What Does the Urologist Expect from the Pathologist (and What Can the Pathologists Give) in Reporting on Adult Kidney Tumour Specimens?

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1 european urology 51 (2007) available at journal homepage: Review Kidney Cancer What Does the Urologist Expect from the Pathologist (and What Can the Pathologists Give) in Reporting on Adult Kidney Tumour Specimens? Ziya Kirkali a, *, Ferran Algaba b, Marina Scarpelli c, Isabel Trias d, Francesco P. Selvaggi e, Hein Van Poppel f a Department of Urology, Dokuz Eylul University School of Medicine, Izmir, Turkey b Section of Pathology, Fundacio Puigvert, Department of Morphological Sciences, Medicine Faculty Universitat Autónoma de Barcelona, Spain c Section of Pathology, Polytechnic University of the Marche-Region, Ancona, Italy d Department of Pathology, Fundació Privada Plató, Barcelona, Spain e Department of Urology, Universita Degli Studio di Bari, Italy f Department of Urology, University Hospital of KU Leuven, Leuven, Belgium Article info Article history: Accepted November 9, 2006 Published online ahead of print on November 17, 2006 Keywords: Kidney cancer Renal cell carcinoma Pathology report Grading Staging Abstract Objective: To identify the parameters required by the urologist to determine the prognosis and the treatment of renal cancer in adults, and to establish the potential therapeutic targets of the new treatments that started to show clinical efficacy. Methods: A literature search of the last 10 yr was done, paying specific attention to TNM 2002 (UICC staging) and Fuhrman s grading. Also, the main genetic characteristics of the different subtypes (according to the WHO 2004 classification) with potential therapeutic implications have been compiled. Results: After the review of the literature, the opinion of the joint meeting including urologists and pathologists is that some aspects of the TNM 2002 classification must be refined. Criteria for nuclear grading should be different for the subtypes of renal cell carcinoma, and the WHO 2004 histological classification is clinically useful. Conclusions: In the workshop held in Palermo, common opinion was achieved on a number of points. The TNM 2002 classification is useful, but some adjustments should be made, particularly as referred to the tumour size cut-off, assessment of the invasion of the renal sinus fat tissue, and invasion of the ipsilateral adrenal gland. The Fuhrman s grading system is useful in clear cell renal cell carcinoma (RCC), and probably also in papillary RCC, but a redefinition for chromophobe RCC is needed. Finally, the determination of certain markers, such as VEGF and HIF, could constitute good target markers for the new therapies, but they remain under investigation. # 2007 Published by Elsevier B.V. on behalf of European Association of Urology. Report of the Kidney and Adrenal Committee of the Second European Uropathology Oncology Workshop held in Palermo, Italy, on 18 June * Corresponding author. Department of Urology, Dokuz Eylul University School of Medicine, Izmir, Turkey Tel ; Fax: address: ziya.kirkali@deu.edu.tr (Z. Kirkali) /$ see back matter # 2007 Published by Elsevier B.V. on behalf of European Association of Urology. doi: /j.eururo

2 european urology 51 (2007) Introduction The pathology report is undoubtedly very important in the decision-making for the urologic oncologist dealing with renal cell carcinoma (RCC). This can only be achieved by collaboration between urologist (uro-oncologist) and (uro)pathologist. Appropriate handling of the pathology specimen by the urologist and the pathologist is the first step in providing maximum information to the clinician [1]. Identifying the essential points to be described in the pathology report will enable the urologist to have the correct diagnosis, obtain information on the prognosis, consider adjuvant treatment if needed, and determine a follow-up schedule. The determination of certain markers, such as VEGF and HIF, can guide the clinician in the use of new therapies. The pathologist should