- Email: [email protected]
Cytological Punctures in the Diagnosis of Renal Tumours: A Study on Accuracy and Reproducibility
european urology 55 (2009) 187–198
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Kidney Cancer
Cytological Punctures in the Diagnosis of Renal Tumours: A Study on Accuracy and Reproducibility Intan P.E.D. Ku¨mmerlin a, Frank Smedts b, Fiebo J.W. ten Kate c, Thomas Horn d, Ferran Algaba e, Isabel Trias f, Hessel Wijkstra a, Jean J.M.C.H. de la Rosette a, M. Pilar Laguna a,* a
Academic Medical Center, University of Amsterdam, Urology, Amsterdam, The Netherlands Eastern Union of Hospitals, Pathology, Groningen, The Netherlands c Academic Medical Center, University of Amsterdam, Pathology, Amsterdam, The Netherlands d Herlev University Hospital, Pathology, Copenhagen, Denmark e Fundacio´ Puigvert I.U.N.A., Pathology, Universitat Autonoma de Barcelona (UAB), Barcelona, Spain f Clı´nica Plato´-Fundacio´ Privada, Pathology, Barcelona, Spain b
Article info
Abstract
Article history: Accepted April 24, 2008 Published online ahead of print on May 7, 2008
Background: Fine needle aspiration (FNA) cytology is under consideration as an auxiliary preoperative diagnostic technique in the diagnosis of renal masses. However, reports for FNA are contradictory with regard to diagnostic accuracy and applicability. Objective: To evaluate the diagnostic accuracy and reproducibility of FNA from renal masses. Design: FNAs performed in-bench (hematoxylin and eosin [H&E] stains) from 66 consecutive renal tumours (58 malignant and 8 benign tumours) were presented twice with a 6-mo interval to five pathologists with little experience in renal cytology. Pathologists were blinded for the results of the first round as well for the surgical specimen. The FNAs were stained for Papanicolaou and Giemsa. Measurements: Diagnostic accuracy, concordance between smears and surgical specimens, and the generalized kappa for interobserver/intraobserver agreement were calculated. Results and limitations: The number of nondiagnostic and nonconclusive cases ranged from 5–14% in the first and 3–8% in the second round. Overall accuracy varied between 73–89% and 71–91% for the first and second round, respectively. Sensitivity (72–97%) and positive predictive value (PPV) (93–100%) to classify a malignant tumour in both rounds was high. Sensitivity (25–100%) and PPV (28–100%) to classify a benign tumour was lower with a wide confidence interval. Overall concordance in subtyping ranged from 39–70% in the first, and from 52–74% in the second round. Interobserver agreement ranged from fair (k = 0.039) to substantial (k = 0.540) for the different subtypes. The intraobserver agreement (mean k = 0.357, CI 95% = 0.304–0.411) was moderate for all pathologists. The low number of benign tumours in this study precludes sound statements regarding the diagnostic accuracy of FNA to classify benignity. Conclusion: Despite the lack of experience in renal cytology, all pathologists showed a high diagnostic yield and good overall accuracy in distinguishing between malignant and benign tumours. Concordance in subtyping varied widely among pathologists and was reliable only for clear cell renal cell carcinoma (ccRCC). These results suggest that FNA may have a potential role in the diagnosis of renal tumours although its value in subtyping was limited in our setting.
Keywords: Kidney Renal neoplasm Classification Pathology Consensus Cytology
# 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel.: +31 20 566 60 30; fax: +31 20 566 95 85. E-mail address: [email protected] (M.P. Laguna). 0302-2838/$ – see back matter # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2008.04.072
188
1.
european urology 55 (2009) 187–198
Introduction
Imaging is the mainstay in the diagnosis of renal masses [1]. However, differentiation between benign and malignant or among subtypes is currently not possible [2]. An accurate preoperative diagnosis would be ideal to prevent overtreatment of benign masses, and to select patients for systemic therapies or ablative therapies. Histologic core biopsies (CB) and fine needle aspiration (FNA) cytology are under consideration as auxiliary preoperative diagnostic techniques to consider in selected cases [3]. A recently performed in-bench study on the diagnostic accuracy of CB, involving five pathologists, found that the diagnostic accuracy of CB was high [4]. However, up to 23% of CBs were scored as nondiagnostic by one or more pathologists, which is consistent with the rate found in literature [5–7]. The reports for FNA are contradictory with regard to diagnostic accuracy and applicability [8–16]. Some groups conclude that the technique is useful [9,14,17], and other groups do not [15,16]. Therefore, FNA is not performed on a routine basis in most institutions, and often pathologists are not experienced in this particular field. Nevertheless, the number of nondiagnostic procedures for FNA is in general lower than for CB [10]. In order to evaluate the potential usefulness of FNA in the workup of renal tumours, we investigated the diagnostic accuracy and intra- and interobserver variability of FNA by five pathologists with limited experience in renal cytology. 2.
Materials and methods
After a partial or total nephrectomy, the specimen (n = 66) was immediately transported to the pathology laboratory. FNA was performed under direct vision of the tumour using a 22-G needle. Two passes were made through the tumour. After each pass, two smears were stained for Giemsa and two for Papanicolaou. The surgical specimen was then processed according to the guidelines of the Uropathology Working Group (European Society of Pathology) and the European Working Group of Uropathology of the European Association of Urology [18,19]. The pathologists were asked to classify the smears of each case according to the latest World Health Organization criteria, if possible [20]. If they could not classify the tumour, they were asked to distinguish between benign or malignant. If this was not possible, they could call the case as not conclusive (NC). When pathologists judged the number of cells in the smear insufficient for diagnostic, they were asked to enter nondiagnostic (ND) on their scoring sheet. The pathologists repeated the above procedure with a 6-mo interval, without knowledge of the results of the first round. During this 6-mo interval, no intervention to improve their cytological knowledge took place. The pathologists were blinded for the definitive diagnosis in both rounds.
Three of the pathologists worked in academic reference centres and two in community hospitals. All pathologists had urogenital pathology as an interest field and considerable experience in general cytology although limited in renal cytology.
2.1.
Statistical method
To assess diagnostic accuracy, the results of the scoring sheet of the two rounds were used for the index test [21]. Overall accuracy was calculated by the sum of correctly scored smears of each case divided by all cases (n = 66). First, diagnostic accuracy was calculated by excluding nonconclusive and nondiagnostic results from the index test. Second, diagnostic accuracy was calculated by including nonconclusive and nondiagnostic results. In this setting, diagnostic accuracy was calculated to classify a malignant or a benign tumour. The results of the index test were compared with the results of the reference standard, ie, the surgical specimen of each case. Diagnostic accuracy, expressed in sensitivity/specificity and positive predictive value (PPV) and negative predictive value (NPV), was calculated for each pathologist. Diagnostic accuracy as confidence intervals for each pathologist were calculated by use of the program Confidence Interval Analysis (CIA) version 2.1.2. The McNemar test was performed to assess whether there were differences in sensitivity or specificity for each pathologist between the two rounds. Data analysis was performed using SPSS (version 12.0.2), with p < 0.05 (2-sided) considered as statistically significant. To measure the agreement for the individual subtypes of renal tumours among the five pathologists as well as the overall intraobserver variability of FNA, the generalized kappa was calculated using the program SAS (version 9, SAS Institute, Cary, NC, USA). The concordance between surgical specimens and FNAs were assessed; for this, all cases were included. The following interpretation of agreement expected by chance alone, within the positive values of kappa was used: fair, 0.00–0.20; moderate, 0.21–0.45; substantial, 0.46–0.75; almost perfect, 0.76–0.99; and perfect, 1.00 [22]. Negative value indicates less than chance agreement.
3.
Results
Patient data are presented in Table 1. The series comprised 58 (87.9%) malignant tumours and 8 (12.1%) benign tumours. There were 30 tumours 4 cm, with a median size of 3.5 cm (SD 0.6) and 36 tumours >4 cm, with a median size of 6.9 (SD 2.3). Three of the 30 tumours (10%) 4 cm were benign (2 oncocytomas and 1 angiomyolipoma [AML]) and 5 of the 36 tumours (14%) bigger than 4 cm were benign (2 oncocytomas and 2 AML). Globally, the number of nondiagnostic and nonconclusive cases ranged from 5–14% in the first and 3–8% in the second round. Corresponding data for tumours or > of 4 cm is displayed in Table 2.
189
89
FNA = fine needle aspiration; ND = nondiagnostic; NC = nonconclusive. Overall accuracy for the complete series irrespective of tumour size.
86 86 87 89 82
2 (67) 1 (20)
0
0
91
92
87
89
92
77
71
67
73
80
86
87
91
94
77
82
86
90
89
2 (40) 0 1 (20) 1 (33) 0 0 1 (20) 0 3 (60) 0 2 (40) 1 (33) 1 (20)
1 (3) 2 (7) 0 3 (11) 1 (3) 2 (7) 1 (3) 5 (19) 7 (23) 6 (22) 0 1 (4) 0 0 0 2 (6) (15)
0
3 (60) 3 (100) 3 (60) 2 (67) 5 (100) 3 (100) 3 (60) 3 (100)
35 1 (3) 29 (94) 27 32 29 3 (10) 4 (11) 1 (3) 21 (76) 28 (90) 24 (89) 35 1 (3) 29 (94) 33 28 3 (8) 2 (7) 28 (90) 23 (85) 34 27 2 (6) 3 (10) 22 (71) 19 (70)
2 (40) 3 (100) 3 (60) 2 (67) 3 (60) 1 (33) 1 (20) 1 (33) 4 (80) (100)
90
*
>4.0 4.0
35 28 31 27 34 28 35 29 1 (3) 2 (7) 5 (14) 3 (10) 2 (6) 2 (7) 1 (3) 1 (3) 28 (90) 25 (93) 30 (97) 26 (96) 30 (97) 24 (89) 30 (97) 20 (74)
>4.0 4.0 >4.0 4.0 >4.0 4.0 >4.0 4.0
First Second First Round
(13) (70)
>4.0 4.0 >4.0 4.0
First Second Second
First
III II I
Overall, 12 different cases (18%) were scored as nondiagnostic by one or more pathologist. In 64% (37/58) of the cases, all pathologists unanimously agreed for the diagnosis malignant in the first round. Twenty-five percent (2/8) of the benign tumours were called benign by all pathologists. Overall, 59% of cases were correctly diagnosed and 41% were incorrectly diagnosed. During the second round, all pathologists unanimously agreed for the diagnosis malignant in 66% (38/58) of cases and for the diagnosis benign in 25% (2/8) of cases. Overall, a unanimously correct diagnosis was reached in 61% of the cases and an incorrect diagnosis in 39% of cases. The pathologists diagnosed between 74–95% of the malignant cases correctly in the first round and between 72–97% in the second round. The percentage of malignant cases diagnosed as benign in the first round varied between 0–10% and in the second round between 0–22%. The percentage of correctly identified benign cases ranged from 25–75% after the first round and after the second round, it was between 50–100%. Benign cases called malignant ranged between 13– 38% in the first round and 0–38% in the second round. Corresponding data according to tumour size or >4 cm is shown in Table 2. Overall accuracy varied between 73–89% and 71– 91% for the first and second round, respectively. The sensitivity (76–100%) and PPV for both rounds was high (Table 3). Specificity (50–100%) and NPV
Pathologist
RCC = renal cell carcinoma.
