- Email: [email protected]
Renal Ewing tumors†
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Annals of Oncology 24: 2455–2461, 2013 doi:10.1093/annonc/mdt215 Published online 11 June 2013
S. Zöllner, U. Dirksen, H. Jürgens & A. Ranft* Department of Pediatric Hematology and Oncology, University Hospital, Muenster, Germany
Received 5 November 2012; revised 6 March 2013; accepted 29 April 2013
Background: Renal Ewing’s sarcoma/primitive neuroectodermal tumor (ES/PNET) is extremely rare. Clinical symptoms are nonspecific presenting abdominal pain, palpable mass, and hematuria. Owing to advanced technology demonstrating the ES-specific EWS/ETS translocation, this differential diagnosis has become feasible. Patients and methods: The German database of GPOH Ewing’s sarcoma trials from 1980 to 2009 was searched for kidney as primary site. Twenty-four patients were identified and analyzed. The median time of observation was 3.71 years (range 0.27–8.75 years). Additionally, we carried out a Medline search for renal ES/PNET. Results: The median age was 24.9 years (range 11–60 years). In 37.5%, patients presented with primary metastases. Tumor thrombi in the adjacent renal vessels occurred in 56.2%. In 90.9%, rearrangements of t(11;22) were found. All patients received a combined chemotherapy according to the EURO-E.W.I.N.G.99 protocol. In accordance, local control consisted predominantly of combined modality surgery and radiation (47%). At 3 years, overall survival (OS) was 0.80 (SE = 0.09), and event-free survival (EFS) 0.66 (SE = 0.11). Conclusions: ES/PNET should be considered in the differential diagnosis of renal tumors. Patients with renal ES/PNET respond to and benefit from conventional ES treatment according to ES study protocols. Therefore, an accurate diagnostic approach and a guideline-adapted therapy should be facilitated. Key words: Ewing’s sarcoma, kidney, outcome, PNET
introduction The major differential consideration for small-round cell tumors of the kidney encompasses a wide range of unrelated neoplasms with overlapping morphologic features, and differing therapeutic approaches and prognosis [1]. This includes malignant lymphoma, embryonal rhabdomyosarcoma, renal neuroblastoma, Wilms tumor, small-cell osteosarcoma, desmoplastic small-cell tumor, synovial sarcoma, small-cell neuroendocrine carcinoma, and Ewing’s sarcoma (ES) or its variant with neural differentiation, primitive neuroectodermal
*Correspondence to: Dr Andreas Ranft, Department of Pediatric Hematology and Oncology, Muenster University Hospital, Albert Schweitzer Campus 1, Building A1, 48149 Muenster, Germany. Tel: +49-251-83-56486; Fax: +49-251-83-56489; E-mail: [email protected] †
Previous presentation of this study: initial and preliminary results were presented at the Annual Meeting of the Société Internationale D’Oncologie Pédiatrique (SIOP), Geneva, September 2006.
tumor (PNET), now both being classified as ES [2]. In this group of tumors, ES is an extremely rare primary tumor of the kidney. Advances in immunohistochemistry and molecular pathology allow for a better differential diagnosis of renal tumors. Thus, case reports have been accumulating in the past few years. In 1975, Seemayer et al. [3] were the first to provide evidence of PNETs affecting the kidney. More than 100 cases have since been reported worldwide. Aside from the Parham Series, which consolidates up to 67 pathologically confirmed malignant neuroepithelial tumors of the kidney into one range [4], there are only four published series with small collectives [5–8]. The remaining literature on renal ES consists of singlecase reports. Our study adds a series of 24 patients who received an ES guideline-based therapy. This represents the largest collective of similarly treated renal ES in today’s literature. Clinical symptoms and signs are nonspecific, comprising a triad of flank or abdominal pain, palpable mass, and hematuria in decreasing order. Systemic symptoms such as weight loss
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cases of venous tumor thrombus [16, 19]. Because renal ES is often unrecognized and diagnosed postoperatively on the grounds of surgical pathology, multiagent chemotherapy is typically delivered adjuvantly [19]. The GPOH (German Society of Pediatric Oncology and Hematology) database of four consecutive ES trials from 1980– 2009 (CESS81/CESS86/EICESS92/EURO-E.W.I.N.G.99) was searched for kidney as primary site of ES. In this context, we discuss the impact of metastatic disease at initial diagnosis and also of venous tumor thrombus on prognosis. Additionally, we carried out a Medline search for renal ES and compared the results.
methods study population No cases of a renal primary were documented in the (EI)CESS 81-92 trials (N = 1549) [20–22]. In the EURO-E.W.I.N.G.99 trial (N = 1565) we identified 24 patients with renal primary, equivalent to 1.5% of the patients’ accrual [23–25] (Figure 1). A Medline search for renal ES was additionally carried out and identified 97 publications equivalent to 156 overall cases.
treatment All patients were treated according to EURO-E.W.I.N.G.99 study. The protocol delivers 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) induction chemotherapy, followed by risk-adapted randomized treatment [26]. Standard-risk patients (R1) were randomized for consolidation treatment with vincristine, actinomycin D, and ifosfamide (VAI) or cyclophosphamide (VAC). High-risk patients (R2) were randomized for VAI versus high dose busulfan/melphalan (Bu-Mel) with
Figure 1. Patient flow sheet.
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(14.5%) and fever (9.7%) may be additionally indicative of the underlying malignant disease. Laboratory findings are mostly unremarkable, but elevated LDH and NSE levels were reported [9]. Apart from a poorly defined, infiltrative large mass with necrotic and hemorrhagic areas, generally imaging studies do not reveal characteristic signs. Thus, a biopsy from a solid tumor inevitably leaves immunohistochemistry and molecular studies to play a key role in establishing an accurate diagnosis. Histologically, ES consists of small, round to ovoid hyperchromatic cells with minimal cytoplasm. The cells may form rosettes and pseudorosettes, which is indicative for PNET. Further distinction of PNETs from ES is possible by the expression of various neural markers with PNET presenting the most differentiated neurogenic form. Most useful are neuronspecific enolase (NSE), vimentin, S-100, and synaptophysin [4, 10]. Overexpression of the surface membrane protein CD99 is a universal feature of ES, though not specific and molecular biological examinations are often required to distinguish ES from other small-round-cell tumors [11]. In 95% of all ES a balanced EWS/ETS translocation is detected [12]. The chimeric fusion protein functions as a powerful transcription activator [13]. Classical ES are typically seen in adolescents and young adults, with a median age of 15 years [14, 15]. In contrast, renal ES usually affects young adults at an older stage, most often between 20 and 30 years. The tumor often (25%–50%) metastasizes in the lung, liver, and bone [16]. Tumor thrombi are reported frequently [6, 17, 18]. Treatment strategies for renal ES include surgery, chemotherapy, and radiation [16]. Nephrectomy is carried out in combination with cavotomy in
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Annals of Oncology autologous stem cell transplantation. Patients with primary disseminated disease and nonpulmonary metastases were assigned to the experimental trial arm (R3). Local control was generally carried out after the sixth cycle of induction chemotherapy, with a preference for surgical intervention with or without additional radiotherapy (Figure 2).
