Urologic Oncology: Seminars and Original Investigations ] (2013) ∎∎∎–∎∎∎

Original article

Chromosome 9p deletions are an independent predictor of tumor progression following nephrectomy in patients with localized clear cell renal cell carcinoma Daniel de Oliveira, M.D., Ph.D.*, Marcos F. Dall’Oglio, M.D., Ph.D., Sabrina T. Reis, Ph.D., Marcelo Zerati, M.D., Ph.D., Isida C. Souza, Ph.D., Katia R. Leite, M.D., Ph.D., Miguel Srougi, M.D., Ph.D. Urology Division, University of Sao Paulo Medical School, Sao Paulo, Brazil Received 14 October 2013; received in revised form 24 November 2013; accepted 19 December 2013

Abstract Objectives: Chromosome 9p deletions have been observed in 14% to 36% of patients with clear cell renal cell carcinoma (ccRCC) and are associated with advanced-stage tumors. We evaluated whether chromosome 9p deletions are an independent predictor of worse outcomes in patients with localized ccRCC. Materials and methods: In this retrospective study, tumor samples from 94 patients with ccRCC NX-0 M0 who underwent radical nephrectomy or conservative renal surgery were analyzed using a fluorescence in situ hybridization technique. Results: The median follow-up period was 11.7 years, and 9p deletions were identified in 15% of cases. The cancer-specific survival rate estimated at 5 and 10 years was 99% and 96%, respectively, for patients without such chromosomal losses and 71% and 57% in patients with a loss of 9p (P o 0.001). Chromosome 9p deletions were an independent prognostic factor in a multivariate analysis, increasing the risk of death due to disease by 28-fold (95% CI: 5–155, P o 0.001). In patients with a low risk of progression, i.e., a low Stage, Size, Grade, and Necrosis score (0–2), low risk according to the University of California at Los Angeles Integrated Staging System, and low risk according to the pathological triad used at University of Sao Paulo, tumors with 9p deletions were significantly associated with a poorer cancer-specific survival at 10 years: 70%, 67%, and 67% vs. 98%, 97%, and 98%, respectively, in patients without 9p deletions. Conclusion: Chromosome 9p deletions independently establish a poorer prognosis for patients with localized ccRCC, providing further relevant clinical information that may improve the predictive ability of the main prognostic systems currently in use. r 2013 Elsevier Inc. All rights reserved. Keywords: Carcinoma; Renal cell; Chromosomes; Humans pair 9; Chromosome deletion; Prognosis; In situ hybridization; Fluorescence

1. Introduction In the past, the identification of patients at risk of disease progression following nephrectomy was important primarily to advise them about their prognosis and the frequency of follow-up appointments. However, with the emergence of novel adjuvant clinical trials in renal cell carcinoma (RCC), predictive models have a potential for increased use as accurate risk stratification and correct inclusion criteria are paramount. Currently, several models that assess the risk of Corresponding author. Tel.: þ55-853-067-6528; fax: þ55-853-2467879. E-mail address: [email protected] (D. de Oliveira). *

1078-1439/$ – see front matter r 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.urolonc.2013.12.008

progression following nephrectomy are available, such as University of California at Los Angeles (UCLA) Integrated Staging System (UISS) [1], the Stage, Size, Grade, and Necrosis (SSIGN) score [2], and the pathological triad [3]. However, despite the availability of important pathological variables for composing these models, patient groups are often heterogeneous, culminating in unexpected disease recurrence in some cases. Thus, identifying cytogenetic and molecular prognostic factors has been shown to be critical. The inclusion of biomarkers in conventional staging models has allowed physicians to more accurately determine a prognosis [4–6]. Chromosome 9p deletions have been observed in 14% to 36% of patients with clear cell RCC (ccRCC) and are

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D. de Oliveira et al. / Urologic Oncology: Seminars and Original Investigations ] (2013) 1–6

associated with high-grade, advanced-stage tumors and with lymphatic and systemic metastases [7–11]. However, most of these studies have included patients with metastatic disease at the time of nephrectomy, which limits this marker’s applicability as an accurate predictor of disease progression following surgery for pathologically localized tumors. In the present study, we evaluated the role of chromosome 9p deletions as independent predictors of recurrence-free and cancer-specific survival in patients with localized ccRCC.

