRCC and 12% of ChRCC. So, the presence of macroscopic scar can be a diagnostic feature of oncocytoma. In the previous studies, this was reported as 53.8% and 33%.
Hale's colloidal iron: In the pervious studies, Hale's colloidal iron was positive strongly in chromophobe RCC with diffuse reticular pattern from 37% to 100% but were only weakly and focally positive in clear RCC and oncocytoma (from 0% to 100%). ,,, In our study, Hale's colloidal iron staining with fine reticular cytoplasmic pattern and with perinuclear halo was seen in 87.5% of ChRCC. But, only 16% of CRCCs and 12.5% of oncocytomas show focal coarse cytoplasmic staining without perinuclear halo. So, we concluded that Hale's colloidal iron staining of tumor cells with fine diffuse reticular pattern and perinuclear halo is diagnostic for chromophobe RCC [Figure 1].
CK7: In previous studies, CK7 was reported as diffuse and had strong reactivity in most chromophobe RCCs (60-100%), but with lower frequency was positive in clear RCC (0-20%) and oncocytoma (0-6%). ,,,,,
In our study also, the same result was seen. CK7 was positive in 100% of ChRCC, 8% of CRCC and was negative in oncocytomas. We concluded that CK7 is a useful marker for the diagnosis of ChRCC [Figure 2].
Vimentin: In the pervious studies, Vimentin was reported to be positive in most CRCCs (64-88%), but only positive in 0-21% of chromophobe RCCs and 0-10% of oncocytomas. ,,,
In our study, Vimentin was positive in 95% of CRCC, 6.3% of ChRCC and 12.5% of oncocytomas. So, we concluded that positivity of Vimentin is against the diagnosis of oncocytoma and ChRCC [Figure 3].
CD10: In most previous studies, CD10 was positive in CRCC (82-100%) but with lower frequency was positive in oncocytoma (0-29%) and ChRCC (0-33%). ,, Only one of the previous studies showed immunoreactivity for CD10 in 100% of ChRCC and CRCC and 66% of oncocytomas. 
In our study, the results showed that CD10 was positive in 79% of CRCC, 6.3% of ChRCC and was absent (0%) in oncocytoma. So, CD10 reactivity is in favor of CRCC [Figure 4].
RCC: RCC marker is another new IHC marker that is used for the diagnosis of RCCs. Previous studies showed that RCC marker was negative in oncocytomas. ,, One of the studies showed that RCC is negative in ChRCC but is positive in 47% of oncocytomas. 
In our study, RCC was positive in 62.5% of CRCC, 12.5% of oncocytomas, but negative in ChRCCs. So, positive RCC marker is another marker for CRCC [Figure 5].
EMA: Previous studies showed that EMA is positive in ChRCCs (75-100%), CRCCs (50-77%) and oncocytomas (51-86%). [ 9]
In our study, EMA was positive in 100% of ChRCCs, 100% of oncocytomas and 75% of CRCC. So, we concluded that EMA is not a good marker for the differentiation of renal tumors.
CK20: Two previous studies showed that CK20 is negative in ChRCC, CRCCs and oncocytomas. ,
In our study also, CK20 was positive in only 8% of CRCCs, 12.5% of ChRCCs and is negative in oncocytomas. Due to low expression of CK20 in all renal tumor subtypes, we concluded that CK20 is not a useful marker in DDx of different subtypes of renal tumors.
CK19: Skinnider and colleagues showed that CK19 was positive in only 13% of CRCCs and 33% of ChRCC. CK19 was negative in oncocytoma.
The same result was seen in our study. 
We noted that CK19 positivity is present in 41% of CRCC, 37.5% of ChRCC and 62.5% in oncocytomas. So, we concluded that CK19 is not a useful marker for the differentiation of renal epithelial neoplasms.
CK18: Skinnider et al , also showed CK18 positivity in 100% of CRCC, ChRCCs and oncocytomas. 
This is the same as our study in which CK18 was positive in 87% of CRCCs, 100% of ChRCCs and 87.5% of oncocytomas.
Because of the presence of CK18 in all subtypes of renal neoplasms, it cannot be a useful marker for differentiation between them.
CK8: Skinnider et al , also showed CK8 positivity in 50% of CRCCs, 50% of ChRCCs and 100% of oncocytomas.  With same results in our study, CK8 was positive in 70% of CRCC, 93% of ChRCC and 87.5% of oncocytomas. So, CK7 is not a useful marker for the differentiation of renal tumors
In conclusion, in the current study, CK8, CK20, CK18, CK19 and EMA were not useful markers for the differentiation between renal oncocytoma, chromophobe RCC and conventional RCC.
