- Email: [email protected]
Ewing Sarcoma of the Kidney
Oncology Clinical and Pathological Features of Primary Neuroectodermal Tumor/Ewing Sarcoma of the Kidney Emanuela Risi, Roberto Iacovelli, Amelia Altavilla, Daniele Alesini, Antonella Palazzo, Claudia Mosillo, Patrizia Trenta, and Enrico Cortesi OBJECTIVE
METHODS
RESULTS
CONCLUSION
To collect and analyze clinical and pathological features of primitive neuroectodermal tumor (PNET)/Ewing sarcoma (EWS), a rare tumor occurring most commonly in bone and soft tissues of young people, which rarely occurs as a primary renal neoplasm and exhibits highly aggressive biological behavior. All cases of PNET/EWS published from 1975 to February 2012 were collected. When available, clinical and pathological data were extracted for each case. Survivals were estimated with the Kaplan-Meier method and compared with the log-rank test with 95% confidence interval (CI). A total of 116 cases were found. All patients had clinical symptoms as first presentation of disease such as pain (54%), hematuria (29%), and bulky renal mass (28%). Sixty-six percent of patients had stage IV disease at diagnosis. Median disease-free survival (DFS) was 5.0 months (95% CI 2.4-7.6). The probability to be alive at 18 months was 60% and 85% for patients with metastatic disease (M1) or not (M0) at diagnosis, respectively. Median overall survival (OS) was 24 months (95% CI 4.5-15.1) in patients with M1 disease, whereas it was not reached in patients with M0 disease (P <.001). In patients with M0 disease, 50% received neoadjuvant chemotherapy and the 12-month OS was 93% compared to 75% of untreated patients (P ¼ .092). In patients with M1 disease who underwent treatment, the median progression-free survival (PFS) was 22.0 months (95% CI 17.9-26.1) with a clinical benefit in 74% of cases. Our findings suggest that PNET/EWS is a rare aggressive tumor affecting principally young people, with a poor prognosis for patients with M1 disease; chemotherapy is an effective strategy in M1 disease and probably also in M0 disease. UROLOGY 82: 382e386, 2013. 2013 Elsevier Inc.
P
rimitive neuroectodermal tumor (PNET)/Ewing sarcoma (EWS) are a group of malignant tumors composed of small uniform round cells that occur most commonly in bone and soft tissues of children and young adults. PNET/EWS represent less than 1% of renal tumors and is characterized by highly aggressive biological behavior.1 The exact diagnosis of this tumor is complicated by the rarity of this disease and should be differentiated by blastemal Wilms tumor, rhabdoid tumor, neuroblastoma, lymphoma, clear cell sarcoma, small cell carcinoma, synovial sarcoma, and desmoplastic small round cell tumor.1 Immunohistochemistry has a role in differential diagnosis of renal round cell tumors, although some of Emanuela Risi and Roberto Iacovelli contributed equally to this work. Financial Disclosure: The authors declare that they have no relevant financial interests. From the Departments of Radiology, Oncology, and Human Pathology, Oncology Unit B, Sapienza University of Rome, Viale Regina Elena, Rome, Italy Reprint requests: Emanuela Risi, M.D., Departments of Radiology, Oncology, and Human Pathology, Oncology Unit B, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy. E-mail: [email protected] Submitted: January 31, 2013, accepted (with revisions): April 9, 2013
382
ª 2013 Elsevier Inc. All Rights Reserved
these entities lack a characteristic immunophenotype and immunophenotypic overlap exists with others tumors. An improvement in diagnosis has come from the identification of specific chromosomal translocation resulting in a fusion transcript of the EWS gene and E– twenty-six (ETS) related family of oncogenes.2 In fact, >90% of PNET/EWS contain the chromosome translocation t(11;22) (q24; q12) and the chimeric fusion protein EWS/Friend leukemia virus integration (FLI) functioning as a powerful transcription activator.3 Since its first description in 1975,4 <120 cases of PNET/ EWS have been published in medical literature as case reports or case series. Recently, a large series of 146 malignant neuroepithelial tumors of the kidney, including 79 cases of PNET/EWS, was published by Parham et al1; however, follow-up information was only provided for 14 cases. Our study aims to describe the clinical characteristics of this rare renal tumor and to correlate the histological features with the expression of immunohistochemical (IHC) markers. 0090-4295/13/$36.00 http://dx.doi.org/10.1016/j.urology.2013.04.015
MATERIAL AND METHODS As previously reported,5 a systematic PubMed search was performed to identify all articles describing patients with primary PNET/EWS of the kidney. The entry term for search was “neuroectodermal renal tumor” and “Ewing sarcoma of the kidney.” Subsequently, all articles or case reports in English, French, German, or Spanish published from 1995 to March 2012 were considered. When available, data that focused on clinical and pathological features were extracted. The clinical features considered were age, gender, presence and type of symptoms, stage of disease at diagnosis, sites of metastasis, disease-free survival (DFS), overall survival (OS), and progression-free survival (PFS) types of treatment for PNET/EWS and its efficacy. The pathological features considered were maximum extension of primary tumor measured in centimeters, the IHC expression (yes/no) of vimentin, neuron specific enolase, CD99, Friend leukemia virus integration 1 (FLI-1), cytokeratin, CD117, chromogranin, synaptophysin, CD45, terminal deoxynucleotidyl transferase, Wilms tumor protein, CD56, CD57, S100, epithelial membrane antigen (EMA), neurofilament, desmin, myogenin, smooth muscle actin, PGP9.5, and glial fibrillary acidic protein. The characterization of genetic analysis to found chromosomal translocation t(11:22) between the genes EWS/FLI-1 was also recorded. All data were used to make a database used for final analysis.
