Pediatr Blood Cancer 2008;51:475–478
Local Lymph Node Involvement in Pediatric Renal Cell Carcinoma:
A Report From the Italian TREP Project
Paolo Indolfi, MD,1* Gianni Bisogno, MD,2Giovanni Cecchetto, MD,2Filippo Spreafico, MD,3
Gian Luca De Salvo, MD,4Paola Collini, MD,5Alessandro Jenkner, MD,6Alessandro Inserra, MD,7
Amalia Schiavetti, MD,8Martina di Martino, MD,1and Fiorina Casale, MD1
Renal cell carcinoma (RCC) in childhood is rare. As in adults,
children with RCC tend to have a worse prognosis with increasing
stage, with 88.9% OS when the tumor is limited to the kidney and
completely resected  and 5–10% OS whendistant metastasis are
present . A direct comparison between adult and pediatric data,
however, is difficult to perform because different stage classifica-
tions are applied. One of the most important adverse prognostic
factors for adult RCC is the regional lymph node involvement with
5-year survival estimates of approximately 20% [3,4]. For this
reason the role of lymph node dissection has been investigated
extensively in adults [5,6]. Recently, the experience at Saint Jude
have suggested that children with lymph node positive RCC had a
nearly triple those of adult historical controls .
To gain more knowledge about this problem, we reviewed the
experience of patients affected by RCC with local lymph node
PATIENTS AND METHODS
In 2002 the AIEOP Committee for rare tumors launched a
project dedicated to children with very rare tumor (the TREP
project) including patients with RCC. Children and adolescents up
to 18 years were identified retrospectively from 1973 to 2002 and
afterwards registered prospectively in the TREP database. Since
children with RCC and nephrectomy with retroperitoneal lymph
node dissection (RLND) is recommended at diagnosis for children
with pathologically lymph nodes positive RCC. Data were also
checked against the registry of all newly diagnosed primitive renal
tumors coordinated by the Wilms Tumor Italian Study. From
January 1973 to April 2007 61 patients with RCC were observed in
recorded from the pathologyreports, were reviewed forthe purpose
of this analysis. Pathologic material from all patients was reviewed
by one of the authors (P.C.). Informed consent for data registration
was obtained from the patients’ guardians at the time of patient
registration in the TREP project.
Tumors were classified according to the 2004 WHO classifica-
Staging and Clinical Data
Pathological staging was performed according to the modified
Robson staging classification system . For the purpose of
the present analysis only patients classifying as having stage 3B
were considered. According to the classification, stage 3B disease
(TxN1–2M0) represents localized disease with invasion of local
Background. One of the most important adverse prognostic
factors for adult renal cell carcinoma (RCC) is the retroperitoneal
lymph node involvement. The aim of this article is to study the
prognostic significance of local lymph node involvement in pediatric
RCC and the role of retroperitoneal lymph node dissection (RLND) at
diagnosis. Procedure. The series included 16 patients with RCC and
lymph nodes involvement registered in the Italian Rare Tumors
Pediatric Age (TREP) project, accounting for 26.2% of 61 pediatric
RCCobservedat AIEOPcenters.Results. A radicalnephrectomywas
performed in all cases: at diagnosis in 12 cases, after preoperative
chemotherapy (CT) in 4 cases. As a part of the same procedure
9 patients underwent RLND, and 7 received a more limited
lymph nodes resection. Five (31.2%) developed disease recurrence
2–34 months after diagnosis (median, 6 months) plus 1 developed
progression; 6 patients died, 1 of them from secondary leukemia.
Among the nine patients receiving RLND, eight are alive and disease
free. This compares with only one patient surviving among the seven
receiving a more limited lymph nodes resection. The estimated
25-year PFS and OS rates for all patients were 61.4% (95% CI
33.2–80.5) and 50.8%(95%
Conclusions. Lymph node involvement is an unfavorable prognostic
factor in children with RCC. RLND appears to be a critical factor to
improve the outcome. However, when compared to similar adult
patients, the outcome in children appears to be better, suggesting
that pediatric RCC, or the host, may be critical differences. Pediatr
Blood Cancer 2008;51:475–478.
? 2008 Wiley-Liss, Inc.
lymph node involvement; rare childhood cancer; renal cell carcinoma
? 2008 Wiley-Liss, Inc.
