Wilms tumor accounts for 90% of all malignant renal tumors of

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1 202 Preoperative Wilms Tumor Rupture A Retrospective Study of 57 Patients Hervé J. Brisse, MD 1 Gudrun Schleiermacher, MD, PhD 2 Sabine Sarnacki, MD, PhD 3 Sylvie Helfre, MD 4 Pascale Philippe-Chomette, MD 5 Liliane Boccon-Gibod, MD 6 Michel Peuchmaur, MD 7 Véronique Mosseri, MD 8 Yves Aigrain, MD 3,5 Sylvia Neuenschwander, MD 1 1 Department of Radiology, Curie Institute, Paris, France. 2 Department of Pediatric Oncology, Curie Institute, Paris, France. 3 Department of Pediatric Surgery, Necker Enfants Malades Hospital, Paris, France. 4 Department of Radiotherapy, Curie Institute, Paris, France. 5 Department of Pediatric Surgery, Robert Debre Hospital, Paris, France. 6 Department of Pathology, Armand Trousseau Hospital, Paris, France. 7 Department of Pathology, Robert Debre Hospital, Paris, France. 8 Department of Biostatistics, Curie Institute, Paris, France. Address for reprints: Hervé Jacques Brisse, MD, Department of Radiology, Institut Curie, 26 rue d Ulm, Paris, France; Fax: (011) ; herve.brisse@curie.net Received November 8, 2007; revision received January 6, 2008; accepted February 12, BACKGROUND. According to current International Society of Pediatric Oncology (SIOP) Wilms recommendations, all preoperative tumor ruptures should be classified as stage IIIc. However, to the authors knowledge, the definition and diagnostic criteria of preoperative rupture have not been defined clearly. METHODS. The authors performed a retrospective analysis of 57 children with clinical and/or radiologic (computed tomography [CT]) signs of preoperative tumor rupture of a series of 250 patients enrolled in Wilms SIOP protocols at their institution. RESULTS. Clinical and radiologic signs of preoperative rupture were observed in 39 patients and 55 patients, respectively. The site of rupture on imaging was retroperitoneal only in 48 patients and both retroperitoneal and intraperitoneal in 7 patients. Surgery was performed after chemotherapy in 55 of 57 patients. Peritoneal disease recurrence occurred in 3 of 57 patients, including 2 patients with stage III tumors who had initial intraperitoneal rupture and 1 patient with a stage I tumor. Among the 48 patients who had radiologic signs of retroperitoneal-only rupture, the final pathologic stage was stage III in 22 patients, stage II in 9 patients, and stage I in 17 patients, and no abdominal disease recurrence was observed, although only 23 of 48 patients received flank radiotherapy. The 5-year local control rate was significantly higher in patients who had retroperitonealonly rupture compared with patients who had intraperitoneal rupture (100% vs 83.3%; standard error, 15.2%; P ). CONCLUSIONS. The use of CT scans significantly increased the number of patients who could be classified with tumor rupture. Intraperitoneal rupture was diagnosed accurately with CT and was associated with a significant risk of peritoneal disease recurrence. In contrast, patients who have radiologic signs of localized retroperitoneal-only rupture at diagnosis most likely should not be upstaged, and their treatment may be determined according to pathologic stage only. Cancer 2008;113: Ó 2008 American Cancer Society. KEYWORDS: Wilms tumor, kidney neoplasms, child, x-ray computed tomography, spontaneous rupture, radiotherapy, chemotherapy, surgery. Wilms tumor accounts for 90% of all malignant renal tumors of childhood and represents approximately 6% of all pediatric cancers. 1 Wilms tumor is a very rapidly growing neoplasm, and it has an estimated doubling rate of 11 days. 2,3 Tumor rupture, although rare, is a complication that has been reported for a long time 4 and commonly is described. 5,6 The International Society of Pediatric Oncology (SIOP) recommends treating patients with neoadjuvant chemotherapy to reduce the risk of intraoperative rupture, which is considered a major risk factor of abdominal recurrence. 5,7 According to the current SIOP staging system (Table 1) and treatment protocol (Table 2), all children with preoperative or ª 2008 American Cancer Society DOI /cncr Published online 5 May 2008 in Wiley InterScience (

2 Preoperative Wilms Tumor Rupture/Brisse et al. 203 TABLE 1 Current International Society of Pediatric Oncology Criteria for Wilms Tumor Staging* Stage I The tumor is limited to the kidney or surrounded with a pseudocapsule if outside of the normal contours of the kidney. The renal capsule or pseudocapsule may be infiltrated with the tumor but it does not reach the outer surface and is completely resected The tumor may be protruding into the pelvic system and dipping into the ureter but is not infiltrating their walls Intrarenal vessel involvement may be present, but not vessels of the renal sinus Necrotic tumor in the renal sinus or perirenal fat does not upstage if completely excised Fine-needle aspiration or percutaneous core-needle biopsy does not upstage Stage II The tumor has extended beyond the kidney or penetrates through the renal capsule and/or fibrous pseudocapsule into the perirenal fat but is completely resected Tumor may infiltrate the renal sinus and/or blood and lymphatic vessels outside the renal parenchyma, but is completely resected Tumor may infiltrate adjacent organs or inferior vena cava but is completely resected Stage III Residual nonhematogenous tumor is present, confined to the abdomen Any 1 of the following may occur: a) incomplete excision (gross or microscopic) of the tumor; b) any abdominal lymph node involved; c) tumor rupture before or intraoperatively (irrespective of other criteria for staging); d) tumor penetration through the peritoneal surface; e) tumor implants on the peritoneal surface; f) tumor thrombi present at resection margin of vessel or ureter, transected or removed piecemeal by surgeon; g) surgical (wedge) biopsy prior to preoperative chemotherapy or surgery The presence of necrotic tumor in a lymph node or at the resection margins also is assigned stage III Stage IV Hematogenous metastases (lung, liver, bone, brain) or lymph node metastases outside the abdominopelvic region Stage V Bilateral renal involvement at diagnosis (each side should be substaged) * See International Society of Pediatric Oncology. Nephroblastoma Clinical Trial and Study Protocol, intraoperative tumor rupture should be upstaged to stage IIIc; thus, most of these patients (intermediate histologic risk) receive abdominal radiotherapy (RT). 8 Because RT is associated with both acute and delayed toxicity, the definition of tumor rupture must be based on precise diagnostic criteria. Most publications are based on the macroscopic (surgical or pathologic) definition of rupture, which currently remains the gold standard. Therefore, the definitions of both intraoperative tumor ruptures 5 and rare preoperative ruptures requiring primary emergency surgery 6,9 are not controversial. However, some patients with preoperative tumor rupture may have minimal clinical signs, limited abdominal bleeding, and currently are treated with primary neoadjuvant chemotherapy. In this situation, the definition of preoperative tumor rupture frequently remains hazy and usually is based on ambiguous clinical or radiologic signs. To our knowledge, the reported radiologic descriptions of preoperative Wilms tumor ruptures are very limited. 