Statistical Analysis Baseline values were expressed as median and interquartile range (IQR) with baseline defined as the date of surgical diagnosis. DFS was defined as the length of time after surgery during which no disease was found. OS was defined as the time from surgery to death or last contact and the PFS was defined as the time from the start of therapy to the progression of disease or death for any cause. The DFS, PFS, and OS were estimated using the Kaplan-Meier method with Rothman’s 95% confidence intervals (CIs) and compared across the groups using the log-rank test. The correlations between tumor extension and histological features were evaluated by the nonparametric Spearman rank test. Chi-square test was used to assess the differences between groups. Association of extension of primary tumor as a continuous variable with DFS and death was evaluated using the Cox proportional hazards model. All variables were considered significant at the level of P <.05. All statistical analyses were performed using the Predictive Analytics software (PASW, v 18, IBM SPSS).
RESULTS Clinical Features The final cohort included a total of 116 cases (Table 1); the majority of which were men (55%), and the median age was 28.0 years (IQR 20.0-42.0) with 22% of patients with an age of 15 years or less. All patients had clinical symptoms as first presentation of disease and pain was the most frequent (54% of patients), followed by hematuria (29%) and renal mass (28%); whereas dysuria, fever, weight loss, fatigue, and abdomen swelling were reported each in about 2% of cases. Most of the patients (89%) had surgery on the primary tumor. Among these patients, 95% had nephrectomy and UROLOGY 82 (2), 2013
Table 1. List of case reports of PNET/EWS of the kidney published from 1995 to 2012 Authors
Year
Tariq et al Alonso et al Ashturkar et al Eggers et al Kumar et al Mellis et al Mohsin et al Rizzo et al Wedde et al Angel et al Asiri et al Badar et al Balakrishnan et al s et al Cabrera-Meira Ohgaki et al Wu et al Berg et al Businger et al Citak et al Fergany et al Godoy et al Ishii et al Mukkunda et al Zhang et al Piastra et al Chea et al Chu Dogra et al Ekram et al Koski et al Maeda et al Ong et al Ellison et al Kang et al Marley et al Moustafellos et al Parada et al Ellinger Erkilic¸ et al Perer et al Saxena et al Sellaturay Mallèn Mateo et al Ruszat et al Mor et al Pomara et al Habermann et al Murphy et al Premalata et al Sivaramakrishna et al Wada et al Jimenez Thomas et al Vicha et al Doerfler et al Karnes et al Kuroda et al Maccioni et al Fontaine et al Herman et al Sheaff et al Gupta et al TOTAL
2012 2011 2011 2011 2011 2011 2011 2011 2011 2010 2010 2010 2010 2010 2010 2010 2009 2009 2009 2009 2009 2009 2009 2009 2008 2008 2008 2008 2008 2008 2008 2008 2007 2007 2007 2007 2007 2006 2006 2006 2006 2006 2005 2005 2004 2004 2003 2003 2003 2003 2003 2002 2002 2002 2001 2000 2000 2000 1997 1997 1997 1995
No. of Cases 1 2 1 1 1 1 4 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 7 1 1 1 3 1 1 1 1 1 30 1 1 1 1 2 1 1 1 1 1 1 1 1 1 1 2 1 1 11 1 1 1 1 1 1 1 1 1 2 116
PubMed ID 20535010 21965263 21768691 21312084 2021548122 21678757 21747604 21612762 21776194 20198399 21749811 20419980 10352208 20800039 20186557 20819561 19737655 19829861 19863203 19815490 1061620418 19784745 2019478963 20070019 18798557 18525097 18712377 12187048 18925450 18758660 16544300 18694498 17134738 17497665 9060607 17310314 17601313 16904430 16868682 16494555 17126256 16904470 15945259 16123576 8084311 14969593 14512656 19127638 12789935 15160528 12614265 11859203 12352425 12547163 11214680 10953145 11123763 10652933 9296224 9211963 9130994 207752342
EWS, Ewing sarcoma; PNET, primitive neuroectodermal tumor.
383
Figure 1. Difference in overall survival according to stage at diagnosis. M0, nonmetastatic disease; M1, metastatic disease.
5% had another type of surgery. The 2-year OS rate was 80% and 30% for patients who underwent nephrectomy or not (P ¼ .017), whereas no comparison was possible between nephrectomy and other types of surgery. One third of patients were metastatic at diagnosis and 40% of nonmetastatic patients developed metastasis after surgery for primary tumor. Data about DFS were available in 45 cases and showed a median DFS of 5.0 months (95% CI 2.4-7.6). The main sites of metastasis were lung (60% of cases), liver (37%), abdominal lymph nodes (20%), and bone and local relapse in 16% and 10% of cases, respectively. In the entire cohort, the median OS was 26.5 months (95% CI 0-58.4). Cox analysis showed that patients with metastatic disease have more than a 4-fold increase in relative risk of death compared to nonmetastatic patients at diagnosis (hazard ratio 4.2, 95% CI 1.8-9.9, P ¼ .001). The probability to be alive at 18 months was 60% and 85% for patients with metastatic disease or not at diagnosis, respectively. In the patients with metastatic disease, the median OS was 24 months (95% CI 4.5-15.1), whereas the median OS was not reached in the nonmetastatic patients (P <.001, Fig. 1). No difference in OS was found based on age greater or lower than 15 years. Half of the patients received neoadjuvant or adjuvant chemotherapy for primary tumors. For patients who received any medical pre- or post-surgical treatment, the 12-month OS was 93% compared to 75% of patients who did not (P ¼ .092, Fig. 2). All patients were treated with a chemotherapy combination; the mean number of drugs was 5 (2-8) and the vincristine-adriamycincyclophosphamide followed by etoposide-ifosfamide was the most commonly used combination. In patients with metastatic disease, the median PFS was 22.0 months (95% CI 17.9-26.1) (Supplementary Figure); 384
Figure 2. Difference in overall survival in patients who received neoadjuvant or adjuvant treatment compared to patients who did not.
