a total of 148 cases of uutuc diagnosed in the department of pathology , seoul national university hospital , were collected from the computerized database between 1998 and 2005 . hematoxylin and eosin  stained slides were reviewed to determine the pathological diagnosis , tumor grading and ptnm staging compared with the pathology report using the world health organization ( who ) classification and american joint committee on cancer ( ajcc ) staging system . four cases were excluded because of an inadequate amount of tissue , and eventually , 144 cases were included . the clinical records including age , sex , recurrence , metastasis and survival were collected . we produced tissue microarray ( tma ) blocks from formalin - fixed , paraffin - embedded tissue blocks ( superbiochips laboratories , seoul , korea ) . two representative core sections ( 2 mm in diameter ) were taken from the viable tumor area . this study was approved by the institutional review board ( irb ) of seoul national university hospital . ihc was performed with the herceptest kit ( dako , glostrup , denmark ) according to the manufacturer s protocols . her2 expression was separately analyzed using fda and asco / cap 2013 criteria . using the fda criteria , the 2+positive cases exhibited weak - to - moderate complete membrane staining in > 10% of tumor cells , whereas the asco / cap 2013 criteria defined the 2+positive cases as circumferential membrane staining that is incomplete and/or weak - to - moderate and present within > 10% of the invasive tumor cells , or complete and circumferential membrane staining that is intense and present within 10% of the tumor cells . the her2 ihc results were subcategorized into low ( 0 , 1 + ) and high ( 2 + , 3 + ) expression groups . fisher exact test and pearson s chi - square test were performed to analyze the correlations between the clinicopathological characteristics and her2 expression . the cancer - specific survival period was measured from the time of primary surgery to cancer - related death or the last follow - up . the kaplan - meier curves were plotted and the log - rank test was used for the univariate analysis of cancer - specific survival . a total of 148 cases of uutuc diagnosed in the department of pathology , seoul national university hospital , were collected from the computerized database between 1998 and 2005 . hematoxylin and eosin  stained slides were reviewed to determine the pathological diagnosis , tumor grading and ptnm staging compared with the pathology report using the world health organization ( who ) classification and american joint committee on cancer ( ajcc ) staging system . four cases were excluded because of an inadequate amount of tissue , and eventually , 144 cases were included . the clinical records including age , sex , recurrence , metastasis and survival were collected . we produced tissue microarray ( tma ) blocks from formalin - fixed , paraffin - embedded tissue blocks ( superbiochips laboratories , seoul , korea ) . two representative core sections ( 2 mm in diameter ) were taken from the viable tumor area . this study was approved by the institutional review board ( irb ) of seoul national university hospital . her2 ihc was performed with the herceptest kit ( dako , glostrup , denmark ) according to the manufacturer s protocols . her2 expression was separately analyzed using fda and asco / cap 2013 criteria . using the fda criteria , the 2+positive cases exhibited weak - to - moderate complete membrane staining in > 10% of tumor cells , whereas the asco / cap 2013 criteria defined the 2+positive cases as circumferential membrane staining that is incomplete and/or weak - to - moderate and present within > 10% of the invasive tumor cells , or complete and circumferential membrane staining that is intense and present within 10% of the tumor cells . the her2 ihc results were subcategorized into low ( 0 , 1 + ) and high ( 2 + , 3 + ) expression groups . fisher exact test and pearson s chi - square test were performed to analyze the correlations between the clinicopathological characteristics and her2 expression . the cancer - specific survival period was measured from the time of primary surgery to cancer - related death or the last follow - up . the kaplan - meier curves were plotted and the log - rank test was used for the univariate analysis of cancer - specific survival . a total of 144 uutuc cases were included in the present study , of which 108 cases were male and 36 cases were female . the mean age was 66 years old ( range , 43 to 87 years ) . the average tumor size was 4.2 cm ( range , 0.2 to 14.0 cm ) . lymph node metastasis was observed in nine cases , and distant metastasis was observed in two cases at the time of surgery . of the 144 cases , 14 were categorized as ptnm stage 0 ( 9.7% ) , 36 as stage 1 ( 25.0% ) , 23 as stage 2 ( 16.0% ) , 39 as stage 3 ( 27.1% ) , and 32 as stage 4 ( 22.2% ) . sixty - one cases were international society of urological pathology ( isup ) low grade and 83 cases were isup high grade . the mean follow - up period was 79 months ( range , 2 to 201 months ) . using the fda criteria , 94 cases ( 65.3% ) were negative , 38 cases ( 26.4% ) had a score of 1 + , nine cases ( 6.3% ) were 2 + , and three cases ( 2.1% ) were 3 + ( fig . 