Table 2 – Scoring results of the FNA for the individual pathologists, according to tumour size = or > 4 cm
(69.7) (6.1) (6.1) (7.6) (4.5) (1.5) (4.5)
# of diagnosed cases 25 32 26 # of ND/NC cases (%) 5 (17) 4 (11) 4 # of correctly diagnosed 18 (67) 25 (81) 19 malignant cases (%) # of correctly diagnosed 2 (67) 3 (60) 3 benign cases (%) # of incorrectly diagnosed 4 (15) 2 (6) 4 malignant lesions (%) # of incorrectly diagnosed 1 (33) 2 (40) 0 benign lesions (%) Overall accuracy (%) 67 78 73 Overall accuracy (%)* 73
46 4 4 5 3 1 3
4.0
Pathological diagnosis of surgical specimen (%) Clear cell RCC Chromophobe RCC Papillary RCC Renal oncocytoma Angiomyolipoma RCC unclassified Urothelial cell carcinoma
>4.0
45 (68.2) 21 (31.8)
4.0
Operation (%) Radical nephrectomy Partial nephrectomy
>4.0
30 (45.5) 31 (47.0) 5 (7.6)
4.0
Side (%) Left Right Not known
First
40 (60.6) 26 (39.4)
Second
Gender (%) Male Female
V
61.7/63.6 (12.5) 25–84 5.5/4.4 (2.6) 2–12
IV
Mean/median age (yr) (SD) Range Mean/median size (cm) (SD) Range
Second
Table 1 – Patient data
>4.0
european urology 55 (2009) 187–198
190
Table 3 – Diagnostic accuracy of FNA for the individual pathologists (nondiagnostic and nonconclusive diagnoses excluded) I Round Sensitivity % (CI95%) Specificity % (CI95%) PPV % (CI95%) NPV % (CI95%)
II
First 88 63 93 45
Second
(76–94) (31–86) (82–98) (21–72)
89 88 98 54
(77–95) (53–98) (89–100) (29–77)
First 100 50 96 100
III Second
(93–100) (15–85) (88–99) (34–100)
100 80 98 100
(94–100) (38–96) (91–100) (51–100)
IV
First 98 63 95 83
Second
(90–100) (31–86) (86–98) (44–97)
76 63 93 28
(64–86) (31–86) (82–98) (12–51)
First 89 86 98 50
V Second
(77–95) (49–97) (89–100) (25–75)
95 100 100 73
(85–98) (93–100) (93–100) (43–90)
94 71 96 63
First
Second
(84–98) (36–92) (87–99) (31–86)
95 75 96 67
(85–98) (41–93) (88–99) (35–88) european urology 55 (2009) 187–198
FNA = fine needle aspiration; CI = confidence interval; PPV= positive predictive value; NPV= negative predictive value.
Table 4 – Diagnostic accuracy of FNA to classify a malignant tumour for the individual pathologists (nondiagnostic and nonconclusive diagnoses included) I Round Sensitivity % (CI95%) Specificity % (CI95%) PPV % (CI95%) NPV % (CI95%)
First 74 63 93 25
(62–84) (31–86) (82–98) (11–47)
II Second 81 88 98 39
(69–89) (53–98) (89–100) (20–61)
First 95 75 96 67
(86–98) (41–93) (88–99) (35–88)
III Second 97 75 97 75
(88–99) (41–93) (88–99) (41–93)
First 93 63 95 56
(84–97) (31–86) (86–98) (27–81)
IV Second 72 63 93 24
(60–82) (31–86) (82–98) (11–45)
FNA = fine needle aspiration; CI = confidence interval; PPV = positive predictive value; NPV = negative predictive value.
First 81 88 98 39
(69–89) (53–98) (89–100) (20–61)
V Second 90 100 100 57
(79–95) (68–100) (93–100) (33–79)
84 75 96 40
First
Second
(73–92) (41–93) (87–99) (20–64)
91 75 96 55
(81–96) (41–93) (88–99) (28–79)
191 (41–93) (86–98) (35–88) (88–99) 75 95 67 96 (31–86) (86–98) (31–86) (86–98) (68–100) (86–98) (43–90) (93–100) 100 95 73 100
Second
63 95 63 95
First
V
(41–93) (79–95) (25–75) (87–99) (31–86) (91–100) (44–97) (86–98) 50 100 100 94
(22–78) (94–100) (51–100) (85–97)
63 98 83 95
First Second
(7–59) (94–100) (34–100) (81–96) 88 90 54 98
(53–98) (79–95) (29–77) (90–100)
25 100 100 91
First Second
(31–86) (79–95) (21–72) (85–98) 63 90 45 95 Sensitivity % (CI95%) Specificity % (CI95%) PPV % (CI95%) NPV % (CI95%)
FNA = fine needle aspiration; CI = confidence interval; PPV= positive predictive value; NPV = negative predictive value.
(31–86) (65–86) (12–51) (83–98) 63 78 28 94
Second
75 90 50 96
First
IV III II First
It was our aim to ascertain how accurately pathologists can classify renal tumours using FNA, in order to assess if renal cytology has a potential in the preoperative diagnosis of renal tumours. FNA may be a useful preoperative diagnostic tool because the aspiration is minimally traumatic and the complication rate is very low [17]. A thin needle is moved back and forth in a tumour under negative pressure. This will suck up surrounding tissue into the syringe. Due to this technique, the chances of harvesting vital tumour cells in partly necrotic tumours are higher than in needle biopsies. For that reason, the number of nonrepresentative procedures for FNA is general lower than it is for needle biopsies [10]. In our study, the number of nondiagnostic and nonconclusive samples ranged from 5–14% in the first and 3–8% in the second round, respectively. A high diagnostic yield (86– 97%), comparable to studies performed in vivo [9,16] was reached in our study. Similar studies performed
Round
Discussion
I
4.
Table 5 – Diagnostic accuracy of FNA to classify a benign tumour for the individual pathologists (nondiagnostic and nonconclusive diagnoses included)
(28–100%) varied broadly among pathologists. When all results were included in the index test (Tables 4, 5), sensitivity (72–97%), and PPV (93–100%) to classify a malignant tumour in both rounds was high. Sensitivity (25–100%) and PPV (28–100%) to classify a benign tumour varied among pathologists for both rounds. Sensitivity and specificity increased or remained the same between rounds, for all but one pathologist (III). This pathologist showed a decrease in sensitivity to classify a malignant tumour ( p = 0.012) and a decrease in specificity to classify a benign tumour ( p < 0.001). The other pathologists showed no statistically significant differences in sensitivity or specificity ( p > 0.05) between the two rounds. The numbers of correct and incorrect diagnoses for each tumour type after the first and second round are shown in Table 6. Correct subtyping of tumours was most difficult for cRCC, papillary renal cell carcinoma (pRCC), and urothelial cell carcinoma (UCC). Table 7 shows the concordance between the FNA diagnosis and the surgical specimen for the individual pathologists and renal tumour types. The overall concordance ranged from 39–70% in the first round and from 53–74% in the second round, respectively. The interobserver agreement for the renal subtypes (Table 8) varied from fair to substantial. The intraobserver variability was moderate for all pathologists with mean k = 0.357 (CI 95% 0.304– 0.411).
Second
european urology 55 (2009) 187–198
192
european urology 55 (2009) 187–198
Table 6 – The number of correct and incorrect diagnoses for each tumour type after each round (nonconclusive and nondiagnostic cases included) ccRCC n = 46 Round
cRCC n = 4
pRCC n = 4
RO N = 5
AML N = 3
UCC N = 3
RCC unclassified N = 1
First Second First Second First Second First Second First Second First Second First Second
All diagnoses correct One incorrect Two incorrect Three incorrect Four incorrect All diagnoses incorrect
6 13 14 5 6 2
18 9 9 4 4 2
1
2 2
1 1 2
1 1 1 1
1 1 2
1 2
1 3 1
1 1 1
1
1 1 1
1
3
1 2
1
ccRCC = clear cell renal cell carcinoma; cRCC = chromophobe renal cell carcinoma; pRCC = papilly renal cell carcinoma; RO = renal oncocytoma; AML = angiomyolipoma; UCC = urothelial cell carcinoma; RCC unclassified = renal cell carcinoma unclassified.
Table 7 – Concordance between FNA diagnosis and definitive diagnosis for each pathologist Renal tumour type (n)
Pathologists I
II
III
IV
V
Concordance (%) Round ccRCC (46) cRCC (4) pRCC (4) RCC unclassified (1) RO (5) AML (3) UCC (3) Overall concordance (%)
1 20 1 0 0 5 0 0 26
(43) (25)
(100)
(39)
2 23 2 3 0 5 2 0 35
1
(50) (50) (75) (100) (67) (53)
44 (96) 0 0 0 2 (40) 0 0 46 (70)
2 40 1 1 0 2 2 1 47
(87) (25) (25) (40) (67) (33) (71)
1 21 1 1 1 5 0 1 30
(46) (25) (25) (100) (100) (33) (46)
2 26 1 1 0 4 1 1 34
(57) (25) (25) (80) (33) (33) (52)
1 29 1 2 0 4 2 2 40
(63) (25) (50) (80) (67) (67) (61)
2 39 1 0 0 5 3 1 49
(85) (25)
(100) (100) (33) (74)
1 26 1 0 0 4 1 0 32
(57) (25)
(80) (33) (48)
2 37 1 1 0 4 2 0 45
(80) (25) (25) (80) (67) (68)
AML = angiomyolipoma; ccRCC = clear cell renal cell carcinoma; cRCC= chromophobe renal cell carcinoma; pRCC= papillary renal cell carcinoma; RCC unclassified= renal cell carcinoma unclassified; RO= renal oncocytoma; UCC= urothelial cell carcinoma.
on CBs found a higher rate of nonconclusive and nondiagnostic samples up to 20% [4,7,23]. These results suggest a potential benefit of FNA over CB regarding the diagnostic yield. Despite the fact that all pathologists had little experience in renal cytology, the overall accuracy of both rounds was high (71–91%). No differences in accuracy could be found when stratifying tumours by size in or > than 4 cm in any of the rounds. Although necrosis was not assessed in the surgical
specimen, those results suggest that the presence of necrosis, more frequent in bigger tumours, did not interfere in the diagnostic. Sensitivity and PPV to classify a malignant tumour was high for all pathologists. However, sensitivity (25–100%) and PPV (28–100%) to classify a benign tumour displayed a wide range. Because only 12% of the tumours were benign, a malignant tumour incorrectly classified as benign in a smear resulted in a large drop in accuracy. The low number of benign tumours in
Table 8 – Interobserver variability for the renal subtypes Renal tumour type (n) ccRCC (46) cRCC (4) pRCC (4) RO (5) RCC unclassified (1) AML (3) UCC (3)
1st round (k)
2nd round (k)
0.278 0.119 0.048 0.590 0.045 0.188 0.039
0.492 0.255 0.159 0.448 0.142 0.540 0.310
Interobserver agreement [20] Moderate to substantial Fair to moderate Fair Substantial to moderate Fair Fair to substantial Fair to moderate
AML = angiomyolipoma; ccRCC = clear cell renal cell carcinoma; cRCC = chromophobe renal cell carcinoma; pRCC = papillary renal cell carcinoma; RCC unclassified = renal cell carcinoma unclassified; RO = renal oncocytoma; UCC = urothelial cell carcinoma.
