Renal Cell Carcinoma in Children: A Clinicopathologic Study By Paolo Indolfi, Monica Terenziani, Fiorina Casale, Modesto Carli, Gianni Bisogno, Amalia Schiavetti, Antonia Mancini, Roberto Rondelli, Andrea Pession, Alessandro Jenkner, Paolo Pierani, Paolo Tamaro, Bruno De Bernardi, Andrea Ferrari, Nicola Santoro, Maria Giuliano, Giovanni Cecchetto, Luigi Piva, Gianmarco Surico, and M. Teresa Di Tullio Purpose: To identify the prognostic factors, treatment, and outcome of children affected by renal cell carcinoma (RCC). Patients and Methods: The series included 41 patients (18 males and 23 females) with a median age of 124 months observed at the 11 Italian Association for Pediatric Hematology and Oncology centers from January 1973 to January 2001. Clinical data, surgical notes, pathologic findings, and summaries of therapy were taken from the charts. Results: Seven (17%) of the 41 patients had a papillary histology, and 34 (82.4%) had nonpapillary histology. Eighteen patients (43.9%) had stage I, one patient (2.4%) had stage II, two patients (4.8%) had stage IIIA, 10 patients (24.3%) had stage IIIB, and nine patients (21.9%) had stage IV disease. One patient had a bilateral involvement at diagnosis. Seven patients experienced disease recurrence. Lung and liver were the most common distant lesions and

usually were fatal. In this study, the major factor influencing the prognosis was the stage. Event-free survival at 20 years was 53.5% for all patients. Overall survival at 20 years was 54.9% for all patients. Conclusion: RCC is a rare disease in children and adolescents. This neoplasm has a different clinical presentation in children compared with adults but the same outcome. In our experience, patients with localized disease could be cured by nephrectomy alone. Prospective studies in a larger number of patients are needed to confirm radiation therapy and biologic response modifiers as effective adjunct therapy in RCC stage III. The alternative therapy seems warranted in patients with advanced disease. J Clin Oncol 21:530-535. © 2003 by American Society of Clinical Oncology.

ENAL CELL carcinoma (RCC) is a malignancy thought to arise from epithelial cells of the renal tubule. Although RCC accounts for 2% to 3% of all adult malignancies, it occurs rarely in children.1 The incidence of this tumor in childhood is estimated to be from 0.1% to 0.3% of all neoplasms2,3 and from 1.8% to 6.3% of all malignant renal tumors.2-5 The Third National Cancer Survey reported an incidence of only four cases of RCC per year compared with 117 per year of Wilms’ tumor.5 Since 1986, approximately 160 well-documented cases have been published in the literature.2-5 A previous study in 84 children reported an actuarial survival rate of 60% at 2 years and 56% at 5 years.6 Patients with tumor localized in the kidney have a good prognosis compared with patients with regional lymph node involvement or distant metastases.4,6-12 So far, no adequate therapy has been defined for children with RCC. Surgery is the mainstay of the treatment and results in cure when the tumor is localized and completely resected. The roles

of radiotherapy and immunotherapy are not clear, and different chemotherapy regimens showed only minimal activity when tested in clinical trials. To gain more knowledge about this rare tumor, we analyzed the characteristics and the treatment results of children with RCC observed in the oncology center associated with the Italian Association for Pediatric Hematology and Oncology.

R

From the Pediatric Oncology Service-Pediatric Department II, University of Napoli, Napoli; Divisione di Urologia, Dipartimento di Terapia Chirurgica, Istituto Nazionale Tumori of Milano, Milano; Pediatric Department, University of Padova, Padova; Pediatric Oncology, University of Roma, and Division of Pediatric Oncology, Bambin Gesu` Hospital, Roma; Pediatric Oncology, University of Bologna, Bologna; Pediatric Oncology University of Ancona, Ancona; Division of Pediatric Oncology Burlo Garofaeo Hospital of Trieste, Trieste; Giannina Gaslini Children’s Hospital of Genova, Genova; and Department of “Biomedicina dell’eta` evolutiva” University of Bari, Bari, Italy. Submitted February 14, 2002; accepted October 7, 2002. Address reprint requests to Paolo Indolfi, MD, Pediatric Oncology Service-Pediatric Department II University of Napoli, Via S Andrea delle Dame, 4 80138 Napoli Italy; email: [email protected]. © 2003 by American Society of Clinical Oncology. 0732-183X/03/2103-530/$20.00

