Journal of Pediatric Surgery (2013) 48, 10201024

www.elsevier.com/locate/jpedsurg

What predicts the risk of recurrent lung metastases?

Zaria Murrell, Roshni Dasgupta
Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati,
OH 45229-3039
Received 25 January 2013; accepted 3 February 2013

Key words:
Recurrence;
Pulmonary metastases;
Children;
Metastasectomy;
PET scan

Abstract
Purpose: The purpose of this study was to determine what factors predict recurrent lung metastatic
disease in pediatric oncology patients.
Methods: A retrospective review of 50 patients who underwent resection of lung nodules that were
positive for metastatic disease from 1998 to 2011 was performed. Risk factors for recurrence were
determined by multi-variable logistic regression models.
Results: Fifty pediatric oncology patients underwent resection of discrete lung nodules seen on CT
scans during work-up for metastasis or for routine surveillance. Out of this patient cohort, 23 (46%)
patients had recurrent disease. The only significant factors that influenced risk of recurrence were
original PET positive study (p b 0.05) and patients with osteosarcoma (p b 0.002). The type of surgical
procedure, margins of original resection, race, age, gender, size, or the number of original nodules was
not found to be significant.
Conclusion: Patients with osteosarcoma and PET positive disease at original presentation appear to be at
the highest risk of recurrent pulmonary metastatic disease. New pulmonary lesions in these patients
should undergo biopsy to confirm metastatic disease.
2013 Elsevier Inc. All rights reserved.

Over the last 3 to 4 decades, survival in pediatric patients

with cancer has improved significantly. This success has
been achieved primarily through the efforts of multidisciplinary treatment, advances in diagnostic modalities,
and widespread use of national and international cooperative group protocols [1,2]. Reported survival rates range
from 70% to 90% in pediatric solid tumors without
metastases [1]. Primary solid tumors of childhood most
commonly metastasize to the lungs; 10%40% of patients
have pulmonary metastases present at the time of diagnosis
Corresponding author. Division of Pediatric Surgery, Cincinnati
Children's Hospital Medical Center, Cincinnati, OH 45229-3039. Tel.: + 1
513 636 4371; fax: +1 513 636 7657.
E-mail address: Roshni.dasgupta@cchmc.org (R. Dasgupta).
0022-3468/$ see front matter 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jpedsurg.2013.02.018

and up to 50% will develop metachronous lesions [3].

Although surgical resection has been shown to increase
survival rates in patients with pulmonary metastases [4], the
5 year survival outcomes for this subset of children
decreases to 20%70% [1].
No pulmonary infiltrate is too small to be a metastasis.
Most clinicians agree that one pulmonary or pleural nodule
of 1 cm or multiple lesions greater than .5 cm are evidence
of pulmonary metastases [2]. The evolution of computed
tomography has enhanced detection of small pulmonary
nodules. These lung nodules can be biopsied either by
thoracotomy, video-assisted thoracoscopy or median sternotomy. Important prognostic predictors are tumor histology, time of identification of the lung metastasis and primary
tumor response to chemotherapy [1,3,5]. In osteosarcoma,

What predicts the risk of recurrent lung metastases?

Table 1 Patient tumor characteristics who developed
malignant pulmonary nodules.
Primary Tumor

First lung
metastasis
(n = 50)

Recurrent pulmonary
metastasis
(n = 23)

Osteosarcoma
Ewing's sarcoma
Hepatic tumors
Lymphomas
Wilms
Rhabdomyosarcoma
Germ cell tumors
Melanoma
Other sarcoma
Other tumors

15
6
6
6
5
5
2
1
1
3

13
3
2
1
1
1
1
0
1
0

1021
and median or range for skewed data. Multivariate logistic
regression was used to identify significant predictors for
recurrent pulmonary metastases; p-value of b 0.05 was
considered statistically significant.

2. Results
2.1. Patient demographics
Fifty patients were identified who developed malignant
lung nodules during the study period. The age range was

recurrent pulmonary metastases should be resected [68], as

resection has been shown to improve overall survival. In
Ewing's sarcoma, small studies have shown improved
survival when pulmonary metastasectomy is performed [9].
Controversies remain as to the risk factors for recurrent
pulmonary metastases in pediatric solid malignancies.
The purpose of this study was to examine what factors
may influence recurrence of metastatic lung nodules.
Hypotheses including the biology of the tumor, characteristics of the original metastatic lesions, the type of surgical
procedure and margins around the original tumor or
specific individual patient characteristics have all been
postulated. By further understanding these issues we can
develop a treatment paradigm to better risk stratify patients
and potentially avoid surgical morbidity of redo thoracic
procedures in patients that may have lower risk of
recurrent disease.