european urology 55 (2009) 187–198
this study precludes sound statements regarding the diagnostic accuracy of FNA to classify benignity. It is difficult to compare our results with other studies. As mentioned, reports on FNA are contradictory with regard to diagnostic accuracy and applicability [8–16]. First, study designs are often different and criteria for patient selection vary. Truong et al evaluated their experience with 108 renal FNA. They concluded that FNA is an excellent method to diagnose space-occupying lesions, but they included also cystic lesions, which was not the case in our study [9]. Niceforo et al studied patients with metastases or contraindications of nephrectomy and concluded that FNA is accurate and safe in these patients [14]. These results are comparable to our results, as diagnostic accuracy to classify malignancy was also high in our study. However, others concluded that diagnostic yield and sensitivity of FNA for small lesions <5.0 cm was too low and that FNA did not contribute at all in the management of renal tumours or does not justify the potential morbidity of the procedure [15,16]. Differences in approach (number of passes made, needle size, experience of pathologists) could be an explanation of these differences. One of the most important limitations of most studies is the fact that not all FNAs were compared with the surgical specimen [8–10,14,16]. Radiological follow-up was taken as reference standard, if an FNA was negative for malignancy. However, two recently conducted studies showed that zero growth of renal masses on imaging does not exclude malignancy [24,25]. In this study, subclassification of the renal masses in FNA was difficult for all subtypes. Pathologists faced difficulties in the subclassification of pRCC, in spite of the highly typical cytomorphologic features [26]. Urothelial carcinomas were also frequently classified incorrectly. Particularly when these tumours are high grade, their morphology may be deceptive and the distinction with ccRCC is difficult. AML is also a difficult tumour to diagnose correctly when one has little cytologic experience [27]. Once one realizes that the optical empty spaces surrounded by spindle-shaped or epitheliod cells are fat vacuoles, it is possible to subclassify these tumours correctly but experience is needed. There was a trend towards improvement in the second round for ccRCC (Tables 6–8), indicating that with limited practice the most frequent malignant renal tumour is easily cytologically recognized [13]. Criteria to subclassify renal tumours in cytological smears have been well described in the literature [17,26–31], but to apply them properly one must not only be familiar with the theory but also have experience in their application [32]. Opposed to this,
193
some diagnostic mistakes in the distinction between malignant and benign have a morphologic and explainable basis. An example is cRCC that can be very difficult to distinguish from a renal oncocytoma (RO), its benign look-alike tumour [28,30,31]. Cases in the benign category that were called malignant tended also to be either arbitrary or to cluster around eosinophilic tumour types with similar morphology. Most probably, this is the explanation for the drop in diagnostic accuracy for one of the pathologists (III) in the second round. In 12 cases pathologist III called a malignant eosinophilic tumour a benign RO. Renshaw et al assessed the accuracy of FNA in distinguishing subtypes of RCC [13]. Seventy-four percent of the primary renal lesions were correctly classified. However, they also experienced difficulties in distinguishing chromophobe renal cell carcinoma (cRCC) from renal oncocytoma (RO). On initial review by the individual authors, 1/2 cRCC and 2/4 RO were incorrectly classified. Concordance in subtyping was lower in our study, indicating that a considerable experience may be required to correctly subclassify a renal tumour other than clear cell carcinoma. A second round, with pathologists blinded for the results of the first round and for the definitive diagnosis, was performed with a 6-mo interval to exclude a high diagnostic accuracy by chance and to confirm reproducibility. When analyzing our results some limitations have to be taken into account. A bigger sample size would have conferred higher power to our study. However, the nature of the masses included in our study (solid and radiologically suspicious for RCC) and the uniformity of the reference standard chosen limited the sample. Secondly, the renal punctures were performed in-bench, and do not represent the everyday clinical practice. FNA was performed under direct vision of the tumour, which may have resulted in higher possibility of avoiding necrosis than in vivo. The possibility remains that the accuracy of the test is overestimated. Pathologists received only Giemsa and Papanicolaou stained slides, and had no access to immunocytochemical stains that could have aided in the nonconclusive cases, and in differentiating some cRCC from oncocytoma, improving diagnostic accuracy and subtyping. Lastly, no relevant clinical information was given, which could have helped in the differential diagnosis in the subclassification of tumours.
5.
Conclusions
Despite the lack of practice in renal cytology, all pathologists showed a good overall accuracy
194
european urology 55 (2009) 187–198
(71–91%) in distinguishing between benign and malignant tumours irrespective of the size. In our setting, with little experience in renal cytology and assessing only H&E stains, subtyping was moderate to substantial for ccRCC and not enough reliable for the rest of the subtypes. These results suggest that FNA has a potential in the preoperative differentiation between malignant and benign renal tumours, although a learning process and full pathological armamentarium will be necessary to optimize results in terms of subtyping. Author contributions: M. Pilar Laguna had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: De la Rosette, Laguna, Kummerlin Acquisition of data: Kummerlin, Smedts, Ten Kate, Horn, Algaba, Trias Analysis and interpretation of data: Kummerlin, Laguna, Smedts, Ten Kate, Horn, Algaba, Trias Drafting of the manuscript: Kummerlin, Smedts, Laguna, de la Rosette Critical revision of the manuscript for important intellectual content: De la Rosette, Wijkstra Statistical analysis: Wijkstra, Kummerlin, Laguna Obtaining funding: none Administrative, technical, or material support: None Supervision: Laguna, de la Rosette, Smedts Other (specify): none Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: none Funding/Support and role of the sponsor: none Acknowledgment statement: The authors acknowledge the departments of Urology and Pathology of the Westfriesgasthuis, (Hoorn, the Netherlands) and the Department of Urology of Stadskanaal (Winschoten, the Netherlands) for their collaboration. Our acknowledgement also to the Department of Epidemiology and Biostatistics of the Academic Medical Center, University of Amsterdam (Amsterdam, the Netherlands).
References [1] Herts BR. Imaging for renal tumours. Curr Opin Urol 2003;13:181–6. [2] Israel GM, Bosniak MA. Renal imaging for diagnosis and staging of renal cell carcinoma. Urol Clin North Am 2003;30:499–514. [3] Ljungberg B, Hanbury DC, Kuczyk MA, et al. Renal cell carcinoma guideline. Eur Urol 2007;51:1502–10.
[4] Ku¨mmerlin I, ten Kate F, Smedts F, et al. Core biopsies of renal tumours: a study on diagnostic accuracy, interobserver, and intraobserver variability. Eur Urol 2008;53:1219–27. [5] Dechet CB, Zincke H, Sebo TJ, et al. Prospective analysis of computerized tomography and needle biopsy with permanent sectioning to determine the nature of solid renal masses in adults. J Urol 2003;169:71–4. [6] Maturen KE, Nghiem HV, Caoili EM, et al. Renal mass core biopsy: accuracy and impact on clinical management. AJR Am J Roentgenol 2007;188:563–70. [7] Lechevallier E. Core biopsy of solid renal masses under CT guidance. Eur Urol Suppl 2007;6:540–3. [8] Zardawi IM. Renal fine needle aspiration cytology. Acta Cytol 1999;43:184–90. [9] Truong LD, Todd TD, Dhurandhar B, Ramzy I. Fine-needle aspiration of renal masses in adults: analysis of results and diagnostic problems in 108 cases. Diagn Cytopathol 1999;20:339–49. [10] Torp-Pedersen S, Juul N, Larsen T, et al. US-guided fine needle biopsy of solid renal masses–comparison of histology and cytology. Scand J Urol Nephrol Suppl 1991;137:41–3. [11] Todd TD, Dhurandhar B, Mody D, Ramzy I, Truong LD. Fine-needle aspiration of cystic lesions of the kidney. Morphologic spectrum and diagnostic problems in 41 cases Am J Clin Pathol 1999;111:317–28. [12] Tabatabai ZL, Staerkel GA. Distinguishing primary and metastatic conventional renal cell carcinoma from other malignant neoplasms in fine-needle aspiration biopsy specimens. Arch Pathol Lab Med 2005;129:1017–21. [13] Renshaw AA, Lee KR, Madge R, Granter SR. Accuracy of fine needle aspiration in distinguishing subtypes of renal cell carcinoma. Acta Cytol 1997;41:987–94. [14] Niceforo J, Coughlin BF. Diagnosis of renal cell carcinoma: value of fine-needle aspiration cytology in patients with metastases or contraindications to nephrectomy. AJR Am J Roentgenol 1993;161:1303–5. [15] Campbell SC, Novick AC, Herts B, et al. Prospective evaluation of fine needle aspiration of small, solid renal masses: accuracy and morbidity. Urology 1997;50:25–9. [16] Brierly RD, Thomas PJ, Harrison NW, et al. Evaluation of fine-needle aspiration cytology for renal masses. BJU Int 2000;85:14–8. [17] Renshaw AA, Granter SR, Cibas ES. Fine-needle aspiration of the adult kidney. Cancer 1997;81:71–88. [18] Algaba F, Trias I, Scarpelli M, et al. Handling and pathology reporting of renal tumour specimens. Eur Urol 2004;45:437–43. [19] Kirkali Z, Algaba F, Scarpelli M, et al. What does the urologist expect from the pathologist (and what can the pathologists give) in reporting on adult kidney tumour specimens? Eur Urol 2007;51:1194–201. [20] Elbe JN, Sauter G, Epstein JI, Sesterhenn IA. Tumours of the urinary system and male genital organs. WHO histological classification of tumours of the kidney. In: Pathology & Genetics. 6th ed. Lyon: IARC; 2004. [21] Bossuyt PM, Reitsma JB, Bruns DE, et al. Towards complete and accurate reporting ofstudies of diagnostic accuracy: the STARD initiative. Standards for Reporting of Diagnostic Accuracy. Clin Chem 2003;49:1–6.
european urology 55 (2009) 187–198
[22] Mun˜oz SR, Bangdiwala SI. Interpretation of Kappa and B statistics measures of agreement. J Appl Statistics 1997;24:105–11. [23] Reichelt O, Gajda M, Chyhrai A, et al. Ultrasound-guided biopsy of homogeneous solid renal masses. Eur Urol 2007;52:1421–7. [24] Kunkle DA, Crispen PL, Chen DY, Greenberg RE, Uzzo RG. Enhancing renal masses with zero net growth during active surveillance. J Urol 2007;177:849–53. [25] Siu W, Hafez KS, Johnston III WK, Wolf Jr JS. Growth rates of renal cell carcinoma and oncocytoma under surveillance are similar. Urol Oncol 2007;25:115–9. [26] Granter SR, Perez-Atayde AR, Renshaw AA. Cytologic analysis of papillary renal cell carcinoma. Cancer 1998;84:303–8. [27] Granter SR, Renshaw AA. Cytologic analysis of renal angiomyolipoma: a comparison of radiologically classic and challenging cases. Cancer 1999;87:135–40.