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PATIENTS AND METHODS A retrospective review of pathologic and hospital records at the 18 Italian Association for Pediatric Hematology and Oncology centers identified 41 patients with RCC presenting from January 1973 to January 2001 at 11 of these centers. These tumors were observed among 1,096 malignant renal tumors, corresponding to 3.7% of all malignant renal tumors in children under the age of 18 years. Clinical data, surgical notes, pathologic findings, and summaries of treatment details were taken from the charts.

Pathology Methods Tumors were classified as either conventional (nonpapillary) or papillary according to the classification of Murphy et al.13 Conventional tumors were further subclassified as clear-cell, granular, chromophobe, and renal cell. The cytologic grading was assigned according to the criteria proposed by Fuhrman et al.14 This system uses nuclear grades that are based on size, irregularity of the membrane, and nucleolar prominence.

Staging and Clinical Data Pathologic staging was performed according to the modified Robson staging classification system15,16: stage I, localized disease confined by the renal capsule; stage II, localized disease invading renal capsule but confined by Gerota’s fascia; stage IIIA, involvement of renal vein or inferior vena cava; stage IIIB, regional lymph node involvement; and stage IV, metastatic disease. The extent of surgical resection was estimated after detailed review of surgical and histopathologic notes as (1) biopsy only; (2) partial nephrectomy, when macroscopic tumor remained; (3) simple nephrectomy, when the kidney with the adrenal gland, surrounding perinephric fat, and Gerota’s fascia, were removed; (4) radical nephrectomy, when the regional lymph nodes were also removed; and (5) metastasectomy.

Journal of Clinical Oncology, Vol 21, No 3 (February 1), 2003: pp 530-535 DOI: 10.1200/JCO.2003.02.072

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ANALYSIS OF CHILDREN WITH RCC

Statistical Methods Standard statistical descriptions of parameters were used to characterize the data (mean, median, and range). Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) probability were calculated by the Kaplan-Meier method; comparisons between probabilities in different patient groups were performed using the log-rank test.15 In OS analysis, all deaths were considered treatment failures. In EFS analysis, induction failure, relapse, second malignant neoplasm, and death in remission as a result of any cause were considered treatment failures. In DFS analysis, relapse, second malignant neoplasm, and death in remission as a result of any cause were considered treatment failures. OS was calculated for all patients from diagnosis to date of death or date of last follow-up, if alive. EFS was calculated for all patients from diagnosis to date of induction failure, relapse, second malignant neoplasm occurrence, death, or date of last follow-up, if alive in complete remission. DFS was calculated for all patients that obtained complete remission from the date of remission to relapse, second malignant neoplasm occurrence, death, or date of last follow-up, if alive in complete remission. Results were expressed as probability (percent) and 95% confidence intervals (95% CIs).

Table 1.

In the univariate analysis of EFS, the following variables were evaluated: sex, age at diagnosis, stage, histology, and side of tumor involvement (right v left). Because none of the variables, except for stage, analyzed in the univariate fashion showed a P ⬍ .1, a multivariate analysis was not applicable. All P values are two-sided, and values less than .05 were considered statistically significant. The SAS package (SAS Institute, Cary, NC) was used for data analysis. The data were analyzed as of September 2001.

RESULTS

Patient Characteristics Forty-one children (18 males and 23 females) were included in this study. The age of patients ranged from 18 to 215 months (median, 124 months). Clinical and pathologic data of the 41 patients are listed in Table 1. At presentation, a palpable mass was found in nine patients (21.9%), gross hematuria was found in 12 patients (29.2%), and abdominal pain was found in 17 patients (42.5%). Six patients

Clinicopathologic Features, Evolution, and Outcome

Patient No.