1. Methods
Institutional review board approval was obtained for this
study. A retrospective chart review of pediatric oncology
patients who had undergone a resection of a pulmonary
nodule between November 1998 and July 2011 was
performed. All lung nodules were identified on CT imaging
performed for the evaluation of metastatic disease or for
routine surveillance, and were resected either by thoracotomy or thoracoscopy. Excluded from the study were those
patients that underwent resection of chest wall, mediastinal,
or pleural based lesions, patients undergoing formal
lobectomy or those patients undergoing random biopsies.
Patient demographics, diagnostic studies (CT PET scan),
location of the lung nodule, procedure performed, pathology of the lesion and its margins of resection were
recorded. The data were examined with SAS system
software version 9.2 (SAS Institute, Cary, NC). All data
were expressed as mean SD for normally distributed data

Fig. 1 A and B: Coronal CT image of a patient with

osteosarcoma showing a peripheral right upper lobe lesion,
measuring 7 mm. PET scan showed no uptake. Biopsy was
positive for metastatic osteosarcoma.

1022

Z. Murrell, R. Dasgupta
tumor (1), rhabdomyosarcoma (1), other sarcomas (1), and
germ cell tumors (1). Seventeen of these 23 patients (78%)
had PET scans; 7/17 (41%) were PET positive lesions and
10/17 (59%) were PET negative. Of the 7 PET positive
scans, 5 had osteosarcoma and 2 had Ewing's sarcoma. The
10 false negative PET scans were in 8 with osteosarcoma, 1
with hepatoblastoma, and 1 with rhabdomyosarcoma. In the
false negative PET scan group, the nodule size on CT scan
had a mean of 8.7 5.2 mm (Fig. 1). The mean CT scan size
of the pulmonary nodules in the PET positive lesions was
18.2 11.2 mm (Fig. 2). The size difference of the nodules
between the PET positive and negative lesions was
statistically significant (p = 0.035).

2.2. Operative data

This group of 23 patients underwent 50 surgical procedures. Twelve patients (52%) had metachronous recurrent
ipsilateral pulmonary nodules requiring re-operative procedures confirming metastatic disease. Twenty-six thoracotomies were performed on 16 patients during the time period
studied with seven patients undergoing more than one
thoracotomy: One patient underwent a median sternotomy.
Twenty-four VATS procedures were performed on 15
patients with discrete lung nodules found on preoperative CT
scans during the time period studied. Six patients had more
than one thoracoscopic procedure performed.

2.3. Statistical analysis

Multivariate logistic regression analysis was used to
identify significant predictors in patients with recurrent
pulmonary metastases. The model was constructed with
Fig. 2 A and B: Coronal CT images of a patient with
osteosarcoma, showing a left upper lobe lesion, measuring
15 mm. PET scan was positive. Biopsy was positive for
metastatic osteosarcoma.

from 9 months to 26 years (median of 13 years 6.4 years).

There were 27 males and 23 females. The primary oncologic
diagnoses of these patients included osteosarcoma (15),
Ewing's sarcoma (6), hepatic tumors (6), lymphoma (6),
Wilm's tumor (5), rhabdomyosarcoma (5), other sarcomas
(1), germ cell tumors (2), melanoma (1), and other tumors
(3). All nodules were identified on preoperative CT scans. Of
the 50 patients with metastatic pulmonary nodules, 23
patients (46%) were found to have recurrent nodules. These
23 patients comprise the final study cohort (see Table 1).
Of the 23 patients with recurrent pulmonary metastases,
14 were male and 9 were female. The age range was from 1
to 22 years (median age was 15 6.1 years). Time to the
development of the recurrence ranged from 3 to 44 months
(median 6 9.7 months). The primary oncologic diagnoses
of these patients included osteosarcoma (13), Ewing's
sarcoma (3), hepatoblastoma (2), lymphoma (1), Wilms

Table 2

Factors that influenced risk of recurrence.