as for adjuvant setting, combined chemotherapy was also the most preferred approach. The overall response rate (complete and partial response) was 66% and the clinical benefit was 74%. Pathological Features The median value for longest tumor diameter was 13 cm (IQR 10-17). No differences in terms of OS or DFS (P ¼ .21 and P ¼ .44, respectively) were found to be related to the primary tumor extension above or under the median value. All tumors presented small cell histology and IHC expression of a variety of markers, as reported in Table 2. All markers were tested for relationship to the primary tumor extension, status of disease at diagnosis, or among each other. The Spearman’s correlation (rs) found a positive relationship between IHC expression of EMA or FLI and the status of metastatic disease at diagnosis (rs ¼ 1, P <.001 for both). Moreover, we were also able to find a relationship between the expression of S100 and synaptophysin proteins (rs ¼ 0.51, P ¼ .03). The presence of translocation (11:22) between the genes EWS/FLI-1 was found in 72% of tested subjects and this was found to be related to IHC expression of the protein FLI-1 (rs ¼ 0.39, P ¼ .03). The presence of translocation was investigated with different techniques: fluorescence in situ hybridization (FISH) was positive in 52.6% of 38 tested subjects and the direct sequencing with reverse transcriptase-polymerase chain reaction (RT-PCR) was positive in 43% of 49 tested subjects. Even if it is impossible to compare the 2 techniques of 31 subjects in which both methods were used, there were discrepancies in 8 cases and, for all, FISH evidenced a gene translocation that RT-PCR did not confirm. Furthermore, patients carrying the translocation seem to have a better DFS (85% and 33% of 2 months for UROLOGY 82 (2), 2013
Table 2. Immunohistochemical expression of tumor markers in primary renal PNET/EWS HIC test
No. of Cases
Expression (%)
VIM NSE CD99 FLI-1 CKs CD117 CHR SYN CD45 TdT WT-1 CD56 CD57 S100 EMA NF DES MYOG SMA PGP9.5 GFAP
33 34 96 33 65 6 34 28 25 7 39 10 1 26 13 7 22 7 5 1 2
81.8 88.2 99 60.6 7.7 33.3 5.9 32.1 0 0 23.1 30 100 38.5 15.4 0 4.5 0 0 100 100
CHR, chromogranin; CKs, cytokeratin; DES, desmin; EMA, epithelial membrane antigen; FLI-1, Friend leukemia integration 1 transcription factor; GFAP, glial fibrillary acidic protein; MYOG, myogenin; NF, neurofilament; NSE, neuron-specific enolase; SMA, smooth muscle actin; SYN, synaptophysin; TdT, terminal deoxynucleotidyl transferase; VIM, vimentin; WT-1, Wilms tumor protein; other abbreviations as in Table 1.
patients with or without translocation, respectively) but the difference was not significant (P ¼ .23). No relationships were found with OS (P ¼ .89).
COMMENT Primary PNET/EWS of the kidney is a small round cell tumor of presumed neuroectodermal origin described in about 120 folds in medical literature during the last 37 years. Because of its rarity, we lack clinical and pathological information that could improve the diagnosis and the management of patients affected by this disease. In this study, we first analyzed the clinical and pathological features of all the reported cases of primary PNET/ EWS of the kidney, then we described the response to therapy, and then we found a possible relationship between molecular and clinical characteristics. This tumor principally affects young men and, in the majority of cases, patients were metastatic at diagnosis or became metastatic after a few months confirming the aggressive nature of this tumor. In fact, the risk of death in patients with metastatic disease was found to be increased only 4-folds compared to nonmetastatic disease. This is different from other types of renal primary sarcoma, such as synovial sarcoma where this risk was found to increase >300-fold.5 Despite this increased attitude to develop metastases, the median survival of these patients of about 2 years was probably influenced by the high response rate to chemotherapy with an overall response rate of 66% and a clinical benefit of 75%. These data are in accord with UROLOGY 82 (2), 2013
published studies that evaluated patients affected by PNET/EWS at any site, in which the 5-year survival was 70% in nonmetastatic disease and only 20%-30% in patients with metastatic disease.6,7 The high response rate to chemotherapy in patients with metastatic disease is an interesting background to hypothesize a possible role for an adjuvant or neoadjuvant therapy to improve the DFS and OS.8 In our analysis, 3 and 31 patients received a neoadjuvant or adjuvant treatment, respectively. Most patients received a polychemotherapy with vincristine, doxorubicin, and cyclophosphamide, alternating with ifosfamide and etoposide. Because of the small number of patients with PNET, most knowledge about treatment has been derived from studies on Ewing’s sarcoma family. Studies seem to show that the addition of ifosfamide and etoposide to a regimen containing doxorubicin, vincristine, dactinomycin, and cyclophosphamide, improved outcomes in patients with nonmetastatic Ewing sarcoma.9 The same chemotherapy can be used