Editorial Comment on: Cytological Punctures in Diagnosis of Renal Tumours: A Study on Accuracy and Reproducibility Eric Lechevallier Department of Urology, Hoˆpital La Conception, Marseille, France [email protected] There is growing evidence that management of renal masses can be tailored to the patient according to nonoperative parameters, such as renal histology, especially in elderly and unfit patients [1]. With advances in interventional radiology and renal pathology, core renal biopsies have replaced fine needle aspiration (FNA), the first nonsurgical tool to evaluate solid renal masses [2,3]. Nevertheless, with a global accuracy rate close to 90%, core biopsy had some limits, and FNA could be an auxiliary nonsurgical tool to increase the diagnostic accuracy of core biopsy [1]. Ku¨mmerlin et al evaluated the role of FNA in the diagnosis of solid renal masses [4]. In this series, with 66 consecutive renal tumours, they showed that FNA, performed in-bench, had an overall accuracy close to 90%. The overall pathologic concordance of FNA was 70%. But FNA was not as good as core biopsy for subtype histology and grade of renal cancer [2,3]. Nevertheless, tumour grade evaluation of core biopsy was not optimal (75%) [2,3]. From this paper, it appears that FNA and
195
[28] Liu J, Fanning CV. Can renal oncocytomas be distinguished from renal cell carcinoma on fine-needle aspiration specimens? A study of conventional smears in conjunction with ancillary studies. Cancer 2001;93: 390–7. [29] Salamanca J, Alberti N, Lopez-Rios F, et al. Fine needle aspiration of chromophobe renal cell carcinoma. Acta Cytol 2007;51:9–15. [30] Wiatrowska BA, Zakowski MF. Fine-needle aspiration biopsy of chromophobe renal cell carcinoma and oncocytoma: comparison of cytomorphologic features. Cancer 1999;87:161–7. [31] Granter SR, Renshaw AA. Fine-needle aspiration of chromophobe renal cell carcinoma. Analysis of six cases. Cancer 1997;81:122–8. [32] Volpe A, Kachura JR, Geddie WR, et al. Techniques, safety and accuracy of sampling of renal tumours by fine needle aspiration and core biopsy. J Urol 2007;178:379–86.
core biopsy are not competitive, but rather complementary, tools. We can well speculate that, in the future, the nonsurgical evaluation of solid renal masses might combine core biopsy and FNA to increase the accuracy of preoperative evaluation of renal masses.
References [1] Volpe A, Kachura JR, Geddie WR, et al. Techniques, safety, and accuracy of sampling of renal tumors by fine needle aspiration and core biopsy. J Urol 2007;178: 379–86. [2] Lechevallier E, Andre M, Barriol D, et al. Fine needle percutaneous biopsy of renal masses with helical CT guidance. Radiology 2000;216:506–10. [3] Neuzillet Y, Lechevallier E, Andre M, Daniel L, Coulange C. Accuracy and clinical role of fine needle percutaneous biopsy with computerized tomography guidance of small (less than 4.0 cm) renal masses. J Urol 2004;171: 1802–5. [4] Ku¨mmerlin IPED, Smedts F, ten Kate FJW, et al. Cytological punctures in diagnosis of renal tumours: a study on accuracy and reproducibility. Eur Urol 2009;55: 187–98.
DOI: 10.1016/j.eururo.2008.04.073 DOI of original article: 10.1016/j.eururo.2008.04.072
196
european urology 55 (2009) 187–198
Editorial Comment on: Cytological Punctures in the Diagnosis of Renal Tumours: A Study on Accuracy and Reproducibility Vincenzo Ficarra Department of Oncological and Surgical Sciences, Urology Clinic, University of Padua, Monoblocco Ospedaliero, IV floor, Via Giustiniani 2, 35100, Padua, Italy [email protected] Giacomo Novara I.R.C.C.S. Istituto Oncologico Veneto (I.O.V.), Padua, Italy
To date, percutaneous fine-needle aspiration (FNA), or core needle biopsies, have had only a limited role in the clinical work-up of patients with parenchymal renal tumours [1]. In the last years, however, the most frequent identification of small, asymptomatic renal neoplasms, the improvement in the techniques used to perform the needle biopsies under computed tomography or ultrasound guidance, and use of a coaxial guiding cannula, as well as the availability of minimally invasive therapies for renal neoplasms [2], have caused a renewed interest in the biopsy of renal tumours, which is today the field of several clinical researches [3]. The literature of FNA cytology of renal neoplasm has been limited, showing conflicting results. Ku¨mmerlin et al have provided a very elegant inbench study, testing the accuracy of FNA cytology in the diagnosis of renal neoplasms. Specifically, five pathologists were asked twice, with a 6-mo interval, to provide diagnosis on FNA cytology, in order to evaluate the diagnostic accuracy and reproducibility of the technique. Using the surgical specimen as internal control, the authors finally showed that pathologists had good diagnostic accuracy in distinguishing between malignant and benign tumours (ranging from 71–91%), despite the lack of previous experience in cytology of renal cancers. However, agreement on the identification of the histologic subtype varied widely among pathologists and was reliable only for clear cell renal cell carcinoma [4]. This study has to be read in tandem with another recent publication of the same group, where the accuracy, interobserver, and intraobserver variability of core biopsies were evaluated in a
similar fashion. Specifically, the authors found overall diagnostic accuracy for core biopsy ranging from 77–90%, according to the different pathologists, with overall concordance between the surgical specimen and the core biopsy being 64–81% for the definition of the histologic subtypes [5]. The data are surprising, because FNA cytology and core biopsy showed similar accuracy in the identification of malignant cancers. Clearly, core biopsy was by far more reliable in the definition of the different subtypes. The two studies do not tell us whether FNA cytology or core biopsies should be taken in patients for which a preoperative definition of the pathologic characteristics of the neoplasms is needed. The main message is clearly that pathologists can provide accurate cytologic and histologic diagnosis in both cases, although core biopsy is more reliable if the clear identification of histologic subtypes is needed. FNA cytology is, however, of some interest, because it is likely that it might be less invasive than renal biopsy in the clinical practice. Further clinical studies are needed to test the diagnostic accuracy of FNA cytology in vivo, as well as to evaluate the possible advantage for the patients in terms of morbidity, compared to core needle biopsy.
References [1] Ljungberg B, Hanbury DC, Kuczyk MA, et al. Renal cell carcinoma guideline. Eur Urol 2007;51:1502–10. [2] Fotiadis NI, Sabharwal T, Morales JP, Hodgson DJ, O’Brien TS, Adam A. Combined percutaneous radiofrequency ablation and ethanol injection of renal tumours: midterm results. Eur Urol 2007;52:777–84. [3] Somani BK, Nabi G, Thorpe P, et al. Image-guided biopsydiagnosed renal cell carcinoma: critical appraisal of technique and long-term follow-up. Eur Urol 2007;51: 1289–97. [4] Ku¨mmerlin IPED, Smedts F, Ten Kate FJW, et al. Cytological punctures in the diagnosis of renal tumours: a study on accuracy and reproducibility. Eur Urol 2009; 55:187–98. [5] Ku¨mmerlin I, Ten Kate F, Smedts F, et al. Core biopsies of renal tumors: a study on diagnostic accuracy, interobserver, and intraobserver variability. Eur Urol 2008; 53:1219–27.
DOI: 10.1016/j.eururo.2008.04.074 DOI of original article: 10.1016/j.eururo.2008.04.072
european urology 55 (2009) 187–198
Editorial Comment on: Cytological Punctures in the Diagnosis of Renal Tumours: A Study on Accuracy and Reproducibility Rodolfo Montironi, Marina Scarpelli Section of Pathological Anatomy, School of Medicine, Polytechnic University of the Marche Region (Ancona), Ancona, Italy [email protected] Antonio Lopez-Beltran Unit of Anatomic Pathology, Cordoba University Medical School, Cordoba, Spain
Liang Cheng Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
Ku¨mmerlin et al [1] have shown that the diagnostic yield and overall accuracy of fine needle aspiration (FNA) in distinguishing between benign and malignant renal cell neoplasms are high. In their experience, subtyping is not reliable. This interesting study follows a recent publication by the same group [2] on the diagnostic accuracy on core biopsies (CB) from renal cell neoplasms. They found that the diagnostic accuracy was high. There are advantages and disadvantages with FNA and CB of renal cell neoplasms. FNA has the great advantage of speed in making a diagnosis. Once the aspirate is smeared onto the slide, this can be stained with toluidine blue, for instance, and the slide read soon after. The diagnosis can be rendered to the urologist in a very short time, typically in less than 5 min. It requires no special instrumentation for processing the material. The pathologist does not need the help of a technician; every step in the analysis is dealt with by the pathologist him/herself. A CB of renal cell neoplasms, as with core biopsies from other organs, such as prostate, has to be fixed and taken to a pathology laboratory for processing, including cutting and staining, and for reading. In a typical pathology laboratory, it could take at least 24 h before a final report is sent to the urologist. The alternative would be either frozen section examination or fast processing. The former can shorten the time to diagnosis to 10–15 min. As with the FNA, a technician is not required, because the pathologist can do both the technical and diagnostic parts. Fast processing systems are becoming popular in pathology laboratories for processing posttransplantation CBs for which a diagnosis is needed in a matter of
197
1–2 h. Fast processing requires dedicated instrumentation and availability of a technician. Should the authors of this editorial comment rank the approaches reported above, our preference is for a good permanent tissue section stained with Haematoxylin and Eosin, obtained following proper fixation and routine processing. Frozen section examination would be the second choice, and FNA third. This ranking is linked to the fact that, due to the complexity of making a diagnosis of the many subtypes of renal cell neoplasms, we would like to evaluate the cytologic appearance of the neoplasm as well as its architecture and, in selected cases, use ancillary techniques, such as immunohistochemistry (IHC). All these three things are perfectly feasible with a CB routinely processed. Frozen section allows for both the cytologic and architectural evaluation of the neoplasm. IHC can be applied to frozen section, even though IHC is usually done on tissue sections from formalinfixed and paraffin-embedded material. FNA allows for cytologic examination. The architecture of the neoplasm is difficult-to-impossible to define. Usually some kind of imagination is needed to ‘‘see’’ the architecture of the neoplasm, mostly based on the pattern of cell aggregation. ICH depends on de-staining of the diagnostic slide and/or on the availability of spare slides. The literature is rich in contributions on FNA and CB diagnosis of renal cell neoplasms [3–5]. Scant information is available on the application of frozen section examination of CBs. What we have to take into consideration is that, to attain accuracy and reproducibility on the diagnosis on FNA and CB, pathologists need sound experience and knowledge on the cytologic and histologic features of the subtypes of renal cell neoplasms [6]. This is usually acquired through the examination of several surgical specimens. We foresee that the future could be the combination of either FNA or CB evaluation with cytogenetics, especially fluorescence in situ hybridization (FISH) analysis. This approach will probably allow for an accurate interpretation of renal cell neoplasms far better than with the traditional cytology and/or histology [7,8].
References [1] Ku¨mmerlin IPED, Ten Kate F, Smedts FJW, et al. Cytological punctures in the diagnosis of renal tumours: a study on accuracy and reproducibility. Eur Urol 2009; 55:187–98.
198
european urology 55 (2009) 187–198
[2] Ku¨mmerlin I, Ten Kate F, Smedts F, et al. Core biopsies of renal tumors: a study on diagnostic accuracy, interobserver, and intraobserver variability. Eur Urol 2008;53: 1219–27. [3] Kirkali Z, Algaba F, Scarpelli M, Trias I, Selvaggi FP, Van Poppel H. What does the urologist expect from the pathologist (and what can the pathologists give) in reporting on adult kidney tumour specimens? Eur Urol 2007;51:1194–201. [4] Ljungberg B, Hanbury DC, Kuczyk MA, et al. Renal cell carcinoma guideline. Eur Urol 2007;51:1502–10. [5] Fotiadis NI, Sabharwal T, Morales JP, Hodgson DJ, O’Brien TS, Adam A. Combined percutaneous radiofrequency ablation and ethanol injection of renal tumours: midterm results. Eur Urol 2007;52:777–84.
[6] Ficarra V, Martignoni G, Galfano A, et al. Prognostic role of the histologic subtypes of renal cell carcinoma after slide revision. Eur Urol 2006;50:786–94. [7] Pospihalj B, Zamparese R, Mazzucchelli R, Morichetti D. Kidney cancer: not a single disease. Anal Quant Cytol Histol 2007;29:377–9. [8] Chadwick B, Willmore-Payne C, Holden J, Layfield L. Fluorescence in situ hybridization determination of aneusomy: criteria and technical considerations. Anal Quant Cytol Histol 2007;29:351–7.