Variable in model

Odds Confidence
ratio interval

Age (above or below

1.91
median age (13)
Race (white versus non-white)
1.36
Gender ( male)
0.87
Location (unilateral vs bilateral) 0.33
Tumor margin (greater than
2.8
median 3 mm)
PET
4.55
Wilms Tumor
0.26
Osteosarcoma
10.4
Hepatoblastoma
1.1
Rhabdomyosarcoma
0.26
Ewing
0.18
Number (solitary
0.75
versus multiple)
Insurance status
0.63
(private versus public)
Thoracoscopy
0.33

P value

(0.61,5.83)

0.27

(.33, 5.55)
(0.55, 1.4)
(0.01, 1.1)
(0.62, 12.9)

0.67
0.55
0.07
0.18

(1.335, 15.5) b 0.02

(0.027, 2.5)
0.25
(2.425, 44.6) b 0.002
(0.15, 9.9)
0.86
(0.027, 2.5)
0.24
(0.21, 6.6)
0.83
(.24, 2.4)
0.63
(0.2, 1.9)

0.42

(.09, 1.3)

0.11

What predicts the risk of recurrent lung metastases?

twelve variables based on original presentation: age, race,
gender, tumor type, size, lung lobe involved, original tumor
margin of resection (based on pathological reports), number
of lung nodules (solitary vs multiple), location of lung
nodule (unilateral vs bilateral), procedure performed, PET
scan positivity, and insurance status. The only significant
factors that influenced risk of recurrence of pulmonary
metastatic lesions were patients with osteosarcoma
(p b 0.002) and an original PET positive study (p b 0.05)
(See Table 2).

3. Discussion
The evolution of better imaging technology allows
improved visualization and the identification of smaller
and smaller lung nodules. Once identified, the management
of these nodules is not clear particularly in a patient who has
had previous lung metastases. Histological diagnosis of these
lesions is important for prognosis and possible cure however
this must be balanced with the surgical morbidity of reoperative thoracic surgery.
There have been several studies in adult patients trying
to understand characteristics of patients with recurrent
disease, however none have been definitive. Bielack's
review of 249 patients with second and subsequent
recurrences of osteosarcoma suggested that those with
unilateral pulmonary metastases which developed ipsilateral
recurrences probably represented local recurrence of an
incompletely removed lung metastases from previous
resection rather than new metastases [7]. However, in
Harting's review of 137 patients with osteosarcoma, of
which 99 underwent an aggressive surgical resection of
pulmonary metastases to render them free of disease, the
results did not demonstrate a statistically significant
difference in overall survival or disease-free interval
survival based on the number of pulmonary metastases
resected, by primary tumor characteristics such as size, site;
chemotherapy; early versus late metastases, unilateral
versus bilateral metastases; and resection margins [5]
similar to our study.
The recent widespread use of positron emission tomography with 18 F-fluorodeoxy-glucose (FDG-PET) has been
demonstrated to be a useful adjunct in differentiating
between benign and malignant pulmonary nodules in adult
patients [10]. Adult studies have established FDG-PET to
have limited sensitivity in metastatic pulmonary nodules
less than 10 mm in size. However, in nodules greater than
10 mm, the sensitivity ranges from 90% to 100% [11,12].
This was also noted in our study with a significant size
differential between PET positive and negative lesions.
Several recent studies have also investigated the use of
standardized uptake values (SUV) by PET/CT as an
independent prognostic variable in adult malignancies
[1315]. PET scanning has been used in pediatric oncologic

1023
patients; however, the diagnostic efficacy is not clear
[1618] consistent with our data. There are several
limitations to our study. The retrospective review over the
13 years with the numerous variables that were collected and
analyzed does not account for the evolution of chemotherapeutic regimens and diagnostic imaging techniques. Also,
the small number of patients with recurrent pulmonary
metastatic disease had different primary malignancies, which
can lead to selection biases given that the majority of our
patients had osteosarcoma.
Patients with recurrent lung nodules present a management dilemma in pediatric oncology. Our data support that
recurrence is likely secondary to biology of the original
tumor and not the method or margins of previous surgical
resection. From these data, it appears that recurrent lung
nodules in patients with a diagnosis of osteosarcoma and
those with PET positive nodules are most likely to be
malignant. However, all pediatric oncologic patients merit
close surveillance for recurrent disease and with the advent
of more refined imaging techniques, we may be able to better
predict which patients should undergo surgical intervention.