diameter of 0.6 mm were removed from each patient’s paraffin block containing the ccRCC from specific areas, corresponding to previously demarcated and most representative areas from respective hematoxylin-eosin-stained slides. These cylinders were transferred at 3-mm intervals to a recipient paraffin block. Next, the tissue microarray recipient block was cut into consecutive and numbered 3-μm histologic sections, and the slides were used for in situ hybridization. Two tumor samples were collected per patient, as it has been demonstrated that analysis of 2 disks is comparable to analysis of a whole tissue section in more than 95% of cases [12].

2. Materials and methods 2.3. Fluorescence in situ hybridization 2.1. Patients After approval by the Institutional Internal Review Board, we retrospectively analyzed surgical specimens from 94 patients diagnosed with localized (NX-0 M0) ccRCC who underwent radical nephrectomy or conservative renal surgery (partial or enucleation nephrectomy) between 1988 and 2006 at our institution. Patients with an anatomically or functionally solitary kidney and patients with small (o4 cm), localized tumors and a normal contralateral kidney underwent conservative renal surgery. For staging purposes, lymph node dissection was limited to the hilar region in those who underwent radical nephrectomy. Only patients who were operated on by the same surgeon (M.S.) and whose pathological analyses were performed by the same pathologist (K.L.) were included. All patients with lymphatic or systemic metastatic disease at the time of surgery were excluded from the study. For each patient, the analyzed clinical and pathological characteristics included age, gender, symptoms at initial presentation, tumor size, pT stage (2010 TNM classification), Fuhrman nuclear grade, coagulative tumor necrosis, microvascular invasion, and perinephric or renal sinus fat involvement by the tumor. To identify patients who are at a low risk of disease progression, 3 postoperative prognostic systems were used, namely, the models used at the University of Sao Paulo (pathological triad), Mayo Clinic (SSIGN score), and UCLA (UISS). Following surgery, all patients received regular follow-up visits based on their staging. Low-risk patients returned for semiannual history taking, physical examination, and routine blood tests, in addition to annual chest radiography and abdominal computed tomography. Chest tomography, bone scintigraphy, and brain imaging were conducted in clinically indicated cases. The survival time was calculated as the time interval between surgery and the last known follow-up. 2.2. Tissue samples The tissue microarray was constructed as previously described. Using a precision mechanical system (Beecher Instruments, Sun Prairie, WI), tissue cylinders with a

The probe used for this study was obtained from Abbott (Des Plaines, IL), and the reactions followed the suggested recommendations [13,14]. Briefly, the slide was serially dehydrated in 70%, 85%, and 100% ethanol solutions for 2 minutes each and then placed in 2 saline sodium citrate (SSC) solution (pH 7.0) at 751C for 10 minutes. Subsequently, the slide was sequentially immersed in a proteinase K/2 SSC solution (0.25 mg/ml) at 371C for 10 minutes and in a 2 SSC solution at room temperature for 5 minutes. The tissue samples were again placed in 70%, 85%, and 100% ethanol solutions for 2 minutes each, airdried, and exposed to the Telvysion 9p probe (8 ml). The slide was then covered with a 24 mm  32 mm coverslip and sealed with glue (rubber cement). Hybridization was accomplished by placing the slide plate at 801C for 10 minutes and then incubating it overnight in a humidified chamber at 371C. Following the hybridization, the glue and coverslip were gently removed, and the slide was immediately immersed in a urea/0.1 SSC buffer at 451C for 30 minutes. Subsequently, the slides were washed with 2 SSC at room temperature for 2 minutes, again serially dehydrated with ethanol, and air-dried. Finally, the slide was counterstained with 10 μl of 4’,6-diamidino-2-phenylindole/antifade and covered with a coverslip. The analysis was performed with a Nikon Eclipse E600 fluorescence microscope using the CytoVision system for documentation. All the cells in each tumor fragment (cylindrical sample) were analyzed; samples were considered to have chromosome 9p deletions when there was no detectable signal in the fragment, i.e., only the samples with homozygous deletions were considered positive. All cytogenetic analyses were prepared by the same pathologist (K.L.) without knowledge of the evolution of each particular case. 2.4. Statistical analysis Data were analyzed using multivariate Cox regression to identify the independent prognostic factors. Cancer-specific survival curves and disease-free survival curves were generated using the Kaplan-Meier method. The differences between the curves were characterized using the log-rank