10,11 Thus, to date, the incidence and prognosis of children with nonsurgical, preoperative tumor rupture remain unknown. The criteria to be used for diagnosing and staging the degree of rupture also have not been clearly defined. Previous attempts to classify the degree of tumor rupture are rare and have been based only on macroscopic descriptions. 5,12 Moreover, the constantly improving quality of imaging could lead to an artificial increase of the incidence of ruptured forms and, consequently, to overstaging and overtreatment. In the current study, our objectives were to perform a retrospective analysis of a large cohort of patients treated for Wilms tumor and 1) to assess the rate of patients with clinical and/or radiologic signs of preoperative tumor rupture at diagnosis; 2) to compare the relative incidence of clinical and radiologic signs of preoperative rupture; 3) to TABLE 2 Summary of Current International Society of Pediatric Oncology Postoperative Treatment Strategies for Patients With Localized Wilms Tumors According to Histologic Risk Group and Local Stage* Postoperative treatment strategy Risk Group Stage I Stage II Stage III Low risk No further treatment ACT-VCR (27 wk) ACT-VCR (27 wk) Intermediate risk ACT-VCR (4 wk) ACT-VCR-DOX (27 wk); randomized vs ACT-VCR (27 wk) RT 1 ACT-VCR-DOX (27 wk); randomized vs RT 1 ACT-VCR (27 wk) High risk ACT-VCR-DOX (27 wk) RT 1 etoposide-carbo-cyclo-dox (34 wk) RT 1 etoposide-carbo-cyclo-dox (34 wk) ACT indicates actinomycin; VCR, vincristine; DOX, doxorubicin; RT, radiotherapy; CARBO, carboplatin; CYCLO, cyclophosphamide; wk, postoperative chemotherapy duration in weeks. y Low risk indicates cystic partially differentiated Wilms tumor or completely necrotic after chemotherapy; high risk, Wilms tumor with diffuse anaplasia or predominantly blastemal after preoperative chemotherapy; intermediate risk, all others. * See SIOP. Nephroblastoma Clinical Trial and Study Protocol, 2001.

3 204 CANCER July 1, 2008 / Volume 113 / Number 1 analyze the follow-up of these patients in terms of abdominal recurrence and survival according to the site of tumor rupture and the treatment regimen; and 4) consequently, to propose a classification of preoperative tumor ruptures for patients who are treated with neoadjuvant chemotherapy that could be used to stratify postoperative treatment in future protocols. MATERIALS AND METHODS Patient Database The medical records of 250 patients with histologically proven Wilms tumor who were enrolled in the SIOP 9, SIOP 93-01, and SIOP 2001 protocols and were treated in our institution between 1989 and 2004 were analyzed retrospectively to look for abdominal recurrences and for clinical, radiologic, or surgical signs associated with possible tumor rupture. According to French law, local ethics committee approval and informed consent were not required for this retrospective review of the patients radiologic images and clinical records. Study Population The study population included all patients with at least 1 clinical or radiologic sign of possible preoperative tumor rupture and for whom imaging data were available for radiologic review. Clinical signs of possible tumor rupture were defined as acute and intense abdominal pain, and/or acute fall of hemoglobin requiring erythrocyte transfusion, and/or a recent history of abdominal trauma. Radiologic criteria of retroperitoneal rupture were as follows: acute hemorrhage located within the tumor, and/or retroperitoneal effusion, and/or acute hemorrhage located in the subcapsular and/or perirenal space, and/or retroperitoneal tumor nodules separated from the primary tumor. Radiologic criteria of intraperitoneal rupture were as follows: intraperitoneal acute hemorrhage, and/or intraperitoneal tumor nodules, and/or tumor fracture communicating with peritoneal effusion, and/or visibility of mesenteric infiltration. Patients who had no preoperative signs of tumor rupture in whom isolated capsular breach occurred during surgery were not included in the study population. Imaging Analysis Radiologic signs of tumor rupture were defined on the initial computed tomography (CT) scan that was obtained at diagnosis. Radiologic data were reviewed consensually by 2 senior radiologists (H.J.B. and S.N.) who were blinded to clinical, surgical, and pathologic findings and follow-up. Acute hemorrhage was defined as a spontaneously hyperdense area or effusion on unenhanced CT images. Nonhemorrhagic peritoneal effusion was not used as a criterion for tumor rupture but was recorded, and its volume was classified into 3 groups: minimal (small amount in the peritoneal Douglas recess), abundant (large effusion visible in hepatorenal or Morrison recess, Douglas recess, and parietocolic areas), or medium (in between). Tumor volume at diagnosis was calculated according to the following formula: volume 5 d 1 3 d 2 3 d , in which d 1, d 2, and d 3 indicate the 3 orthogonal dimensions. Pathologic Examination and Staging Pathologic examination was performed first by the local pathologists then was reviewed prospectively by either the SIOP referent pathologist (Prof. Sandstedt, Amsterdam, Netherlands) for SIOP 9 and SIOP protocols and/or by the national referent pathologist (Prof. Boccon-Gibod, Paris, France) for the SIOP 2001 protocol. The staging classification used in the current study was the Revised International Society of Pediatric Oncology Working Classification of Renal Tumors of Childhood, 13 which currently is used in the SIOP 2001 protocol. Because the classifications changed between the SIOP 9, SIOP 93-01, and SIOP 2001 protocols, local stage was converted into the current classification according to the surgical and pathologic descriptions. Postoperative treatment was based on pathologic stage and risk group. Statistical Analysis The Yates-corrected chi-square test was used to analyze the relations between site of tumor rupture, tumor side, clinical symptoms, and occurrence of peritoneal effusion. The nonparametric Mann-Whitney U test was used to compare tumor volumes according to rupture site on imaging and symptoms. Event-free survival (EFS) and overall survival (OS), reported with the standard error (SE), were estimated by using the Kaplan-Meier method and were compared by using the log-rank test. EFS was calculated from the date of diagnosis to the date of last followup or event (tumor progression or disease recurrence). OS was calculated from the date of diagnosis to the date of last follow-up or disease-related death. Tests were performed with MedCalc statistical software (available at: Accessed April 18, 2008) and P values <.05 were considered statistically significant.