References
[1] Fuchs J, Seitz G, Handgretinger R, et al. Surgical treatment of lung
metastases in patients with embryonal pediatric solid tumors: an
update. Semin Pediatr Surg 2012;21:79-87.
[2] Rechnitzer C. Increased survival of children with solid tumours: how
did we get there and how to keep the success going? Cancer Imaging
2011; 11 Spec No A:S65-69.
[3] Tsuchiya H. Effect of timing of pulmonary metastases identification on
prognosis of patients with osteosarcoma: the Japanese Musculoskeletal
Oncology Group Study. J Clin Oncol 2002;20:3470-7.
[4] Friedel G, Pastorino U, Buyse M, et al. Resection of lung metastases:
long-term results and prognostic analysis based on 5206 casesthe
International Registry of Lung Metastases. Zentralbl Chir 1999;124:
96-103.
[5] Harting M, Blakely M, Jaffe N, et al. Long-term survival after
aggressive resection of pulmonary metastases among children and
adolescents with osteosarcoma. J Pediatr Surg 2006;41:194-9.
[6] Briccoli A, Rocca M, Salone M, et al. High grade osteosarcoma of the
extremities metastatic to the lung: long-term results in 323 patients
treated combining surgery and chemotherapy, 19852005. Surg Oncol
2010;19:193-9.
[7] Bielack SS, Kempf-Bielack B, Delling G, et al. Prognostic factors in
high-grade osteosarcoma of the extremities or trunk: an analysis of
1,702 patients treated on neoadjuvant cooperative osteosarcoma study
group protocols. J Clin Oncol 2002;20:776-90.
[8] Chen F, Miyahara R, Bando T, et al. Repeat resection of pulmonary
metastasis is beneficial for patients with osteosarcoma of the
extremities. Interact Cardiovasc Thorac Surg 2009;9:649-53.
[9] Letourneau PA, Shackett B, Xiao L, et al. Resection of pulmonary
metastases in pediatric patients with Ewing sarcoma improves
survival. J Pediatr Surg 2011;46:332-5.
[10] Lowe VJ, Fletcher JW, Gobar L, et al. Prospective investigation of
positron emission tomography in lung nodules. J Clin Oncol 1998;16:
1075-84.
[11] Fortes DL, Allen MS, Lowe VJ, et al. The sensitivity of 18Ffluorodeoxyglucose positron emission tomography in the evaluation of
metastatic pulmonary nodules. Eur J Cardiothorac Surg 2008;34:
1223-7.

1024
[12] Nomori H, Watanabe K, Ohtsuka T, et al. Evaluation of F-18
fluorodeoxyglucose (FDG) PET scanning for pulmonary nodules less
than 3 cm in diameter, with special reference to the CT images. Lung
Cancer 2004;45:19-27.
[13] Morris PG, Ulaner GA, Eaton A, et al. Standardized uptake value
by positron emission tomography/computed tomography as a
prognostic variable in metastatic breast cancer. Cancer 2012;118:
5454-62.
[14] Liao S, Penney BC, Wroblewski K, et al. Prognostic value of
metabolic tumor burden on 18F-FDG PET in nonsurgical patients with
non-small cell lung cancer. Eur J Nucl Med Mol Imaging 2012;39:
27-38.

Z. Murrell, R. Dasgupta
[15] Oh HH, Lee SE, Choi IS, et al. The peak-standardized uptake value (PSUV) by preoperative positron emission tomography-computed
tomography (PET-CT) is a useful indicator of lymph node metastasis
in gastric cancer. J Surg Oncol 2011;104:530-3.
[16] Mody RJ, Bui C, Hutchinson RJ, et al. FDG PET imaging of childhood
sarcomas. Pediatr Blood Cancer 2010;54:222-7.
[17] Franzius C, Daldrup-Link HE, Sciuk J, et al. FDG-PET for detection of
pulmonary metastases from malignant primary bone tumors: comparison with spiral CT. Ann Oncol 2001;12:479-86.
[18] Yeung HW, Sanches A, Squire OD, et al. Standardized uptake value in
pediatric patients: an investigation to determine the optimum
measurement parameter. Eur J Nucl Med Mol Imaging 2002;29:61-6.