ORIGINAL ARTICLE

Prognostic Value of Primary Tumor FDG Uptake for Occult

Mediastinal Lymph Node Involvement in Clinically N2/N3
Node-negative NonSmall Cell Lung Cancer
Andrew D. Trister, MD, PhD,* Daniel A. Pryma, MD,w Eric Xanthopoulos, MD, JD,z
John Kucharczuk, MD,y Daniel Sterman, MD,8 and Ramesh Rengan, MD, PhDz

Objectives: The objective of this study was to identify predictive

factors of occult mediastinal nodal involvement on staging positron
emission tomography with 18F-fluorodeoxyglucose in patients with
nonsmall cell lung cancer.
Methods: We performed a retrospective review of 665 patients with
suspected nonsmall cell lung cancer who underwent staging positron
emission tomography with 18F-fluorodeoxyglucose from January 1,
2000 through August 31, 2010 at the Hospital of the University of
Pennsylvania with clinical stage I or II disease and no evidence of N2
or N3 involvement on staging positron emission tomography (PET). A
total of 201 of these patients underwent invasive pathologic staging of
the mediastinum at the Hospital of the University of Pennsylvania with
pathology reports available at the time of review.
Results: A total of 63 of the 201 patients were found to have N2
disease at the time of pathologic staging. The mean standardized
uptake value (SUV) of the primary tumor for patients with occult N2
metastases was significantly higher than the node-negative patients
(SUV 9.31 vs. 7.24, P = 0.04). Histology, tumor location (central vs.
peripheral), sex, and age were not predictive for occult N2 disease. A
multivariate analysis was performed and identified primary tumor
SUV > 6 was the only significant predictor (P = 0.02). An analysis by
quartile identified a primary tumor SUV > 10 to have an odds ratio of
1.72 compared with an SUV < 4 of occult N2 involvement.
Conclusions: Increased primary tumor SUV predicted for increased
risk of mediastinal nodal disease. Tumor location was not predictive of
PET-occult mediastinal nodal involvement, in contrast to previous
publications. Pathologic staging of the mediastinum should be strongly
considered in these patients even with a negative mediastinum on PET.
Key Words: NSCLC, FDG-PET, imaging, mediastinum, staging

(Am J Clin Oncol 2014;37:135139)

he National Cancer Institute estimates that there were

222,520 new cases of lung cancer in the United States and
157,300 deaths from the disease in 2010.1 Although the total
annual mortality shows a modest decrease compared with 5
years prior,2 the 5-year survival rates by stage have remained
largely unchanged in the past decade.3,4 Patients with locally
From the *Department of Radiation Oncology, University of Washington,
Seattle, WA; Departments of wRadiology; zRadiation Oncology;
ySurgery, Division of Thoracic Surgery; and 8Department of Medicine,
Division of Pulmonary, Allergy & Critical Care, University of
Pennsylvania, Philadelphia, PA.
The authors declare no conflicts of interest.
Reprints: Ramesh Rengan, MD, PhD, Department of Radiation Oncology,
Hospital of the University of Pennsylvania, 3400 Spruce Street, 2
Donner, Philadelphia, PA 19104. E-mail: rengan@xrt.upenn.edu.
Copyright r 2012 by Lippincott Williams & Wilkins
ISSN: 0277-3732/14/3702-0135
DOI: 10.1097/COC.0b013e31826b9cd3