4 Preoperative Wilms Tumor Rupture/Brisse et al. 205 TABLE 3 Radiologic Signs of Preoperative Tumor Rupture No. of patients Variable Retroperitonealonly rupture Intraperitoneal rupture Total FIGURE 1. Distribution of clinical signs of possible preoperative tumor rupture among the 39 symptomatic patients. RESULTS Among the 250 patients who were treated for Wilms tumor at our institution during the study period, 57 patients (23%) met the inclusion criteria. The study population included 30 girls and 27 boys (sex ratio, 0.9) ages 1.5 years to 9 years at diagnosis (median age, 4 years) who were enrolled on the SIOP 9(n5 7 patients), SIOP (n 5 29 patients), and SIOP 2001 (n 5 21 patients) protocols. Forty-seven patients (82%) presented with localized disease, whereas 10 patients had metastases at diagnosis (lung only). Wilms tumors were unilateral in 54 children (30 right-sided, 24 left-sided) and bilateral in 3 children (all with predominant right-sided disease). Therefore, the preoperative rupture was globally right-sided in 33 of 57 children (58%). Clinical signs (Fig. 1) of possible preoperative rupture were observed in 39 of 57 patients (68%). All but 2 children had associated radiologic signs of tumor rupture. Among patients with radiologic signs of tumor rupture, 18 of 55 patients (33%) had no symptoms. Radiologic signs (Table 3) of tumor rupture were observed in 55 of 57 patients (96%). All 55 patients had at least 1 sign of retroperitoneal rupture (Fig. 2), and 7 patients also had at least 1 additional sign of intraperitoneal rupture (Fig. 3); ie, 48 patients presented with signs of retroperitoneal-only rupture on CT. Intraperitoneal rupture occurred more frequently (86%) in patients who had right-sided tumors compared with retroperitoneal-only rupture (52%), but this difference was not statistically significant (P 5.20). Patients who had radiologic signs of retroperitoneal-only rupture more frequently were symptomatic (69%) than patients who had radiologic signs of intraperitoneal rupture (57%), but this difference was not significant (P 5.85). No. of patients Associated clinical signs Tumor side, right/left 25/23 6/1 31/24 Median tumor volume: 357 [ ] 375 [ ] 369 [ ] [range], ml Retroperitoneal signs Intratumoral hemorrhage Subcapsular effusion* 15 (8) 2 (1) 17 Perirenal effusion* 24 (6) 5 (1) 29 Retroperitoneal tumor nodules Intraperitoneal signs Intraperitoneal hemorrhage 1 1 Intraperitoneal tumor nodules 4 4 Tumor fracture communicating 1 1 with peritoneal cavity Mesenteric infiltration 1 1 Associated peritoneal effusion Abundant Medium Minimal * Numbers in parentheses represent the number of patients for whom the effusion was spontaneously hyperdense on computed tomography scan, ie, corresponding to acute hemorrhage. The median tumor volume in patients with retroperitoneal-only rupture did not differ statistically from that of patients with intraperitoneal rupture (P 5.20). The median tumor volume of symptomatic patients (328 ml; range, ml) also did not differ statistically from that of asymptomatic patients (418 ml; range, ml; P 5.07). Peritoneal effusion was visible on CT scans in 27 patients and was significantly more frequent in patients who had signs of intraperitoneal rupture than in patients who had signs of retroperitoneal-only rupture (100% vs 42%; P 5.015). Comparison between radiologic and macroscopic patterns was available at diagnosis for 3 patients, including 1 patient who underwent surgical biopsy and 2 patients for whom primary emergency surgery was required because of uncontrolled intraperitoneal bleeding. The suspected intraperitoneal rupture was confirmed macroscopically by the surgeon who observed a tumor extending to the Morrison recess in 1 patient and a huge retroperitoneal hematoma extending to the left mesocolon in another patient. In the third patient, a hemoperitoneum was observed together with a huge renal and tumor fracture with mixed urinoma and retroperitoneal hematoma. The remaining 4 patients who had CT signs of intraperi-

5 206 CANCER July 1, 2008 / Volume 113 / Number 1 FIGURE 2. Wilms tumor in a boy aged 9 years. Computed tomography scans at diagnosis (a,b, unenhanced axial images; c, contrast-enhanced axial image) demonstrate a heterogeneous tumor at the lower pole of the left kidney (asterisk) associated with acute subcapsular hemorrhage (spontaneously hyperdense area; arrows), without any associated peritoneal abnormality, corresponding to a retroperitoneal-only rupture. The boy was treated by neoadjuvant chemotherapy (International Society of Pediatric Oncology protocol 93-01), and pathologic examination showed a local stage I intermediaterisk tumor. Postoperative treatment consisted of chemotherapy only (2 drugs, 4 weeks), and the child is currently in first complete remission with a 6-year follow-up. toneal rupture were treated by neoadjuvant chemotherapy; therefore, macroscopic examination was delayed until they underwent secondary surgery. Residual peritoneal implants were confirmed histologically in 3 patients. In the last patient, adhesions between the tumor pseudocapsule, the liver, and the diaphragm were obvious; and capsular breach occurred during tumor removal, suggesting an initially localized peritoneal extension. Conversely, no peritoneal seeding was observed by