renal cell carcinoma ( rcc ) is traditionally divided into 5 major subtypes : clear cell , papillary , chromophobe ( chrcc ) , collecting duct , and unclassified types . first described in 1985 , chrcc is characterized by recognizable pathognomonic features . although chrcc is generally thought to portend a favorable prognosis when compared with its clear cell counterpart , debate on this issue still exists . in most studies , patients with chrcc have a significantly increased 5-year survival when compared to patients with clear cell rcc ; however , the actual 5-year survival estimates vary widely . moreover , in several of these studies , rcc subtype was not shown to be statistically significant in a multivariable analysis of risk . the grading system proposed by fuhrman in 1982 has long been used to stratify rcc into a four - tiered grading system based on nuclear size , nuclear irregularity , and nucleolar prominence . however , this system was proposed before the current classification scheme of rccs , and it was recently demonstrated that fuhrman grading is not useful as a prognostic indicator for chrcc . by definition , chrcc is comprised of tumor cells with irregular nuclei with variation in nuclear size , and as a result , chrccs would generally be assigned a fuhrman grade of 3 . because of this issue , paner et al . recently proposed a three - tiered chromophobe tumor grade ( ctg ) system , that they report , demonstrates a positive association of ctg with both pathologic stage and outcome ( fig . 1 ) . a subsequent study of 203 patients with chrcc utilized a modified grading scheme similar to that in the paner et al . study ; however , this scheme was not shown to be significantly associated with outcome . another study of 84 patients with chrcc utilized the ctg system of paner et al . and found that ctg was not an independent predictor of outcome in multivariable analysis of non - sarcomatoid tumors . given these continuing controversies in chrcc , we reviewed and analyzed 81 cases of chrcc that were surgically removed at our institution to better understand potential prognostic variables in this specific subtype of rcc . we evaluated all available chrccs identified from the surgical pathology archives of our hospital from 1997 - 2010 . the consultation cases of chrcc did not undergo surgery by the providers in our department . pathology consultation cases ( i.e. , cases in which the glass slides were sent to our institution by a pathologist with a request to help with histologic classification ) were excluded to avoid bias towards cases that were difficult to classify and/or ones with adverse features at the time of diagnosis . basic demographic data was recorded , and two pathologists ( e.p.w . and j.k.m . ) reviewed all slides to confirm tumor subtype and pathologic stage . specifically , slides were individually examined to confirm that the pathologic features were consistent with the diagnosis of chrcc , such as voluminous cytoplasm , prominent cytoplasmic borders / membranes , and nuclei with irregular " raisin - like " nuclear membranes . eosinophilic variants consisting of abundant , pink , granular cytoplasm and a distinctive perinuclear halo were also recognized as chrcc . institutional review board approval was obtained prior to the initiation of the study . from the database , demographic data , surgical details , disease status , follow - up interval , ctg grading was assigned to each case , as was the percentage of tumor comprised of each grade . the hallmark of the ctg system is that it downplays the common nuclear atypia seen in chrcc and instead includes such features such as nuclear crowding , anaplasia , nuclear pleomorphism , and sarcomatoid change . statistical analysis using fisher exact test was then performed on the patient cohort with follow - up information available . 1 illustrates some of the distinctive pathologic features of chrcc and of ctg 1 - 3 . eighty - eight cases with available glass slides were identified and reviewed and of these , 81 independent cases of chrcc were found . these excluded cases comprised of 5 cases that were similar to renal neoplasms that have been reported as " hybrid oncocytic tumor " or " oncocytic renal neoplasm of low / uncertain malignant potential " , 1 rcc unclassified type , and 1 clear cell rcc . these 81 cases of chrcc represented 7% of all of the 1,150 total rcc cases diagnosed in that time interval . twenty one of the eighty one surgical resections ( 26% ) included at least one lymph node for evaluation ; of these , only one , at pt3 stage , demonstrated involvement by chrcc . after reassignment of the cases using the proposed ctg system both ctg3 cases were found to have sarcomatoid differentiation . all cases with ctg2 also had foci of ctg1 ; the percentage of tumor comprised of ctg2 ranged from less than 5% to 60% . cases presenting at american joint committee on cancer 7th edition   stage > 3 were as follows : 8/52 ctg1 ( 15% ) , 5/27 ctg2 ( 18.5% ) , and 2/2 ctg3 ( 100% ) . sixteen patients underwent partial nephrectomy , 7 of which were performed laparoscopically or robotically , and 57 underwent radical nephrectomy , 26 of which were performed laparoscopically . of the 3 patients ( 4.1% ) who experienced cancer specific death or recurrence , the patient who died of disease had pt3 , ctg3 disease at diagnosis , and died 2.9 years postdiagnosis . one