statistical analysis
results patient’s characteristics and symptoms The study population of 24 patients with a renal primary tumor included 15 males (62.5%) and 9 females (37.5%). The median age was 24.9 years (range 11–59.8 years). Presenting symptoms (data available for 10 patients) included abdominal pain (4 cases), hematuria (4 cases), and a palpable mass (1 case). Laboratory findings were unremarkable. Fifteen patients (62.5%) presented with localized disease (R1&R2loc), 4 patients (16.7%) in advanced stage with metastases to the lungs only (R2pulm), and 5 patients (20.8%) with multisystem disease (R3) including lungs, bone, liver, lymphnode, and other metastatic sites. Information on tumor thrombus was available for 16 patients. In 43.8% (7 of 16 patients), patients displayed tumor thrombi in the inferior vena cava, of which more than half (4 of 7 patients) presented with initial pulmonary metastases. Two more patients presented with a vena renalis thrombus only. The clinicopathologic features are presented partly in Figure 1 and juxtaposed to the obtained literature data in Table 1.
The tumors analyzed in the present study often extensively replaced the normal renal parenchyma. The tumor size varied from 5.5 to 30 cm (median: 11.3 cm) and the primary tumor side was balanced. Immunohistochemistry was carried out in 23 cases and revealed 100% positive stained tumors for CD99, 92.3% for vimentin, 70% for NSE, 62.5% for PAS, and 81.3% for S-100, respectively. Molecular biology was documented in 12 cases with 11 rearrangements of t(11;22): three times EWS-FLI1 type 1 translocation. Type 2 translocation between EWS exon 7 and FLI1 exon 5 was detected seven times. The rare EWS-exon 10/FLI-exon 7 translocation was found in one patient. Both our study results and findings from previously published research are summarized in Table 2.
therapy Patients with renal ES were allocated to risk groups (R1–R3) according to disease stage at primary diagnosis. All 17 patients, where treatment documentation was complete, received VIDE induction chemotherapy; in 15 of 17 patients (88.2%), six courses were administrated. Local control was carried out in 16 patients: 7 (41.2%) received definitive surgery, 8 (47%) combined modality treatment, and 1 (5.9%) definitive radiotherapy. Nine patients (52.9%) received VIDE induction chemotherapy after nephrectomy. Consolidation chemotherapy consisted of VAI and/or VAC in 11 patients; in 7 of 11 patients (63.6%) eight courses were given. Six patients received high-dose chemotherapy (bulsulfan–melphalan or treosulfan–melphalan) with stem cell rescue. In addition to nephrectomy, surgical treatment included cavotomy in patients with venous tumor thrombus and was extended to partial organ resection if indicated. Radiation included the initial tumor bed. Therapy modalities of our study and the reviewed literature are outlined in Table 1. For dose intensity and cumulative dose of systemic treatment see Figure 1.
outcome and prognostic markers Follow-up information was available in 22 of 24 patients. The median follow-up was 3.71 years (range 0.27–8.75). Of these 22
Figure 2. EURO-E.W.I.N.G.99 protocol scheme and treatment doses.
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Statistical analyses were carried out with SPSS Statistics 20 (IBM Corporation, Armonk, NY) and SAS 9.2 (SAS Institute, Cary, NC) software packages. Event-free survival (EFS) and overall survival (OS) were calculated by using the Kaplan-Meier method. EFS (OS)-time was calculated from primary diagnosis to first event (death) or last follow-up. Events were defined as relapse, second malignancy or death. Univariate comparisons were estimated by the log-rank test. Multivariate analyses were carried out by Cox’s proportional hazard method. Chi-square or Fisher’s test was used to test proportions. The significance level was set at P < 0.05 (two-sided). No alpha corrections were done for multiple testing, as the nature of analyses was exploratory.
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Table 1. Patient’ characteristics: diagnosis, therapy, and follow-up
Sex
Age at diagnosis (years)
Metastasis at diagnosis
Metastasis sites (R2pulm + R3)
Risk groupa
Longest diameter (cm)
Local therapy
Chemotherapy
Relapse
Follow-up
Literature (N = 156)
EE99 (N = 24)
P-value
Data available Male Female Data available Mean (range) Median Data available No Yes Data available Lung Bone/bone marrow CNS Liver Lymph node Other Data available Yes Vena renalis Vena cava Heart ventricles Data available R1/R2loc (localized) R2pulm R3 Data available Mean (range) Median Data available No Surgery (OP) Radiotherapy (RT) OP + RT Data available No chemotherapy Conventional chemo HD Data available Total relapse Local relapse Distant relapse Combined relapse SNM Data available Alive Dead
152 82 (53.9%) 70 (46.1%) 132 27.4 (3–78) 27 147 98 (66.7%) 49 (33.3%) 49 28 (57.1%) 14 (28.6%) 0 (0) 12 (24.5%) 21 (42.9%) 2 (4.1%) 147 46 (31.3%) 46 (100%) 36 (78.3%) 7 (15.2%) 147 98 (66.7%) 10 (6.8%) 39 (26.5%) 93 12.3 (0.4–25) 12 112 15 (13.4%) 73 (65.2%) 4 (3.6%) 20 (17.8%) 112 12 (10.7%) 91 (81.3%) 9 (8%) 87b 25 (28.7%) 5 (20%) 17 (68%) 3 (12%) 0 (0%) 108 71 (65.7%) 37 (34.3%)
24 15 (62.5%) 9 (37.5%) 24 27.2 (11–60) 24.9 24 15 (62.5%) 9 (37.5%) 9 8 (88.9%) 1 (11.1%) 0 (0%) 2 (22.2%) 3 (33.3%) 1 (11.1%) 16 9 (56.3%) 9 (100%) 7 (77.8%) 0 (0%) 24 15 (62.5%) 4 (16.7%) 5 (20.8%) 19 11.3 (5.5–30) 12 17 1 (5.9%) 7 (41.2%) 1 (5.9%) 8 (47%) 17 0 (0%) 11 (64.7%) 6 (35.3%) 22 6 (27.3%) 0 (0%) 4 (66.7%) 2 (33.3%) 0 (0%) 22 16 (72.7%) 6 (27.3%)
0.434
0.972
0.301
0.133 0.422 0.999 0.999 0.722 0.403
0.999 0.999 0.585 0.251
0.421
0.046
0.007
0.340
0.526
a
According to the stratification criteria of EURO-E.W.I.N.G. 99. Twenty-one cases without information about relapse were excluded.