American Journal of Clinical Oncology

advanced stage cancers (IIIA to IIIB) have an expected 5-year

survival of 9% to 24%,3,4 whereas patients with earlier stages
(I to II) of disease have an expected 5-year survival of 40% to
80%.3,4 Therefore, mediastinal nodal involvement has a
significant negative impact upon prognosis. In addition,
mediastinal nodal involvement significantly changes the
management of the disease. Whereas surgical resection alone
is an appropriate standard of care for early-stage disease,
combined modality therapy, either with chemotherapy and
surgery or chemoradiotherapy is the treatment of choice for
stage III disease. Furthermore, the expanded role of noninvasive approaches such as stereotactic body radiation therapy
for the management of early-stage disease highlights the need
for accurate staging of the mediastinum in the patient with
nonsmall cell lung cancer (NSCLC). Without accurate
mediastinal staging, patients treated with stereotactic body
radiation therapy may be inappropriately undertreated if they
harbor unrecognized nodal dissemination of their disease.
The current gold standard for accurate staging of the
mediastinum is invasive interrogation of the nodes either
through mediastinoscopy or endobronchial ultrasound.5,6 In
multiple analyses, computed tomography (CT) alone has a
relatively high false-negative rate of 30% to 50% in identification of nodal disease.7 In the 1990s, the use of positron
emission tomography with 18F-fluorodeoxyglucose (FDGPET) emerged as a new technology that had the advantage of
detecting metabolically active sites of disease even when not
pathologically enlarged by CT criteria.8 Since that time, FDGPET has come into increased use for noninvasive staging of the
mediastinum and represents a significant advance over CT
alone; however, this modality can have a false-negative rate of
as high as 25%.923 Despite these concerns, FDG-PET has
become rapidly integrated into the staging of the patient with
NSCLC and now represents the standard of care for identification of metastatic disease in these patients. Furthermore,
FDG-PET is increasingly used as the sole methodology to
stage the mediastinum, especially in the setting of the higher
risk patient planned for treatment with a nonsurgical approach.
Numerous studies have shown the correspondence
between primary tumor metabolic rate as measured by maximum standardized uptake value (SUV) on staging FDG-PET
and survival of patients.2427 Among patients who had similar
stage disease, patients with higher SUV had a worse cumulative survival than those with lower SUV.26 We hypothesize
that primary tumor SUV may be a significant predictor of
occult mediastinal nodal disease in patients with otherwise
resectable tumors.
The overall objective of this study is to identify metabolic
predictive factors on FDG-PET for occult mediastinal nodal
metastases in clinical early-stage NSCLC patients. The goal
being to identify patients for whom invasive staging of the

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Trister et al

mediastinum may be of benefit as they are at high risk for

nodal dissemination. Conversely, patients who are at low risk
for nodal dissemination may be adequately staged with FDGPET alone without need for additional interrogation of the
mediastinum. Here, we present a single-observer review of 201
clinically early-stage NSCLC patients who underwent an
FDG-PET or positron emission tomography (PET)/CT study at
the Hospital of the University of Pennsylvania (HUP) from
January 1, 2000 through August 31, 2010 for NSCLC who
subsequently underwent invasive staging of the mediastinum.

PATIENTS AND METHODS

Patients
We performed a retrospective analysis of patients who
underwent an FDG-PET or PET/CT study in the University of
Pennsylvania Health System from January 1, 2000 through
August 31, 2010. All patients who were billed by University of
Pennsylvania Health System for a nuclear medicine study
during the retrospective period were eligible for inclusion in
the study. The requisition for the first FDG-PET study for each
patient was examined, and only those patients who underwent
the study for evaluation of pulmonary disease were included.
This group of 18,112 patients was further culled to include
only patients who had staging or diagnosis of a lung nodule
and no previously known primary cancer. Of these 2262
patients, 665 patients had biopsy confirmation of NSCLC in
the HUP and no radiographic evidence of mediastinal disease
on FDG-PET or contrast-enhanced CT. Patients with evidence
of direct extension into mediastinum or pleura were excluded.
From the group of patients who had no radiographic
evidence of mediastinal disease, 201 patients underwent
invasive pathologic staging of the mediastinum either through
mediastinoscopy, endobronchial ultrasound-transbronchial
needle aspiration, or mediastinal lymph node dissection at
HUP with pathology reports available at the time of review.
All scans were available for single-observer review by an
attending nuclear medicine physician (D.A.P.). The remaining
patients had no further workup or treatment within the University of Pennsylvania system and were presumed to be
treated at a separate medical system.

Imaging
The FDG-PET studies were obtained on a C-PET
(ADAC/UGM, Philadelphia, PA) (n = 83), Allegro PET
(Philips Medical Systems, Cleveland, OH) (n = 37), and Philips
Gemini TF PET/CT (Philips Medical Systems) (n = 81). There
were no statistically significant differences among the patients
who underwent evaluation with these different technologies.
Patients scanned on C-PET were injected with a median of
5.3 mCi FDG (range, 1.8 to 14.5 mCi) and were scanned a
median of 64 minutes after injection (range, 47 to 173 min).
Allegro PET scans were performed after injection of a median
of 11.7 mCi of FDG (range, 5.9 to 16.4 mCi) and were scanned
70 minutes after injection (range, 50 to 106 min). Patients
scanned on Gemini TF received a median of 15.2 mCi FDG
(range, 13.7 to 17.1 mCi) and were scanned 72 minutes after
injection (range, 54 to 123 min). All images included, at a
minimum, images from the lung apices through the adrenals.
All patients were weighed immediately before FDG injection.
SUV was corrected for body weight. Images of completed
scans from stand-alone PET were fused with clinically available diagnostic thoracic CT using MIMfusion (MIMsoftware,
Cleveland, OH). The tumor volume was surrounded by
a contour containing all voxels with standardized uptake value