DOI: 10.1016/j.eururo.2008.04.075 DOI of original article: 10.1016/j.eururo.2008.04.072
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Kidney Cancer
Cytological Punctures in the Diagnosis of Renal Tumours: A Study on Accuracy and Reproducibility Intan P.E.D. Ku¨mmerlin a, Frank Smedts b, Fiebo J.W. ten Kate c, Thomas Horn d, Ferran Algaba e, Isabel Trias f, Hessel Wijkstra a, Jean J.M.C.H. de la Rosette a, M. Pilar Laguna a,* a
Academic Medical Center, University of Amsterdam, Urology, Amsterdam, The Netherlands Eastern Union of Hospitals, Pathology, Groningen, The Netherlands c Academic Medical Center, University of Amsterdam, Pathology, Amsterdam, The Netherlands d Herlev University Hospital, Pathology, Copenhagen, Denmark e Fundacio´ Puigvert I.U.N.A., Pathology, Universitat Autonoma de Barcelona (UAB), Barcelona, Spain f Clı´nica Plato´-Fundacio´ Privada, Pathology, Barcelona, Spain b
Article info
Abstract
Article history: Accepted April 24, 2008 Published online ahead of print on May 7, 2008
Background: Fine needle aspiration (FNA) cytology is under consideration as an auxiliary preoperative diagnostic technique in the diagnosis of renal masses. However, reports for FNA are contradictory with regard to diagnostic accuracy and applicability. Objective: To evaluate the diagnostic accuracy and reproducibility of FNA from renal masses. Design: FNAs performed in-bench (hematoxylin and eosin [H&E] stains) from 66 consecutive renal tumours (58 malignant and 8 benign tumours) were presented twice with a 6-mo interval to five pathologists with little experience in renal cytology. Pathologists were blinded for the results of the first round as well for the surgical specimen. The FNAs were stained for Papanicolaou and Giemsa. Measurements: Diagnostic accuracy, concordance between smears and surgical specimens, and the generalized kappa for interobserver/intraobserver agreement were calculated. Results and limitations: The number of nondiagnostic and nonconclusive cases ranged from 5–14% in the first and 3–8% in the second round. Overall accuracy varied between 73–89% and 71–91% for the first and second round, respectively. Sensitivity (72–97%) and positive predictive value (PPV) (93–100%) to classify a malignant tumour in both rounds was high. Sensitivity (25–100%) and PPV (28–100%) to classify a benign tumour was lower with a wide confidence interval. Overall concordance in subtyping ranged from 39–70% in the first, and from 52–74% in the second round. Interobserver agreement ranged from fair (k = 0.039) to substantial (k = 0.540) for the different subtypes. The intraobserver agreement (mean k = 0.357, CI 95% = 0.304–0.411) was moderate for all pathologists. The low number of benign tumours in this study precludes sound statements regarding the diagnostic accuracy of FNA to classify benignity. Conclusion: Despite the lack of experience in renal cytology, all pathologists showed a high diagnostic yield and good overall accuracy in distinguishing between malignant and benign tumours. Concordance in subtyping varied widely among pathologists and was reliable only for clear cell renal cell carcinoma (ccRCC). These results suggest that FNA may have a potential role in the diagnosis of renal tumours although its value in subtyping was limited in our setting.
Keywords: Kidney Renal neoplasm Classification Pathology Consensus Cytology
# 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel.: +31 20 566 60 30; fax: +31 20 566 95 85. E-mail address: [email protected] (M.P. Laguna). 0302-2838/$ – see back matter # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2008.04.072
188
1.
european urology 55 (2009) 187–198
Introduction
Imaging is the mainstay in the diagnosis of renal masses [1]. However, differentiation between benign and malignant or among subtypes is currently not possible [2]. An accurate preoperative diagnosis would be ideal to prevent overtreatment of benign masses, and to select patients for systemic therapies or ablative therapies. Histologic core biopsies (CB) and fine needle aspiration (FNA) cytology are under consideration as auxiliary preoperative diagnostic techniques to consider in selected cases [3]. A recently performed in-bench study on the diagnostic accuracy of CB, involving five pathologists, found that the diagnostic accuracy of CB was high [4]. However, up to 23% of CBs were scored as nondiagnostic by one or more pathologists, which is consistent with the rate found in literature [5–7]. The reports for FNA are contradictory with regard to diagnostic accuracy and applicability [8–16]. Some groups conclude that the technique is useful [9,14,17], and other groups do not [15,16]. Therefore, FNA is not performed on a routine basis in most institutions, and often pathologists are not experienced in this particular field. Nevertheless, the number of nondiagnostic procedures for FNA is in general lower than for CB [10]. In order to evaluate the potential usefulness of FNA in the workup of renal tumours, we investigated the diagnostic accuracy and intra- and interobserver variability of FNA by five pathologists with limited experience in renal cytology. 2.
Materials and methods
After a partial or total nephrectomy, the specimen (n = 66) was immediately transported to the pathology laboratory. FNA was performed under direct vision of the tumour using a 22-G needle. Two passes were made through the tumour. After each pass, two smears were stained for Giemsa and two for Papanicolaou. The surgical specimen was then processed according to the guidelines of the Uropathology Working Group (European Society of Pathology) and the European Working Group of Uropathology of the European Association of Urology [18,19]. The pathologists were asked to classify the smears of each case according to the latest World Health Organization criteria, if possible [20]. If they could not classify the tumour, they were asked to distinguish between benign or malignant. If this was not possible, they could call the case as not conclusive (NC). When pathologists judged the number of cells in the smear insufficient for diagnostic, they were asked to enter nondiagnostic (ND) on their scoring sheet. The pathologists repeated the above procedure with a 6-mo interval, without knowledge of the results of the first round. During this 6-mo interval, no intervention to improve their cytological knowledge took place. The pathologists were blinded for the definitive diagnosis in both rounds.
Three of the pathologists worked in academic reference centres and two in community hospitals. All pathologists had urogenital pathology as an interest field and considerable experience in general cytology although limited in renal cytology.
2.1.
Statistical method
To assess diagnostic accuracy, the results of the scoring sheet of the two rounds were used for the index test [21]. Overall accuracy was calculated by the sum of correctly scored smears of each case divided by all cases (n = 66). First, diagnostic accuracy was calculated by excluding nonconclusive and nondiagnostic results from the index test. Second, diagnostic accuracy was calculated by including nonconclusive and nondiagnostic results. In this setting, diagnostic accuracy was calculated to classify a malignant or a benign tumour. The results of the index test were compared with the results of the reference standard, ie, the surgical specimen of each case. Diagnostic accuracy, expressed in sensitivity/specificity and positive predictive value (PPV) and negative predictive value (NPV), was calculated for each pathologist. Diagnostic accuracy as confidence intervals for each pathologist were calculated by use of the program Confidence Interval Analysis (CIA) version 2.1.2. The McNemar test was performed to assess whether there were differences in sensitivity or specificity for each pathologist between the two rounds. Data analysis was performed using SPSS (version 12.0.2), with p < 0.05 (2-sided) considered as statistically significant. To measure the agreement for the individual subtypes of renal tumours among the five pathologists as well as the overall intraobserver variability of FNA, the generalized kappa was calculated using the program SAS (version 9, SAS Institute, Cary, NC, USA). The concordance between surgical specimens and FNAs were assessed; for this, all cases were included. The following interpretation of agreement expected by chance alone, within the positive values of kappa was used: fair, 0.00–0.20; moderate, 0.21–0.45; substantial, 0.46–0.75; almost perfect, 0.76–0.99; and perfect, 1.00 [22]. Negative value indicates less than chance agreement.
3.
Results
Patient data are presented in Table 1. The series comprised 58 (87.9%) malignant tumours and 8 (12.1%) benign tumours. There were 30 tumours 4 cm, with a median size of 3.5 cm (SD 0.6) and 36 tumours >4 cm, with a median size of 6.9 (SD 2.3). Three of the 30 tumours (10%) 4 cm were benign (2 oncocytomas and 1 angiomyolipoma [AML]) and 5 of the 36 tumours (14%) bigger than 4 cm were benign (2 oncocytomas and 2 AML). Globally, the number of nondiagnostic and nonconclusive cases ranged from 5–14% in the first and 3–8% in the second round. Corresponding data for tumours or > of 4 cm is displayed in Table 2.
189
89
FNA = fine needle aspiration; ND = nondiagnostic; NC = nonconclusive. Overall accuracy for the complete series irrespective of tumour size.
86 86 87 89 82
2 (67) 1 (20)
0
0
91
92
87
89
92
77
71
67
73
80
86
87
91
94
77
82
86
90
89
2 (40) 0 1 (20) 1 (33) 0 0 1 (20) 0 3 (60) 0 2 (40) 1 (33) 1 (20)
1 (3) 2 (7) 0 3 (11) 1 (3) 2 (7) 1 (3) 5 (19) 7 (23) 6 (22) 0 1 (4) 0 0 0 2 (6) (15)
0
3 (60) 3 (100) 3 (60) 2 (67) 5 (100) 3 (100) 3 (60) 3 (100)
35 1 (3) 29 (94) 27 32 29 3 (10) 4 (11) 1 (3) 21 (76) 28 (90) 24 (89) 35 1 (3) 29 (94) 33 28 3 (8) 2 (7) 28 (90) 23 (85) 34 27 2 (6) 3 (10) 22 (71) 19 (70)
2 (40) 3 (100) 3 (60) 2 (67) 3 (60) 1 (33) 1 (20) 1 (33) 4 (80) (100)
90
*
>4.0 4.0
35 28 31 27 34 28 35 29 1 (3) 2 (7) 5 (14) 3 (10) 2 (6) 2 (7) 1 (3) 1 (3) 28 (90) 25 (93) 30 (97) 26 (96) 30 (97) 24 (89) 30 (97) 20 (74)
>4.0 4.0 >4.0 4.0 >4.0 4.0 >4.0 4.0
First Second First Round
(13) (70)
>4.0 4.0 >4.0 4.0
First Second Second
First
III II I
Overall, 12 different cases (18%) were scored as nondiagnostic by one or more pathologist. In 64% (37/58) of the cases, all pathologists unanimously agreed for the diagnosis malignant in the first round. Twenty-five percent (2/8) of the benign tumours were called benign by all pathologists. Overall, 59% of cases were correctly diagnosed and 41% were incorrectly diagnosed. During the second round, all pathologists unanimously agreed for the diagnosis malignant in 66% (38/58) of cases and for the diagnosis benign in 25% (2/8) of cases. Overall, a unanimously correct diagnosis was reached in 61% of the cases and an incorrect diagnosis in 39% of cases. The pathologists diagnosed between 74–95% of the malignant cases correctly in the first round and between 72–97% in the second round. The percentage of malignant cases diagnosed as benign in the first round varied between 0–10% and in the second round between 0–22%. The percentage of correctly identified benign cases ranged from 25–75% after the first round and after the second round, it was between 50–100%. Benign cases called malignant ranged between 13– 38% in the first round and 0–38% in the second round. Corresponding data according to tumour size or >4 cm is shown in Table 2. Overall accuracy varied between 73–89% and 71– 91% for the first and second round, respectively. The sensitivity (76–100%) and PPV for both rounds was high (Table 3). Specificity (50–100%) and NPV
Pathologist
RCC = renal cell carcinoma.