D. de Oliveira et al. / Urologic Oncology: Seminars and Original Investigations ] (2013) 1–6

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test. Student t tests and analysis of variance were used when the data had a normal distribution, whereas a MannWhitney test was used for data with an abnormal distribution. The chi-square test was used to analyze the categorical variables. All statistical analyses were performed with SPSS 16.0 (IBM Corp, Armonk, NY).

3. Results In 94 patients studied, chromosome 9p deletions were detected in 14 tumors (15%) and the median follow-up time was 11.7 years (mean = 11.6; 95% CI: 10.6–12.7). The Table 1 Clinical and pathological characteristics of the patient cohort, stratified by chromosome 9p status All n ¼ 94 Age, y Mean (SD) Range Sex, no. (%) Male Female

9p deletions No 9p deletions P value n ¼ 14 n ¼ 80

59.7 (12.3) 60.3 (11.6) 23–90 32–76

59.5 (12.5) 23–90

0.838a

67 (71.3) 27 (28.7)

9 (64.3) 5 (35.7)

58 (72.5) 22 (27.5)

0.531b

Performance status, no. (%) ECOG 0 82 (87.2) ECOG Z1 12 (12.8)

12 (85.7) 2 (14.3)

70 (87.5) 10 (12.5)

0.426b

Mean size, cm Mean (SD) Range

4.7 (2.6) 1.2–12

5.1 (3.0) 1.5–12

4.6 (2.5) 1.2–12

0.599c

52 (65) 28 (35)

0.572b

Initial presentation, no. (%) Incidental 60 (63.8) Symptomatic 34 (36.2)

8 (57.1) 6 (42.9)

Tumor classification, no. (%) pT1 70 (74.5) pT2 7 (7.4) pT3 17 (18.1)

11 (78.5) 1 (7.2) 2 (14.3)

59 (73.8) 6 (7.5) 15 (18.7)

0.689b

Fuhrman, no. (%) Low grade: 1 e 2 High grade: 3 e 4

65 (69.1) 29 (30.9)

10 (71.4) 4 (28.6)

55 (68.8) 25 (31.2)

0.841b

Histologic necrosis, no. (%) Absent 76 (80.1) Present 18 (19.1)

12 (85.7) 2 (14.3)

64 (80) 16 (20)

0.616b

Microvascular invasion, no. (%) Absent 73 (77.7) Present 21 (22.3)

12 (85.7) 2 (14.3)

61 (76.3) 19 (23.7)

0.433b

65 (81.3) 15 (18.7)

0.689b

Perinephric or renal sinus fat invasion, no. (%) Absent 77 (81.9) 12 (85.7) Present 17 (18.1) 2 (14.3)

SD ¼ standard deviation; ECOG ¼ Eastern Cooperative Oncology Group. a Student t test. b 2 χ test. c Mann-Whitney test.

