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Oncology

rimitive Neuroectodermal Tumorf the Kidney: A Single Instituteeries of 16 Patients

uvaraja B. Thyavihally, Hemant B. Tongaonkar, Sudeep Gupta, Purna A. Kurkure,ratibha Amare, Mary Ann Muckaden, and Sangita B. Desai

BJECTIVES Primitive neuroectodermal tumor (PNET) of the kidney is a rare entity, the diagnosis usuallybeing made at histopathology. Few cases reported in literature revealed a variable presentationand an aggressive behavior. The purpose of our study was to review our experience in diagnosisand the management of patients with renal PNET.

ETHODS The records of 16 patients of renal PNET treated between 1995 and 2003 were reviewedretrospectively and our data compared with the literature.

ESULTS There were 10 male and 6 female patients with median age of 27 years. At presentation, 10patients (63%) had localized disease, 5 (31%) had metastatic disease and 1 (6%) had locallyadvanced disease. The presence of Homer-Wright type rosettes on hematoxylin and eosinstaining and CD99 (cluster differentiation) products positivity on immunohistochemistry sup-ported the diagnosis. Radical nephrectomy was performed in operable cases and all patientsreceived chemotherapy. Nine patients received adjuvant radiotherapy to the renal bed. Medianfollow-up was 31 months (range 4 to 92). Overall median survival was 40 months with 3- and5-year survival of 60% and 42%, respectively.

ONCLUSIONS The diagnosis of renal PNET must be considered in young patients presenting with renal mass.Standard therapy consists of combination of surgical resection, postoperative irradiation andchemotherapy. Chemotherapy regimen used is either RCT II (round cell tumor) protocol or EFT2001 (Ewing’s family of tumors) protocol. However, further studies are required to validate the

appropriate chemotherapy protocol. UROLOGY 71: 292–296, 2008. © 2008 Elsevier Inc.

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rimitive neuroectodermal tumor (PNET) is a ma-lignant small round cell tumor that exhibits neu-roepithelial differentiation, most often presenting

s a bone or soft tissue mass in the trunk or axial skeletonn adolescents and young adults.1 Rarely has PNET beenescribed to arise in the genitourinary system such asidney,2 bladder,3 prostate,4 testis, epididymis, ovary, andterus.5 PNET of the kidney is rare and the distinctionrom other primary malignancies of the kidneys is crucialor management.6 It frequently arises during childhood ordolescence, having a potential clinical course towardetastatic disease and death. The diagnosis is usuallyade by histopathology supported by immunohistochem-

stry (IHC) and cytogenetics studies.7,8 We describe theathologic and clinical features and treatment outcomesf renal PNET (rPNET) treated at our institution andeviewed the literature.

rom the Departments of Genito-urinary Oncology, Medical Oncology, Cancer Cyto-enitics, Radiation Oncology, and Pathology, Tata Memorial Hospital, Mumbai, India

Reprint requests: Yuvaraja B. Thyavihally, M.S., M.Ch., D.N.B., Room No. 52,epartment of Genito-urinary Oncology, Tata Memorial Hospital, Dr E. Borges Road,

warel, Mumbai-400 012, India. E-mail: uroraj@rediffmail.comSubmitted: November 29, 2006, accepted (with revisions): September 24, 2007

92 © 2008 Elsevier Inc.All Rights Reserved

ATERIAL AND METHODS

rom 1995 to 2003, 16 patients had rPNET diagnosed and treatedt our institution. Median age at presentation was 27 years, andhere were 10 male and 6 female patients. The predominantymptoms were abdominal pain (n � 11), abdominal mass (n �), and hematuria (n � 5). Patient evaluation consisted of history,hysical examination, complete blood count, renal and liver func-ion tests, chest x-ray films, computerized tomography (CT) scanf abdomen, and bone scan. On CT scan, mean size of the tumoras 10.5 cm (range 6 to 18), with heterogenous contrast enhance-ent and few showed calcific areas. (Fig. 1A). The management of

hese patients was by radical surgery and chemotherapy with orithout radiotherapy. Two patients were referred from other hos-itals after radical nephrectomy for localized disease, for furtheranagement. Surgical treatment consisted of radical nephrectomy,

long with regional lymph nodal dissection.The survival was calculated by the Kaplan-Meier method, and

nivariate analysis was performed by the using log-rank test (SPSS1.5, SPSS, Inc, Chicago, Ill) for prognostic factor analysis.