b
patients, 6 patients presented with recurrence of disease: None developed a local recurrence. Two (33.3%), showed a combined local and distant recurrence, and 4 (66.7%), had distant metastases only. Five of 6 patients who experienced either local recurrence or distant metastases died of their disease. Overall survival (OS) at 3 years was 0.80 (SE = 0.09), and event-free survival (EFS) was 0.66 (SE = 0.11). Patients with metastatic
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disease showed a 3y-OS (EFS) of 0.58 (0.45) compared with a 3y-OS (EFS) of 0.92 (0.78) in patients with localized disease (P = .091; P = .164) (Figure 3). EFS for patients without tumor thrombus (N = 7) was 0.83 compared with an EFS of 0.65 in patients with initial tumor thrombus (N = 9; P = .475) (Figure 4), which is biased in the light of more initial metastatic patients in the latter collective (14.3% versus 44.4%). A
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Tumor thrombus
Variable
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Immunohistochemistry
Histopathology
Literature (N = 156)
EE99 (N = 24)
116 – 113/116 (97.4%) 18/35 (51.4%) 69/78 (88.5%) 42/60 (70%) 1/18 (5.6%) 0/2 (0%) 86 85 (98.8%) 1 (1.2%) 73 (46.8%) 68 (93.2%) 67 (98.5%)a 13 (50%) 11 (42.3%) 2 (7.7%) 0 (0%) 1 (1.5%)
20 5/8 (62.5%) 20/20 (100%) 13/16 (81.3%) 7/10 (70%) 12/13 (92.3%) 0/10 (0%) 0/3 (0%) 23 23 (100%) 0 12 (50%) 11 (91.7%) 10 (90.9%) 3 (30%) 7 (70%) 0 (0%) 0 (0%) 1 (9.1%)
P-value – 0.467 0.064 0.109 0.162 0.999 0.999 0.999
0.261
a
Forty-one cases with undifferentiated FLI1 translocation type.
Figure 3. Event-free survival (EFS) according to disease stage at diagnosis (N = 22).
Figure 4. Event-free survival (EFS) according to presence of tumor thrombus (N = 16).
multivariate analysis of prognostic factors was not done due to limited sample size.
is strongly needed to improve recurrence-free survival and the prevention of recurrent disease. We have retrospectively analyzed 24 patients from the EUROE.W.I.N.G.99 trial with renal ES and compared our data with published data using a Medline search that identified 97 publications presenting 156 cases. The trial data are consistent with the previously published data analyzed in terms of median age at diagnosis. Both point at an older collective compared with classical ES patients, who present at a median age of 15 years [15]. Also consistent are initial metastasis, metastatic sites, tumor growth, and presenting symptoms, which comprise the classical, but nonspecific triad of pain, hematuria, and palpable tumor. Furthermore, the immunohistochemical profile of
discussion Renal ES is an extremely rare tumor. Larger collectives are scarce due to its low incidence. This explains the controversy surrounding published treatment approaches. Therapeutic strategies are often based on current regimens used for osseous Ewing’s sarcoma (ESB). In light of local distinctive features such as tumor thrombi with a possible source for pulmonary metastases, a standardized therapeutic approach for this entity
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Molecular biology
Variable Data available PAS CD99 S100 NSE Vimentin Desmin CD45 Data available ES/PNET Peripheral neuroepithelioma Total performed Translocation EWS/FLI1 Typ I Typ II Typ I + II EWS/ERG Other
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Another unanswered question is whether the presence of tumor thrombus in the inferior vena cava is associated with a higher rate of pulmonary metastatic embolism. If so, should such emboli be treated with similar strategies as are used in metastatic disease, e.g. more intense chemotherapy and/or extended fields of radiation. While vascular tumor thrombus is not specific for renal ES/PNET [33], it is distinctive. Facing an aggressive malignant entity, its adequate treatment appears more important in ES/PNET than in other malignancies. In the literature, tumor thrombi with varying extension from the renal vein up to the pulmonary arteries were documented in 31.3%. All 36 patients who presented with tumor thrombus in the inferior vena cava at diagnosis either had primary or had developed secondary pulmonary metastases [6, 17, 18, 34]. Owing to insufficient follow-up data in the literature and the low number of cases in our study, it remains uncertain whether the outcome of patients with tumor thrombi is worse compared with patients with tumor-free vessels. Whether the presence of thrombus affected surgical approach also remains uncertain (N = 11). Although more than 50% of the operated patients (8 of 15 patients) received nephrectomy before chemotherapy, with 71% of the patients (5 patients; N = 7) having initial tumor thrombus formation in comparison to 25% (1 patient; N = 4) in patients who received neoadjuvant chemotherapy, it is more likely that the first-line nephrectomy resulted from a false diagnostic assumption rather than from being indicated by the presence of tumor thrombus. Our data are inconclusive regarding tumor thrombus regression following neoadjuvant chemotherapy. Using aggressive multimodal treatment, the survival expectancy of patients for ES with localized disease is ∼70%, whereas the outcome for patients with metastatic disease at initial diagnosis remains poor, with survival rates from 9% to 41% [25]. The latter was confirmed in the retrospective study by Thyavihally in which the OS was 15 months compared with 60 months for patients with localized disease [8]. In our analysis, the median OS for patients with metastatic disease was 1.99 years [95% confidence interval (CI) 0.93–3.05]. Concerning the literature review, follow-up data were available in 108 patients (69.2%). Fifty-four patients were free of disease (mean 18.9 months). Thirty-seven patients died of their disease (mean 10.6 months), of which 19 had displayed initial metastases, including 12 patients with tumor thrombi. Three of these 12 patients showed primary tumor thrombus formation in the right heart ventricles and in two cases affection of the pulmonary artery was denoted as cause of death. While anticoagulation in case of thrombus was not provided in our study, prophylactic use is discussible in settings with extended thrombus formation affecting the heart ventricles and pulmonary vessels causing clinical symptoms. About 30%–40% of patients with ESB experience tumor recurrence [29]. Review of the literature showed 25% of patients with recurrent disease, which is concordant with the results of our study. The consistency of our study results with previously published data, show that more than half of the patients experience distant recurrence, predominantly to the lungs. ES is a rare kidney tumor that affects young adults with rapid clinical progression and significant mortality owing to late diagnosis, early metastasis, and advanced stage at presentation. The fundamental challenge remains the proper