the surgeons in the remaining 48 patients who had radiologic signs of retroperitoneal-only rupture. Histopathologically, among the 57 tumors, 51 were classified as intermediate-risk, tumors, 2 were classified as low-risk tumors (both were completely necrotic after chemotherapy), and 4 were classified high-risk tumors (3 were predominantly blastemal after chemotherapy, and 1 had diffuse anaplasia). The final local stage (ie, the stage on which postoperative treatment was based) was stage I in 18 patients, stage II in 10 patients, and stage III in 29 patients (Fig. 4). All 7 patients who had ruptures classified as intraperitoneal on CT were staged pathologically as stage III. Among those who had ruptures classified as retroperitoneal-only on CT, only 22 of 48 patients finally were staged as stage III, including the 3 upstaged patients (otherwise stage II in 2 patients and stage I in 1 patient). Consequently, 26 patients who presented radiologic signs of retroperitoneal-only rupture at diagnosis were treated postoperatively for stage I disease (17 patients) or stage II disease (9 patients). Treatment of this population included chemotherapy and surgery in all patients and RT in 30 of 57 patients (53%) (Fig. 4). Preoperative chemotherapy was based on weekly injections of vincristine and actinomycin every 2 weeks for a total duration of 4 weeks in patients with localized disease and for 6 weeks with additional anthracyclines in patients with metastatic disease. Surgery consisted of total nephrectomy after primary inspection of the abdominal cavity. In 2 of the 3 patients who had bilateral tumors, wedge resection of a contralateral lesion was performed during the same operation. In patients who had intraperitoneal rupture and implants, the surgical objective was to remove all macroscopic peritoneal disease. This was achieved in 4 of the 5 patients who received primary chemotherapy and in 1 of the 2 patients who underwent primary surgery. Stratification of postoperative chemotherapy was based on SIOP protocols, ie, on the metastatic status, local stage, and histologic risk group. For 56 patients, postoperative treatment consisted of a combination

6 Preoperative Wilms Tumor Rupture/Brisse et al. 207 FIGURE 3. Wilms tumor in a girl aged 4 years with a painless right-flank mass. Computed tomography scans at diagnosis (a,b, enhanced axial images; c, sagittal reconstruction) demonstrate a heterogeneous tumor (asterisk) extending into the Morrison recess (b, arrow) and the peritoneal cavity (a, arrows), surrounded by peritoneal effusion (a, arrowhead), corresponding to an intraperitoneal rupture. A distant peritoneal implant (c, arrows) is observed in the Douglas recess. The girl was treated by neoadjuvant chemotherapy (International Society of Pediatric Oncology 2001 protocol) and secondary nephrectomy with resection of residual peritoneal implants. Pathologic examination showed a local stage III intermediate-risk tumor. Postoperative treatment consisted of chemotherapy (3 drugs, 26 weeks) and radiotherapy (whole abdominal radiotherapy, 10.5 grays [Gy]; flank radiotherapy, 9 Gy). The child is currently in first complete remission with a 2.5-year follow-up. of actinomycin and vincristine, with anthracyclines (doxorubicin) used in 36 patients and with secondline chemotherapy in 2 other patients. One other patient received upfront treatment that consisted of etoposide, carboplatin, and high-dose chemotherapy. Overall, 37 of 57 patients (65%) received anthracyclines. Postoperative RT (Table 4) was received by 30 of 57 patients (29 patients with stage III disease and 1 patient with stage II disease for whom anthracyclines had to be discontinued because of cardiac toxicity). Only 4 patients received whole abdominal RT (WART) because of peritoneal contamination with a 15- to 20-gray (Gy) abdominal dose according to patient age (and a 9- to 15-Gy boost to the tumor bed for 3 patients, for a total 30-Gy dose to the tumor bed). Renal shielding was used according to SIOP recommendations so that the remaining kidney received a maximum dose of 12 Gy. The remaining 26 patients received flank RT (14.4 Gy for 23 patients, 25.2 Gy for 1 patient, and 30 Gy for 2 patients because of high-risk histology). Three of the 4 patients who had intraperitoneal rupture were treated with flank RT only, because peritoneal involvement was considered localized. At a median follow-up of 72 months (range, months), 48 of 57 patients currently are in first complete remission (CR) (Fig. 4). Metastatic disease recurrence occurred in 6 patients, including 4 patients who initially had stage IV disease (including 2 with high-risk histology), 1 patient who initially had stage III disease, and 1 patient