1 ) . using the asco / cap criteria , 94 cases ( 65.3% ) were negative , 34 cases ( 23.6% ) were 1 + , 13 cases ( 9.0% ) were 2 + , and three cases ( 2.1% ) were 3 + . four cases showing 2 + ihc result according to the asco / cap 2013 criteria were reclassified as 1 + by the fda criteria due to the incomplete membrane staining ( fig . isup high grade was associated with high her2 expression using both the fda criteria ( p=.001 ) and asco / cap 2013 criteria ( p<.001 ) . other clinical and pathologic characteristics such as sex ( p > .990 and p=.547 ) , age ( p=.761 and p=.430 ) , size ( p=.374 and p=.289 ) , t stage ( p>.990 and p=.604 ) , n stage ( p=.554 and p>.990 ) , m stage ( p>.990 and p>.990 ) , and ptnm stage ( p=.560 and p>.990 ) were not associated with her2 expression using both the fda and asco / cap 2013 criteria . the isup high grade , ptnm high stage , and her2 high expression groups , as classified by the fda criteria , were significantly associated with a shorter cancer - specific survival ( fig . 3a , her2 high expression group , as classified by the asco / cap 2103 criteria , did not show a significant association with a shorter cancer - specific survival ( p=.161 ) ( fig . ptnm and her2 expression , as determined by using the fda criteria , were independent prognostic factors for cancer - specific survival ( table 2 ) . a total of 144 uutuc cases were included in the present study , of which 108 cases were male and 36 cases were female . the mean age was 66 years old ( range , 43 to 87 years ) . the average tumor size was 4.2 cm ( range , 0.2 to 14.0 cm ) . lymph node metastasis was observed in nine cases , and distant metastasis was observed in two cases at the time of surgery . of the 144 cases , 14 were categorized as ptnm stage 0 ( 9.7% ) , 36 as stage 1 ( 25.0% ) , 23 as stage 2 ( 16.0% ) , 39 as stage 3 ( 27.1% ) , and 32 as stage 4 ( 22.2% ) . sixty - one cases were international society of urological pathology ( isup ) low grade and 83 cases were isup high grade . the mean follow - up period was 79 months ( range , 2 to 201 months ) . using the fda criteria , 94 cases ( 65.3% ) were negative , 38 cases ( 26.4% ) had a score of 1 + , nine cases ( 6.3% ) were 2 + , and three cases ( 2.1% ) were 3 + ( fig . 1 ) . using the asco / cap criteria , 94 cases ( 65.3% ) were negative , 34 cases ( 23.6% ) were 1 + , 13 cases ( 9.0% ) were 2 + , and three cases ( 2.1% ) were 3 + . four cases showing 2 + ihc result according to the asco / cap 2013 criteria were reclassified as 1 + by the fda criteria due to the incomplete membrane staining ( fig . isup high grade was associated with high her2 expression using both the fda criteria ( p=.001 ) and asco / cap 2013 criteria ( p<.001 ) . other clinical and pathologic characteristics such as sex ( p > .990 and p=.547 ) , age ( p=.761 and p=.430 ) , size ( p=.374 and p=.289 ) , t stage ( p>.990 and p=.604 ) , n stage ( p=.554 and p>.990 ) , m stage ( p>.990 and p>.990 ) , and ptnm stage ( p=.560 and p>.990 ) were not associated with her2 expression using both the fda and asco / cap 2013 criteria . the isup high grade , ptnm high stage , and her2 high expression groups , as classified by the fda criteria , were significantly associated with a shorter cancer - specific survival ( fig . , her2 high expression group , as classified by the asco / cap 2103 criteria , did not show a significant association with a shorter cancer - specific survival ( p=.161 ) ( fig . ptnm and her2 expression , as determined by using the fda criteria , were independent prognostic factors for cancer - specific survival ( table 2 ) . in this study , we evaluated her2 protein expression by immunohistochemistry in 144 cases of uutuc using the following two guidelines : the fda criteria and asco / cap 2013 criteria . the definitions of ihc 1 + and 2 + are different between the two guidelines , and the ihc results from two guidelines showed different prognostic significance in this study . the numbers of 1 + and 2 + positive cases were different , depending on the scoring system . four cases that scored 2 + using the asco / cap 2013 criteria were reclassified as 1 + by the fda criteria . this discrepancy resulted from differences in the definitions of 2 + and 1 + positive cases between the two criteria . the fda criteria classified the 2 + positive cases as having weak - to - moderate complete  membrane staining in more than 10% of tumor cells , whereas the asco / cap 2013 criteria defined the 2 + positive cases as having