in patients with metastatic disease. For these patients, other combination regimens have also been tested. Ifosfamide combined with etoposide and cisplatin have been shown to be effective in patients with primary refractory or recurrent disease.10 In an attempt to improve long-term survival, especially for high-risk patients, high-dose myeloablative therapy followed by stem cell rescue has been considered.11 In our study, 4 patients experimented with this approach with discordant outcomes. Unfortunately, the results reported in the current study were not extrapolated from a homogeneous prospective cohort of patients and the rarity of disease did not permit a definitive conclusion. In the same manner, the survival difference found between patients who received or did not receive radical nephrectomy could not be considered an absolute criteria for radical nephrectomy in patients with advanced disease at diagnosis because, in this case series, the eligibility of a patient for surgery may be influenced by several factors such as comorbidities and performance status. On the other hand, the high rate of symptoms because of local extension of disease, such as pain, hematuria, and mass, could be effectively palliated by surgical extirpation of disease; furthermore, this could facilitate the histological and molecular diagnosis. The invasion of locoregional lymph nodes is an expression of the metastatic spread of a tumor that principally affects distant organs, such as lung and liver, and then the role of lymphadenectomy may be considered for a better definition of stage and not as a curative procedure. IHC analysis confirms the high expression rate of CD99 previously described by Parham and Jimenez1,12; we also found a high expression of vimentin and neuronspecific enolase in more than 80% of the cases and the expression of FLI-1 protein in 60% of cases. Then, even if this marker is considered to be more specific for the diagnosis of PNET/EWS, about 40% of cases could be 385
misdiagnosed. The expression of cytokeratin is possible even if this was found in less than 10% of cases; whereas S100 and synaptophysin were expressed in 30%-40% of cases confirming the possible origin of this tumor from neuroectodermal cells. The neural ramification that invests the kidney has been postulated as the possible origin of this tumor. This comes from adrenergic fibers originating in the celiac plexus and accompanying efferent arterioles and descending vasa recta.1,13 Primary PNET/EWS of the kidney have been found to be associated with a specific chromosome translocation t(11; 22) (q24; q12), resulting in the production of the EWS/FLI-1 fusion gene.14 The resultant fusion gene has an oncogenic role and it includes the N-terminal transactivation domain of EWS and the C-terminal DNAbinding domain of the FLI-1 gene.15 The chimeric EWS/FLI-1 fusion protein functions as a powerful transcription activator and it has been demonstrated to be able to transform NIH3T3 cells.8,16,17 In our cohort, 72% of patients had chromosome translocation that results in the fusion of the EWS gene on chromosome 11; this data were higher compared to those previously reported (14%).1 The translocations can be detected indirectly from standard cytogenetic studies or directly by FISH or RT-PCR.18 In our study, we found a discrepancy between the diagnostic sensitivity of FISH and RT-PCR in 25% of cases; but this data should be interpreted with caution considering the several types of techniques that have been used and the long amount of time in which these have been performed. Additionally, patients with translocation seem to have a better DFS even if the difference was not significant. IHC has an important role in establishing an accurate diagnosis of PNET/EWS. We noticed that EMA and FLI expression was in direct relationship with metastatic disease at diagnosis. The present study has some important limitations. Its retrospective nature and the small number of patients evaluable for each variable increase the risk of bias. Furthermore, authors of different articles did not use the same variables for evaluation and the sensitivity of diagnostic techniques used has been increased in recent years. Patients treated with chemotherapy received several different regimens and there were no uniform criteria for the time of discontinuation. In addition, the published cases do not reflect the general population, even though the rarity of the disease is itself a reason to submit a case report.
CONCLUSIONS PNET/EWS of the kidney is a rare disease with a welldefined genetic background, clinically characterized by a very poor prognosis in patients with metastatic disease and by a high recurrence rate in patients with nonmetastatic disease. Considering the high response rate to chemotherapy, these patients should be treated when possible and a role for adjuvant therapy may also be considered.
386