patient who presented with metastatic disease with pt4 , ctg2 disease at diagnosis had further disease spread to the liver and is alive at 4.5 years of follow - up . the other patient who developed recurrent disease had pt3 , ctg2 disease at diagnosis and developed bony metastasis and aortocaval nodal recurrence and is alive at 3 years of follow - up . among the remaining 70 patients with follow - up , 59 are alive with no evidence of disease , and 11 have died without evidence of disease . of these 70 patients , 45 had pt1 disease , 16 had pt2 disease , and 9 had pt3 disease at diagnosis . additionally , of these 70 patients , 45 had ctg1 tumors and 25 had ctg 2 tumors . using fisher exact test , pathologic stage demonstrated a significant association with the occurrence of cancer specific death or recurrence ( p=0.001 ) . when ctg1 was compared with ctg2 , there was no significant association with recurrence or death ( p=0.140 ) but when ctg1/ctg2 tumors were combined and compared to ctg3 tumors , this association with cancer recurrence or death was significant ( p=0.040 ) . when chrcc cancer specific survival was compared to that of clear cell rcc with a control group matched by stage and tumor size , chrcc demonstrated an overall statistically better survival ( log rank test , p<0.003 ) . chrcc is a well described subtype of rcc , and has been reported to comprise from 1.6%   to 6.5%   of all rccs , behind clear cell and papillary subtypes . in our cohort , we had very few cancer specific deaths or recurrences . similarly , a recent study by przybycin et al .   evaluated 203 consecutive cases of chrcc and determined a similarly low 5-year disease - specific event rate ( 3.7% ) . this low rate of disease - specific events is also consistent with several previous studies that demonstrated an increased cancer - specific survival for chrcc over clear cell rcc . in one of the largest studies to date , reviewed 2,385 rcc cases , including 102 cases of chrcc , and reported improved 5-year cancer specific survivals , respectively , for chrcc versus clear cell rcc for both pt1 stage ( 100% vs. 88.7% ) , and pt2 stage ( 84.1% vs. 65.1% ) . also , a large 2009 study by teloken et al .   included 220 cases of chrcc and reported similar 5-year event free survival in favor of chrcc when compared with clear cell rcc ( 92% vs. 86% , respectively ) . this difference in outcome has also been corroborated by several smaller studies that demonstrated rates of progression - free and cancer - specific survival for chrcc above 90% for all stages combined . other studies have corroborated the increased survival of chrcc over clear cell rcc , but with 5-year survivals for chrcc between 80 and 90% . a 2000 swiss study by moch et al .   demonstrated a 5-year survival of only 78% for chrcc . however , only 21 of their 31 cases ( 68% ) were organ - confined , whereas in our series , 61 of our 73 cases ( 84% ) with follow - up were organ - confined , suggesting that the decreased survival seen in the moch study is potentially due to their increased proportion of higher stage disease . demonstrated that there was no significant difference in 5-year cancer specific survival between chrcc and clear cell rcc for pt3 or pt4 disease , although the number of cases of chrcc at high pt stage was limited . only one large study , to our knowledge , has demonstrated a 5-year cancer specific survival for chrcc lower than its clear cell counterpart ( 88.8% vs. 92.2% ) . although this study included 148 reported cases of non - metastatic chrcc , it included a large number of cases of clear cell rcc at pt1 stage ( 77% of all clear cell rccs ) , potentially decreasing the number of events associated with clear cell rcc . additionally , this study included cases from 26 institutions and lacked central pathology review , potentially limiting its pathologic consistency . although many studies have confirmed subtype to be an independent prognostic indicator by multivariable analysis , at least in low stage disease , several studies have determined subtype to be insignificant in such analysis . several of these studies , however , were limited by insufficient sample size , lack of central pathologic review , and/or relatively large numbers of chrcc with high stage disease , suggesting that pt3 or pt4 rcc may have a poor prognosis regardless of subtype . interestingly , although one large - scale study found histologic subtype to be an independent prognostic indicator by multivariable analysis , the incorporation of subtype did not significantly improve the prognostic model . many of the aforementioned studies that compared rcc subtypes included fuhrman grading in their analysis . recently , however , it has been recognized that this grading system is not useful for chrcc , since its nuclei are essentially fuhrman grade 3 by definition . to address this controversial grading issue , paner et al . recently developed a three - tiered ctg system which downplays the expected nuclear atypia of chrcc . this new grading system , but not traditional fuhrman grading , demonstrated a strong positive association with pathologic stage and outcome in their series of 124 chrccs . interestingly , in this multivariable analysis of outcome , pathologic stage was no a longer a significant prognostic variable , suggesting that the newly defined ctg and pathologic stage may be interdependent . following