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Volume 37, Number 2, April 2014

> 43% of maximum. Nodal stations in the lung and mediastinum were observed, and any mediastinal lymph node clearly
above mediastinal background was considered metastatic
regardless of size. Patients who did not have mediastinal nodes
meeting these criteria were deemed clinically negative. The
SUV of the primary tumor as well as the tumor volume,
intensity, and presence of mediastinal or hilar metastatic disease was recorded. The SUVmax is reported throughout the
manuscript. The single reviewer was blinded to the pathologic
staging for each patient during review of the PET scans.

Statistics
Exact nonparametric tests were used to examine the
differences between the node-negative (N0) and occult
mediastinal data sets with respect to patient and tumor characteristics. Univariate comparison analysis was performed
using age, sex, histology, primary tumor laterality, and primary
tumor SUV. Continuous biological variables were dichotomized and logistic regression of multiple dichotomized variables
was performed using R.28 Survival was measured from the date
of PET scan to death as listed in Social Security Death Index
records on July 1, 2011. The Kaplan-Meier estimator was used
to demonstrate predicted survival for each group.29 A log-rank
test was used to determine significance of the Kaplan-Meier
estimator.

RESULTS
Patient Characteristics
A total of 201 patients with biopsy-confirmed NSCLC
without evidence of FDG-avid mediastinal nodal disease were
identified. A total of 169 patients were N0 and 32 patients had
clinical evidence of hilar metastasis without mediastinal nodal
involvement. Fifty-one percent of patients were male with an
average age of 69.1 years (Table 1). The majority of patients
had adenocarcinoma histology.

Likelihood of Pathologic Mediastinal Nodepositive Disease Based on Primary Tumor SUV

Patients with increased primary tumor SUV are more
likely to have pathologic mediastinal node-positive disease
(Fig. 1). For patients in the highest quintile (SUV > 10), there
was a 44% chance of pathologic nodal involvement despite the
negative FDG-PET. Twenty-six percent of the patients in the
lowest quintile of primary (tumor SUV < 4) were found to have
occult mediastinal nodal disease. The difference between these
2 groups was significant (P = 0.05), although there was no
significant difference across the 4 groups with a Pearson w2
test. The mean SUV of the primary tumor for the 63 patients

TABLE 1. Patient Characteristics. The Number of Patients in Each

Group, Along With Distribution of Age, Sex, Histology and
Laterality of Primary Tumor

All

Clinical N0 Clinical N1

Number
201
169
Age (y)
69.1 (42-92) 69.6 (42-92)
Sex (%)
51 male
51 male
Adenocarcinoma (%)
54
60
Squamous (%)
17
15
Large cell (%)
3
2
Poorly differentiated (%)
26
23
Laterality (%)
38 left
37 left

32
66.5 (50-86)
50 male
25
25
6
44
41 left

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American Journal of Clinical Oncology

Volume 37, Number 2, April 2014

0.6

Primary Tumor SUV as Predictor for Occult N2 Nodal Disease

TABLE 3. Multivariate Logistic Regression of all Patients. The

Odds Ratio for Occult Mediastinal Disease for Patients With
Values Greater Than the Median for the Population

0.5

Percent occult disease

Odds Ratio (95% CI)

Age greater than 70 y
Female sex
SUVmax >6
Clinical N1 disease
Left lung primary tumor
Tumor volume >10 mL

0.4

0.3

0.1

0.83
0.08
0.02
0.31
0.10
0.71

<4

46
610
Primary tumor SUV

nodes, histology, tumor location, primary tumor SUV. The

median value of the SUV (6) was used to dichotomize the
patients within the multivariate analysis. Primary tumor SUV
was significantly predictive of mediastinal nodal involvement
with SUV > 6 being significantly predictive of mediastinal
nodal involvement with an odds ratio of 2.2 (P = 0.02).