The most useful marker for the differentiation of renal tumors are Vimentin (positive in CRCC and negative in ChRCC and oncocytoma), CK7 (positive in ChRCC and negative in oncocytoma and CRCC), RCC marker and CD10 (positive in CRCC and negative in ChRCC and oncocytoma) and Hale's colloidal iron staining with diffuse reticular pattern and perinuclear halo (which is present in ChRCC and absent in Oncocytoma and CRCC).
|1||Kovacs G, Akhtar M, Beck with BJ. The Heidelberg classification of renal cell tumor. J Pathol 1997;183:131-3.|
|2||Eble JN, Sauter G, Epstein JI, et al. World health organization classification of tumors. Pathology and genetics of tumors of urinary system and male genital organs. Lyon, France: IARC Press: 2004.|
|3||Crotty TB, Farrow GM, Leiber MM. Chromophobe renal cell carcinoma, clinicopathologic feature of 50 cases. J Urol 1995;154:964-7.|
|4||Cochand-Priollet B, Molinie V, Bougaran J, Bouvier R, Dauge-Geffroy MC, Deslignieres S, et al. Renal chromophobe cell carcinoma and oncocytoma a comparative morphologic, histological and immunohistochemial study of 124 cases. Arch Pathol Lab Med 1997;121:181-6.|
|5||Langer C, Wegscheider BJ, Ratschek M, Schips L, Zigeuner R. Keratin immunohistochemistry in renal cell carcinoma subtypes and renal oncocytomas: A systematic analysis of 223 tumors. Virchows Arch 2004;444:127-34.|
|6||Wang HY, Mills ES. Kit and RCC are useful in distinguishing chromophbe renal cell carcinoma from the granular variant of clear cell renal carcinoma. Am J Surg Pathol 2005;29:640-6.|
|7||Mazal PR, Exner M, Haietel A, Krieger S, Thomson RB, Aronson PS, Susani M. Expression of Kidney-specific cadherin distinguishes chromophobe renal cell carcinoma from renal oncocytoma. Hum Pathol 2005;36:22-8.|
|8||Mai KT, Burns BF. chromophobe cell carcinoma and renal cell neoplasm with mucin-like changes. Acta Histochem 2000;102:103-13.|
|9||Skinnider BF, Flope AL, Hennigar RA, Lim SD, Cohen C, Tomboli P, et al. Distribution of cytokeratins and Vimentin in adult renal neoplasms and normal renal tissue. Am J Surg Pathol 2005;29:747-54.|
|10||Mathers ME, Pollock AM, Marshc Donnell Mo. Cyktokeratin 7: A useful adjunct in diagnosis of chromophobe renal cell carcinoma. Histopathology 2002;40:563-7.|
|11||Kuroda N, Toi M, Nakamura H, Miyazaki E, Haysahi Y, Yamamoto M, et al. Immunohistochemical identification of intracytoplasmic lumen by cytokeratin typing may differentiate renal oncocytoma from chromophobe renal cell carcinoma. Histol Histopathol 2004;19:23-8.|
|12||Leroy X, Moukassa D, Copin MC, Saint F, Mazeman E, Gosselin B. Utility of cytokeratin 7 for distinguishing chromophobe renal cell carcinoma from renal oncocytoma. Eur Urol 2000;37:484-7.|
|13||Abrahams NA, MacLennan GT, Khoury JD, Ormsby AH, Tamboli P, Doglioni C, et al. Chromophobe renal cell carcinoma: A comparative study of histological immunohistochemical and ultrastructural features using high through put tissue microoarray. Histopathology 2004;45:593-602.|
|14||Dai L, Lu XH, Li ZH, Li R, Liu H, Liu Yl, et al. Value of special stain and immunohistochemistry in the diagnosis of renal neoplasm. Zhonghua Bing Li Xue Za Zhi 2004;33:140-2.|
|15||Avery AK, Beckstead J, Renshow AA, Christopher L, Corless L. Use of antibodies to RCC and CD10 in the differential diagnosis of renal neoplasia. Am J Surg Pathol 2000;24:203-10.|
|16||Pan CC, Chen PC, Ho DM. The diagnostic utility of MOC31, Ber Ep4, RCC marker and CD10 in classification of renal cell carcinoma and oncocytoma. Histopathology 2004;45:452-9.|
|17||Yang B, Ali SZ, Rosenthal DI. CD10 facilitates the diagnosis of metastatic renal cell carcinoma from primary adrenal cortical neoplasm in adrenal fine-needle aspiration. Diagn Cytopathol 2002:27:149-52.|
|18||Langner C, Ratschek M, Rehak P, Tsybrovskyy O, Zigeuner R. CD10 is a diagnostic and prognostic marker in renal malignancy. Histopathology 2004;45:460-7.|
|19||Skinnider BF, Jones EC. Renal oncocytoma and chromophobe renal cell carcinoma. A comparison of colloidal iron staining and electron microscopy. Am J Clin Pathol 1999;111:796-803|