the introduction of the ctg system a recent 2011 study of 203 patients with chrcc found that outcomes did not show association with a tumor grading scheme similar to the ctg scheme . their modified grading scheme retained a 4-tiered system and did not take nuclear overcrowding into consideration , which was a major histologic criterion in the grading system proposed by paner et al . another recent study of 84 cases of chrcc at university of california , los angeles ( ucla ) found that , although there was a significant difference in recurrence - free survival between ctg1 and ctg2 tumors ( hazard ratio , 5.63 ) , only pathologic stage was retained as a significant independent variable in multivariable analysis of nonsarcomatoid tumors . some studies have shown that foci of poorly differentiated carcinoma or sarcomatoid differentiation do predict a poor prognosis and the cumulative reported evidence strongly suggests that these high grade chrccs have prognostic significance . in the memorial sloan kettering series , similarly , the ucla study found that 9 of 11 patients with sarcomatoid transformation developed metastatic disease . indeed , many case reports and series have similarly documented that chrcc with sarcomatoid differentiation is often associated with clinically aggressive disease . in our series , we found no significant difference between ctg1 and ctg2 in the occurrence of cancer mortality or recurrence , but there was a significant difference between a combined ctg1/2 group and ctg3 . this is not surprising given that ctg3 tumors represent sarcomatoid tumors , which , as mentioned in the above studies , do poorly . also , our results suggest that those with ctg1 and ctg2 tumors might be better stratified by pathologic stage for prognostic purposes , as all of the cancer specific deaths and recurrences were associated with tumors diagnosed at pt3 stage , and this association of stage with outcome was statistically significant , as has been shown in numerous other studies . since these histologically high grade / sarcomatoid carcinomas ( ctg 3 ) often present at high stage , it is often difficult to separate the two variables ; however , both our and the aggregate data support regarding these chrccs with sarcomatoid / poorly differentiated areas as high risk carcinomas . overall , although our study demonstrated a remarkably low rate of recurrence and death among patients with chrcc , current discrepancies in the literature remain with regard to outcome , grading , and the significance of this subtype . our study was limited in its prognostic scope by the retrospective nature of the study , the paucity of adverse events , and the presence of few high stage or grade tumors in our series ; however , given that our series was comprised of consecutive cases of chrcc surgically excised at a single tertiary referral institution , this paucity may indeed reflect the expected distribution of such variables in the disease . even the largest study of chrcc to date , which contained 220 cases , included only 9 chrcc - related metastasis or disease - specific death . chrcc may demonstrate such a favorable prognosis that only very few variables , such as pathologic stage or sarcomatoid dedifferentiation , may be important for clinical outcome . given the low rate of adverse events for chrcc , sufficient statistical power to address these prognostic issues will only be achieved by comparing outcomes of exceedingly large numbers of cases . chrcc is associated with a very favorable clinical course in the majority of cases with a very low incidence of cancer related death and recurrence at 5 years in this series . similar to recent reports , we found sarcomatoid differentiation to be rare ( approximately 2%-3% ) . we did not find an association between ctg 1 and ctg 2 and clinical outcome . in this study , only pathologic stage and ctg 3 was associated with cancer recurrence or death from chrcc .
purposethe chromophobe subtype of renal cell carcinoma ( chrcc ) has generally been associated with a better prognosis than the clear cell type ; however , debate continues as to absolute prognosis as well as the significance of certain prognostic variables . 
 we investigated the significance of pathologic stage and a recently proposed chromophobe tumor grading ( ctg ) scheme in predicting chrcc outcomes.materials and methodsall available chrccs were identified from our surgical pathology archives from 1987 - 2010 . 
 original slides were reviewed to verify diagnoses and stage , and each case was graded following a novel chromophobe tumor grade system criteria . 
 disease status was obtained from a clinical outcome database , and cancer specific deaths and recurrences were recorded.resultseighty-one cases of chrcc were identified , and 73 had adequate follow - up information available . 
 there were only 3 instances of cancer related recurrence or mortality , which included 1 disease specific mortality and 2 disease recurrences . 
 pathologic stage and ctg 3 were found to be significantly associated with the recurrences or death from chrcc , but there was no association with ctg 1 and ctg 2.conclusionschrcc is associated with a very low rate of cancer specific events ( 4.1% ) even at a tertiary referral center . in our study , 
 pathologic stage and ctg 3 , but not ctg 1 or 2 , were significantly associated with the development of these events .