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tumors in our study resembles the published data. As still presumable confusion exists between ES and other differential diagnoses, e.g. neuroblastoma, monomorphic and poorly differentiated synovial sarcoma, rhabdomyosarcoma, clear-cell sarcoma, and blastema-predominant Wilms’ tumor [5], an immunohistochemical panel including antibodies to CD99, NSE, vimentin, chromogranin, cytokeratin, SMA, and WT-1 is recommended. Against a background of a distinctive balanced translocation between the FLI1 and EWS gene in more than 90% of patients in both previous publications and our study, RT-PCR and FISH can distinguish from other renal tumors and help to confirm the diagnosis of ES [27, 28]. While cases in this study showed a slight predominance of the type 2 translocation, type 1 and type 2 fusions were evenly spread in the reviewed literature. ES is known to be relatively sensitive to chemotherapy and radiotherapy [29], suggesting that patients with renal ES should benefit from a combined treatment. Facing a systemic disease marked by early metastatic spread renders chemotherapy fundamental for the treatment regimen. The EURO-E.W.I.N.G. 99 study recommends a multiagent chemotherapy delivered prior (VIDE induction therapy) and continued after local control (consolidation therapy consisting of VAI or VAC). Previously published data confirms the value of chemotherapy (overall 89.3%) in a multimodal treatment approach (EE99 study manual) [26], although most patients had received combination chemotherapy in an adjuvant setting. Owing to rarity of the renal affection by this disease, no randomized studies have been published. While most of the regimens contained vincristine, ifosfamide, doxorubicin, etoposide or cyclophosphamide (69.2%) similar to GPOH-Ewing Sarcoma study protocols, our literature search revealed that the combination of used substances differed extensively interindividually. The main challenge of ES remains proper diagnosis and its confirmation facilitating a patient’s adequate treatment in due time [30]. In previous studies, most cases were diagnosed following a first-line nephrectomy (N = 99). When ES treatment strategies are being applied with success, this may be used as an argument for primary chemotherapy following biopsy proven diagnosis. Reviewing the literature, there appears to be a trend over the last 4 years, as neoadjuvant chemotherapy became more accepted in the therapy regimen (15.4%). In 14 patients, chemotherapy represented the only therapeutic approach (12.5%): 8 of these patients died of disease (median 14.9 months), 4 were free of disease (median 27 months) and 2 were lost to follow-up. Published data on dose intensification with autologous stem cell transplantation are rare and based on single-patient observations (N = 9) [31]. Surgery is a valuable tool for local control and, as cited, is frequently carried out as the first line of treatment. In 14.3%, nephrectomy remained the sole treatment. In addition, surgical intervention may encompass cavotomy in cases of venous tumor thrombus and metastasectomy, e.g. of pulmonary nodules. Radiotherapy was used in 21.4%. Yet, no consensus exists regarding radiation of the nephrectomy bed. Some contributors irradiate the surgical site with 50–60 Gys, achieving complete responses in terms of reducing residual local disease [32].
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diagnosis and its confirmation for a patient’s adequate and timely treatment, as this tumor requires more extensive therapy compared with Wilms tumor for example [30]. Therefore, patients benefit from an accurate and fast diagnostic approach, followed by combined modality therapy. It is imperative to assemble these patients in prospective studies to acquire more knowledge on the biology of this disease and on the impact of different therapeutic approaches in the face of specific characteristics such as the link between tumor thrombi and pulmonary metastasis.
acknowledgements
funding Supported by Deutsche Krebshilfe Grants 70-2551-Jü3, 108128, and Bundesministerium für Bildung und Forschung (BMBF) Grants 01GM0869, 01KT1310, 01ER0807.
disclosure The authors have declared no conflict of interest.
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13. Toretsky JA, Connell Y, Neckers L et al. Inhibition of EWS-FLI-1 fusion protein with antisense oligodeoxynucleotides. J Neurooncol 1997; 31: 9–16. 14. Glass AG, Fraumeni JF, Jr. Epidemiology of bone cancer in children. J Natl Cancer Inst 1970; 44: 187–199. 15. Miller RW. Contrasting epidemiology of childhood osteosarcoma, Ewing’s tumor, and rhabdomyosarcoma. Natl Cancer Inst Monogr 1981; 15: 9–15. 16. Ellinger J, Bastian PJ, Hauser S et al. Primitive neuroectodermal tumor: rare, highly aggressive differential diagnosis in urologic malignancies. Urology 2006; 68: 257–262. 17. Lazzara BM, Scalcione LR, Garnet DJ et al. Radiology-pathology conference: primary perinephric and renal extraosseous Ewing’s sarcoma. Clin Imaging 2012; 36: 77–79. 18. Mohsin R, Hashmi A, Mubarak M et al. Primitive neuroectodermal tumor/Ewing’s sarcoma in adult uro-oncology: a case series from a developing country. Urol Ann 2011; 3: 103–107. 19. Fergany AF, Dhar N, Budd GT et al. Primary extraosseous Ewing sarcoma of the kidney with level III inferior vena cava thrombus. Clin Genitourin Cancer 2009; 7: E95–E97. 20. Jurgens H, Bier V, Dunst J et al. [The German Society of Pediatric Oncology Cooperative Ewing Sarcoma Studies CESS 81/86: report after 6 1/2 years]. Klin Padiatr 1988; 200: 243–252. 21. Paulussen M, Craft AW, Lewis I et al. Results of the EICESS-92 Study: two randomized trials of Ewing’s sarcoma treatment–cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol 2008; 26: 4385–4393. 22. Schuck A, Ahrens S, Paulussen M et al. Local therapy in localized Ewing tumors: results of 1058 patients treated in the CESS 81, CESS 86, and EICESS 92 trials. Int J Radiat Oncol Biol Phys 2003; 55: 168–177. 23. Haeusler J, Ranft A, Boelling T et al. The value of local treatment in patients with primary, disseminated, multifocal Ewing sarcoma (PDMES). Cancer 2010; 116: 443–450. 24. Le Deley MC, Delattre O, Schaefer KL et al. Impact of EWS-ETS fusion type on disease progression in Ewing’s sarcoma/peripheral primitive neuroectodermal tumor: prospective results from the cooperative Euro-E.W.I.N.G. 99 trial. J Clin Oncol 2010; 28: 1982–1988. 25. Ladenstein R, Potschger U, Le Deley MC et al. Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol 2010; 28: 3284–3291. 26. Juergens C, Weston C, Lewis I et al. Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-E.W.I.N.G. 99 clinical trial. Pediatr Blood Cancer 2006; 47: 22–29. 27. Folpe AL, Goldblum JR, Rubin BP et al. Morphologic and immunophenotypic diversity in Ewing family tumors: a study of 66 genetically confirmed cases. Am J Surg Pathol 2005; 29: 1025–1033. 28. Yang Y, Zhang L, Wei Y et al. Detection of EWSR1 translocation with nuclear extraction-based fluorescence in situ hybridization for diagnosis of Ewing’s sarcoma/primitive neuroectodermal tumor. Anal Quant Cytol Histol 2007; 29: 221–230. 29. Miser JS, Kinsella TJ, Triche TJ et al. Treatment of peripheral neuroepithelioma in children and young adults. J Clin Oncol 1987; 5: 1752–1758. 30. Casella R, Moch H, Rochlitz C et al. Metastatic primitive neuroectodermal tumor of the kidney in adults. Eur Urol 2001; 39: 613–617. 31. Citak EC, Oguz A, Karadeniz C et al. Primitive neuroectodermal tumor of the kidney in a child. Pediatr Hematol Oncol 2009; 26: 481–486. 32. Thomas JC, Sebek BA, Krishnamurthi V. Primitive neuroectodermal tumor of the kidney with inferior vena cava and atrial tumor thrombus. J Urol 2002; 168: 1486–1487. 33. Kato S, Tanaka T, Kitamura H et al. Resection of the inferior vena cava for urological malignancies: single-center experience. Int J Clin Oncol 2012 September 6 [epub ahead of print], doi: 10.1007/s10147-012-0473-x. 34. Castro EC, Parwani AV. Ewing sarcoma/primitive neuroectodermal tumor of the kidney: two unusual presentations of a rare tumor. Case Report Med 2012; 2012: 190581.