therefore provide the urologist with as many data as possible in patients with earlystage disease with special mention of the cellular subtype. This information may have possible future therapeutic implications. The Uropathology Working Group (European Society of Pathology) and the European Working Group of Uropathology of the EAU, with the participation of different EAU urologists and pathologists, met in Palermo, Italy, on 18 June 2005 for a workshop held during the 78th Congress of the Italian Society of Urology. Consensus was achieved on the main issues. In this paper, the points that need to be reported in pathology reports of adult kidney tumour specimens are described in an attempt to aid the urologist in good clinical practice. 2. Tumour staging: a critical review The global usefulness of TNM 2002 staging [2] is acceptable, but in the literature the prognostic validity of some individual variables is controversial. This is mainly due to the greater frequency of localized tumours and more commonly applied conservative therapies. The most debated aspects are discussed below Tumour size In the 2002 UICC classification, T1 (pt1) tumours are subclassified as T1a (pt1a; 4 cm or less) and T1b (pt1b; larger than 4 cm but not larger than 7 cm). However, some authors have recently proposed that the different cut-offs (5 or 5.5 cm) have a greater statistical significance [3 5]. In contrast, tumour diameter appears to be a continuous variable and nomograms maybe more appropriate for the individual patient [6]. Tumours larger than 7 cm but limited to the kidney are the T2 (pt2) category. Some authors have proposed subdividing this category in tumours larger than 7 cm but smaller than 10 cm, and 10 cm or larger (risk ratio 1.42 vs 1.22) [5]. There is enough evidence and obviously a need for readjusting the tumour size for a more accurate staging of the T1 and T2 categories, but there is no consensus as to the exact cut-off size. The controversy regarding size categories is related to prognosis and should not solely influence the decision concerning nephron-sparing surgery [7], because, in addition to size, localization of the tumour within the kidney particularly will determine the possibility of a nephron-sparing surgery Fat tissue invasion The fat tissue is usually invaded through the renal capsule (perirenal fat tissue; only perinephric 79%), and less commonly through the renal sinus (sinus fat tissue; only sinus fat tissue 7.8%, sinus fat and perinephric fat 13.2%) [8]. The incidence of sinus fat tissue invasion is underestimated because the existing studies were only retrospective, and samples of such fat tissue are not systematically taken. The presence of renal capsular invasion is often difficult to determine with accuracy because, while growing, the tumour normally surrounds itself with a pseudocapsule that can be mistaken for the actual renal capsule. This is why definitive pathological criteria for recognizing the genuine transcapsular invasion are necessary. The opinion of the members of the workshop is to consider a true fat tissue when the tumoural cells contact directly with the fat tissue. It is probably the difficulty of distinguishing perirenal indenting from real invasion and penetration towards the fat tissue that caused some authors to believe that tumour size has better predictive value than renal capsular invasion [9,10]. Therefore, tumour size remains one of the most significant prognostic parameters of RCC. According to a prospective study, invasion of the sinus fat tissue entails greater aggressiveness (5-yr cancer-specific survival 25.9%) than perinephric fat tissue invasion (5-yr cancer-specific survival 50.9%; Table 1) [11], probably because sinus fat tissue contains numerous large thin-walled veins and lymphatics [12]. Because tumour invasion into the perinephric tissue is important for prognosis [13], an accurate analysis of the surgical specimens is mandatory according to previously published guidelines [1], in which the need to analyze the status of the renal sinus fat tissue was specified.