Fig. 1. Kaplan-Meier analysis of cancer-specific survival, stratified by chromosome 9p status. (Color version of figure is available online.)

pathological characteristics of the patients’ tumors with and without chromosome 9p deletions are listed in Table 1. At follow-up, 83 (88%) patients were alive and disease free, whereas 10 (11%) died of RCC and 1 (1%) died of other causes. The cancer-specific survival estimated at 5 and 10 years was 71.4% and 57.1%, respectively, for patients with chromosome 9p deletions and 98.7% and 96.1%, respectively, for the patients without such deletions (logrank test, P o 0.001; Fig. 1). The estimated mean survival time was 141 months (95% CI: 95–187) and 279 months (95% CI: 269–289) for patients with and without 9p deletions, respectively (P o 0.001). Simultaneously, the recurrence-free survival estimated at 5 and 10 years was 71.4% and 50%, respectively, for those patients with deletions and 93.7% and 92.4%, respectively, for those patients without deletions (log-rank test, P o 0.001; Fig. 2). In the multivariate analysis using the Cox regression model, the only variables that had an independent effect on the cancer-specific survival were tumor size and 9p deletions (Table 2). Examining the low-risk patient subgroup, based on the previously described pathological triad, 53 patients had tumors smaller than 7 cm, without microvascular invasion and with a low Fuhrman grade. The survival analysis was performed for those patients with low risk of progression based on these classifications (Table 3). The incidence of

Fig. 2. Kaplan-Meier analysis of recurrence-free survival, stratified by chromosome 9p status. (Color version of figure is available online.)

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Table 2 Multivariable Cox proportional hazards model for risk of cancer-specific mortality Variable

Categories

HR

Tumor classification Fuhrman Microvascular invasion Histologic necrosis Size, cm 9p deletion

pT3/T4  pT1/T2 0.22 High  low 0.68 Present  absent 2.44 Present  absent 2.98 Z7  o7 7.23 Yes  no 28.86

95% CI

P

0.20–0.47 0.222 0.05–8.90 0.769 0.46–12.89 0.291 0.43–20.34 0.265 1.29–40.3 0.024 5.3–155.5 o0.001

HR ¼ hazard ratio.

chromosome 9p deletions in these subgroups was between 16% and 18%. Thus, in all the 3 prognostic models, the cancer-specific survival at 10 years in the patients with 9p deletions was significantly lower than in those patients without this deletion.

4. Discussion The main contribution of this study was the determination that patients with localized ccRCC (NX-0 M0) and chromosome 9p deletions have an increased likelihood of dying of the disease. Chromosome 9p deletions are also present in tumors that are considered low risk by the current, major stratification systems and are a marker of relapses and unforeseen deaths, including such events in this particular group. Thus, 9p deletions may predict the aggressive behavior of ccRCC even at extremely early stages. Furthermore, in these low-risk patients, the absence of 9p deletions provides important information. The cancerspecific survival at 5 and 10 years in all the 3 models are identical, remaining close to 100% in these cases, Table 3 Cancer-specific survival in low-risk patients, stratified by chromosome 9p status Cancer-specific survival 5 y, %

10 y, %

USP low risk, n ¼ 53 Entire group Subgroup without 9p deletiona Subgroup with 9p deletiona

94.3 97.7 77.8

92.5 97.7 66.7

SSIGN score 0–2, n ¼ 60 Entire group Subgroup without 9p deletiona Subgroup with 9p deletiona

94.9 98.0 80.0

93.2 98.0 70.0

UISS low risk, n ¼ 50 Entire group Subgroup without 9p deletionb Subgroup with 9p deletionb