References 1. Parham DM, Roloson GJ, Feely M, et al. Primary malignant neuroepithelial tumors of the kidney: a clinicopathologic analysis of 146 adult and pediatric cases from the National Wilms’ Tumor Study Group Pathology Center. Am J Surg Pathol. 2001;25:133-146. 2. Hu-Lieskovan S, Zhang J, Wu L, et al. EWS-FLI1 fusion protein upregulates critical genes in neural crest development and is responsible for the observed phenotype of Ewing’s family of tumors. Cancer Res. 2005;65:4633-4644. 3. Ellison DA, Parham DM, Bridge J, Beckwith JB. Immunohistochemistry of primary malignant neuroepithelial tumors of the kidney: a potential source of confusion? A study of 30 cases from the National Wilms Tumor Study Pathology Center. Hum Pathol. 2007;38:205-211. 4. Seemayer TA, Thelmo WL, Bolande RP, Wiglesworth FW. Peripheral neuroectodermal tumors. Perspect Pediatr Pathol. 1975;2:151-172. 5. Iacovelli R, Altavilla A, Ciardi A, et al. Clinical and pathological features of primary renal synovial sarcoma: analysis of 64 cases from 11 years of medical literature. BJU Int. 2012;110:1449-1454. 6. de Alava E, Kawai A, Healey JH, et al. EWS-FLI1 fusion transcript structure is an independent determinant of prognosis in Ewing’s sarcoma. J Clin Oncol. 1998;16:1248-1255. 7. Rodrıguez-Galindo C, Liu T, Krasin MJ, et al. Analysis of prognostic factors in Ewing sarcoma family of tumors: review of St. Jude Children’s Research Hospital studies. Cancer. 2007;110:375-384. 8. Bernstein M, Kovar H, Paulussen M, et al. Ewing’s sarcoma family of tumors: current management. Oncologist. 2006;11:503-519. 9. Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003;348:694-701. 10. El Weshi A, Memon M, Raja M, et al. VIP (etoposide, ifosfamide, cisplatin) in adult patients with recurrent or refractory Ewing sarcoma family of tumors. Am J Clin Oncol. 2004;27:529-534. 11. Kushner BH, Meyers PA. How effective is dose-intensive/ myeloablative therapy against Ewing’s sarcoma/primitive neuroectodermal tumor metastatic to bone or bone marrow? The Memorial Sloan-Kettering experience and a literature review. J Clin Oncol. 2001;19:870-880. 12. Jimenez RE, Folpe AL, Lapham RL, et al. Primary Ewing’s sarcoma/ primitive neuroectodermal tumor of the kidney: a clinicopathologic and immunohistochemical analysis of 11 cases. Am J Surg Pathol. 2002;26:320-327. 13. Clapp WL. Adult kidney. In: Sternberg SS, ed. Histology for pathologists. New York: Raven Press; 1992:677-708. 14. Sorensen PH, Liu XF, Delattre O, et al. Reverse transcriptase PCR amplification of EWS/FLI-1 fusion transcripts as a diagnostic test for peripheral primitive neuroectodermal tumors of childhood. Diagn Mol Pathol. 1993;2:147-157. 15. Saxena R, Sait S, Mhawech-Fauceglia P. Ewing sarcoma/primitive neuroectodermal tumor of the kidney: a case report. Diagnosed by immunohistochemistry and molecular analysis. Ann Diagn Pathol. 2006;10:363-366. 16. Teitell MA, Thompson AD, Sorensen PH, et al. EWS/ETS fusion genes induce epithelial and neuroectodermal differentiation in NIH 3T3 fibroblasts. Lab Invest. 1999;79:1535-1543. 17. Bing Z, Zhang P, Tomaszewski JE, Maclennan GT. Primary Ewing sarcoma/primitive neuroectodermal tumor of the kidney. J Urol. 2009;181:1341-1342. 18. Godoy A, Liuzzi J, Parada D, et al. Primitive renal neuroectodermic tumor. Extraosseous Ewing sarcoma: A case presentation. Rev Venez Oncol. 2009;21:240-243.
APPENDIX SUPPLEMENTARY DATA
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.urology. 2013.04.015.
UROLOGY 82 (2), 2013
METHODS
RESULTS
CONCLUSION
To collect and analyze clinical and pathological features of primitive neuroectodermal tumor (PNET)/Ewing sarcoma (EWS), a rare tumor occurring most commonly in bone and soft tissues of young people, which rarely occurs as a primary renal neoplasm and exhibits highly aggressive biological behavior. All cases of PNET/EWS published from 1975 to February 2012 were collected. When available, clinical and pathological data were extracted for each case. Survivals were estimated with the Kaplan-Meier method and compared with the log-rank test with 95% confidence interval (CI). A total of 116 cases were found. All patients had clinical symptoms as first presentation of disease such as pain (54%), hematuria (29%), and bulky renal mass (28%). Sixty-six percent of patients had stage IV disease at diagnosis. Median disease-free survival (DFS) was 5.0 months (95% CI 2.4-7.6). The probability to be alive at 18 months was 60% and 85% for patients with metastatic disease (M1) or not (M0) at diagnosis, respectively. Median overall survival (OS) was 24 months (95% CI 4.5-15.1) in patients with M1 disease, whereas it was not reached in patients with M0 disease (P <.001). In patients with M0 disease, 50% received neoadjuvant chemotherapy and the 12-month OS was 93% compared to 75% of untreated patients (P ¼ .092). In patients with M1 disease who underwent treatment, the median progression-free survival (PFS) was 22.0 months (95% CI 17.9-26.1) with a clinical benefit in 74% of cases. Our findings suggest that PNET/EWS is a rare aggressive tumor affecting principally young people, with a poor prognosis for patients with M1 disease; chemotherapy is an effective strategy in M1 disease and probably also in M0 disease. UROLOGY 82: 382e386, 2013. 2013 Elsevier Inc.