7 208 CANCER July 1, 2008 / Volume 113 / Number 1 FIGURE 4. Pathologic distribution, treatment and follow-up of 57 patients with Wilms tumor who had clinical and/or radiologic signs of preoperative tumor rupture. The 7 patients with radiologic signs of intraperitoneal rupture are those included in the box labeled Peritoneal Rupture (IIId,e). N1 indicates lymph node invasion; WART, whole abdominal radiotherapy; RT, radiotherapy; CR, complete remission; DOD, died of disease; M1, metastatic; PD, progressive disease; f-u, follow-up. who initially had stage I disease. The site of metastaticdiseaserecurrencewasthelungin6patients, pleura in 1 patient, and liver and bone in 1 patient. Three patients currently are in second CR (followup, 43 months, 93 months, and 147 months), 2 patients have died from disease progression, and 1 patient has been lost to follow-up after disease progression. All metastatic recurrences occurred in patients with retroperitoneal-only rupture signs. No patient experienced both distant and abdominal disease recurrence. Among the 4 patients who received WART, renal function remained normal (mean follow-up, 108 months; range, months). Abdominal disease recurrences, all located within the peritoneal cavity, occurred in 3 patients (Fig.4,Table5).Onepatientcurrentlyisinsecond remission, and 2 patients have died from progressive peritoneal disease. Two of the 3 peritoneal recurrences occurred in patients who presented initially with radiologic signs of intraperitoneal rupture and had final stage III disease (Fig. 5) and in 1 patient who had only clinical signs of rupture and TABLE 4 Radiotherapy Technique and Follow-up of 55 Patients With Wilms Tumor According to Initial Site of Rupture on Imaging and Pathologic Stage Variable Site of rupture on imaging: no. of patients Retroperitoneal and intraperitoneal Total no. of patients 7 48 Final pathologic local stage III 7 22 II 0 9 I 0 17 Proportion of patients who received RT, % No. of patients who received RT Flank RT 3 23 WART 4 0 No. of recurrences Peritoneal recurrences 2 0 Metastatic recurrences 0 6 RT indicates radiotherapy; WART, whole abdominal radiotherapy. Retroperitoneal only

8 Preoperative Wilms Tumor Rupture/Brisse et al. 209 TABLE 5 Description of the 3 Patients With Peritoneal Recurrence in the Study Population of Patients With Preoperative Wilms Tumor Rupture (n557) Characteristic Patient 1 Patient 2 Patient 3 Age at diagnosis, y Sex Girl Boy Girl Protocol SIOP 9 SIOP SIOP 2001 Clinical signs of preoperative rupture History of abdominal trauma Abdominal pain; fall of hemoglobin Tumor site Right Left Right Tumor size at diagnosis Greatest dimension, cm Volume, ml Radiologic signs of preoperative rupture Mesenteric infiltration; retroperitoneal hemorrhage (intratumoral, perirenal); peritoneal effusion None Retroperitoneal effusion; peritoneal nodules (Morrison recess) Neoadjuvant chemotherapy ACT-VCR ACT-VCR Surgeon s description at initial surgery Liver adherences Intraperitoneal rupture; left mesocolon infiltration Infiltration of Morrison recess; liver adherences Local stage I III III Histologic risk group Intermediate Intermediate Intermediate Postoperative chemotherapy ACT-VCR ACT-VCR-epirubicin; VP16-Carbo ACT-VCR-DOX Postoperative radiotherapy WART/15 Gy Flank RT/14.4 Gy Time to recurrence, y Mo Site(s) of recurrence Left flank; perihepatic Mesocolon, inguinal ligament, Douglas recess Douglas recess Treatment of peritoneal VP-16-Carbo, ifosfamidedoxorubicin; Conventional and high-dose ICE; MEC; surgery; RT recurrence MEC; RT chemotherapy; surgery; RT FU Died of disease (peritoneal progression) Died of disease (peritoneal progression) Second CR (54-mo FU) SIOP indicates International Society of Pediatric Oncology; ACT, actinomycin; VCR, vincristine; VP16, etoposide; Carbo, carboplatin; DOX, doxorubicin; WART, whole abdominal radiotherapy; Gy, grays; RT, radiotherapy; MEC, melphalan, etoposide, and carboplatin; ICE, ifosfamide, etoposide, and carboplatin; FU, follow-up; CR, complete remission. had stage I disease after surgery. Among the 3 patients who had intraperitoneal rupture and received flank RT only (ie, not WART), only 1 patient experienced a peritoneal disease recurrence. The 2 other patients received a more intensive postoperative chemotherapy schedule. All 3 currently are in first or second CR. It is interesting to note that, in the subgroup of 26 patients with stage I/II disease who initially had signs of retroperitoneal-only rupture on CT images and were not upstaged, no peritoneal disease recurrence was observed after they received local treatment adapted to their local pathologic stage. The 5-year OS and EFS rates for the study population were 94.4% (SE, 3.1%) and 85.5% (SE, 4.7%), respectively. The 5-year overall local control rate for the study population was 98.1% (SE, 1.9%). The 5-year overall local control rate for the 48 patients who had radiologic signs of retroperitoneal-only rupture was significantly higher than that for the 7 patients who had radiologic signs of intraperitoneal rupture (100% vs 83.3%, respectively; SE, 15.2%; P ). DISCUSSION The role of imaging at diagnosis in children with Wilms tumor is to assess local extension (renal vein, inferior vena cava, lymph nodes), look for distant metastases (lung, liver), and look for possible contralateral disease in the other kidney. 14 In the current study, we demonstrated that, in approximately 25% of patients, CT also demonstrates signs of associated tumor rupture, whereas approximately 33% of these children do not have any suggestive clinical signs of tumor rupture. According to the current SIOP recommendations, 8 these patients with preoperative tumor rupture theoretically should be upstaged to stage IIIc. Accurate diagnosis of preoperative rupture is critical, because patients may require immediate surgery if they have massive abdominal bleeding.