>10

FIGURE 1. Occult mediastinal disease risk and standardized

uptake value (SUV) of primary tumor site. Quartiles of entire
study population along primary tumor SUV and percentage of
patients with occult mediastinal disease within each quartile.

with occult N2 metastases was significantly higher than the N0

patients (SUV of 9.31 vs. 7.24; P = 0.04) (Table 2). Histology,
tumor location (central vs. peripheral), sex, and age were not
predictive for occult N2 disease (Table 2). In review of the
methods for obtaining the PET scans, we found that there was
no difference in the techniques used among the 3 generations
of scanners included in this study, nor was there a statistical
difference in the length of uptake time. There was a lower
false-negative rate using the newer PET/CT scanners. Of note,
the mean SUV of the primary tumor was significantly higher in
patients with occult nodal disease than in the N0 patients
independent of the PET/CT scanner that was employed.
A multivariate analysis was performed with mediastinal
nodal involvement as an endpoint including age, sex, hilar

TABLE 2. Univariate Analysis of Patients. The Differences in Age,

Sex, Histology, and Laterality Between Groups of Patients Who
Were Found to Have Occult Mediastinal Metastatic Disease

Number
Mean age (y)
Sex
Adenocarcinoma
Squamous
Large cell
Poorly differentiated
Clinical N1 disease
Laterality
SUV
Median interval from PET to
invasive staging

Pathologic
N0 or N1

Pathologic
N2

138
69.4
(SD = 9.62)
55% male
56%
16%
2%
26%
13%
36% left
7.24
(SD = 5.15)
36 d

63
68.4
(SD = 11.03)
42% male
48%
19%
5%
28%
22%
44% left
9.31
(SD = 7.2)
31 d

2012 Lippincott Williams & Wilkins

Multivariate Analysis of Predictive Factors for

Occult Mediastinal Disease
A logistic regression of the dichotomized multiple variables in each group demonstrated that only the primary tumor
SUV had a significant correlation with pathologic mediastinal
node involvement (Table 3) with an odds ratio of 2.2 for
patients with primary tumors with SUV > 6 (P = 0.02). There
was also a trend toward significance for laterality with leftsided tumors conferring an odds ratio of 1.73, however, the
95% confidence interval crossed 1 and the P-value did not
reach statistical significance (P = 0.1). Differences in sex, age,
and volume of primary tumor had no statistical significance.

Survival of Patients With Pathologic Mediastinal

Node-positive Disease Versus Pathologic
Mediastinal N0 Patients
The Kaplan-Meier survival curves for the patient population are shown in Figure 2. After pathologic sampling of the
mediastinum was complete, the patients followed expected
survival based on stage. The median estimated survival of the
patients with pathologic nodal disease was 2.4 years and
median estimated survival for patients with no pathologic
nodes was not reached in this analysis (P < 0.0005).

DISCUSSION
0.56
0.11
0.25
0.60
0.39
0.64
0.13
0.24
0.04
0.59

PET indicates positron emission tomography; SUV, standardized uptake

value.
Value in bold is statistically significant (P < 0.05).

(0.49-1.76)
(0.31-1.08)
(1.14-4.4)
(0.67-3.46)
(0.91-3.27)
(0.6-2.13)

CI indicates confidence interval; SUV, standardized uptake value.

Value in bold is statistically significant (P < 0.05).

0.2

0.0

0.93
0.57
2.2
1.53
1.73
1.13

Accurate staging in NSCLC is an important aid in predicting the clinical course and prognosis of treatment. For
patients with early-stage NSCLC, surgery and complete lymph
node dissection is the most effective mode of treatment. Use of
FDG-PET or PET/CT scans for preoperative staging and
diagnosis has become routine for noninvasive staging, particularly of the mediastinal compartment for N2 disease. Previously, authors have reported a false-negative rate of up to
25% in investigating the mediastinum. It has been previously
shown that primary tumor SUV is independently prognostic for
survival in similarly staged patients with NSCLC.2426 The
rationale proposed for this observation is that primary tumor
FDG avidity is a marker for tumor aggressiveness and perhaps
early distant spread of disease. In this retrospective study, we
examined the hypothesis that primary tumor FDG uptake was
predictive of early nodal dissemination of disease.
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American Journal of Clinical Oncology

Trister et al

1.0

HR = 2.9 (1.9 4.4)

logrank P = 8.9e08

Fraction Surviving

0.8

0.6

0.4

0.2
N0
N Pos

0.0
0

6
Years

10

100

65

39

20

44

25

12

Number at risk
N0 120
N Pos 81

FIGURE 2. Kaplan-Meier predicted survival of study population,

comparing those patients who were clinical N0 and N1 at time of
positron emission tomography and had no mediastinal involvement on pathology with patients who were found to have occult
nodal disease. HR indicates hazard ratio.