ESULTSf 16 patients, 10 patients (63%) had localized disease (2

ere operated outside of the histology reviewed), 5

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UROLOGY 71 (2), 2008

31%) had metastasis (2 lungs, 1 lung and lymph nodes,lymph nodes, and 1 liver), and 1 (6%) had locally

dvanced disease based on clinical and imaging studies.rucut biopsy (n � 3) and fine needle aspiration cytology

FNAC) (n � 1) were performed in 4 patients (3 withistant metastasis and 1 locally advanced) that wereeported as PNET. These patients received neoadjuvanthemotherapy. Three patients had partial response and 1ad progressive disease. Treatment details are summa-ized in Table 1.

Radical nephrectomy was attempted in 8 patients withocalized disease, in 3 patients who had partial responseith regional and metastatic disease and 1 patient with

ocally advanced disease and 1 patient with metastaticisease in whom the diagnosis was not possible by FNAC/iopsy preoperatively. The patient who had progressiveisease on chemotherapy did not undergo surgery. Theumor was inoperable in 1 patient because it was infil-rating the liver and duodenum and only a biopsy waserformed to confirm the diagnosis. Of 2 patients whoad regional lymph nodal enlargement, a complete

ymph node dissection was possible in 1 patient and wasot possible in another patient because of adherence to

nferior vena cava (IVC). One patient required resectionf a segment of descending colon because it was infil-rated by tumor. One patient each had renal vein throm-osis and renal and IVC level I thrombus, which wasemoved. There were no major intraoperative and post-perative complications and postoperative deaths.All cases were reviewed and IHC was performed to

onfirm the diagnosis. A histopathology report revealedmall round cells with prominent chromatin and clearytoplasm suggestive of primitive neuroectodermal tumorFig. 1B). The Homer-Wright rosette formation was mi-roscopically shown in 10 patients. The Gerota’s fasciaas involved in 5 patients. IHC features include CD99

cluster differentiation) positive and negative for cyto-eratin (CK), vimentin, neuron-specific enolase (NSE),-100, synaptophysin, and desmin (Fig. 1C). Cytogeneticnalysis was performed by fluorescent in situ hybridiza-ion technique (FISH) by using locus-specific EWS/R1Ewing’s sarcoma break point region 1) (22q12) dualolor break apart rearrangement probe in last 5 cases thathowed translocation of 11 to 22 chromosomes, t (11; 22)q24; q12).

All patients received chemotherapy and various re-imes were used. Chemotherapeutic agents used wereincristine (V), dactinomycin (D), adriamycin (A), cy-lophosphamide (C), ifosfamide (I), and etoposide (E).he current standard chemotherapeutic treatment of thisroup involves the use of a dose-intensive combinationegimen that uses these 6 drugs in a modified protocolalled Ewing’s family of tumors (EFT)-2001. This proto-ol has evolved from previous round cell tumor II (RCTI), protocol. The main difference between the previousnd current protocols is additional courses of dose-inten-

igure 1. A, Computed tomographic scan showing hetero-eneously enhancing lesion in the right kidney with postaval lymph nodal metastasis. B, Highly cellular and infil-rative neoplasm consisting of sheets of round cells withosette formation (hematoxylin-eosin staining; original mag-ification �400). C, Immuno positivity for CD99 (MIC2)

ive ifosfamide plus etoposide in the maintenance phase

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nd weekly administration of vincristine in the inductionhase in the current protocol. RCT II protocol includesmg/m2 of vincristine (maximal dose, 2 mg), doxorubi-

in given as a bolus infusion at a dose of 75 mg/m2, and200 mg/m2 of cyclophosphamide. Dactinomycin at 1.25g/m2 per dose was substituted for doxorubicin when a

otal doxorubicin dose of 375 mg/m2 was reached. In EFT001 protocol 1800 mg/m2 of ifosfamide per day for 5ays, given with mesna, and 100 mg/m2 of etoposide peray over the same 5 days are added. The courses ofhemotherapy were administered every 3 weeks for aotal of 17 courses. The total duration of chemotherapy is9 weeks.Overall disease-free status was achieved in 11(69%)