Age (months)

Sex

Stage

Site of Metastasis

Histology

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

122 65 160 184 189 141 172 166 111 66 120 110 151 85 156 225 109 194 102 124 171 187 94 142 94 66 168 94 18 126 39 172 131 171 107 95 124 116 153 27 98

M M M M F M F M M M F M M F F F M F F F M F F F F M M F M F F M F M F F F F F F M

I I IV I I IV I I I I I I IV IIIB IIIB IIIB IIIB IV L, UK, R, II I IV IV I IV IIIB I IIIA I IIIB I II IIIB IIIB I I IIIB I IIIA IV IIIB IV

— — Lung, MI — — Lung, bone, S1 — — — — — — Lung, bone Lymph node Lymph node Lymph node IVC, lymph node Lung, liver, bone — — Diaphragm CNS — MI, liver, lung, bone Lymph node — Renal vein — Lymph node — — Lymph node Lymph node — — Lymph node — Renal vein Lung Lymph node Liver

Clear-cell Granular-cell Papillary Granular-cell Renal-cell Clear-cell Clear-cell Granular-cell Clear-cell Clear-cell Clear-cell Papillary Clear-cell Papillary Papillary Renal-cell Clear-cell Clear-cell Renal-cell Clear-cell Clear-cell Clear-cell Clear-cell Renal-cell Clear-cell Clear-cell Clear-cell Clear-cell Clear-cell Chromophobe-cell Granular-cell Clear-cell Renal-cell Clear-cell Papillary Papillary Clear-cell Clear-cell Papillary Clear-cell Clear-cell

Site(s) of Recurrence

Time to Recurrence (months)

Outcome

Follow-Up (months)

None None None None None None None None None None None Peritoneum None None None None Lymph node mediastinum None None None Lung None None None None None Liver, lung None Liver None None None Secondary LANL None None None None Lung None Liver, lung None

NA NA NA NA NA NA NA NA NA NA NA 98 NA NA NA NA 17 NA NA NA 8 NA NA NA NA NA 10 NA 2 NA NA NA 27 NA NA NA NA 14 NA 32 NA

NED NED DOD NED NED DOD NED NED NED NED Lost DOD DOD NED AWD NED Lost DOD NED DOD DOD DOD NED DOD NED NED DOD NED DOD NED NED NED DOD NED NED NED NED NED DOD DOD DOD

266 278 5 183 78 10 171 16 58 65 39 108 3 7 11 155 26 4 19 274 33 16 280 5 252 85 11 167 3 49 15 140 39 58 20 18 261 89 12 115 1

Abbreviations: M, male; F, female; NA, not applicable; L, left; R, right; UK, unknown; MI, mediastinal lymph node; SI, sovraclavear lymph node; IVC, inferior vena cava; NED, no evidence of disease; DOD, dead of disease; AWD, alive with disease; LANL, acute nonlymphoblastic leukemia.