P
rimitive neuroectodermal tumor (PNET)/Ewing sarcoma (EWS) are a group of malignant tumors composed of small uniform round cells that occur most commonly in bone and soft tissues of children and young adults. PNET/EWS represent less than 1% of renal tumors and is characterized by highly aggressive biological behavior.1 The exact diagnosis of this tumor is complicated by the rarity of this disease and should be differentiated by blastemal Wilms tumor, rhabdoid tumor, neuroblastoma, lymphoma, clear cell sarcoma, small cell carcinoma, synovial sarcoma, and desmoplastic small round cell tumor.1 Immunohistochemistry has a role in differential diagnosis of renal round cell tumors, although some of Emanuela Risi and Roberto Iacovelli contributed equally to this work. Financial Disclosure: The authors declare that they have no relevant financial interests. From the Departments of Radiology, Oncology, and Human Pathology, Oncology Unit B, Sapienza University of Rome, Viale Regina Elena, Rome, Italy Reprint requests: Emanuela Risi, M.D., Departments of Radiology, Oncology, and Human Pathology, Oncology Unit B, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy. E-mail: [email protected] Submitted: January 31, 2013, accepted (with revisions): April 9, 2013
382
ª 2013 Elsevier Inc. All Rights Reserved
these entities lack a characteristic immunophenotype and immunophenotypic overlap exists with others tumors. An improvement in diagnosis has come from the identification of specific chromosomal translocation resulting in a fusion transcript of the EWS gene and E– twenty-six (ETS) related family of oncogenes.2 In fact, >90% of PNET/EWS contain the chromosome translocation t(11;22) (q24; q12) and the chimeric fusion protein EWS/Friend leukemia virus integration (FLI) functioning as a powerful transcription activator.3 Since its first description in 1975,4 <120 cases of PNET/ EWS have been published in medical literature as case reports or case series. Recently, a large series of 146 malignant neuroepithelial tumors of the kidney, including 79 cases of PNET/EWS, was published by Parham et al1; however, follow-up information was only provided for 14 cases. Our study aims to describe the clinical characteristics of this rare renal tumor and to correlate the histological features with the expression of immunohistochemical (IHC) markers. 0090-4295/13/$36.00 http://dx.doi.org/10.1016/j.urology.2013.04.015
MATERIAL AND METHODS As previously reported,5 a systematic PubMed search was performed to identify all articles describing patients with primary PNET/EWS of the kidney. The entry term for search was “neuroectodermal renal tumor” and “Ewing sarcoma of the kidney.” Subsequently, all articles or case reports in English, French, German, or Spanish published from 1995 to March 2012 were considered. When available, data that focused on clinical and pathological features were extracted. The clinical features considered were age, gender, presence and type of symptoms, stage of disease at diagnosis, sites of metastasis, disease-free survival (DFS), overall survival (OS), and progression-free survival (PFS) types of treatment for PNET/EWS and its efficacy. The pathological features considered were maximum extension of primary tumor measured in centimeters, the IHC expression (yes/no) of vimentin, neuron specific enolase, CD99, Friend leukemia virus integration 1 (FLI-1), cytokeratin, CD117, chromogranin, synaptophysin, CD45, terminal deoxynucleotidyl transferase, Wilms tumor protein, CD56, CD57, S100, epithelial membrane antigen (EMA), neurofilament, desmin, myogenin, smooth muscle actin, PGP9.5, and glial fibrillary acidic protein. The characterization of genetic analysis to found chromosomal translocation t(11:22) between the genes EWS/FLI-1 was also recorded. All data were used to make a database used for final analysis.
Statistical Analysis Baseline values were expressed as median and interquartile range (IQR) with baseline defined as the date of surgical diagnosis. DFS was defined as the length of time after surgery during which no disease was found. OS was defined as the time from surgery to death or last contact and the PFS was defined as the time from the start of therapy to the progression of disease or death for any cause. The DFS, PFS, and OS were estimated using the Kaplan-Meier method with Rothman’s 95% confidence intervals (CIs) and compared across the groups using the log-rank test. The correlations between tumor extension and histological features were evaluated by the nonparametric Spearman rank test. Chi-square test was used to assess the differences between groups. Association of extension of primary tumor as a continuous variable with DFS and death was evaluated using the Cox proportional hazards model. All variables were considered significant at the level of P <.05. All statistical analyses were performed using the Predictive Analytics software (PASW, v 18, IBM SPSS).
RESULTS Clinical Features The final cohort included a total of 116 cases (Table 1); the majority of which were men (55%), and the median age was 28.0 years (IQR 20.0-42.0) with 22% of patients with an age of 15 years or less. All patients had clinical symptoms as first presentation of disease and pain was the most frequent (54% of patients), followed by hematuria (29%) and renal mass (28%); whereas dysuria, fever, weight loss, fatigue, and abdomen swelling were reported each in about 2% of cases. Most of the patients (89%) had surgery on the primary tumor. Among these patients, 95% had nephrectomy and UROLOGY 82 (2), 2013
Table 1. List of case reports of PNET/EWS of the kidney published from 1995 to 2012 Authors
Year
Tariq et al Alonso et al Ashturkar et al Eggers et al Kumar et al Mellis et al Mohsin et al Rizzo et al Wedde et al Angel et al Asiri et al Badar et al Balakrishnan et al s et al Cabrera-Meira Ohgaki et al Wu et al Berg et al Businger et al Citak et al Fergany et al Godoy et al Ishii et al Mukkunda et al Zhang et al Piastra et al Chea et al Chu Dogra et al Ekram et al Koski et al Maeda et al Ong et al Ellison et al Kang et al Marley et al Moustafellos et al Parada et al Ellinger Erkilic¸ et al Perer et al Saxena et al Sellaturay Mallèn Mateo et al Ruszat et al Mor et al Pomara et al Habermann et al Murphy et al Premalata et al Sivaramakrishna et al Wada et al Jimenez Thomas et al Vicha et al Doerfler et al Karnes et al Kuroda et al Maccioni et al Fontaine et al Herman et al Sheaff et al Gupta et al TOTAL
2012 2011 2011 2011 2011 2011 2011 2011 2011 2010 2010 2010 2010 2010 2010 2010 2009 2009 2009 2009 2009 2009 2009 2009 2008 2008 2008 2008 2008 2008 2008 2008 2007 2007 2007 2007 2007 2006 2006 2006 2006 2006 2005 2005 2004 2004 2003 2003 2003 2003 2003 2002 2002 2002 2001 2000 2000 2000 1997 1997 1997 1995
No. of Cases 1 2 1 1 1 1 4 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 7 1 1 1 3 1 1 1 1 1 30 1 1 1 1 2 1 1 1 1 1 1 1 1 1 1 2 1 1 11 1 1 1 1 1 1 1 1 1 2 116
PubMed ID 20535010 21965263 21768691 21312084 2021548122 21678757 21747604 21612762 21776194 20198399 21749811 20419980 10352208 20800039 20186557 20819561 19737655 19829861 19863203 19815490 1061620418 19784745 2019478963 20070019 18798557 18525097 18712377 12187048 18925450 18758660 16544300 18694498 17134738 17497665 9060607 17310314 17601313 16904430 16868682 16494555 17126256 16904470 15945259 16123576 8084311 14969593 14512656 19127638 12789935 15160528 12614265 11859203 12352425 12547163 11214680 10953145 11123763 10652933 9296224 9211963 9130994 207752342
EWS, Ewing sarcoma; PNET, primitive neuroectodermal tumor.