9 210 CANCER July 1, 2008 / Volume 113 / Number 1 FIGURE 5. Wilms tumor in a girl aged 7.5 years with a painless right-flank mass (Patient 3 in Table 4). Computed tomography (CT) scans at diagnosis (a,b, enhanced axial images) demonstrate a heterogeneous tumor of the upper part of the right kidney (asterisk). Localized intraperitoneal rupture into the Morrison recess (arrows) was confirmed on initial surgical biopsy. The girl was treated according to the International Society of Pediatric Oncology 2001 protocol by neoadjuvant chemotherapy with a 95% volume response (c, CT scan after chemotherapy; enhanced axial images show the residual tumor, arrows) and subsequent total nephrectomy. Pathologic examination showed a stage III intermediate-risk tumor. Postoperative treatment consisted of chemotherapy (26 weeks) and flank radiotherapy (14.4 grays [Gy]). Four months after the end of treatment, routine follow-up abdominal sonography (d, axial view of the pelvis) showed a peritoneal disease recurrence in the Douglas recess (arrows). After intensive chemotherapy, surgical resection of the residual mass and radiotherapy (whole abdominal radiotherapy: 15-Gy plus a 36-Gy boost to the pelvis), the child is currently in second complete remission with a 4.5-year follow-up. The emergency surgery rate for tumor rupture previously was estimated at between 3% 9 and 1.8% 6 and was only 0.8% (2 of 250 patients) in our series. In clinically stable patients who are treated with neoadjuvant chemotherapy, knowledge of initial tumor rupture also is crucial, because it may modify the postoperative treatment strategy. Our data demonstrate that detailed analysis of the CT pattern may distinguish intraperitoneal ruptures from retroperitoneal-only ruptures and that this distinction may help to stratify treatment. The survival rate of patients who have Wilms tumor is relatively high 15,16 compared with patients who have other pediatric cancers, even after disease recurrence. 17 The most common site of recurrence is the lung (58%), whereas abdominal recurrences represent only 29% of all disease recurrences. 18 However, the survival rate of children with no high-risk histology who are treated for abdominal recurrence is significantly lower than for patients with disease recurrence confined to the lung. 18 In the National Wilms Tumor Study 4 (NWTS-4) trial, 7 the 2-year survival rate of children after local recurrence was 43%. Although it is rare, tumor rupture is a major risk factor for abdominal recurrence. 5,7 The current SIOP recommendation for tumor rupture includes abdom-

10 Preoperative Wilms Tumor Rupture/Brisse et al. 211 inal RT, even in the absence of local residue or lymph node involvement. The target volume in flank RT includes the renal and tumor bed (recommended doses: 14.4 Gy for patients with stage III, intermediate-risk disease; 25.2 Gy for patients with stage II/III, high-risk histology with or without a 10.8-Gy boost on local residue). In the case of peritoneal spillage, the whole peritoneal cavity is at risk of disease recurrence 5 and, thus, should be treated (to a maximum dose of 21 Gy or Gy if <1 year with consideration of a boost to a limited area for flank RT). 8,12 Abdominal RT has been associated with both acute complications (hepatic veno-occlusive disease, radiation enteritis, myelotoxicity) and long-term effects, including impaired bone and soft tissue growth, reduced fertility in women, and increased risk of second malignancies. Because WART is associated with a higher incidence of both acute toxicity and longterm morbidity, 12,19 it is of major importance to use an accurate definition of tumor rupture in Wilms protocols. Nevertheless, the diagnostic criteria for tumor rupture remain difficult to identify in the literature, mainly because of lack of a definite gold standard in patients who are treated with neoadjuvant chemotherapy. In these patients, the macroscopic examination performed by the surgeon and pathologist is delayed after the initial event. Pathologists may demonstrate a capsular breach macroscopically, but the rupture also may have closed during chemotherapy. This phenomenon most likely explains why 26 of our patients with retroperitoneal tumor rupture on initial CT finally were classified with stage I or II disease. Microscopically, tumor extension through the renal capsule (or fibrous pseudocapsule) and hemosiderin deposits related to previous hemorrhage may be observed. However, a completely resected perirenal hematoma entirely surrounded by a neocapsule induced by preoperative chemotherapy is not a reason for upstaging and currently is considered stage I disease. Extracapsular extension, if it is resected completely, currently is classified as stage II disease. Moreover, pathologists are unaware of the status of distant retroperitoneal and peritoneal areas if these areas are not removed by the surgeon. The predictive values of clinical and radiologic signs for the diagnosis of rupture could not be assessed exactly in our study but only could be estimated based on the small number of patients with either macroscopic confirmation of peritoneal extension during secondary surgery or peritoneal disease recurrence. According to the NWTS definition, tumor spill refers to direct surgical visualization of transgression of the tumor capsule and should be designated by the surgeon as either local when it is confined to the renal bed or diffuse when it extends beyond the renal bed. Ehrlich et al. 20 reported a spill rate of 19% (253 of 1305 patients) in the NWTS-5 study. Of those 253 patients who underwent upfront nephrectomy, the most common cause of tumor spill was intraoperative rupture (139 of 253 patients). Thus, after the exclusion of 17 preoperative biopsies, only 7.5% of patients (97 of 1305 patients) experienced preoperative spill. We acknowledge that our 23% rate is artificially high because of the radiologic definition that we used. The National Wilms Tumor Study Group would not consider an intratumoral or subcapsular bleed to be a rupture or spill. However, because the definition of rupture remains unclear for patients who receive primary chemotherapy, in the current study, we decided first to include all acute events that may be associated with radiologic and/or clinical signs, then to study the follow-up of these patients, and subsequently to define which sign should and should not require upstaging. The accuracy of clinical signs for the diagnosis of preoperative rupture currently is unknown. In our cohort, the positive predictive value of clinical signs appeared to be relatively high. However, the sensitivity was relatively low, because only 68% of our study population was symptomatic. Moreover, clinical signs do not allow assessment of the degree or site of rupture. It is known that the positive predictive value of clinical signs for the diagnosis of intraperitoneal rupture is insufficient and has been estimated in previous surgical series between 16% and 54%. 