Table 2 – Scoring results of the FNA for the individual pathologists, according to tumour size = or > 4 cm
(69.7) (6.1) (6.1) (7.6) (4.5) (1.5) (4.5)
# of diagnosed cases 25 32 26 # of ND/NC cases (%) 5 (17) 4 (11) 4 # of correctly diagnosed 18 (67) 25 (81) 19 malignant cases (%) # of correctly diagnosed 2 (67) 3 (60) 3 benign cases (%) # of incorrectly diagnosed 4 (15) 2 (6) 4 malignant lesions (%) # of incorrectly diagnosed 1 (33) 2 (40) 0 benign lesions (%) Overall accuracy (%) 67 78 73 Overall accuracy (%)* 73
46 4 4 5 3 1 3
4.0
Pathological diagnosis of surgical specimen (%) Clear cell RCC Chromophobe RCC Papillary RCC Renal oncocytoma Angiomyolipoma RCC unclassified Urothelial cell carcinoma
>4.0
45 (68.2) 21 (31.8)
4.0
Operation (%) Radical nephrectomy Partial nephrectomy
>4.0
30 (45.5) 31 (47.0) 5 (7.6)
4.0
Side (%) Left Right Not known
First
40 (60.6) 26 (39.4)
Second
Gender (%) Male Female
V
61.7/63.6 (12.5) 25–84 5.5/4.4 (2.6) 2–12
IV
Mean/median age (yr) (SD) Range Mean/median size (cm) (SD) Range
Second
Table 1 – Patient data
>4.0
european urology 55 (2009) 187–198
190
Table 3 – Diagnostic accuracy of FNA for the individual pathologists (nondiagnostic and nonconclusive diagnoses excluded) I Round Sensitivity % (CI95%) Specificity % (CI95%) PPV % (CI95%) NPV % (CI95%)
II
First 88 63 93 45
Second
(76–94) (31–86) (82–98) (21–72)
89 88 98 54
(77–95) (53–98) (89–100) (29–77)
First 100 50 96 100
III Second
(93–100) (15–85) (88–99) (34–100)
100 80 98 100
(94–100) (38–96) (91–100) (51–100)
IV
First 98 63 95 83
Second
(90–100) (31–86) (86–98) (44–97)
76 63 93 28
(64–86) (31–86) (82–98) (12–51)
First 89 86 98 50
V Second
(77–95) (49–97) (89–100) (25–75)
95 100 100 73
(85–98) (93–100) (93–100) (43–90)
94 71 96 63
First
Second
(84–98) (36–92) (87–99) (31–86)
95 75 96 67
(85–98) (41–93) (88–99) (35–88) european urology 55 (2009) 187–198
FNA = fine needle aspiration; CI = confidence interval; PPV= positive predictive value; NPV= negative predictive value.
Table 4 – Diagnostic accuracy of FNA to classify a malignant tumour for the individual pathologists (nondiagnostic and nonconclusive diagnoses included) I Round Sensitivity % (CI95%) Specificity % (CI95%) PPV % (CI95%) NPV % (CI95%)
First 74 63 93 25
(62–84) (31–86) (82–98) (11–47)
II Second 81 88 98 39
(69–89) (53–98) (89–100) (20–61)
First 95 75 96 67
(86–98) (41–93) (88–99) (35–88)
III Second 97 75 97 75
(88–99) (41–93) (88–99) (41–93)
First 93 63 95 56
(84–97) (31–86) (86–98) (27–81)
IV Second 72 63 93 24
(60–82) (31–86) (82–98) (11–45)
FNA = fine needle aspiration; CI = confidence interval; PPV = positive predictive value; NPV = negative predictive value.
First 81 88 98 39
(69–89) (53–98) (89–100) (20–61)
V Second 90 100 100 57
(79–95) (68–100) (93–100) (33–79)
84 75 96 40
First
Second
(73–92) (41–93) (87–99) (20–64)
91 75 96 55
(81–96) (41–93) (88–99) (28–79)
191 (41–93) (86–98) (35–88) (88–99) 75 95 67 96 (31–86) (86–98) (31–86) (86–98) (68–100) (86–98) (43–90) (93–100) 100 95 73 100
Second
63 95 63 95
First
V
(41–93) (79–95) (25–75) (87–99) (31–86) (91–100) (44–97) (86–98) 50 100 100 94
(22–78) (94–100) (51–100) (85–97)
63 98 83 95
First Second
(7–59) (94–100) (34–100) (81–96) 88 90 54 98
(53–98) (79–95) (29–77) (90–100)
25 100 100 91
First Second
(31–86) (79–95) (21–72) (85–98) 63 90 45 95 Sensitivity % (CI95%) Specificity % (CI95%) PPV % (CI95%) NPV % (CI95%)
FNA = fine needle aspiration; CI = confidence interval; PPV= positive predictive value; NPV = negative predictive value.
(31–86) (65–86) (12–51) (83–98) 63 78 28 94
Second
75 90 50 96
First
IV III II First
It was our aim to ascertain how accurately pathologists can classify renal tumours using FNA, in order to assess if renal cytology has a potential in the preoperative diagnosis of renal tumours. FNA may be a useful preoperative diagnostic tool because the aspiration is minimally traumatic and the complication rate is very low [17]. A thin needle is moved back and forth in a tumour under negative pressure. This will suck up surrounding tissue into the syringe. Due to this technique, the chances of harvesting vital tumour cells in partly necrotic tumours are higher than in needle biopsies. For that reason, the number of nonrepresentative procedures for FNA is general lower than it is for needle biopsies [10]. In our study, the number of nondiagnostic and nonconclusive samples ranged from 5–14% in the first and 3–8% in the second round, respectively. A high diagnostic yield (86– 97%), comparable to studies performed in vivo [9,16] was reached in our study. Similar studies performed
Round
Discussion
I
4.
Table 5 – Diagnostic accuracy of FNA to classify a benign tumour for the individual pathologists (nondiagnostic and nonconclusive diagnoses included)
(28–100%) varied broadly among pathologists. When all results were included in the index test (Tables 4, 5), sensitivity (72–97%), and PPV (93–100%) to classify a malignant tumour in both rounds was high. Sensitivity (25–100%) and PPV (28–100%) to classify a benign tumour varied among pathologists for both rounds. Sensitivity and specificity increased or remained the same between rounds, for all but one pathologist (III). This pathologist showed a decrease in sensitivity to classify a malignant tumour ( p = 0.012) and a decrease in specificity to classify a benign tumour ( p < 0.001). The other pathologists showed no statistically significant differences in sensitivity or specificity ( p > 0.05) between the two rounds. The numbers of correct and incorrect diagnoses for each tumour type after the first and second round are shown in Table 6. Correct subtyping of tumours was most difficult for cRCC, papillary renal cell carcinoma (pRCC), and urothelial cell carcinoma (UCC). Table 7 shows the concordance between the FNA diagnosis and the surgical specimen for the individual pathologists and renal tumour types. The overall concordance ranged from 39–70% in the first round and from 53–74% in the second round, respectively. The interobserver agreement for the renal subtypes (Table 8) varied from fair to substantial. The intraobserver variability was moderate for all pathologists with mean k = 0.357 (CI 95% 0.304– 0.411).
Second
european urology 55 (2009) 187–198
192
european urology 55 (2009) 187–198
Table 6 – The number of correct and incorrect diagnoses for each tumour type after each round (nonconclusive and nondiagnostic cases included) ccRCC n = 46 Round
cRCC n = 4
pRCC n = 4
RO N = 5
AML N = 3
UCC N = 3
RCC unclassified N = 1
First Second First Second First Second First Second First Second First Second First Second
All diagnoses correct One incorrect Two incorrect Three incorrect Four incorrect All diagnoses incorrect
6 13 14 5 6 2
18 9 9 4 4 2
1
2 2
1 1 2
1 1 1 1
1 1 2
1 2
1 3 1
1 1 1
1
1 1 1
1
3
1 2
1
ccRCC = clear cell renal cell carcinoma; cRCC = chromophobe renal cell carcinoma; pRCC = papilly renal cell carcinoma; RO = renal oncocytoma; AML = angiomyolipoma; UCC = urothelial cell carcinoma; RCC unclassified = renal cell carcinoma unclassified.
Table 7 – Concordance between FNA diagnosis and definitive diagnosis for each pathologist Renal tumour type (n)
Pathologists I
II
III
IV
V
Concordance (%) Round ccRCC (46) cRCC (4) pRCC (4) RCC unclassified (1) RO (5) AML (3) UCC (3) Overall concordance (%)
1 20 1 0 0 5 0 0 26
(43) (25)
(100)
(39)
2 23 2 3 0 5 2 0 35
1
(50) (50) (75) (100) (67) (53)
44 (96) 0 0 0 2 (40) 0 0 46 (70)
2 40 1 1 0 2 2 1 47
(87) (25) (25) (40) (67) (33) (71)
1 21 1 1 1 5 0 1 30
(46) (25) (25) (100) (100) (33) (46)
2 26 1 1 0 4 1 1 34
(57) (25) (25) (80) (33) (33) (52)
1 29 1 2 0 4 2 2 40
(63) (25) (50) (80) (67) (67) (61)
2 39 1 0 0 5 3 1 49
(85) (25)
(100) (100) (33) (74)
1 26 1 0 0 4 1 0 32
(57) (25)
(80) (33) (48)
2 37 1 1 0 4 2 0 45
(80) (25) (25) (80) (67) (68)
AML = angiomyolipoma; ccRCC = clear cell renal cell carcinoma; cRCC= chromophobe renal cell carcinoma; pRCC= papillary renal cell carcinoma; RCC unclassified= renal cell carcinoma unclassified; RO= renal oncocytoma; UCC= urothelial cell carcinoma.
on CBs found a higher rate of nonconclusive and nondiagnostic samples up to 20% [4,7,23]. These results suggest a potential benefit of FNA over CB regarding the diagnostic yield. Despite the fact that all pathologists had little experience in renal cytology, the overall accuracy of both rounds was high (71–91%). No differences in accuracy could be found when stratifying tumours by size in or > than 4 cm in any of the rounds. Although necrosis was not assessed in the surgical
specimen, those results suggest that the presence of necrosis, more frequent in bigger tumours, did not interfere in the diagnostic. Sensitivity and PPV to classify a malignant tumour was high for all pathologists. However, sensitivity (25–100%) and PPV (28–100%) to classify a benign tumour displayed a wide range. Because only 12% of the tumours were benign, a malignant tumour incorrectly classified as benign in a smear resulted in a large drop in accuracy. The low number of benign tumours in
Table 8 – Interobserver variability for the renal subtypes Renal tumour type (n) ccRCC (46) cRCC (4) pRCC (4) RO (5) RCC unclassified (1) AML (3) UCC (3)
1st round (k)
2nd round (k)
0.278 0.119 0.048 0.590 0.045 0.188 0.039
0.492 0.255 0.159 0.448 0.142 0.540 0.310
Interobserver agreement [20] Moderate to substantial Fair to moderate Fair Substantial to moderate Fair Fair to substantial Fair to moderate
AML = angiomyolipoma; ccRCC = clear cell renal cell carcinoma; cRCC = chromophobe renal cell carcinoma; pRCC = papillary renal cell carcinoma; RCC unclassified = renal cell carcinoma unclassified; RO = renal oncocytoma; UCC = urothelial cell carcinoma.