93.9 97.5 77.8

91.8 97.5 66.7

USP ¼ University of Sao Paulo. P ¼ 0.001. b P ¼ 0.002. a

suggesting the possibility of a decrease in the duration of postoperative follow-up. In ccRCC, the loss of 9p has been observed in 14% to 36% of cases [7–11] and is detected more frequently in metastatic renal carcinomas, suggesting that changes in this region contribute to tumor progression [15]. Brunelli et al. [10] evaluated the chromosome 9p deletions in 73 all-stage ccRCC patients undergoing nephrectomy with a mean follow-up time of 45 months. The cancer-specific survival at 5 years was 88% in patients without a loss of 9p and 43% in patients with a loss of 9p. Upon analyzing the cytogenetic profile of patients undergoing nephrectomy for ccRCC, a group at UCLA reported that certain cytogenetic aberrations were related to pathological parameters and cancer-specific survival [7]. The loss of chromosome 9p was associated with a more advanced stage, a greater propensity for distant metastases, and a worse Fuhrman grade. La Rochelle et al. [11] subsequently published a study with similar findings for all-stage ccRCC with a mean follow-up time of 40 months; the incidence of chromosome 9p deletions was 14% and the deletions were associated with a poor nuclear grade, worse pT classification, and the presence of lymphatic and distant metastases. It was also demonstrated [11] that 9p-deleted tumors are more likely to demonstrate recurrence at 5 years after nephrectomy for small renal masses (o4 cm), a result similar to that found in the current study. Therefore, we were able to validate 9p deletions as an important prognostic factor as we investigated its effect on the cancer-specific survival at 10 years in a series of patients with localized ccRCC. By limiting the prediction of any factor or prognostic model to 5 years, short-term follow-up studies do not consider the 15% to 19% of patients who will show disease progression only after the fifth year following nephrectomy for a localized tumor [16]. Chromosome 9p deletions not only were considered an independent prognostic factor using a multivariate analysis (Table 2) but were also the most important predictor of cancer-specific mortality, superior to any other pathological factor analyzed, including the tumor size. We believe that wellestablished prognostic factors such as T stage, grade, and necrosis were not significant prognostic factors on this multivariate analyses because the group studied consisted mostly of pT1/pT2 tumors (77/94 patients, 82%), low-grade Fuhrman (65/94, 70%), and tumors without histologic necrosis (76/94, 80%). The deletion or otherwise inactivation of CDKN2A/ARF tumor suppressor gene located at 9p21 region has been suggested to play a role in ccRCC aggressiveness. It encodes 2 major cell cycle regulatory proteins, p16 and p14, which are involved in the normal retinoblastoma (Rb/E2F) and p53 pathways, respectively [17,18]. Loss of the CDKN2A tumor suppressor gene caused by chromosome 9p deletions leads to unrestricted stimulation of the cell cycle and simultaneous Rb and p53 inactivation, which is a much more aggressive disease than the deletion of

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either function alone [19]. The CDKN2B tumor suppressor gene that encodes the protein p15 is also located in this identical region of 9p21. Similar to p14, p15 is a cyclin Ddependent kinase inhibitor that regulates the cell cycle via the Rb pathway [20]. Chromosome 9p deletions may also disrupt important antitumor immune mechanisms as the interferon-alfa and interferon-beta genes are located on 9p. There is still no consensus on the ideal criteria for a tumor to be considered deleted of 9p using fluorescence in situ hybridization on paraffin-embedded tissue, and previous studies in ccRCC [10,11] used distinguished ways of interpreting the samples. Only samples with homozygous deletions were considered positive because 9p deletions are associated with loss of function of tumor suppressor genes and so they act as recessive mutations at the genetic level, i. e., both copies of these genes must be eliminated or inactivated to cause the mutant phenotype. Another issue that can render interpretation of results more difficult and imprecise is the recently reported intratumoral heterogeneity owing to sampling bias [21]. Reconstructing tumor clonal architectures and the identification of common mutations located in the trunk of the phylogenetic tree may contribute to a more accurate approach [21]. The main prognostic models [1,2], which were created based on a population with high percentages of advanced tumors (i.e., undergoing surgery during the 1980s and 1990s), may no longer be as effective in stratifying the risk of progression in contemporary patients, who tend to present with localized disease. Thus, the integration of biomarkers into classical staging models has been useful. Researchers at Mayo Clinic developed a combined approach in which the outcome of patients with ccRCC may be improved based on molecular data collected using immunohistochemical analyses of tumor tissue [22]. In a subgroup analysis, however, the BioScore did not provide any benefit to patients with a low risk of cancerspecific death, as defined by the nuclear grade, UISS, or SSIGN. Despite the limitations of the present investigation (i.e., a retrospective study that used data from a single center), it was possible to associate chromosome 9p deletions with cancer-specific mortality even in these low-risk patients. In this scenario, the study of 9p would be an important application for renal biopsies aimed at evaluating small renal masses. There are currently no reliable preoperative prognostic factors that can be used to confidently predict the malignant potential of these small tumors, which leaves extremely few data upon which the decision for immediate treatment or active surveillance may be based [23,24]. As reported by La Rochelle et al. [11] and the present study, small and supposedly low-risk tumors that also harbor 9p deletions are not good candidates for observation. Chromosome 9p deletions are a good candidate for integration into new prognostic models or for incorporation into systems that are already well established and validated. However, multicenter studies with a larger number of

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patients are necessary to indisputably validate the routine investigation of 9p deletions in clinical practice.