atients after surgery. Four patients received RCT IIrotocol and 1 each received VAC and VA only. Threeelapsed at local and distant sites and 1 remain alive freef disease at last follow-up. The remaining 5 (45%)atients received EFT2001 protocol, 3 were disease freeuring the last follow-up, and 2 patients relapsed. Theemaining 5 (31%) patients had measurable residual dis-ase after surgery and/or chemotherapy (2 in lungs, 1iver, 1 lung plus lymph node, and 1 inoperable) receivedither RCT II or EFT2001 protocol. One patient hadomplete response and others had stable (n � 2), partialesponse (n � 1), or progressive disease (n � 1). Severeeutropenic bone marrow depression was seen in 1 pa-ient and 6 patients had mild chemotoxicity.

Nine patients received adjuvant radiotherapy to theenal bed. The indications of radiotherapy were not uni-orm among treating physicians. The dose of radiotherapyaried from 5000 to 6000 rads. There was no majoradiation toxicity. The patient who had residual diseasen the regional lymphnodes also received radiotherapynd a complete response was achieved.

Follow-up of these patients ranged from 4 to 92onths with a median of 31 months. Overall median

urvival was 40 months with a 3-year survival of 60% and-year survival of 42% (Fig. 2A). The overall survival inatients who had localized disease and disease-free statusfter surgery was 60 months when compared with 5atients who had disease at regional nodes or distant sitesn whom the survival was 15 months, and the differenceetween survival curves was statistically significant (P �.002) (Fig. 2B). Of 11 patients who were disease free

Table 1. Treatment details of patients with renal PNET

Disease Group

Surgery

R0 R� ND

1. Localized n � 10 10 0 02. Locally advanced n � 1 1 0 03. Metastatic n � 5 1 2 2

ND � not done; R0 � complete gross surgical resection; R� � rRCT II � round cell tumor; RT � radiotherapy.

fter primary surgery, 4 were disease free at last follow-up S

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ho had complete treatment. Seven patients had relapset either local and/or distant sites during varying periodf follow-up. A 5-year disease-free survival rate of 36%as observed in this group of 11 patients.

OMMENThe peripheral PNET, first recognized by Arthur Purdy

igure 2. A, Kaplan-Meier curve showing overall survival. B,aplan-Meier curve showing overall survival curves in patientsith localized disease (n � 11) and metastatic (n � 5) dis-ase at presentation (P � 0.002).

Treatment Received

Chemotherapy RT

EFT-01 RCT-II Others Yes No

5 3 2 6 40 1 0 1 01 3 1 2 3

al disease after surgery; EFT-01 � Ewing’s family tumors 2001;

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ound-cell tumors.”9 The first report of rPNET was byeemayer et al.5 in 1975. Primitive renal localization isery rare.1,2,6,8,10 Because of the rarity of the disease andew cases reported over a long period, preclude a mean-ngful analysis of clinical outcome of rPNET.

These tumors typically manifest in adolescents andoung adults and have aggressive behavior. In a review byuroda et al.,11 average age at diagnosis was 27.7 years.ur series also suggest that these tumors are common in

ounger age group (median age 27 years). In our series,he majority of patients presented when the disease wasocalized to the kidney (63%) when compared with othereries in which the majority of the patients were meta-tatic at presentation.1 Surgical excision remains theost important modality of management which has

hown the survival advantage.12–14 The differential diag-osis of rPNET includes rhabdomyosarcoma, Wilms’ tu-or, carcinoid, neuroblastoma, clear cell sarcoma of the

idney, lymphoma, small cell variant of osteosarcoma,esmoplastic small RCT, small cell anaplastic neuroen-ocrine carcinoma, and nephroblastoma.15 Parham et al.8

howed in their series that PNET are high-grade lesionshat are difficult to characterize without immunohisto-hemistry. The Homer-Wright-type rosettes are a typicalistologic feature for PNET and can confirm the diagno-is although they can be found also in neuroblastoma.16

mmunohistochemical analysis is necessary for the diag-osis of these tumors. The presence of macrophage in-ibitory cytokine (MIC-2) gene products, known also asD99, 12E7, E2, 013, and HBA71, suggests a PNETiagnosis.7,16 The reactivity to vimentin, NSE, and S-100ay facilitate the diagnosis but is not pathognomonic,hereas CD 99 positivity is nowadays a clue for theiagnosis. All of our cases had confirmation by IHC and/orresence of Homer-Wright rosette formation. Cytogeneticstudies demonstrate that PNET and Ewing’s sarcoma canoth be associated with a translocation of the long arms ofhromosome 11 and 22, t (11; 22) (q22; q12).5,17–19