6,21,22 In our series, only 5 of 39 symptomatic patients (13%) finally had intraperitoneal tumor extension (based on imaging and surgery in 4 patients and on the occurrence of peritoneal disease recurrence in 1 patient), because acute abdominal pain in patients with Wilms tumor may be related to intraperitoneal rupture or to abrupt stretching of the retroperitoneum caused by subcapsular or retroperitoneal-only hemorrhage Therefore, in patients with Wilms tumor who receive neoadjuvant chemotherapy, imaging is the only reliable method for depicting the presence of tumor rupture and assessing its extension. Despite the associated ionizing radiation, CT is most likely the best imaging modality in this situation. Compared with magnetic resonance imaging, CT usually is available in most institutions, and multidetector row CT now allows rapid examinations without motion artifact. Compared with ultrasonography, CT is a highly sensitive method for depicting acute bleeding. The accuracy of CT scanning for peritoneal staging was good in the current series, because perito-

11 212 CANCER July 1, 2008 / Volume 113 / Number 1 neal dissemination was not described by the surgeon in patients who had radiologic signs of retroperitoneal-only rupture, and no peritoneal disease recurrences occurred in this subgroup. Conversely, the intraperitoneal extension suggested by CT scanning was confirmed macroscopically and/or pathologically in our 7 patients. Although it was not significant statistically, a trend toward more frequent right-sided tumors (86%) was observed in patients who had intraperitoneal rupture compared with patients who had retroperitoneal-only rupture (52%). This trend also was observed by Godzinski et al. 25 in the SIOP series (64% of right-sided tumors). In our series, part or all of the peritoneal nodules were located within the Morrison recess and were associated with a right-sided tumor. This may explain the more frequent right-sided location of tumors associated with intraperitoneal rupture and also may explain the peritoneal disease recurrence in 1 patient of our series (Patient 1 in Table 5) who had neither radiologic nor surgical signs of peritoneal dissemination but who presented with a right-sided tumor (418 ml) bulging against the liver. Isolated, small amounts of peritoneal fluid, usually located in the Douglas recess, frequently are observed at diagnosis in patients with Wilms tumor, and it is believed that this fluid corresponds either to nonspecific inflammatory reaction of the peritoneum because of rapid tumor growth or to inferior vena cava compression or thrombosis. Our data demonstrated that peritoneal effusions may be observed in both retroperitoneal and intraperitoneal ruptures. To our knowledge, the role of cytopathologic examination of peritoneal fluid at diagnosis has never been assessed prospectively in Wilms tumor, although it has high prognostic value in other abdominal tumors, such as malignant ovarian tumors. 26 The prognostic value of the site of preoperative tumor rupture in our series can be analyzed with regard to treatment and follow-up. The rate of peritoneal disease recurrence was high in the subgroup of patients with intraperitoneal rupture, despite the receipt of abdominal RT. Conversely, no abdominal disease recurrence was observed in the subgroup of patients with radiologic signs of retroperitoneal-only rupture, although none of those patients received WART, and only 50% received flank RT. Most of the patients of this subgroup actually received treatment according to their postoperative pathologic stage and histologic risk group without systematic upstaging (because only 3 patients were upstaged). The decision not to upstage in the majority of patients was a deliberate choice by our institution to avoid over treatment because of the higher sensitivity of imaging. There was no correlation in our series between histologic group and peritoneal disease recurrence. Two of our 4 patients with high-risk histology died from distant recurrence without local recurrence, and the 3 patients who had peritoneal disease recurrence had intermediate-risk tumors. The number of patients included in our study was relatively small, and the findings need to be validated in a larger subset of patients. However, our results suggest that patients with stage I or II Wilms tumor who have localized retroperitoneal-only rupture at diagnosis may be treated less aggressively than patients with stage III disease, notably without RT. In the SIOP series reported by Godzinski et al., 25 among 39 patients with nonmetastatic, unilateral Wilms tumor who presented with pretreatment rupture and were treated with preoperative chemotherapy and nephrectomy, the outcome of patients who received 3-drug chemotherapy and RT was not better than the outcome of patients who were treated less aggressively. Therefore, those authors also suggested that pretreatment tumor rupture itself most likely does not require postoperative RT. In the United Kingdom Wilms Tumor Protocol 2- United Kingdom Children s Cancer Study Group series, Grundy et al. 12 addressed the outcome of 31 children with stage III disease who had tumor rupture. Those results also suggested that flank RT is most likely sufficient for localized and retroperitoneal tumor ruptures, whereas patients with disseminated intra-abdominal tumors most likely should continue to receive WART despite its toxicity. In conclusion, according to our results and the literature, the following radiologic-surgical classification can be proposed to stratify patients with preoperative signs of tumor rupture: 1) An isolated, small amount of nonhemorrhagic peritoneal fluid should not be interpreted as a sign of tumor rupture. 