european urology 55 (2009) 187–198
this study precludes sound statements regarding the diagnostic accuracy of FNA to classify benignity. It is difficult to compare our results with other studies. As mentioned, reports on FNA are contradictory with regard to diagnostic accuracy and applicability [8–16]. First, study designs are often different and criteria for patient selection vary. Truong et al evaluated their experience with 108 renal FNA. They concluded that FNA is an excellent method to diagnose space-occupying lesions, but they included also cystic lesions, which was not the case in our study [9]. Niceforo et al studied patients with metastases or contraindications of nephrectomy and concluded that FNA is accurate and safe in these patients [14]. These results are comparable to our results, as diagnostic accuracy to classify malignancy was also high in our study. However, others concluded that diagnostic yield and sensitivity of FNA for small lesions <5.0 cm was too low and that FNA did not contribute at all in the management of renal tumours or does not justify the potential morbidity of the procedure [15,16]. Differences in approach (number of passes made, needle size, experience of pathologists) could be an explanation of these differences. One of the most important limitations of most studies is the fact that not all FNAs were compared with the surgical specimen [8–10,14,16]. Radiological follow-up was taken as reference standard, if an FNA was negative for malignancy. However, two recently conducted studies showed that zero growth of renal masses on imaging does not exclude malignancy [24,25]. In this study, subclassification of the renal masses in FNA was difficult for all subtypes. Pathologists faced difficulties in the subclassification of pRCC, in spite of the highly typical cytomorphologic features [26]. Urothelial carcinomas were also frequently classified incorrectly. Particularly when these tumours are high grade, their morphology may be deceptive and the distinction with ccRCC is difficult. AML is also a difficult tumour to diagnose correctly when one has little cytologic experience [27]. Once one realizes that the optical empty spaces surrounded by spindle-shaped or epitheliod cells are fat vacuoles, it is possible to subclassify these tumours correctly but experience is needed. There was a trend towards improvement in the second round for ccRCC (Tables 6–8), indicating that with limited practice the most frequent malignant renal tumour is easily cytologically recognized [13]. Criteria to subclassify renal tumours in cytological smears have been well described in the literature [17,26–31], but to apply them properly one must not only be familiar with the theory but also have experience in their application [32]. Opposed to this,
193
some diagnostic mistakes in the distinction between malignant and benign have a morphologic and explainable basis. An example is cRCC that can be very difficult to distinguish from a renal oncocytoma (RO), its benign look-alike tumour [28,30,31]. Cases in the benign category that were called malignant tended also to be either arbitrary or to cluster around eosinophilic tumour types with similar morphology. Most probably, this is the explanation for the drop in diagnostic accuracy for one of the pathologists (III) in the second round. In 12 cases pathologist III called a malignant eosinophilic tumour a benign RO. Renshaw et al assessed the accuracy of FNA in distinguishing subtypes of RCC [13]. Seventy-four percent of the primary renal lesions were correctly classified. However, they also experienced difficulties in distinguishing chromophobe renal cell carcinoma (cRCC) from renal oncocytoma (RO). On initial review by the individual authors, 1/2 cRCC and 2/4 RO were incorrectly classified. Concordance in subtyping was lower in our study, indicating that a considerable experience may be required to correctly subclassify a renal tumour other than clear cell carcinoma. A second round, with pathologists blinded for the results of the first round and for the definitive diagnosis, was performed with a 6-mo interval to exclude a high diagnostic accuracy by chance and to confirm reproducibility. When analyzing our results some limitations have to be taken into account. A bigger sample size would have conferred higher power to our study. However, the nature of the masses included in our study (solid and radiologically suspicious for RCC) and the uniformity of the reference standard chosen limited the sample. Secondly, the renal punctures were performed in-bench, and do not represent the everyday clinical practice. FNA was performed under direct vision of the tumour, which may have resulted in higher possibility of avoiding necrosis than in vivo. The possibility remains that the accuracy of the test is overestimated. Pathologists received only Giemsa and Papanicolaou stained slides, and had no access to immunocytochemical stains that could have aided in the nonconclusive cases, and in differentiating some cRCC from oncocytoma, improving diagnostic accuracy and subtyping. Lastly, no relevant clinical information was given, which could have helped in the differential diagnosis in the subclassification of tumours.
5.
Conclusions
Despite the lack of practice in renal cytology, all pathologists showed a good overall accuracy
194
european urology 55 (2009) 187–198
(71–91%) in distinguishing between benign and malignant tumours irrespective of the size. In our setting, with little experience in renal cytology and assessing only H&E stains, subtyping was moderate to substantial for ccRCC and not enough reliable for the rest of the subtypes. These results suggest that FNA has a potential in the preoperative differentiation between malignant and benign renal tumours, although a learning process and full pathological armamentarium will be necessary to optimize results in terms of subtyping. Author contributions: M. Pilar Laguna had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: De la Rosette, Laguna, Kummerlin Acquisition of data: Kummerlin, Smedts, Ten Kate, Horn, Algaba, Trias Analysis and interpretation of data: Kummerlin, Laguna, Smedts, Ten Kate, Horn, Algaba, Trias Drafting of the manuscript: Kummerlin, Smedts, Laguna, de la Rosette Critical revision of the manuscript for important intellectual content: De la Rosette, Wijkstra Statistical analysis: Wijkstra, Kummerlin, Laguna Obtaining funding: none Administrative, technical, or material support: None Supervision: Laguna, de la Rosette, Smedts Other (specify): none Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: none Funding/Support and role of the sponsor: none Acknowledgment statement: The authors acknowledge the departments of Urology and Pathology of the Westfriesgasthuis, (Hoorn, the Netherlands) and the Department of Urology of Stadskanaal (Winschoten, the Netherlands) for their collaboration. Our acknowledgement also to the Department of Epidemiology and Biostatistics of the Academic Medical Center, University of Amsterdam (Amsterdam, the Netherlands).
References [1] Herts BR. Imaging for renal tumours. Curr Opin Urol 2003;13:181–6. [2] Israel GM, Bosniak MA. Renal imaging for diagnosis and staging of renal cell carcinoma. Urol Clin North Am 2003;30:499–514. [3] Ljungberg B, Hanbury DC, Kuczyk MA, et al. Renal cell carcinoma guideline. Eur Urol 2007;51:1502–10.
[4] Ku¨mmerlin I, ten Kate F, Smedts F, et al. Core biopsies of renal tumours: a study on diagnostic accuracy, interobserver, and intraobserver variability. Eur Urol 2008;53:1219–27. [5] Dechet CB, Zincke H, Sebo TJ, et al. Prospective analysis of computerized tomography and needle biopsy with permanent sectioning to determine the nature of solid renal masses in adults. J Urol 2003;169:71–4. [6] Maturen KE, Nghiem HV, Caoili EM, et al. Renal mass core biopsy: accuracy and impact on clinical management. AJR Am J Roentgenol 2007;188:563–70. [7] Lechevallier E. Core biopsy of solid renal masses under CT guidance. Eur Urol Suppl 2007;6:540–3. [8] Zardawi IM. Renal fine needle aspiration cytology. Acta Cytol 1999;43:184–90. [9] Truong LD, Todd TD, Dhurandhar B, Ramzy I. Fine-needle aspiration of renal masses in adults: analysis of results and diagnostic problems in 108 cases. Diagn Cytopathol 1999;20:339–49. [10] Torp-Pedersen S, Juul N, Larsen T, et al. US-guided fine needle biopsy of solid renal masses–comparison of histology and cytology. Scand J Urol Nephrol Suppl 1991;137:41–3. [11] Todd TD, Dhurandhar B, Mody D, Ramzy I, Truong LD. Fine-needle aspiration of cystic lesions of the kidney. Morphologic spectrum and diagnostic problems in 41 cases Am J Clin Pathol 1999;111:317–28. [12] Tabatabai ZL, Staerkel GA. Distinguishing primary and metastatic conventional renal cell carcinoma from other malignant neoplasms in fine-needle aspiration biopsy specimens. Arch Pathol Lab Med 2005;129:1017–21. [13] Renshaw AA, Lee KR, Madge R, Granter SR. Accuracy of fine needle aspiration in distinguishing subtypes of renal cell carcinoma. Acta Cytol 1997;41:987–94. [14] Niceforo J, Coughlin BF. Diagnosis of renal cell carcinoma: value of fine-needle aspiration cytology in patients with metastases or contraindications to nephrectomy. AJR Am J Roentgenol 1993;161:1303–5. [15] Campbell SC, Novick AC, Herts B, et al. Prospective evaluation of fine needle aspiration of small, solid renal masses: accuracy and morbidity. Urology 1997;50:25–9. [16] Brierly RD, Thomas PJ, Harrison NW, et al. Evaluation of fine-needle aspiration cytology for renal masses. BJU Int 2000;85:14–8. [17] Renshaw AA, Granter SR, Cibas ES. Fine-needle aspiration of the adult kidney. Cancer 1997;81:71–88. [18] Algaba F, Trias I, Scarpelli M, et al. Handling and pathology reporting of renal tumour specimens. Eur Urol 2004;45:437–43. [19] Kirkali Z, Algaba F, Scarpelli M, et al. What does the urologist expect from the pathologist (and what can the pathologists give) in reporting on adult kidney tumour specimens? Eur Urol 2007;51:1194–201. [20] Elbe JN, Sauter G, Epstein JI, Sesterhenn IA. Tumours of the urinary system and male genital organs. WHO histological classification of tumours of the kidney. In: Pathology & Genetics. 6th ed. Lyon: IARC; 2004. [21] Bossuyt PM, Reitsma JB, Bruns DE, et al. Towards complete and accurate reporting ofstudies of diagnostic accuracy: the STARD initiative. Standards for Reporting of Diagnostic Accuracy. Clin Chem 2003;49:1–6.
european urology 55 (2009) 187–198
[22] Mun˜oz SR, Bangdiwala SI. Interpretation of Kappa and B statistics measures of agreement. J Appl Statistics 1997;24:105–11. [23] Reichelt O, Gajda M, Chyhrai A, et al. Ultrasound-guided biopsy of homogeneous solid renal masses. Eur Urol 2007;52:1421–7. [24] Kunkle DA, Crispen PL, Chen DY, Greenberg RE, Uzzo RG. Enhancing renal masses with zero net growth during active surveillance. J Urol 2007;177:849–53. [25] Siu W, Hafez KS, Johnston III WK, Wolf Jr JS. Growth rates of renal cell carcinoma and oncocytoma under surveillance are similar. Urol Oncol 2007;25:115–9. [26] Granter SR, Perez-Atayde AR, Renshaw AA. Cytologic analysis of papillary renal cell carcinoma. Cancer 1998;84:303–8. [27] Granter SR, Renshaw AA. Cytologic analysis of renal angiomyolipoma: a comparison of radiologically classic and challenging cases. Cancer 1999;87:135–40.
Editorial Comment on: Cytological Punctures in Diagnosis of Renal Tumours: A Study on Accuracy and Reproducibility Eric Lechevallier Department of Urology, Hoˆpital La Conception, Marseille, France [email protected] There is growing evidence that management of renal masses can be tailored to the patient according to nonoperative parameters, such as renal histology, especially in elderly and unfit patients [1]. With advances in interventional radiology and renal pathology, core renal biopsies have replaced fine needle aspiration (FNA), the first nonsurgical tool to evaluate solid renal masses [2,3]. Nevertheless, with a global accuracy rate close to 90%, core biopsy had some limits, and FNA could be an auxiliary nonsurgical tool to increase the diagnostic accuracy of core biopsy [1]. Ku¨mmerlin et al evaluated the role of FNA in the diagnosis of solid renal masses [4]. In this series, with 66 consecutive renal tumours, they showed that FNA, performed in-bench, had an overall accuracy close to 90%. The overall pathologic concordance of FNA was 70%. But FNA was not as good as core biopsy for subtype histology and grade of renal cancer [2,3]. Nevertheless, tumour grade evaluation of core biopsy was not optimal (75%) [2,3]. From this paper, it appears that FNA and
195
[28] Liu J, Fanning CV. Can renal oncocytomas be distinguished from renal cell carcinoma on fine-needle aspiration specimens? A study of conventional smears in conjunction with ancillary studies. Cancer 2001;93: 390–7. [29] Salamanca J, Alberti N, Lopez-Rios F, et al. Fine needle aspiration of chromophobe renal cell carcinoma. Acta Cytol 2007;51:9–15. [30] Wiatrowska BA, Zakowski MF. Fine-needle aspiration biopsy of chromophobe renal cell carcinoma and oncocytoma: comparison of cytomorphologic features. Cancer 1999;87:161–7. [31] Granter SR, Renshaw AA. Fine-needle aspiration of chromophobe renal cell carcinoma. Analysis of six cases. Cancer 1997;81:122–8. [32] Volpe A, Kachura JR, Geddie WR, et al. Techniques, safety and accuracy of sampling of renal tumours by fine needle aspiration and core biopsy. J Urol 2007;178:379–86.
core biopsy are not competitive, but rather complementary, tools. We can well speculate that, in the future, the nonsurgical evaluation of solid renal masses might combine core biopsy and FNA to increase the accuracy of preoperative evaluation of renal masses.