3 1196 european urology 51 (2007) Table 1 Fat tissue invasion and survival Site of fat tissue invasion 5-yr survival 2.3. Adrenal gland invasion Ipsilateral adrenal gland invasion by the tumour because of contiguity extension is rare (2.5%). The TNM 2002 considers it as category T3a (pt3a), but its prognosis is reportedly worse than that of perinephric fat tissue invasion [14], and it has no significant differences with pt4 (5-yr survival = 18.1%; cf. Table 2) [15]. Therefore, some authors suggested that ipsilateral adrenal gland invasion should be assigned directly to category T4 (pt4) [15]. This direct tumoural extension needs to be differentiated from metastatic adrenal gland invasion Inferior vena cava invasion Lymph node metastasis Metastasis Perinephric 50.9% 7% 28% Sinus 25.9% 19% 30% Data from [8,11]. There is controversy on the prognostic impact of the macroscopic venous invasion. The 5-yr survival rate of patients with confined tumour and N0M0 patients is 72%, whereas this is 68% in patients with similarly confined tumours and renal vein thrombus [16]. Tumoural venous thrombus in the vena cava apparently does not entail such a poor prognosis in the absence of local invasion, as long as there is no nodal or distant metastasis at the time of surgery. Tumour thrombus level in the inferior vena cava does not significantly affect long-term survival when the thrombus can be completely removed [17]. However, if there is local invasion (pt3a), these patients have worse prognosis than pt3b patients [15]. This is why perhaps subcategories of T3 (pt3) could be redefined. A recent study shows that if there is simultaneous perinephric fat infiltration and vena cava thrombus, the prognosis is even worse [15]. The new targeted therapies must be tested in patients with inferior vena cava invasion [18]. Table 2 Adrenal gland invasion and survival pt3a 5-yr survival pt3b 5-yr survival With adrenal gland invasion 20.2% 20.2% Without adrenal gland invasion 53.9% 42.7% Data from [14] Lymph node invasion The number of lymph nodes examined (<13 vs 13) may have an impact on the rate of metastases and thus the N status of the current TNM system is challenged [19]. Similar to what happens in other organs, it might be important that the minimum number of lymph nodes, still to be defined, should be examined to give a result with more prognostic meaning. All of these considerations in the literature call for adaptation and improvement of the actual TNM classification. In spite of such problems, however, it is remarkable that 5-yr survival rates in patients with distant metastases and different T categories were comparable (20% for T1, 25% for T3c) [10] Involvement of the pelvicalyceal system This issue is currently under discussion because some authors feel it indicates a worse prognosis [20], whereas others believe it does not represent an independent prognostic factor, except in organconfined tumours [21]. 3. Tumour grading adjustment Despite criticisms about its reproducibility, the Fuhrman s nuclear grade (based on the size and shape of the nucleus and also on the presence or absence of nucleoli) [22] is the most widely used system. It is a good prognostic marker with a 5-yr cancer-specific survival rates of 89%, 65% and 46% for grades 1, 2, and 3 4, respectively [23]. Although in short series a grading system with two grades had better reproducibility [24], the largest multi-centre series have clearly shown that a four-tier system is applicable [25]. The wider use of ultrasound and other imaging modalities favours the detection of asymptomatic renal tumours at an earlier stage [26]. Even in this situation, Fuhrman s grading is helpful. Nuclear grade greater than 2 correlates with significantly shorter survival ( p = 0.018) in stage I (T1, N0, M0) tumours [27]. Although the Fuhrman s grade was applied only to clear cell RCC initially, this is now recommended in all cell subtypes. In chromophobe RCC, irregular nuclei and prominent nucleoli are typically seen. Therefore, Fuhrman s grade is often reported to be worse even in patients with favourable outcomes. Some authors propose an adaptation of the classification for this RCC subtype with redefinition of three grades for chromophobe RCC: grade 1, cells with wide nuclear