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We gratefully acknowledge the contribution of the participating Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) institutions and the staff of the Ewing trial center Münster, Gabriele Braun-Munzinger, Susanne Jabar and Regina Kloss. We thank Stephanie Klco-Brosius for critical reading of the manuscript.
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Annals of Oncology 24: 2455–2461, 2013 doi:10.1093/annonc/mdt215 Published online 11 June 2013
S. Zöllner, U. Dirksen, H. Jürgens & A. Ranft* Department of Pediatric Hematology and Oncology, University Hospital, Muenster, Germany
Received 5 November 2012; revised 6 March 2013; accepted 29 April 2013
Background: Renal Ewing’s sarcoma/primitive neuroectodermal tumor (ES/PNET) is extremely rare. Clinical symptoms are nonspecific presenting abdominal pain, palpable mass, and hematuria. Owing to advanced technology demonstrating the ES-specific EWS/ETS translocation, this differential diagnosis has become feasible. Patients and methods: The German database of GPOH Ewing’s sarcoma trials from 1980 to 2009 was searched for kidney as primary site. Twenty-four patients were identified and analyzed. The median time of observation was 3.71 years (range 0.27–8.75 years). Additionally, we carried out a Medline search for renal ES/PNET. Results: The median age was 24.9 years (range 11–60 years). In 37.5%, patients presented with primary metastases. Tumor thrombi in the adjacent renal vessels occurred in 56.2%. In 90.9%, rearrangements of t(11;22) were found. All patients received a combined chemotherapy according to the EURO-E.W.I.N.G.99 protocol. In accordance, local control consisted predominantly of combined modality surgery and radiation (47%). At 3 years, overall survival (OS) was 0.80 (SE = 0.09), and event-free survival (EFS) 0.66 (SE = 0.11). Conclusions: ES/PNET should be considered in the differential diagnosis of renal tumors. Patients with renal ES/PNET respond to and benefit from conventional ES treatment according to ES study protocols. Therefore, an accurate diagnostic approach and a guideline-adapted therapy should be facilitated. Key words: Ewing’s sarcoma, kidney, outcome, PNET
introduction The major differential consideration for small-round cell tumors of the kidney encompasses a wide range of unrelated neoplasms with overlapping morphologic features, and differing therapeutic approaches and prognosis [1]. This includes malignant lymphoma, embryonal rhabdomyosarcoma, renal neuroblastoma, Wilms tumor, small-cell osteosarcoma, desmoplastic small-cell tumor, synovial sarcoma, small-cell neuroendocrine carcinoma, and Ewing’s sarcoma (ES) or its variant with neural differentiation, primitive neuroectodermal
*Correspondence to: Dr Andreas Ranft, Department of Pediatric Hematology and Oncology, Muenster University Hospital, Albert Schweitzer Campus 1, Building A1, 48149 Muenster, Germany. Tel: +49-251-83-56486; Fax: +49-251-83-56489; E-mail: [email protected] †
Previous presentation of this study: initial and preliminary results were presented at the Annual Meeting of the Société Internationale D’Oncologie Pédiatrique (SIOP), Geneva, September 2006.
tumor (PNET), now both being classified as ES [2]. In this group of tumors, ES is an extremely rare primary tumor of the kidney. Advances in immunohistochemistry and molecular pathology allow for a better differential diagnosis of renal tumors. Thus, case reports have been accumulating in the past few years. In 1975, Seemayer et al. [3] were the first to provide evidence of PNETs affecting the kidney. More than 100 cases have since been reported worldwide. Aside from the Parham Series, which consolidates up to 67 pathologically confirmed malignant neuroepithelial tumors of the kidney into one range [4], there are only four published series with small collectives [5–8]. The remaining literature on renal ES consists of singlecase reports. Our study adds a series of 24 patients who received an ES guideline-based therapy. This represents the largest collective of similarly treated renal ES in today’s literature. Clinical symptoms and signs are nonspecific, comprising a triad of flank or abdominal pain, palpable mass, and hematuria in decreasing order. Systemic symptoms such as weight loss
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Renal Ewing tumors†
original articles
cases of venous tumor thrombus [16, 19]. Because renal ES is often unrecognized and diagnosed postoperatively on the grounds of surgical pathology, multiagent chemotherapy is typically delivered adjuvantly [19]. The GPOH (German Society of Pediatric Oncology and Hematology) database of four consecutive ES trials from 1980– 2009 (CESS81/CESS86/EICESS92/EURO-E.W.I.N.G.99) was searched for kidney as primary site of ES. In this context, we discuss the impact of metastatic disease at initial diagnosis and also of venous tumor thrombus on prognosis. Additionally, we carried out a Medline search for renal ES and compared the results.
methods study population No cases of a renal primary were documented in the (EI)CESS 81-92 trials (N = 1549) [20–22]. In the EURO-E.W.I.N.G.99 trial (N = 1565) we identified 24 patients with renal primary, equivalent to 1.5% of the patients’ accrual [23–25] (Figure 1). A Medline search for renal ES was additionally carried out and identified 97 publications equivalent to 156 overall cases.
treatment All patients were treated according to EURO-E.W.I.N.G.99 study. The protocol delivers 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) induction chemotherapy, followed by risk-adapted randomized treatment [26]. Standard-risk patients (R1) were randomized for consolidation treatment with vincristine, actinomycin D, and ifosfamide (VAI) or cyclophosphamide (VAC). High-risk patients (R2) were randomized for VAI versus high dose busulfan/melphalan (Bu-Mel) with
Figure 1. Patient flow sheet.