References [1] Volpe A, Kachura JR, Geddie WR, et al. Techniques, safety, and accuracy of sampling of renal tumors by fine needle aspiration and core biopsy. J Urol 2007;178: 379–86. [2] Lechevallier E, Andre M, Barriol D, et al. Fine needle percutaneous biopsy of renal masses with helical CT guidance. Radiology 2000;216:506–10. [3] Neuzillet Y, Lechevallier E, Andre M, Daniel L, Coulange C. Accuracy and clinical role of fine needle percutaneous biopsy with computerized tomography guidance of small (less than 4.0 cm) renal masses. J Urol 2004;171: 1802–5. [4] Ku¨mmerlin IPED, Smedts F, ten Kate FJW, et al. Cytological punctures in diagnosis of renal tumours: a study on accuracy and reproducibility. Eur Urol 2009;55: 187–98.
DOI: 10.1016/j.eururo.2008.04.073 DOI of original article: 10.1016/j.eururo.2008.04.072
196
european urology 55 (2009) 187–198
Editorial Comment on: Cytological Punctures in the Diagnosis of Renal Tumours: A Study on Accuracy and Reproducibility Vincenzo Ficarra Department of Oncological and Surgical Sciences, Urology Clinic, University of Padua, Monoblocco Ospedaliero, IV floor, Via Giustiniani 2, 35100, Padua, Italy [email protected] Giacomo Novara I.R.C.C.S. Istituto Oncologico Veneto (I.O.V.), Padua, Italy
To date, percutaneous fine-needle aspiration (FNA), or core needle biopsies, have had only a limited role in the clinical work-up of patients with parenchymal renal tumours [1]. In the last years, however, the most frequent identification of small, asymptomatic renal neoplasms, the improvement in the techniques used to perform the needle biopsies under computed tomography or ultrasound guidance, and use of a coaxial guiding cannula, as well as the availability of minimally invasive therapies for renal neoplasms [2], have caused a renewed interest in the biopsy of renal tumours, which is today the field of several clinical researches [3]. The literature of FNA cytology of renal neoplasm has been limited, showing conflicting results. Ku¨mmerlin et al have provided a very elegant inbench study, testing the accuracy of FNA cytology in the diagnosis of renal neoplasms. Specifically, five pathologists were asked twice, with a 6-mo interval, to provide diagnosis on FNA cytology, in order to evaluate the diagnostic accuracy and reproducibility of the technique. Using the surgical specimen as internal control, the authors finally showed that pathologists had good diagnostic accuracy in distinguishing between malignant and benign tumours (ranging from 71–91%), despite the lack of previous experience in cytology of renal cancers. However, agreement on the identification of the histologic subtype varied widely among pathologists and was reliable only for clear cell renal cell carcinoma [4]. This study has to be read in tandem with another recent publication of the same group, where the accuracy, interobserver, and intraobserver variability of core biopsies were evaluated in a
similar fashion. Specifically, the authors found overall diagnostic accuracy for core biopsy ranging from 77–90%, according to the different pathologists, with overall concordance between the surgical specimen and the core biopsy being 64–81% for the definition of the histologic subtypes [5]. The data are surprising, because FNA cytology and core biopsy showed similar accuracy in the identification of malignant cancers. Clearly, core biopsy was by far more reliable in the definition of the different subtypes. The two studies do not tell us whether FNA cytology or core biopsies should be taken in patients for which a preoperative definition of the pathologic characteristics of the neoplasms is needed. The main message is clearly that pathologists can provide accurate cytologic and histologic diagnosis in both cases, although core biopsy is more reliable if the clear identification of histologic subtypes is needed. FNA cytology is, however, of some interest, because it is likely that it might be less invasive than renal biopsy in the clinical practice. Further clinical studies are needed to test the diagnostic accuracy of FNA cytology in vivo, as well as to evaluate the possible advantage for the patients in terms of morbidity, compared to core needle biopsy.
References [1] Ljungberg B, Hanbury DC, Kuczyk MA, et al. Renal cell carcinoma guideline. Eur Urol 2007;51:1502–10. [2] Fotiadis NI, Sabharwal T, Morales JP, Hodgson DJ, O’Brien TS, Adam A. Combined percutaneous radiofrequency ablation and ethanol injection of renal tumours: midterm results. Eur Urol 2007;52:777–84. [3] Somani BK, Nabi G, Thorpe P, et al. Image-guided biopsydiagnosed renal cell carcinoma: critical appraisal of technique and long-term follow-up. Eur Urol 2007;51: 1289–97. [4] Ku¨mmerlin IPED, Smedts F, Ten Kate FJW, et al. Cytological punctures in the diagnosis of renal tumours: a study on accuracy and reproducibility. Eur Urol 2009; 55:187–98. [5] Ku¨mmerlin I, Ten Kate F, Smedts F, et al. Core biopsies of renal tumors: a study on diagnostic accuracy, interobserver, and intraobserver variability. Eur Urol 2008; 53:1219–27.
DOI: 10.1016/j.eururo.2008.04.074 DOI of original article: 10.1016/j.eururo.2008.04.072
european urology 55 (2009) 187–198
Editorial Comment on: Cytological Punctures in the Diagnosis of Renal Tumours: A Study on Accuracy and Reproducibility Rodolfo Montironi, Marina Scarpelli Section of Pathological Anatomy, School of Medicine, Polytechnic University of the Marche Region (Ancona), Ancona, Italy [email protected] Antonio Lopez-Beltran Unit of Anatomic Pathology, Cordoba University Medical School, Cordoba, Spain
Liang Cheng Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
Ku¨mmerlin et al [1] have shown that the diagnostic yield and overall accuracy of fine needle aspiration (FNA) in distinguishing between benign and malignant renal cell neoplasms are high. In their experience, subtyping is not reliable. This interesting study follows a recent publication by the same group [2] on the diagnostic accuracy on core biopsies (CB) from renal cell neoplasms. They found that the diagnostic accuracy was high. There are advantages and disadvantages with FNA and CB of renal cell neoplasms. FNA has the great advantage of speed in making a diagnosis. Once the aspirate is smeared onto the slide, this can be stained with toluidine blue, for instance, and the slide read soon after. The diagnosis can be rendered to the urologist in a very short time, typically in less than 5 min. It requires no special instrumentation for processing the material. The pathologist does not need the help of a technician; every step in the analysis is dealt with by the pathologist him/herself. A CB of renal cell neoplasms, as with core biopsies from other organs, such as prostate, has to be fixed and taken to a pathology laboratory for processing, including cutting and staining, and for reading. In a typical pathology laboratory, it could take at least 24 h before a final report is sent to the urologist. The alternative would be either frozen section examination or fast processing. The former can shorten the time to diagnosis to 10–15 min. As with the FNA, a technician is not required, because the pathologist can do both the technical and diagnostic parts. Fast processing systems are becoming popular in pathology laboratories for processing posttransplantation CBs for which a diagnosis is needed in a matter of
197
1–2 h. Fast processing requires dedicated instrumentation and availability of a technician. Should the authors of this editorial comment rank the approaches reported above, our preference is for a good permanent tissue section stained with Haematoxylin and Eosin, obtained following proper fixation and routine processing. Frozen section examination would be the second choice, and FNA third. This ranking is linked to the fact that, due to the complexity of making a diagnosis of the many subtypes of renal cell neoplasms, we would like to evaluate the cytologic appearance of the neoplasm as well as its architecture and, in selected cases, use ancillary techniques, such as immunohistochemistry (IHC). All these three things are perfectly feasible with a CB routinely processed. Frozen section allows for both the cytologic and architectural evaluation of the neoplasm. IHC can be applied to frozen section, even though IHC is usually done on tissue sections from formalinfixed and paraffin-embedded material. FNA allows for cytologic examination. The architecture of the neoplasm is difficult-to-impossible to define. Usually some kind of imagination is needed to ‘‘see’’ the architecture of the neoplasm, mostly based on the pattern of cell aggregation. ICH depends on de-staining of the diagnostic slide and/or on the availability of spare slides. The literature is rich in contributions on FNA and CB diagnosis of renal cell neoplasms [3–5]. Scant information is available on the application of frozen section examination of CBs. What we have to take into consideration is that, to attain accuracy and reproducibility on the diagnosis on FNA and CB, pathologists need sound experience and knowledge on the cytologic and histologic features of the subtypes of renal cell neoplasms [6]. This is usually acquired through the examination of several surgical specimens. We foresee that the future could be the combination of either FNA or CB evaluation with cytogenetics, especially fluorescence in situ hybridization (FISH) analysis. This approach will probably allow for an accurate interpretation of renal cell neoplasms far better than with the traditional cytology and/or histology [7,8].
References [1] Ku¨mmerlin IPED, Ten Kate F, Smedts FJW, et al. Cytological punctures in the diagnosis of renal tumours: a study on accuracy and reproducibility. Eur Urol 2009; 55:187–98.
198
european urology 55 (2009) 187–198
[2] Ku¨mmerlin I, Ten Kate F, Smedts F, et al. Core biopsies of renal tumors: a study on diagnostic accuracy, interobserver, and intraobserver variability. Eur Urol 2008;53: 1219–27. [3] Kirkali Z, Algaba F, Scarpelli M, Trias I, Selvaggi FP, Van Poppel H. What does the urologist expect from the pathologist (and what can the pathologists give) in reporting on adult kidney tumour specimens? Eur Urol 2007;51:1194–201. [4] Ljungberg B, Hanbury DC, Kuczyk MA, et al. Renal cell carcinoma guideline. Eur Urol 2007;51:1502–10. [5] Fotiadis NI, Sabharwal T, Morales JP, Hodgson DJ, O’Brien TS, Adam A. Combined percutaneous radiofrequency ablation and ethanol injection of renal tumours: midterm results. Eur Urol 2007;52:777–84.
[6] Ficarra V, Martignoni G, Galfano A, et al. Prognostic role of the histologic subtypes of renal cell carcinoma after slide revision. Eur Urol 2006;50:786–94. [7] Pospihalj B, Zamparese R, Mazzucchelli R, Morichetti D. Kidney cancer: not a single disease. Anal Quant Cytol Histol 2007;29:377–9. [8] Chadwick B, Willmore-Payne C, Holden J, Layfield L. Fluorescence in situ hybridization determination of aneusomy: criteria and technical considerations. Anal Quant Cytol Histol 2007;29:351–7.
DOI: 10.1016/j.eururo.2008.04.075 DOI of original article: 10.1016/j.eururo.2008.04.072