2) The diagnosis of intraperitoneal rupture should be based on either surgical description or initial CT images with special attention to the Morrison recess in right-sided tumors. Some of these patients will require immediate surgery and/or embolization to control abdominal bleeding; however, clinically stable patients may be treated by neoadjuvant chemotherapy and secondary surgery. These patients should be classified as stage III regardless of other pathologic criteria and should be treated by chemotherapy and WART despite toxicity. 3) There is no evidence either in this series or in the literature that the risk of abdominal disease recurrence is increased in patients with localized retroperitoneal-only rupture on initial CT. This subgroup of patients, there-

12 Preoperative Wilms Tumor Rupture/Brisse et al. 213 fore, most likely could be treated according to the pathologic staging criteria only, without systematic upstaging. However, RT still should be considered in patients who have initial, diffuse retroperitoneal extension if the surgical margins cannot include the whole initial extent of the disease. REFERENCES 1. Grundy PE, Green DM, Coppes MJ, et al. Renal tumors. In: Pizzo PA, Poplack DG, eds. Principles and Practice of Pediatric Oncology. Philadelphia: Lippincott Williams and Wilkins, Inc.; 2002: Craft AW. Growth rate of Wilms tumour [letter]. Lancet. 1999;354: Zoubek A, Slavc I, Mann G, Trittenwein G, Gadner H. Natural course of a Wilms tumour. Lancet. 1999;354: Tanner C. Intraperitoneal rupture of a Wilm s tumor. BMJ. 1943;2: Burgers JM, Tournade MF, Bey P, et al. Abdominal recurrences in Wilms tumours: a report from the SIOP Wilms tumour trials and studies. Radiother Oncol. 1986;5: Godzinski J, Weirich A, Tournade MF, et al. Primary nephrectomy for emergency: a rare event in the International Society of Paediatric Oncology Nephroblastoma Trial and Study no. 9. Eur J Pediatr Surg. 2001;11: Shamberger RC, Guthrie KA, Ritchey ML, et al. Surgeryrelated factors and local recurrence of Wilms tumor in National Wilms Tumor Study 4. Ann Surg. 1999;229: SIOP. Nephroblastoma Clinical Trial and Study Protocol, Available at URL: Accessed April 18, Leape LL, Breslow NE, Bishop HC. The surgical treatment of Wilms tumor: results of the National Wilms Tumor Study. Ann Surg. 1978;187: Slasky BS, Bar-Ziv J, Freeman AI, Peylan-Ramu N. CT appearances of involvement of the peritoneum, mesentery and omentum in Wilms tumor. Pediatr Radiol. 1997;27: Rutigliano DN, Kayton ML, Steinherz P, Wolden S, La Quaglia MP. The use of preoperative chemotherapy in Wilms tumor with contained retroperitoneal rupture. J Pediatr Surg. 2007;42: Grundy RG, Hutton C, Middleton H, et al. Outcome of patients with stage III or inoperable WT treated on the second United Kingdom WT protocol (UKWT2); a United Kingdom Children s Cancer Study Group (UKCCSG) study. Pediatr Blood Cancer. 2004;42: Vujanic GM, Sandstedt B, Harms D, Kelsey A, Leuschner I, de Kraker J. Revised International Society of Paediatric Oncology (SIOP) Working Classification of Renal Tumors of Childhood. Med Pediatr Oncol. 2002;38: Cushing B, Slovis TL. Imaging of Wilms tumor: what is important? Urol Radiol. 1992;14: Green DM, Breslow NE, Beckwith JB, et al. Effect of duration of treatment on treatment outcome and cost of treatment for Wilms tumor: a report from the National Wilms Tumor Study Group. J Clin Oncol. 1998;16: Tournade MF, Com-Nougue C, de Kraker J, et al. Optimal duration of preoperative therapy in unilateral and nonmetastatic Wilms tumor in children older than 6 months: results of the Ninth International Society of Pediatric Oncology Wilms Tumor Trial and Study. J Clin Oncol. 2001; 19: Green DM, Cotton CA, Malogolowkin M, et al. Treatment of Wilms tumor relapsing after initial treatment with vincristine and actinomycin D: a report from the National Wilms Tumor Study Group. Pediatr Blood Cancer. 2007; 48: Grundy P, Breslow N, Green DM, Sharples K, Evans A, D Angio GJ. Prognostic factors for children with recurrent Wilms tumor: results from the second and third National Wilms Tumor Study. J Clin Oncol. 1989;7: Taylor RE. Morbidity from abdominal radiotherapy in the First United Kingdom Children s Cancer Study Group Wilms Tumour Study. United Kingdom Children s Cancer Study Group. Clin Oncol (R Coll Radiol). 1997;9: Ehrlich PF, Ritchey ML, Hamilton TE, et al. Quality assessment for Wilms tumor: a report from the National Wilms Tumor Study-5. J Pediatr Surg. 2005;40: ; discussion Rosenfeld M, Rodgers BM, Talbert JL. Wilms tumor with acute abdominal pain. Arch Surg. 1977;112: Davidoff AM, Soutter AD, Shochat SJ. Wilms tumor presenting with abdominal pain: a special subgroup of patients. Ann Surg Oncol. 1998;5: Ramsay NK, Dehner LP, Coccia PF, D Angio GJ, Nesbit ME. Acute hemorrhage into Wilms tumor: a cause of rapidly developing abdominal mass with hypertension, anemia, and fever. J Pediatr. 1977;91: Erdag N, Dicle O, Igci E, Koyuncuoglu M, Pirnar T. Subcapsular hemorrhage of adult Wilms tumor. Clin Imaging. 1999;23: Godzinski J, Heij H, Cecchetto G, et al. Does the pre-treatment tumour rupture influences the outcome in patients with nephroblastoma submitted to preoperative chemotherapy? SIOP 2005 [abstract]. Abstracts of the 37th Annual Conference on the International Society of Paediatric Oncology, Vancouver, Canada, September 21 24, Pediatr Blood Cancer. 2005; 45: Billmire D, Vinocur C, Rescorla F, et al. Outcome and staging evaluation in malignant germ cell tumors of the ovary in children and adolescents: an intergroup study. J Pediatr Surg. 2004;39: ; discussion