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(14.5%) and fever (9.7%) may be additionally indicative of the underlying malignant disease. Laboratory findings are mostly unremarkable, but elevated LDH and NSE levels were reported [9]. Apart from a poorly defined, infiltrative large mass with necrotic and hemorrhagic areas, generally imaging studies do not reveal characteristic signs. Thus, a biopsy from a solid tumor inevitably leaves immunohistochemistry and molecular studies to play a key role in establishing an accurate diagnosis. Histologically, ES consists of small, round to ovoid hyperchromatic cells with minimal cytoplasm. The cells may form rosettes and pseudorosettes, which is indicative for PNET. Further distinction of PNETs from ES is possible by the expression of various neural markers with PNET presenting the most differentiated neurogenic form. Most useful are neuronspecific enolase (NSE), vimentin, S-100, and synaptophysin [4, 10]. Overexpression of the surface membrane protein CD99 is a universal feature of ES, though not specific and molecular biological examinations are often required to distinguish ES from other small-round-cell tumors [11]. In 95% of all ES a balanced EWS/ETS translocation is detected [12]. The chimeric fusion protein functions as a powerful transcription activator [13]. Classical ES are typically seen in adolescents and young adults, with a median age of 15 years [14, 15]. In contrast, renal ES usually affects young adults at an older stage, most often between 20 and 30 years. The tumor often (25%–50%) metastasizes in the lung, liver, and bone [16]. Tumor thrombi are reported frequently [6, 17, 18]. Treatment strategies for renal ES include surgery, chemotherapy, and radiation [16]. Nephrectomy is carried out in combination with cavotomy in
Annals of Oncology
original articles
Annals of Oncology autologous stem cell transplantation. Patients with primary disseminated disease and nonpulmonary metastases were assigned to the experimental trial arm (R3). Local control was generally carried out after the sixth cycle of induction chemotherapy, with a preference for surgical intervention with or without additional radiotherapy (Figure 2).
statistical analysis
results patient’s characteristics and symptoms The study population of 24 patients with a renal primary tumor included 15 males (62.5%) and 9 females (37.5%). The median age was 24.9 years (range 11–59.8 years). Presenting symptoms (data available for 10 patients) included abdominal pain (4 cases), hematuria (4 cases), and a palpable mass (1 case). Laboratory findings were unremarkable. Fifteen patients (62.5%) presented with localized disease (R1&R2loc), 4 patients (16.7%) in advanced stage with metastases to the lungs only (R2pulm), and 5 patients (20.8%) with multisystem disease (R3) including lungs, bone, liver, lymphnode, and other metastatic sites. Information on tumor thrombus was available for 16 patients. In 43.8% (7 of 16 patients), patients displayed tumor thrombi in the inferior vena cava, of which more than half (4 of 7 patients) presented with initial pulmonary metastases. Two more patients presented with a vena renalis thrombus only. The clinicopathologic features are presented partly in Figure 1 and juxtaposed to the obtained literature data in Table 1.
The tumors analyzed in the present study often extensively replaced the normal renal parenchyma. The tumor size varied from 5.5 to 30 cm (median: 11.3 cm) and the primary tumor side was balanced. Immunohistochemistry was carried out in 23 cases and revealed 100% positive stained tumors for CD99, 92.3% for vimentin, 70% for NSE, 62.5% for PAS, and 81.3% for S-100, respectively. Molecular biology was documented in 12 cases with 11 rearrangements of t(11;22): three times EWS-FLI1 type 1 translocation. Type 2 translocation between EWS exon 7 and FLI1 exon 5 was detected seven times. The rare EWS-exon 10/FLI-exon 7 translocation was found in one patient. Both our study results and findings from previously published research are summarized in Table 2.
therapy Patients with renal ES were allocated to risk groups (R1–R3) according to disease stage at primary diagnosis. All 17 patients, where treatment documentation was complete, received VIDE induction chemotherapy; in 15 of 17 patients (88.2%), six courses were administrated. Local control was carried out in 16 patients: 7 (41.2%) received definitive surgery, 8 (47%) combined modality treatment, and 1 (5.9%) definitive radiotherapy. Nine patients (52.9%) received VIDE induction chemotherapy after nephrectomy. Consolidation chemotherapy consisted of VAI and/or VAC in 11 patients; in 7 of 11 patients (63.6%) eight courses were given. Six patients received high-dose chemotherapy (bulsulfan–melphalan or treosulfan–melphalan) with stem cell rescue. In addition to nephrectomy, surgical treatment included cavotomy in patients with venous tumor thrombus and was extended to partial organ resection if indicated. Radiation included the initial tumor bed. Therapy modalities of our study and the reviewed literature are outlined in Table 1. For dose intensity and cumulative dose of systemic treatment see Figure 1.
outcome and prognostic markers Follow-up information was available in 22 of 24 patients. The median follow-up was 3.71 years (range 0.27–8.75). Of these 22
Figure 2. EURO-E.W.I.N.G.99 protocol scheme and treatment doses.