4 european urology 51 (2007) range without nuclear crowding or anaplasia; grade 2, presence of nuclear pleomorphism and nuclear crowding; and grade 3, nuclear anaplasia including giant cells and sarcomatoid transformation. This new system accepts the more pleomorphic nuclear aspect in low grades that correlates better with the pt category and predicts the clinical outcome independently [28]. This new approach, however, should be validated by other series before its introduction into clinical practice. Finally, the mucinous tubular and spindle cell carcinoma, a new subtype in the WHO 2004 classification, is not graded. Likewise, the oncocytoma, as a benign tumour, is not graded. 4. Microvascular invasion Microvascular invasion has been considered an important prognostic factor after radical nephrectomy for clinically nonmetastatic RCC, with a progression rate of 29% to 39.2% (with microvascular invasion) versus 6.2% to 17% (without microvascular invasion) [29,30]. There are discrepancies among authors as to whether this finding has any independent statistical significance in the kidney [30,31], but recent reports seem to confirm this [32,33]. So far, there are no strict criteria for microvascular diagnosis in any tumour. The first issue would be to determine the location in which microvascular invasion has clinical significance. According to the observations of breast cancer [34] that were confirmed in prostate cancer [35] and in RCC [29,30], peritumoral or outside cancer perimeter-positive invasion has a better correlation than intratumoural-positive invasion. The second issue would be to determine whether lymphatic vessels and blood vessels have different meanings. In bladder cancer, microvascular invasion correlates with prognosis [36]. However, in most cases only capillary structures are recognized and it is very difficult to distinguish between lymphatic vessels and blood vessels. The general trend is not to distinguish between them and to use the common terms microvascular or lymphovascular. The third issue which is the most important one is how to distinguish invasion from an image of pseudoinvasion by the retraction of the surrounding stromal tissue. Some authors believe it is very difficult to ascertain the image interpreted as lymphovascular by means of the usual hematoxylin-eosin (H&E) method, without systematic immunohistochemical markers. Others, however, suggest that vessel identification is possible with H&E with enough reliability, provided that the observation is rigorous [37]. It is advisable to reach an agreement about this topic as soon as possible because an obvious clinical fact exists despite all the criticisms of the interobserver variability. 5. Tumour necrosis Another prognostic marker with similar problems of reproducibility is tumour necrosis. Coagulative necrosis in the primary tumour is associated with poor survival in localized RCC for clear cell and chromophobe types, while the prognostic impact for the other histological subtypes is debated [38]. Necrosis correlates with a higher expression of the cell proliferation factor (Ki67) and the vascular endothelial growth factor (VEGF) [39]. These findings have led to re-evaluation of some morphologic prognostic markers as their molecular basis may be directly involved in the molecular alterations of the cellular cycle [40]. Once again, consensus methods for reproducible quantification criteria were established. 6. Histological subtypes For a long time only a few cellular subtypes of RCC were recognized, with little clinical significance except for the more undifferentiated cases (sarcomatoid carcinoma). The advent of immunohistochemical methods, together with genetic studies, has made it possible to recognize multiple cell subtypes with both genetic and biological differences. The WHO s 2004 classification (Table 3) makes a clear distinction between certain tumour subtypes that have a different prognosis than the others. These differences between the most common types (clear cell, papillary, chromophobe) are statistically significant in univariate studies [41,42], but no independent statistical significance was found in Table 3 WHO histological classification of renal cell tumours Clear cell renal cell carcinoma Multilocular clear cell renal cell carcinoma Papillary renal cell carcinoma Chromophobe renal cell carcinoma Carcinoma of the collecting ducts of Bellini Renal medullary carcinoma Xp11 translocation carcinomas Carcinoma associated with neuroblastoma Mucinous tubular and spindle cell carcinoma Renal cell carcinoma, unclassified Papillary adenoma Oncocytoma

5 1198 european urology 51 (2007) other studies when standardized for grade and stage [43]. In spite of this, some cell subtypes do seem to be related to different carcinogenesis pathways [44], and their response to future therapies may be different as well [45]. This is the reason why in our clinical approach we must consider the morphology and the genetics of the different RCC subtypes. Recent publications have thoroughly reviewed the different cell subtypes and recognized the morphologic criteria that were extensively described [46,47]. Some aspects of the different histological types relate to new treatments with angiogenesis inhibitors, and these will probably become relevant in the near future. They are currently under investigation, however, and their roles remain undefined. Clear cell RCC is characterized by LOH 3p (with germline mutation in the von Hippel Lindau [VHL] tumour suppressor gene in the hereditary forms, or the somatic VHL inactivation in the sporadic forms). VHL inactivation results in normoxic overexpression of the hypoxia-inducible transcription