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(14.6%) presented with paraneoplastic phenomena (fever, n ⫽ 2; significant weight loss, n ⫽ 2; malaise, n ⫽ 1; and hepatic dysfunction, n ⫽ 1). Two patients had nonspecific symptoms; one had respiratory distress, and the other had neurologic signs related to metastases. In one patient, the primary tumor was not palpable and the diagnosis was fortuitous by ultrasound examination performed for enuresis, whereas in another patient, no symptoms could be found. The classic triad of a palpable mass, flank pain, and hematuria was not found in any of the patients. The left side was affected in 60% of patients. One child had bilateral involvement. Tumor size, examined in 26 patients, was more than 5 cm in 20 patients (76.9%) and more than 10 cm in six patients (23.1%). Three patients had a pre-existing condition (tetralogy of Fallot, n ⫽ 1; horseshoe kidney, n ⫽ 1; and thyroiditis, n ⫽ 1). Pathology Seven patients (17%) had a papillary RCC. Thirty-four patients had nonpapillary histotype; 24 (58.5%) of the 34 had clear-cell, four (9.7%) had granular-cell, five (14.7%) had renal-cell, and one (2.4%) had chromophobe-cell type (this was diagnosed in the patient with Fallot tetralogy). Most females (five of seven) were found to have papillary histology. The grading was assigned to 19 patients (46.3%); three patients were classified as grade 1; four patients were grade 2; 10 patients were grade 3; and two patients were grade 4. Staging According to the modified Robson classification system, 18 patients (43.9%) were classified as stage I, one (2.4%) was stage II, two (4.8%) were stage IIIA, 10 (24.3%) were stage IIIB, and nine patients (21.9%) were stage IV. The patient with a bilateral tumor was classified as stage II on the right side, whereas the left side was not assessable. In the nine stage IV patients, metastatic sites included lung in six patients, mediastinal lymph node and bone in five patients, and liver, diaphragm, or CNS involvement in one patient each. Treatment Surgery. Nephrectomy was performed at diagnosis in 35 patients (63.4%), simple nephrectomy was performed on 20 patients, and radical nephrectomy was performed on 15 patients. In five stage IV patients, a diagnostic biopsy of the primary tumor (n ⫽ 2) or metastatic lesions (n ⫽ 3) was performed. The patient with bilateral RCC underwent partial nephrectomy on the left side, followed by simple nephrectomy on the contralateral side. In two patients, patients 17 (stage IIIB) and 21 (stage IV), radical nephrectomy was associated with endocaval thrombectomy and partial resection of the diaphragm, respectively. Surgery was the only treatment in 11 patients with localized tumor. Chemotherapy. Twenty-four patients (58.5%) received chemotherapy according to diverse institutional choices. Most of the drugs (vincristine, dactinomycin, epirubicin, ifosfamide, etoposide, doxorubicin, and carboplatin) were also included in the protocols for childhood Wilms’ tumor. In 13 patients, the combination of vincristine and dactinomycin was used; in all patients, with the exception of one (patient 7), preoperative chemotherapy was administered according to the recommenda-

tions of the International Society of Pediatric Oncology Wilms’ tumor protocols. In two of these patients, epirubicin was also given. Unusual therapeutic agents, such as gemcitabine and vinorelbine (patient 24), were also used. At follow-up, five of five stage I to II patients who did receive and nine of 11 who did not receive preoperative chemotherapy were well and disease-free. Six stage III to IV patients underwent both preoperative and various schedules of postoperative chemotherapy. Five of them relapsed; four died, and one was lost to follow-up during active disease. Twelve subjects received only postoperative chemotherapy. At last follow-up, three stage I patients and one stage IIIB patient were alive without evidence of disease, whereas the remaining patients relapsed. Immunotherapy. Eleven patients (26.8%) received interferon alfa (IFN␣), with associated interleukin-2 (IL-2) in four of the patients. Two other patients received only IL-2. After a median of 89 months of follow-up, five of the seven treated stage III patients were alive and relapse-free. In contrast, out of the five stage III patients who were not treated, four relapsed; three patients died of disease, and one was lost to follow-up. One stage I patient who received postsurgery IFN␣ was alive and well. Radiotherapy. Seven patients (17.1%) underwent radiation therapy as part of their initial treatment; four had stage IV and three had stage IIIB disease. In these patients, radiation was delivered to the tumor bed in doses ranging from 30 to 40 Gy. Local control of disease was maintained in the stage IIIB patients, with only one patient relapsing outside the irradiated field and two alive without evidence of disease 7 months and 20.5 years, respectively, after diagnosis. All patients with stage IV disease died of disease progression. Outcome Evolution and outcome of the 41 RCC patients are listed in Table 1. Overall, 23 patients (56%) were disease-free, with a follow-up ranging from 7 to 280 months (median follow-up, 85 months). One patient was alive with disease at 11 months after diagnosis (patient 15), and 15 patients (36.5%) died; 13 died from their disease, one from secondary acute nonlymphoblastic leukemia, and one from drug abuse. Two patients were lost to follow-up. Estimated 20-year EFS and OS rates for all patients were 53.5% (95% CI, 36% to 71%) and 54.9% (95% CI, 36% to 73%), respectively (Fig 1). Estimated 20-year DFS for all patients was 68.6% (SD, ⫾ 18.1%). Figures 2 and 3 show EFS and OS by stages; the estimated 20-year EFS and OS rates for patients with stage I to II disease were 88.9% (95% CI, 63% to 100%) and 88.9% (95% CI, 63% to 100%), respectively. Patients with stage III to IV disease had significantly worse survival; the estimated 20-year EFS and OS rates were 18% (95% CI, 0% to 36%; P ⫽ .0001) and 22.6% (95% CI, 2% to 43%; P ⫽ .0001), respectively. Fifteen out of 18 stage I patients were alive without evidence of disease from 15 to 280 months from diagnosis (median, 96.5 months). The only stage II patient was alive and well 12 months after nephrectomy plus preoperative chemotherapy. Of the two patients with stage IIIA disease, one was well and disease-free 66 months after the resection of an isolated pulmonary relapse, whereas the other died after hepatic and lung metastases. Five of 10 stage IIIB patients were alive without evidence of disease