383
Figure 1. Difference in overall survival according to stage at diagnosis. M0, nonmetastatic disease; M1, metastatic disease.
5% had another type of surgery. The 2-year OS rate was 80% and 30% for patients who underwent nephrectomy or not (P ¼ .017), whereas no comparison was possible between nephrectomy and other types of surgery. One third of patients were metastatic at diagnosis and 40% of nonmetastatic patients developed metastasis after surgery for primary tumor. Data about DFS were available in 45 cases and showed a median DFS of 5.0 months (95% CI 2.4-7.6). The main sites of metastasis were lung (60% of cases), liver (37%), abdominal lymph nodes (20%), and bone and local relapse in 16% and 10% of cases, respectively. In the entire cohort, the median OS was 26.5 months (95% CI 0-58.4). Cox analysis showed that patients with metastatic disease have more than a 4-fold increase in relative risk of death compared to nonmetastatic patients at diagnosis (hazard ratio 4.2, 95% CI 1.8-9.9, P ¼ .001). The probability to be alive at 18 months was 60% and 85% for patients with metastatic disease or not at diagnosis, respectively. In the patients with metastatic disease, the median OS was 24 months (95% CI 4.5-15.1), whereas the median OS was not reached in the nonmetastatic patients (P <.001, Fig. 1). No difference in OS was found based on age greater or lower than 15 years. Half of the patients received neoadjuvant or adjuvant chemotherapy for primary tumors. For patients who received any medical pre- or post-surgical treatment, the 12-month OS was 93% compared to 75% of patients who did not (P ¼ .092, Fig. 2). All patients were treated with a chemotherapy combination; the mean number of drugs was 5 (2-8) and the vincristine-adriamycincyclophosphamide followed by etoposide-ifosfamide was the most commonly used combination. In patients with metastatic disease, the median PFS was 22.0 months (95% CI 17.9-26.1) (Supplementary Figure); 384
Figure 2. Difference in overall survival in patients who received neoadjuvant or adjuvant treatment compared to patients who did not.
as for adjuvant setting, combined chemotherapy was also the most preferred approach. The overall response rate (complete and partial response) was 66% and the clinical benefit was 74%. Pathological Features The median value for longest tumor diameter was 13 cm (IQR 10-17). No differences in terms of OS or DFS (P ¼ .21 and P ¼ .44, respectively) were found to be related to the primary tumor extension above or under the median value. All tumors presented small cell histology and IHC expression of a variety of markers, as reported in Table 2. All markers were tested for relationship to the primary tumor extension, status of disease at diagnosis, or among each other. The Spearman’s correlation (rs) found a positive relationship between IHC expression of EMA or FLI and the status of metastatic disease at diagnosis (rs ¼ 1, P <.001 for both). Moreover, we were also able to find a relationship between the expression of S100 and synaptophysin proteins (rs ¼ 0.51, P ¼ .03). The presence of translocation (11:22) between the genes EWS/FLI-1 was found in 72% of tested subjects and this was found to be related to IHC expression of the protein FLI-1 (rs ¼ 0.39, P ¼ .03). The presence of translocation was investigated with different techniques: fluorescence in situ hybridization (FISH) was positive in 52.6% of 38 tested subjects and the direct sequencing with reverse transcriptase-polymerase chain reaction (RT-PCR) was positive in 43% of 49 tested subjects. Even if it is impossible to compare the 2 techniques of 31 subjects in which both methods were used, there were discrepancies in 8 cases and, for all, FISH evidenced a gene translocation that RT-PCR did not confirm. Furthermore, patients carrying the translocation seem to have a better DFS (85% and 33% of 2 months for UROLOGY 82 (2), 2013
Table 2. Immunohistochemical expression of tumor markers in primary renal PNET/EWS HIC test
No. of Cases
Expression (%)
VIM NSE CD99 FLI-1 CKs CD117 CHR SYN CD45 TdT WT-1 CD56 CD57 S100 EMA NF DES MYOG SMA PGP9.5 GFAP
33 34 96 33 65 6 34 28 25 7 39 10 1 26 13 7 22 7 5 1 2
81.8 88.2 99 60.6 7.7 33.3 5.9 32.1 0 0 23.1 30 100 38.5 15.4 0 4.5 0 0 100 100
CHR, chromogranin; CKs, cytokeratin; DES, desmin; EMA, epithelial membrane antigen; FLI-1, Friend leukemia integration 1 transcription factor; GFAP, glial fibrillary acidic protein; MYOG, myogenin; NF, neurofilament; NSE, neuron-specific enolase; SMA, smooth muscle actin; SYN, synaptophysin; TdT, terminal deoxynucleotidyl transferase; VIM, vimentin; WT-1, Wilms tumor protein; other abbreviations as in Table 1.
patients with or without translocation, respectively) but the difference was not significant (P ¼ .23). No relationships were found with OS (P ¼ .89).