factors HIF-1 and HIF-2 and activation of a wide range of hypoxia-inducible gene targets, such as VEGF and PDGF, both of which play an essential role in angiogenesis, glucose transport, glycolysis, ph control, epithelial proliferation, cell migration, and apoptosis and can help the hypoxic adaptation of clear cell carcinoma [48]. Therefore, a therapeutic multi-targeted approach that selectively and simultaneously blocks these growth factors represents an attractive means of treatment [49,50]. Papillary RCC can be subdivided in a less malignant type 1 and a more aggressive type 2. Recent studies have discovered that the allelic imbalances on 17q are almost exclusively confined to type 1, in contrast to the allelic imbalances on 9p, which are confined to type 2, suggesting that each of these cell types can originate from different molecular genetic pathways [51]. The analysis of familial forms of this subtype has shown than in papillary type 1 there may be germline mutation of the MET proto-oncogene, and the latter is related to HGF-R. In contrast, certain forms of type 2, associated with familial leiomyomatosis, are associated with germline fumarate hydratase mutations with HIF-1 and HIF-2 overexpression. Therefore, a way of treatment similar to that of clear cell RCC is possible. VEGF antibodies and tyrosine kinase inhibitors might thus be useful in clear cell and type 2 papillary RCC but not in type 1 papillary cancer. All of this may mean that in the near future the pathological demonstration of target markers such as HIF and VEGF will be important. Chromophobe RCCs and oncocytomas present with a similar immunophenotype, so the differential diagnosis of such tumours is occasionally difficult. Apparently, kidney-specific cadherin is able to distinguish between them [52]. Some authors believe that the apparent similarity means that a subgroup of oncocytomas is simply the adenoma form of chromophobe RCC. Some tumours were characterized with a translocation involving chromosome Xp11.2, resulting in gene fusions involving the TFE3 gene, including t(x;1)(p11,2;q21) fusion PRCC and TFE3 (the most frequent one), t(x;17) (p11.2;q25) fusion ASPL and TFE3 (less aggressive) [53], t(x;1) (p11.2;p34) fusion PSF and TFE3, and Inv(X)(p11;q12) fusion Non- O(p54nrb) and TFE3. Another translocation is t(6;11)(p21;q12) fusion TFEB [54]. All of these variants are more frequent in children and young adults, and so some therapeutic target could be developed. Generally the histological subtype is not an independent prognostic factor. We should not forget, however, that the WHO s histological classification enables us to recognize mucinous tubular and spindle cell carcinomas as tumours with an excellent prognosis and carcinoma of the collecting ducts of Bellini and renal medullary carcinoma as another, very aggressive group; this highlights the fact that the sarcomatoid transformation, even in small areas, has a negative impact on prognosis [55]. Finally, it should be stressed that an unclassified carcinoma category is also accepted. The incidence of unclassified RCC varies between 3% and 5% [56]. If we analyze the cases included under this label, we will observe that they are from various origins. This turns this group into a quite heterogeneous one, but its acceptance has enabled homogeneity within the other subtypes. The points discussed above apply to a kidney specimen that is removed intact. Although most kidney tumours today are operated on using laparoscopy, the pathologist most of the time is given a non-morcellated specimen. If the removed kidney is morcellated, then some of the abovementioned points may be difficult or even impossible for the pathologist to report. Likewise, nephron-sparing surgery, which is used more frequently today, was not the topic of this workshop and will be addressed in the future planned workshops. 7. Conclusions There have been many recent developments in our understanding of RCC. Similar changes observed in

6 european urology 51 (2007) sporadic conventional RCC and VHL disease now enables us to realize why different histological subtypes behave differently and why the classical prognostic tools are incapable of being helpful to the urologist. Refinement of the classical methods is a result of our improved genetic and molecular knowledge, and it will not be long before clinical practice will also start using some molecular markers related to the new treatments. This is why various prognostic models have been formulated integrating TNM stage, tumour size, histology (grade, tumour necrosis) [57 59] and even pathologic and molecular data [60,61]. However, external validation of molecular markers remains difficult, and we should be cautious when comparing the published data on gene expression. Prompt and accurate reporting of kidney tumour specimens by the pathologist will enable the urologist to better treat patients with various types of RCC. 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