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Statistical analyses were carried out with SPSS Statistics 20 (IBM Corporation, Armonk, NY) and SAS 9.2 (SAS Institute, Cary, NC) software packages. Event-free survival (EFS) and overall survival (OS) were calculated by using the Kaplan-Meier method. EFS (OS)-time was calculated from primary diagnosis to first event (death) or last follow-up. Events were defined as relapse, second malignancy or death. Univariate comparisons were estimated by the log-rank test. Multivariate analyses were carried out by Cox’s proportional hazard method. Chi-square or Fisher’s test was used to test proportions. The significance level was set at P < 0.05 (two-sided). No alpha corrections were done for multiple testing, as the nature of analyses was exploratory.
pathologic findings and immunohistochemistry
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Annals of Oncology
Table 1. Patient’ characteristics: diagnosis, therapy, and follow-up
Sex
Age at diagnosis (years)
Metastasis at diagnosis
Metastasis sites (R2pulm + R3)
Risk groupa
Longest diameter (cm)
Local therapy
Chemotherapy
Relapse
Follow-up
Literature (N = 156)
EE99 (N = 24)
P-value
Data available Male Female Data available Mean (range) Median Data available No Yes Data available Lung Bone/bone marrow CNS Liver Lymph node Other Data available Yes Vena renalis Vena cava Heart ventricles Data available R1/R2loc (localized) R2pulm R3 Data available Mean (range) Median Data available No Surgery (OP) Radiotherapy (RT) OP + RT Data available No chemotherapy Conventional chemo HD Data available Total relapse Local relapse Distant relapse Combined relapse SNM Data available Alive Dead
152 82 (53.9%) 70 (46.1%) 132 27.4 (3–78) 27 147 98 (66.7%) 49 (33.3%) 49 28 (57.1%) 14 (28.6%) 0 (0) 12 (24.5%) 21 (42.9%) 2 (4.1%) 147 46 (31.3%) 46 (100%) 36 (78.3%) 7 (15.2%) 147 98 (66.7%) 10 (6.8%) 39 (26.5%) 93 12.3 (0.4–25) 12 112 15 (13.4%) 73 (65.2%) 4 (3.6%) 20 (17.8%) 112 12 (10.7%) 91 (81.3%) 9 (8%) 87b 25 (28.7%) 5 (20%) 17 (68%) 3 (12%) 0 (0%) 108 71 (65.7%) 37 (34.3%)
24 15 (62.5%) 9 (37.5%) 24 27.2 (11–60) 24.9 24 15 (62.5%) 9 (37.5%) 9 8 (88.9%) 1 (11.1%) 0 (0%) 2 (22.2%) 3 (33.3%) 1 (11.1%) 16 9 (56.3%) 9 (100%) 7 (77.8%) 0 (0%) 24 15 (62.5%) 4 (16.7%) 5 (20.8%) 19 11.3 (5.5–30) 12 17 1 (5.9%) 7 (41.2%) 1 (5.9%) 8 (47%) 17 0 (0%) 11 (64.7%) 6 (35.3%) 22 6 (27.3%) 0 (0%) 4 (66.7%) 2 (33.3%) 0 (0%) 22 16 (72.7%) 6 (27.3%)
0.434
0.972
0.301
0.133 0.422 0.999 0.999 0.722 0.403
0.999 0.999 0.585 0.251
0.421
0.046
0.007
0.340
0.526
a
According to the stratification criteria of EURO-E.W.I.N.G. 99. Twenty-one cases without information about relapse were excluded.
b
patients, 6 patients presented with recurrence of disease: None developed a local recurrence. Two (33.3%), showed a combined local and distant recurrence, and 4 (66.7%), had distant metastases only. Five of 6 patients who experienced either local recurrence or distant metastases died of their disease. Overall survival (OS) at 3 years was 0.80 (SE = 0.09), and event-free survival (EFS) was 0.66 (SE = 0.11). Patients with metastatic
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disease showed a 3y-OS (EFS) of 0.58 (0.45) compared with a 3y-OS (EFS) of 0.92 (0.78) in patients with localized disease (P = .091; P = .164) (Figure 3). EFS for patients without tumor thrombus (N = 7) was 0.83 compared with an EFS of 0.65 in patients with initial tumor thrombus (N = 9; P = .475) (Figure 4), which is biased in the light of more initial metastatic patients in the latter collective (14.3% versus 44.4%). A
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Tumor thrombus
Variable
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Annals of Oncology Table 2. Pathology
Immunohistochemistry
Histopathology
Literature (N = 156)
EE99 (N = 24)
116 – 113/116 (97.4%) 18/35 (51.4%) 69/78 (88.5%) 42/60 (70%) 1/18 (5.6%) 0/2 (0%) 86 85 (98.8%) 1 (1.2%) 73 (46.8%) 68 (93.2%) 67 (98.5%)a 13 (50%) 11 (42.3%) 2 (7.7%) 0 (0%) 1 (1.5%)
20 5/8 (62.5%) 20/20 (100%) 13/16 (81.3%) 7/10 (70%) 12/13 (92.3%) 0/10 (0%) 0/3 (0%) 23 23 (100%) 0 12 (50%) 11 (91.7%) 10 (90.9%) 3 (30%) 7 (70%) 0 (0%) 0 (0%) 1 (9.1%)
P-value – 0.467 0.064 0.109 0.162 0.999 0.999 0.999
0.261
a
Forty-one cases with undifferentiated FLI1 translocation type.
Figure 3. Event-free survival (EFS) according to disease stage at diagnosis (N = 22).
Figure 4. Event-free survival (EFS) according to presence of tumor thrombus (N = 16).
multivariate analysis of prognostic factors was not done due to limited sample size.