COMMENT Primary PNET/EWS of the kidney is a small round cell tumor of presumed neuroectodermal origin described in about 120 folds in medical literature during the last 37 years. Because of its rarity, we lack clinical and pathological information that could improve the diagnosis and the management of patients affected by this disease. In this study, we first analyzed the clinical and pathological features of all the reported cases of primary PNET/ EWS of the kidney, then we described the response to therapy, and then we found a possible relationship between molecular and clinical characteristics. This tumor principally affects young men and, in the majority of cases, patients were metastatic at diagnosis or became metastatic after a few months confirming the aggressive nature of this tumor. In fact, the risk of death in patients with metastatic disease was found to be increased only 4-folds compared to nonmetastatic disease. This is different from other types of renal primary sarcoma, such as synovial sarcoma where this risk was found to increase >300-fold.5 Despite this increased attitude to develop metastases, the median survival of these patients of about 2 years was probably influenced by the high response rate to chemotherapy with an overall response rate of 66% and a clinical benefit of 75%. These data are in accord with UROLOGY 82 (2), 2013
published studies that evaluated patients affected by PNET/EWS at any site, in which the 5-year survival was 70% in nonmetastatic disease and only 20%-30% in patients with metastatic disease.6,7 The high response rate to chemotherapy in patients with metastatic disease is an interesting background to hypothesize a possible role for an adjuvant or neoadjuvant therapy to improve the DFS and OS.8 In our analysis, 3 and 31 patients received a neoadjuvant or adjuvant treatment, respectively. Most patients received a polychemotherapy with vincristine, doxorubicin, and cyclophosphamide, alternating with ifosfamide and etoposide. Because of the small number of patients with PNET, most knowledge about treatment has been derived from studies on Ewing’s sarcoma family. Studies seem to show that the addition of ifosfamide and etoposide to a regimen containing doxorubicin, vincristine, dactinomycin, and cyclophosphamide, improved outcomes in patients with nonmetastatic Ewing sarcoma.9 The same chemotherapy can be used in patients with metastatic disease. For these patients, other combination regimens have also been tested. Ifosfamide combined with etoposide and cisplatin have been shown to be effective in patients with primary refractory or recurrent disease.10 In an attempt to improve long-term survival, especially for high-risk patients, high-dose myeloablative therapy followed by stem cell rescue has been considered.11 In our study, 4 patients experimented with this approach with discordant outcomes. Unfortunately, the results reported in the current study were not extrapolated from a homogeneous prospective cohort of patients and the rarity of disease did not permit a definitive conclusion. In the same manner, the survival difference found between patients who received or did not receive radical nephrectomy could not be considered an absolute criteria for radical nephrectomy in patients with advanced disease at diagnosis because, in this case series, the eligibility of a patient for surgery may be influenced by several factors such as comorbidities and performance status. On the other hand, the high rate of symptoms because of local extension of disease, such as pain, hematuria, and mass, could be effectively palliated by surgical extirpation of disease; furthermore, this could facilitate the histological and molecular diagnosis. The invasion of locoregional lymph nodes is an expression of the metastatic spread of a tumor that principally affects distant organs, such as lung and liver, and then the role of lymphadenectomy may be considered for a better definition of stage and not as a curative procedure. IHC analysis confirms the high expression rate of CD99 previously described by Parham and Jimenez1,12; we also found a high expression of vimentin and neuronspecific enolase in more than 80% of the cases and the expression of FLI-1 protein in 60% of cases. Then, even if this marker is considered to be more specific for the diagnosis of PNET/EWS, about 40% of cases could be 385
misdiagnosed. The expression of cytokeratin is possible even if this was found in less than 10% of cases; whereas S100 and synaptophysin were expressed in 30%-40% of cases confirming the possible origin of this tumor from neuroectodermal cells. The neural ramification that invests the kidney has been postulated as the possible origin of this tumor. This comes from adrenergic fibers originating in the celiac plexus and accompanying efferent arterioles and descending vasa recta.1,13 Primary PNET/EWS of the kidney have been found to be associated with a specific chromosome translocation t(11; 22) (q24; q12), resulting in the production of the EWS/FLI-1 fusion gene.14 The resultant fusion gene has an oncogenic role and it includes the N-terminal transactivation domain of EWS and the C-terminal DNAbinding domain of the FLI-1 gene.15 The chimeric EWS/FLI-1 fusion protein functions as a powerful transcription activator and it has been demonstrated to be able to transform NIH3T3 cells.8,16,17 In our cohort, 72% of patients had chromosome translocation that results in the fusion of the EWS gene on chromosome 11; this data were higher compared to those previously reported (14%).1 The translocations can be detected indirectly from standard cytogenetic studies or directly by FISH or RT-PCR.18 In our study, we found a discrepancy between the diagnostic sensitivity of FISH and RT-PCR in 25% of cases; but this data should be interpreted with caution considering the several types of techniques that have been used and the long amount of time in which these have been performed. Additionally, patients with translocation seem to have a better DFS even if the difference was not significant. IHC has an important role in establishing an accurate diagnosis of PNET/EWS. We noticed that EMA and FLI expression was in direct relationship with metastatic disease at diagnosis. The present study has some important limitations. Its retrospective nature and the small number of patients evaluable for each variable increase the risk of bias. Furthermore, authors of different articles did not use the same variables for evaluation and the sensitivity of diagnostic techniques used has been increased in recent years. Patients treated with chemotherapy received several different regimens and there were no uniform criteria for the time of discontinuation. In addition, the published cases do not reflect the general population, even though the rarity of the disease is itself a reason to submit a case report.
CONCLUSIONS PNET/EWS of the kidney is a rare disease with a welldefined genetic background, clinically characterized by a very poor prognosis in patients with metastatic disease and by a high recurrence rate in patients with nonmetastatic disease. Considering the high response rate to chemotherapy, these patients should be treated when possible and a role for adjuvant therapy may also be considered.
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APPENDIX SUPPLEMENTARY DATA
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.urology. 2013.04.015.
UROLOGY 82 (2), 2013