5. Conclusions Chromosome 9p deletions are an independent marker of postoperative death in patients with localized ccRCC. Despite its limitations, our data also indicate that loss of 9p is associated with increased risk of cancer-specific death in patients with low-risk localized ccRCC and thus predicts its aggressive behavior even at extremely early stages. The future incorporation of additional predictive biomarkers into the current stratification systems will further improve our ability to determine prognosis, and the chromosome 9p deletions might be a good candidate. References [1] Zisman A, Pantuck AJ, Wieder J, et al. Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma. J Clin Oncol 2002; 20:4559–66. [2] Frank I, Blute ML, Cheville JC, et al. An outcome prediction model for patients with clear cell renal cell carcinoma treated with radical nephrectomy based on tumor stage, size, grade and necrosis: the SSIGN score. J Urol 2002;168:2395–400. [3] Dall’Oglio MF, Ribeiro-Filho LA, Antunes AA, et al. Microvascular tumor invasion, tumor size and Fuhrman grade: a pathological triad for prognostic evaluation of renal cell carcinoma. J Urol 2007; 178:425–8. [4] Jones J, Out H, Spentzos D, et al. Gene signatures of progression and metastasis in renal cell cancer. Clin Cancer Res 2005;11:5730–9. [5] Soung-Sullivan P, Rao J, Cheng L, et al. Classical pathology versus molecular pathology in renal cell carcinoma. Curr Urol Rep 2007;8:5–11. [6] Kim HL, Seligson D, Liu X, et al. Using tumor markers to predict the survival of patients with metastatic renal cell carcinoma. J Urol 2005;173:1496–501. [7] Klatte T, Rao PN, de Martino M, et al. Cytogenetic profile predicts prognosis of patients with clear cell renal cell carcinoma. J Clin Oncol 2009;27:746–53. [8] Schullerus D, Herbers J, Chudek J, et al. Loss of heterozygosity at chromosomes 8p, 9p, and 14q is associated with stage and grade of non-papillary renal cell carcinomas. J Pathol 1997;183:151–5. [9] Presti JC Jr, Wilhelm M, Reuter V, et al. Allelic loss on chromosomes 8 and 9 correlates with clinical outcome in locally advanced clear cell carcinoma of the kidney. J Urol 2002;167:1464–8. [10] Brunelli M, Eccher A, Gobbo S, et al. Loss of chromosome 9p is an independent prognostic factor in patients with clear cell renal cell carcinoma. Mod Pathol 2008;21:1–6. [11] La Rochelle J, Klatte T, Dastane A, et al. Chromosome 9p deletions identify an aggressive phenotype of clear cell renal cell carcinoma. Cancer 2010;116:4696–703. [12] Camp RL, Charette LA, Rimm DL. Validation of tissue microarray technology in breast carcinoma. Lab Invest 2000;80:1943–9. [13] Varella-Garcia M. Stratification of non-small cell lung cancer patients for therapy with epidermal growth factor receptor inhibitors: the EGFR fluorescence in situ hybridization assay. Diagn Pathol 2006;1:19–28. [14] Reid-Nicholson MD, Motiwala N, Drury SC, et al. Chromosomal abnormalities in renal cell carcinoma variants detected by Urovysion

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Chromosome 9p deletions are an independent predictor of tumor progression following nephrectomy in patients with localized clear cell renal cell carcinoma.

Chromosome 9p deletions have been observed in 14% to 36% of patients with clear cell renal cell carcinoma (ccRCC) and are associated with advanced-sta...
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