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533

ANALYSIS OF CHILDREN WITH RCC

Fig 1. Overall survival (SUR) and event-free survival (EFS). CI, confidence interval.

after 3 months to 20.5 years of follow-up (median, 136 months). All nine patients with stage IV disease died from progressive disease 3 to 36 months from diagnosis (median, 7 months). The patient with the bilateral tumor was alive and well 15 months after surgery, without any further treatment. Seven (17%) of 41 patients developed disease recurrence from 2 to 98 months after diagnosis (median, 15 months). At last follow-up, one patient (patient 38) was disease-free 4 years after recurrence; another patient who relapsed to mediastinum was lost to follow-up with active phase of disease. Five patients died of the disease. Sex, left-side versus right-side involvement, tumor size (⬍ 5 v ⬎ 5 cm), length of follow-up period (1972 to 1980 v 1981 to 1990 v 1991 to 2001), and papillary growth pattern versus other histology did not significantly influence EFS by univariate analysis. However, patients with stage III or IV disease had significantly poorer EFS and OS compared with patients with

stage I to II disease (P ⫽ .0001). We were unable to show an association between survival and this grading system. DISCUSSION

RCC is a rare disease in children and adolescents.1 This study of 41 children provided the opportunity to further define the pathology and natural history of this neoplasm. Speculation exists about whether RCC in children represents a different entity from its adult counterpart.16 However, the overall prognosis of children seems similar to that of adult patients6-8,12,17-19 and worsens as tumor stage increases. In adults, RCC exhibits a 2:1 male predominance,1 as it does in some pediatric series.7,20,21 Our study6-8 does not support a sex predominance, in contrast to other studies. The disagreement is probably because of the small numbers of patients included in several reports.

Fig 2.

Event-free survival according to stage.

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INDOLFI ET AL

Fig 3.

Overall survival according to stage.

The average age of children investigated in this study was approximately 10 years (mean, 122 months; range, 18 to 215 months; median 124, months). This is in concordance with the findings of Dehner et al22 who reported an average age of 9 years. Conversely, Wilms’ tumor is diagnosed mainly in children younger than the age of 5 years. Rarely, RCC has been reported in children younger than 1 year of age.23 Paraneoplastic phenomena in adults are common and well reported24 but are infrequently documented in children.6,25 Compared with our experience, Carcao et al16 reported a higher frequency of paraneoplastic phenomena (31%) but in a smaller group of patients. RCC in adults is often associated with tuberous sclerosis complex26 or the von Hippel-Lindau disease.27-29 RCC with nonpapillary histology is associated with translocations or terminal deletions of the short arm of chromosome 3 beginning at 3p13.30 This chromosome 3p cytogenetic abnormality is uncommon in children with RCC, and in our study, von Hippel-Lindau syndrome was not reported in any child. Several studies analyzing prognostic factors in RCC have been published. In this study and most published series,6,16,19 the tumor stage seems to be the most important factor correlated with outcome. The patients with a localized stage (stage I and II) have the best prognosis.7,8,19 In agreement with the literature, in our study, 17 of 19 stage I to II patients are well and disease-free at last follow-up (EFS, 88.9%). In these patients, at diagnosis, nephrectomy seems to be the sufficient treatment, without preoperative and/or postoperative chemotherapy. In contrast, in our population, the patients with lymph node involvement had poorer survival (20-year EFS rate, 50%). This result is worse than that reported by Carcao et al,16 in which six patients (100%) are alive and well after a median follow-up of 38.5 months (range, 13 to 192 months). Five of six patients underwent radical nephrectomy, with locoregional radiotherapy in two patients. In the other study, the survival rate at 5 years was 75% for seven patients with stage IIC disease (lymph node involvement).6 In this article, an attempt was made to correlate the type of surgical procedure (ie, simple v radical nephrectomy) with survival rates, but no correlation was noted. In our experience, a postoperative different chemotherapy regimen showed only minimal activity in stage III patients. To our knowledge, the role of radiotherapy has