is strongly needed to improve recurrence-free survival and the prevention of recurrent disease. We have retrospectively analyzed 24 patients from the EUROE.W.I.N.G.99 trial with renal ES and compared our data with published data using a Medline search that identified 97 publications presenting 156 cases. The trial data are consistent with the previously published data analyzed in terms of median age at diagnosis. Both point at an older collective compared with classical ES patients, who present at a median age of 15 years [15]. Also consistent are initial metastasis, metastatic sites, tumor growth, and presenting symptoms, which comprise the classical, but nonspecific triad of pain, hematuria, and palpable tumor. Furthermore, the immunohistochemical profile of
discussion Renal ES is an extremely rare tumor. Larger collectives are scarce due to its low incidence. This explains the controversy surrounding published treatment approaches. Therapeutic strategies are often based on current regimens used for osseous Ewing’s sarcoma (ESB). In light of local distinctive features such as tumor thrombi with a possible source for pulmonary metastases, a standardized therapeutic approach for this entity
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Molecular biology
Variable Data available PAS CD99 S100 NSE Vimentin Desmin CD45 Data available ES/PNET Peripheral neuroepithelioma Total performed Translocation EWS/FLI1 Typ I Typ II Typ I + II EWS/ERG Other
original articles
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Another unanswered question is whether the presence of tumor thrombus in the inferior vena cava is associated with a higher rate of pulmonary metastatic embolism. If so, should such emboli be treated with similar strategies as are used in metastatic disease, e.g. more intense chemotherapy and/or extended fields of radiation. While vascular tumor thrombus is not specific for renal ES/PNET [33], it is distinctive. Facing an aggressive malignant entity, its adequate treatment appears more important in ES/PNET than in other malignancies. In the literature, tumor thrombi with varying extension from the renal vein up to the pulmonary arteries were documented in 31.3%. All 36 patients who presented with tumor thrombus in the inferior vena cava at diagnosis either had primary or had developed secondary pulmonary metastases [6, 17, 18, 34]. Owing to insufficient follow-up data in the literature and the low number of cases in our study, it remains uncertain whether the outcome of patients with tumor thrombi is worse compared with patients with tumor-free vessels. Whether the presence of thrombus affected surgical approach also remains uncertain (N = 11). Although more than 50% of the operated patients (8 of 15 patients) received nephrectomy before chemotherapy, with 71% of the patients (5 patients; N = 7) having initial tumor thrombus formation in comparison to 25% (1 patient; N = 4) in patients who received neoadjuvant chemotherapy, it is more likely that the first-line nephrectomy resulted from a false diagnostic assumption rather than from being indicated by the presence of tumor thrombus. Our data are inconclusive regarding tumor thrombus regression following neoadjuvant chemotherapy. Using aggressive multimodal treatment, the survival expectancy of patients for ES with localized disease is ∼70%, whereas the outcome for patients with metastatic disease at initial diagnosis remains poor, with survival rates from 9% to 41% [25]. The latter was confirmed in the retrospective study by Thyavihally in which the OS was 15 months compared with 60 months for patients with localized disease [8]. In our analysis, the median OS for patients with metastatic disease was 1.99 years [95% confidence interval (CI) 0.93–3.05]. Concerning the literature review, follow-up data were available in 108 patients (69.2%). Fifty-four patients were free of disease (mean 18.9 months). Thirty-seven patients died of their disease (mean 10.6 months), of which 19 had displayed initial metastases, including 12 patients with tumor thrombi. Three of these 12 patients showed primary tumor thrombus formation in the right heart ventricles and in two cases affection of the pulmonary artery was denoted as cause of death. While anticoagulation in case of thrombus was not provided in our study, prophylactic use is discussible in settings with extended thrombus formation affecting the heart ventricles and pulmonary vessels causing clinical symptoms. About 30%–40% of patients with ESB experience tumor recurrence [29]. Review of the literature showed 25% of patients with recurrent disease, which is concordant with the results of our study. The consistency of our study results with previously published data, show that more than half of the patients experience distant recurrence, predominantly to the lungs. ES is a rare kidney tumor that affects young adults with rapid clinical progression and significant mortality owing to late diagnosis, early metastasis, and advanced stage at presentation. The fundamental challenge remains the proper
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tumors in our study resembles the published data. As still presumable confusion exists between ES and other differential diagnoses, e.g. neuroblastoma, monomorphic and poorly differentiated synovial sarcoma, rhabdomyosarcoma, clear-cell sarcoma, and blastema-predominant Wilms’ tumor [5], an immunohistochemical panel including antibodies to CD99, NSE, vimentin, chromogranin, cytokeratin, SMA, and WT-1 is recommended. Against a background of a distinctive balanced translocation between the FLI1 and EWS gene in more than 90% of patients in both previous publications and our study, RT-PCR and FISH can distinguish from other renal tumors and help to confirm the diagnosis of ES [27, 28]. While cases in this study showed a slight predominance of the type 2 translocation, type 1 and type 2 fusions were evenly spread in the reviewed literature. ES is known to be relatively sensitive to chemotherapy and radiotherapy [29], suggesting that patients with renal ES should benefit from a combined treatment. Facing a systemic disease marked by early metastatic spread renders chemotherapy fundamental for the treatment regimen. The EURO-E.W.I.N.G. 99 study recommends a multiagent chemotherapy delivered prior (VIDE induction therapy) and continued after local control (consolidation therapy consisting of VAI or VAC). Previously published data confirms the value of chemotherapy (overall 89.3%) in a multimodal treatment approach (EE99 study manual) [26], although most patients had received combination chemotherapy in an adjuvant setting. Owing to rarity of the renal affection by this disease, no randomized studies have been published. While most of the regimens contained vincristine, ifosfamide, doxorubicin, etoposide or cyclophosphamide (69.2%) similar to GPOH-Ewing Sarcoma study protocols, our literature search revealed that the combination of used substances differed extensively interindividually. The main challenge of ES remains proper diagnosis and its confirmation facilitating a patient’s adequate treatment in due time [30]. In previous studies, most cases were diagnosed following a first-line nephrectomy (N = 99). When ES treatment strategies are being applied with success, this may be used as an argument for primary chemotherapy following biopsy proven diagnosis. Reviewing the literature, there appears to be a trend over the last 4 years, as neoadjuvant chemotherapy became more accepted in the therapy regimen (15.4%). In 14 patients, chemotherapy represented the only therapeutic approach (12.5%): 8 of these patients died of disease (median 14.9 months), 4 were free of disease (median 27 months) and 2 were lost to follow-up. Published data on dose intensification with autologous stem cell transplantation are rare and based on single-patient observations (N = 9) [31]. Surgery is a valuable tool for local control and, as cited, is frequently carried out as the first line of treatment. In 14.3%, nephrectomy remained the sole treatment. In addition, surgical intervention may encompass cavotomy in cases of venous tumor thrombus and metastasectomy, e.g. of pulmonary nodules. Radiotherapy was used in 21.4%. Yet, no consensus exists regarding radiation of the nephrectomy bed. Some contributors irradiate the surgical site with 50–60 Gys, achieving complete responses in terms of reducing residual local disease [32].
Annals of Oncology
Annals of Oncology
diagnosis and its confirmation for a patient’s adequate and timely treatment, as this tumor requires more extensive therapy compared with Wilms tumor for example [30]. Therefore, patients benefit from an accurate and fast diagnostic approach, followed by combined modality therapy. It is imperative to assemble these patients in prospective studies to acquire more knowledge on the biology of this disease and on the impact of different therapeutic approaches in the face of specific characteristics such as the link between tumor thrombi and pulmonary metastasis.
acknowledgements
funding Supported by Deutsche Krebshilfe Grants 70-2551-Jü3, 108128, and Bundesministerium für Bildung und Forschung (BMBF) Grants 01GM0869, 01KT1310, 01ER0807.
disclosure The authors have declared no conflict of interest.
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doi:10.1093/annonc/mdt215 |
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We gratefully acknowledge the contribution of the participating Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) institutions and the staff of the Ewing trial center Münster, Gabriele Braun-Munzinger, Susanne Jabar and Regina Kloss. We thank Stephanie Klco-Brosius for critical reading of the manuscript.
original articles