circumferential membrane staining that is  incomplete  and/or weak - to - moderate and present within > 10% of the invasive tumor cells , or complete and circumferential membrane staining that is intense and present within 10% of the invasive tumor cells . in previous studies , the rates of 2+/3 + her2 ihc in uutuc ranged from 14% to 18% [ 1 - 3 ] . in this study , the 2+/3 + her2 ihc rate was somewhat lower than those of previous studies ( 8.3% fda criteria and 11.1% asco / cap 2013 criteria in this study ) . the high ptnm stage , high isup grade , and high her2 expression group , as classified by the fda criteria , showed significantly shorter cancer - specific survival , whereas her2 expression classified using the asco / cap 2013 criteria did not show a significant association with shorter cancer - specific survival . the multivariate cox regression analysis indicated that the her2 ihc results classified by the fda criteria could be an independent prognostic factor for cancer - specific survival in patients with uutuc . these results suggest that the fda guidelines would be more suitable for analyzing her2 ihc in uutuc than the asco / cap 2013 guidelines . we think that these results may be important for predicting survival in actual clinical settings . some studies have tried to clarify the association between her2 status and the prognosis of urothelial carcinoma , and the results were diverse . langner et al .   reported that patients with score 2 + with the fda guidelines had a significant correlation with metastasis - free survival . used the asco / cap criteria and their result showed that her2 overexpression was not correlated with specific survival or recurrence . sasaki et al .   revealed that her2 positive patients showed a significant association with shorter time to recurrence using their own criteria according to the asco / cap criteria and the results of the trastuzumab for gastric cancer ( toga ) trial . tsai et al .   also used their own scoring system and showed the result that her2 expression predicted for disease progression and disease - related survival . we thought that the diverse results could be caused by the different scoring system for her2 ihc . furthermore , there has been no study that compared the fda and asco / cap guidelines for interpretation of her2 ihc in uutuc . in this study , we compared the fda and asco / cap guidelines for her2 ihc in uutuc , and found that the prognostic significance of her2 ihc was different between the two guidelines . we did not confirm the her2 gene amplification status by fluorescence in situ hybridization analysis , and this is the limitation of the present study . there have been some studies reporting good correlation between her2 protein overexpression and gene amplification in uutuc . in conclusion , our study indicated that the her2 ihc result has significant prognostic implications and the fda criteria are more suitable for interpreting the her2 ihc results in uutuc than the asco / cap criteria in uutuc .
backgroundhuman epidermal growth factor receptor 2 ( her2 ) is one of the known oncogenes in urothelial carcinoma . 
 however , the association between her2 and the prognosis of upper urinary tract urothelial carcinoma ( uutuc ) has not yet been fully clarified . 
 the aim of this study was to evaluate her2 expression using the united states food and drug administration ( fda ) criteria and american society of clinical oncology / college of american pathologists ( asco / cap ) criteria and compare their prognostic significance in uutuc.methodsher2 expression was evaluated in 144 cases of uutuc by immunohistochemistry ( ihc ) using tissue microarrays . 
 we separately analyzed her2 expression using the fda and asco / cap criteria . 
 the ihc results were categorized into low ( 0 , 1 + ) and high ( 2 + , 3 + ) groups.resultsusing the fda criteria , 94 cases were negative , 38 cases were 1 + , nine cases were 2 + , and three cases were 3 + . using the asco / cap criteria , 94 cases were negative , 34 cases were 1 + , 13 cases were 2 + , and three cases were 3 + . 
 four cases showing 2 + according to the asco / cap criteria were reclassified as 1 + by the fda criteria . 
 high her2 expression by both the fda criteria and asco / cap criteria was significantly associated with international society of urological pathology high grade ( p = .001 and p < .001 ) . 
 the high her2 expression group classified with the fda criteria showed significantly shorter cancer - specific survival ( p = .004 ) , but the her2 high and low expression groups classified with the asco / cap criteria did not show significant differences ( p = .161 ) in cancer - specific survival.conclusionsher2 high expression groups were significantly associated with shorter cancer - specific survival , and our study revealed that the fda criteria are more suitable for determining her2 expression in uutuc .