1Pediatric Oncology Service, Pediatric Department, Second University
of Napoli, Napoli, Italy;2Pediatric Department, University of Padova,
Padova, Italy;3Pediatric Oncology Unit, Istituto Nazionale Tumori of
Milano, Milano, Italy;4Clinical Trials and Biostatistics Unit, Istituto
Oncologico Veneto IRCSS of Padova, Padova, Italy;5Pathology Unit,
Istituto Tumori of Milano, Milano, Italy;6Pediatric Oncology Division
Bambin Gesu `, Hospital of Roma, Rome, Italy;7Pediatric Surgery Unit,
Bambin Gesu ` Hospital of Roma, Rome, Italy;8Pediatric Department
University La Sapienza of Roma, Rome, Italy
Grant sponsor: Citta ` della Speranza Foundation of Padua, Italy.
*Correspondence to: Paolo Indolfi, Pediatric Oncology Service
Pediatric Department, Second University of Napoli, via S.Andrea
delle Dame, 4 80138 Napoli, Italy. E-mail: firstname.lastname@example.org
Received 8 January 2008; Accepted 7 May 2008
lymph nodes. The extent of surgical lymph node resection
was estimated after detailed review of surgical and histopathologic
notes, as elsewhere published , and for the purpose of the
analysis this surgical procedure was divided in three categories as
(1) Retroperitoneal lymph node dissection (RLND) included for
the left-sided tumors ipsilateral hilar, periaortic, and common
iliac lymph node dissection; for the right RCC hilar,
intercavoaortic, retro-paracaval, and ipsilateral common iliac
lymph node dissection.
(2) Para-aortic lymph node dissection: removal of para-aortic
(3) Renal hilum lymphadenectomy: removal of the lymph nodes
at the hilum of renal vessels.
Fisher exact test was used for analyzing association between
RLND and progression or death. Overall survival (OS) and
progression free survival (PFS) were estimated using the Kaplan–
Meier method . Survival was calculated for all patients from
the date of surgery to the date of death or last follow-up, if alive.
PFS was calculated from the date of surgery to the date of disease
recurrence, death or date of last follow-up, if alive in complete
remission. Twenty-five-year OS and PFS were estimated with their
95% confidence interval (95% CI). All P values are two-sided and
values less than 0.05 were considered statistically significant. The
SAS package (v 9.1.3; SAS Institute, Cary, NC) was used for data
analysis. The data were analyzed as of June 2007.
Sixteen patients (nine females) with lymph nodes involvement
were included in this study. The age of patients ranged from 18 to
215 months(median 120 months), at diagnosis, was consistent with
other series of pediatric RCC [1,7]. Clinical characteristics and
outcome are presented in Table I.
patient. The classic clinical triad of a palpable mass, flank pain, and
had urolithiasis as an underlying disease. RCC were classified as
clear cell subtype in 12 cases, papillary in 3 and collecting duct in
1 case. All papillary RCC patients were females. According to the
N2; T1: n¼5; T2: n¼3; T3: n¼6; Tx: n¼2.
Nephrectomy was performed at diagnosis in 12 cases and after
preoperativechemotherapy in4.At thesame timeasprimary tumor
resection, 9 patients underwent RLND, 4 had the para-aortic lymph
node removal, and 3 had the renal hilum lymph nodes removal.
A second surgery to perform RLND was never carried out in the
group of patients with limited lymph node resection. Six patients
(37.5%) received chemotherapy according to different institutional
choices. Four patients received pre-operative chemotherapy
(vincristine and actinomycin D) according to the SIOP nephro-
blastoma protocols because of the clinical diagnosis of Wilms
Pediatr Blood Cancer DOI 10.1002/pbc
TABLE I. Clinicopathologic Features, and Outcome
(months) Sex SideExtent of surgery Histology
14. B.A.80F LeftClear cellLocalþ
15. I.I. 137MRight Duct
3 IL-2 DOD5
16. B.R. 30MLeft NaIL-2 NED9
CT, chemotherapy; pre, preoperatory; post, postoperatory; IFN, interferon; IL-2, interleukin 2; RT, radiotherapy; NED, no evidence of disease;
DOD, dead of disease
476 Indolfi et al.
tumor. In three patients the responsible physician decided to give
postoperative chemotherapy (vinblastine and epirubicin in two
site as part of their initial treatment with doses ranging from 30 to
After a median follow-up of 68 months (range 9–311 months),
9 patients are alive and disease free, 6 patients died, and 1 patient
was lost to follow-up with evidence of disease. The estimated
compare with 88.9% 25-year EFS obtained in 30 patients with
localized disease without lymph nodes involvement (stages 1–2)
registered in the TREP project over the same period of time.