We found that patients with higher FDG uptake in the

primary tumor had a significantly higher risk of occult
mediastinal disease. Forty-four percent of patients with a primary tumor SUV > 10 but negative mediastinum on FDG-PET
had mediastinal nodal disease identified by pathologic sampling. Previous studies have demonstrated that increased FDG
avidity of primary tumors also correlated with poorer survival
for patients, when matched for stage at diagnosis.26 The
presence of clinically occult mediastinal disease may explain
the decreased survival observed in these patients. It has also
recently been proposed that increased glucose metabolism may
be associated with metastatic transformation, and metabolic
activity measured by FDG uptake in these tumors may be a
gross marker of metastatic potential.30
On univariate analysis, left lung tumors were more likely
to have occult mediastinal disease than those tumors on the
right in patients with N0 disease on PET. Although this did not
retain significance on multivariate analysis, previous cadaveric
studies have shown that direct lymphatic drainage to mediastinal nodes from lung parenchyma is more likely from the left
lung (nearly 25%) and from the upper lobes in both the
lungs.31,32 Interestingly, in our study, the likelihood of occult
mediastinal disease was not significantly different for patients
with central or peripheral disease, even though it has been
noted previously that central tumors are more likely to involve
the mediastinum at time of preoperative CT scan or PET.33,34
Finally, the odds ratio of mediastinal nodal dissemination
in patients with N1 nodal disease when compared with those
patients with clinical N0 disease on staging PET was 1.51
(P = 0.008). This finding did not retain significance on multivariate analysis. There were no significant differences in the
populations that had N0 and N1 disease in terms of tumor
histology, age, and sex of patients as shown in Table 1. A total
of 50% of the patients with N1 disease and no evidence of
mediastinal nodal disease on PET had occult mediastinal disease discovered on pathology. Even with the low numbers of
patients in the N1 group, this significant difference is not

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Volume 37, Number 2, April 2014

surprising given the demonstration of hilar nodal metastases

and the remainder of the lymphatic drainage of the lung runs
through the hilar nodes to the mediastinal nodes.31 Furthermore, previous studies have shown similar risk for patients
with N1 disease.33,35
Although the purpose of our study was to investigate the
likelihood of clinically occult mediastinal disease, the greater
picture of whether this has an impact on overall survival is also
interesting. We performed an analysis of the survival probability of patients included in the study who were found to have
no mediastinal nodal disease and compared it to the patients
who had occult mediastinal disease at time of pathologic
staging. Figure 2 shows the Kaplan-Meier survival prediction
curves for patients who were staged as clinically N0 or N1 and
found to have no mediastinal nodal disease at biopsy compared
with those patients who had pathologic N2 disease. The
stratified survival curves show similarities to those previously
published.36
Previous studies investigating the role of FDG-PET in
staging NSCLC have shown predictive significance in N1
nodal status as well as location, histology, and size of
tumors.33,35,37,38 In our review, we have found that these are
not independent significant predictors of occult N2 metastasis,
whereas primary tumor SUV remains predictive. The differences in these results may demonstrate confounders in determining these predictors as well as a limitation in retrospective
studies. The use of multiple scanners in our study over a large
period of time made the scanning protocols heterogeneous in
our study, however, these results may allow for a greater
reproducibility in other centers using individual protocols.
A limitation of our study is it that it was not possible to
histologically confirm all positive nodal findings on PET,
therefore, the true positive rate of PET for each individual
nodal station could not be determined. Because this study
spanned a significant period of time, there was heterogeneity in
PET equipment used and many of the patients were scanned on
an early-generation PET scanner using curved sodium iodide
detectors. The resolution, contrast recovery and limits of
detectability with PET tomographs have significantly
improved. Future studies will need to evaluate whether modern
PET/CT systems are better able to accurately detect N2 disease
as suggested in our analysis. Nevertheless, we found that
among patients who were evaluated on the latest-generation
PET/CT, a higher SUV of the primary tumor is correlated with
a higher risk for occult mediastinal disease. A prospective
study of patients with newly diagnosed NSCLC will be
instrumental in determining the predictive value of FDG-PET
in staging the mediastinum in early clinical disease.
On the basis of our retrospective review of patients
treated within the HUP for early-stage NSCLC, we recommend
invasive staging of mediastinum in addition to staging FDGPET or PET/CT in patients with increased FDG uptake
(SUV > 6) of the primary tumor to most accurately stage
patients.

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