Because of biologic similarities with Ewing’s sarcoma,NET is treated with similar chemotherapy. Despite ag-ressive treatment of these tumors by combination ther-py with surgery, chemotherapy, and radiotherapy, therognosis remains poor and overall 5-year survival ratesave been reported at 45% to 55%.6,13,14 Before theoutine use of adjuvant chemotherapy, the 5-year sur-ival rate in patients with EFT was less than 10%. Cy-lophosphamide (C), actinomycin (A), and vincristineV) were found to be effective in this group of diseases inhe 1960s. Later, it was demonstrated that doxorubicinD) was also an active agent. The most recent additionso the list of active agents in this disease have beenfosfamide (I)20 and etoposide (E). The addition of latter

drugs to the previous standard treatment of VAClternating with VCD has been shown to improve theverall and disease-free survival in patients with non-etastatic skeletal Ewing’s sarcoma.21 The current stan-

ard chemotherapeutic treatment of this group involves c

ROLOGY 71 (2), 2008

he use of dose-intensive combination regimen lastingbout 49 weeks. At our institution we have used these 6rugs in EFT-2001 protocol. Because of the high inci-ence of febrile neutropenia, all patients receive prophy-actic granulocyte-colony stimulating factor (G-CSF) af-er IE courses.

Kushner et al.22 from Memorial Sloan Kettering Can-er Centre presented the series of 54 cases of extracranialNETs, none of them from the kidney, revealed disease-

ree survival of 24% at 2 years.22 Radiation therapy isseful in treating these patients, especially when theesection is not possible or residual disease is present. It isogical to give radiotherapy in the presence of Gerota’sascia involvement and positive surgical margins. Radia-ion dose varied from 5040 to 6000 rads. The uniformadiation therapy approach of Miser et al.23 has producedood local control in PNET. Only 9 of our patientseceived radiotherapy to the renal bed.

Thomas et al.24 and Karnes et al.25 have described aase of PNET kidney associated with IVC thrombushich was removed at the time of nephrectomy. Renalein and IVC thrombosis is also reported in the litera-ure. In our series 1 case had renal vein thrombosis and 1ore had IVC thrombus below hepatic vein, which were

esected.The 5-year disease-free survival rate, for patients pre-

enting well-confined extraskeletal PNET, is around 45%o 55% and cases with advanced disease at presentationave a median relapse-free survival of only 2 years.25,26,27

n our series, overall median survival was 40 months with-year survival of 60% and 5-year survival of 42%. Theverall survival in patients who had localized disease was0 months when compared with 5 patients who hadisease at regional nodes or distant sites at presentationn whom the survival was 15 months, which was statis-ically significant. The relatively small number of pa-ients with rPNET presented in our series limits statisticalomparisons of treatment outcomes. To our knowledge,his is the largest experience of rPNET from a singlenstitution with a focus on treatment schedule and weelieve that multimodal treatment improves the survival.

ONCLUSIONSNET are small round cell tumors of presumed neuralrest origin arising outside the central and sympatheticervous system. PNET of the kidney is a distinct clinicalntity with aggressive behavior. This tumor should beonsidered in the differential diagnosis of renal tumors indolescents and young adults. The tumor diagnosis isased on a classical histologic and IHC features comple-ented by cytogenetics and molecular analysis.We conclude that aggressive multimodality treatment

s recommended to manage these tumors. Complete re-ection of the kidney with node dissection should beerformed if at all feasible. The best results are seen withombination chemotherapy that is used for other round

ell tumors like Ewing’s sarcoma. The role of radiother-

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py is not clear but may be advocated in locally advancedisease and involvement of Gerota’s fascia.

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