Five patients (31.2%) developed metastatic disease, one of them
or the renal hilum lymph nodes removal were performed at
diagnosis. Among the nine patients with RLND, eight are alive and
disease free, one died of progressive disease. Only one is alive and
disease free among the four children who received para-aortic
lymph node dissection: two died after local and/or metastatic
relapse and onewith a distant metastases was lost tofollow-up. The
three patients who had dissection of the renal hilum lymph nodes
died, two after metastatic relapse, and one from secondary acute
non-lymphoblastic leukemia (ANLL). Three of seven N1 patients
and five of nine N2 patients were alivewithout evidence of disease,
at last follow-up.
When compared with those who received limited lymph node
(5/7 vs. 1/9, difference between proportions 60.3%, 95% CI 12.2–
82.6; P¼0.03), and significantly better survival (DOD 5/7 vs. 1/9,
difference between proportions 60.3%, 95% CI 12.2–82.6;
P¼0.03). Concerning postoperative treatment, all 16 patients
received some kind of adjuvant therapy. Six patients received
interleukin 2 (IL-2), with the addition of interferon (IFN) in 1 case.
Six other patients received IFN, along with chemotherapy (CT) in
two cases and radiotherapy (RT) in one of the patients. At last
them who underwent RLND as the initial treatment. Four patients
died, all of them who underwent non-RLND as primary surgery.
in one case. At last follow-up, two patients died and one was lost
to follow-up but with active disease. Only one patient received
RLND and RTas the initial treatment and was alive and well at last
As a consequence of the rarity of RCC in children, only limited
series of pediatric RCC have been published and treatment options
are largely deduced from reports of adults. In most adult series,
tumor stage seems to be the most important prognostic indicator
[1,2,10–12]. Patients with localized disease (stages 1 and 2) have
the best outcome with survival of approximately 80%. When
regional lymph nodes are involved by the tumor the survival drops
dramatically to 20% [3,4]. This is likely to explain why RLND is
is attempted in such patients. Previous reports have observed that
children with regional lymph node positive RCC may have a better
prognosis than their adult counterparts [7,12,13]. In a recent review
of published studies, Geller and Dome analyzed 243 pediatric RCC
cases; the overall and disease free survival rates of 58 patients with
stage 3B were 77.6% and 72.4%, respectively. The authors state
that few children with RCC in the review underwent RLND.
The conclusion is that second-look lymph node dissection was
unnecessary for children who did not receive it as part of their
the German childhood cancer registry and the Kiel pediatric tumor
patients with 5-year EFS and OS rates of 68.8% and 75%,
respectively. The authors support the hypothesis that a complete
resection of all tumor lesions, including lymph nodes seemed to be
the crucial mainstay of successful treatment in these patients .
Other studies suggest that lymph node dissection has a positive
effect on the survival of children with RCC [12,14].
In our experience, four patients had surgery after preoperative
However, three of them did not undergo lymph node dissection. Of
these, two patients died of disease and one with active diseasewere
Pediatr Blood Cancer DOI 10.1002/pbc
Kaplan–Meier method (CI: confidence interval). B: Overall survival
(OS) of patients calculated by Kaplan–Meier method (CI: confidence
A: Progression free survival (PFS) of patients calculated by
Pediatric Renal Cell Carcinoma477
lost to follow-up. The patients classified as having stage 3B RCC Download full-text
hada poorer survival (20-year EFSrate, 50%)in our previousstudy
confirm that the stage 3BRCC patients had a relatively unfavorable
long-term prognosis with an estimated 25-year PFS and OS rates
of 61.4% and 50.8%, respectively. Renshaw  speculates that
children with NþRCC had favorable outcome because of the
biology of their tumors, namely many of the pediatric RCC were
translocation-associated carcinomas rather than clear cell. For this
reason, we are planning to review all samples of our patients to
address this important point. Probably the proportion of trans-
absence of additional TFE3 immunostaining in all RCC tumor
specimens as in the study by Bruder et al. . Other biologic
features are implicated in clinical differences between adult and
pediatric RCC. Only a very small subgroup of adult RCC patients
adult RCC shows VHL gene abnormalities in contrast to childhood
Several trials in adults have demonstrated a moderate response
to immunotherapy (IFNa or IL-2) in patients with advanced stage
RCC [20,21]. Given the small number of patients included in our
study, little can be said about the value, if any, of adjuvant therapy.
Probably, in our cohort of children the quality of surgery, namely
complete nephrectomy with RLND, seems to be the main stay of
the treatment, but a larger number of patients is needed to support
report, we cannot confirm the Geller and Dome conclusions who
propose that RLND is unnecessary. As a consequence, until more
data are available to clarify this issue, we recommend performing
nephrectomy with RLND in patients with RCC and lymph node
involvement at diagnosis.
This study was part of the TREP project and partially supported
by the Citta ` della Speranza Foundation of Padua, Italy.
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478Indolfi et al.