not been defined on a statistically significant level. In our study, radiotherapy controlled the disease in three stage IIIB patients, whereas two patients with the same stage, without radiotherapy, presented liver relapse. Castellanos et al6 reported five of six patients with lymph node involvement alive and with no evidence of disease after radiotherapy at 5 years from diagnosis. A larger number of patients are needed to confirm the role of radiotherapy in the treatment of RCC. Numerous trials in adults have demonstrated complete or partial responses to IFN␣31 or high-dose IL-2.32 Given the small number of patients treated with these drugs, little can be said about the value, if any, of adjuvant therapy in advanced RCC. It is our opinion that preliminary experience would suggest adjuvant therapy might be useful. Conversely, there was no benefit noted with standard immunotherapy in patients with diffuse disease. Metastatic disease at presentation is more often described in adults.33 However, recently, several reports in children have described the same incidence.7,8,19 This last consideration is confirmed by our data (21.9% of children presented with metastatic disease). Lung and bone are the most common distant lesions and are usually fatal.6,16,19 The dismal results in the nine patients with diffuse metastatic disease in our study (OS rate, 0%) are in agreement with those in other pediatric and adult series.6-8,12,18,19 For these latter patients, there has been no effective therapy, despite the use of surgery, radiation therapy, and chemotherapy. In adults with advanced RCC, response rates of 3% to 30% have been seen using recombinant IL-2 or IFN␣, and some of these responses have been durable.34-36 Few reports in children have shown that RCC stage IV may prove amenable to therapy with an intravenous continuous infusion of recombinant IL-237 or standard chemotherapy associated to floxuridine infusion by circadian schedule.38,39 Prospective studies in a larger number of patients are needed to confirm these findings. Additional promising approaches include the use of nonmyeloablative allogenic peripheral-blood stem-cell transplantation, as described in adults.40,41 Another factor that might influence the prognosis is the histologic growth pattern. Pathologically, in our experience, the majority of the patients (70.7%) have a nonpapillary histology. Only one patient with chromophobe-cell type had an underlying disease (tetralogy of Fallot), as in the study of Carcao et al16 (tuberous sclerosis). In our experience, tumors with papillary growth pattern were associated with advanced stage; six of seven patients presented with stage IIIB or IV disease, and of them, two were alive and well without disease recurrence. One stage I patient (patient 12) with papillary histology developed relapse to peritoneum and died of disease. Unfortunately, the small number of patients in our study is not enough to draw any conclusions about the role of histopathology on outcome. Seven patients in our study relapsed, and the lung and liver are the sites that should receive careful monitoring. Most recurrences and deaths occur within the first 2 years after diagnosis, but late recurrences are not infrequent.42 Our data seem to confirm these findings. These events occurred in our patients after a median of 15 months from the time of diagnosis. However, a recurrence of the disease occurring 98 months after diagnosis (patient 12) suggests that long-term monitoring of lung and bone may be prudent.

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ANALYSIS OF CHILDREN WITH RCC

In conclusion, we have observed the following from our study: (1) RCC in childhood represents a group of tumors of different clinical presentation than in adults but with the same outcome; (2) patients with localized disease could be treated with surgery alone; (3) lymph node involvement seems to worsen the prognosis; (3) biologic response modifiers could be an effective

adjunct therapy with which to manage stage III patients (however, a larger number of patients are needed to confirm this); and (4) alternative therapy seems warranted in patients with advanced disease. Because of the very low incidence of RCC in children, an international clinical trial will be required to answer the question of appropriate therapy for children with advanced RCC.

APPENDIX

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