ORIGINAL ARTICLE

Lymphovascular Invasion in Non–Small-Cell Lung Cancer

Implications for Staging and Adjuvant Therapy
Kristin A Higgins, MD,* Junzo P Chino, MD,† Neal Ready, MD,‡ Thomas A D’Amico, MD,§
Mark F Berry, MD,§ Thomas Sporn, MD,|| Jessamy Boyd, MD,# and Chris R Kelsey MD†

Background: Lymphovascular space invasion (LVI) is an established

negative prognostic factor and an indication for postoperative radia-
S tage is currently the dominant factor affecting adjuvant-
treatment recommendations in resected non–small-cell
lung cancer (NSCLC).1 Practice guidelines have been pro-
tion therapy in many malignancies. The purpose of this study was to
foundly influenced by three recent randomized trials dem-
evaluate LVI in patients with early-stage non–small-cell lung cancer,
onstrating a survival benefit with the addition of adjuvant
undergoing surgical resection.
chemotherapy.2–4 This benefit has been largely confined to N1
Methods: All patients who underwent initial surgery for pT1-3N0-2
to N2 disease,5 although subset analyses have suggested that
non–small-cell lung cancer at Duke University Medical Center from
chemotherapy is also advantageous for patients with larger
1995 to 2008 were identified. A multivariate ordinal regression was
stage I tumors.4,6 The role of postoperative radiation therapy is
used to assess the relationship between LVI and pathologic hilar and/
less well defined, but is generally recommended for patients
or mediastinal lymph node (LN) involvement. A multivariate Cox
with involved mediastinal lymph nodes (LNs) (N2) or positive
regression analysis was used to evaluate the relationship of LVI and
surgical margins.
other clinical and pathologic factors on local failure (LF), freedom
Elucidation of high-risk pathologic features in resected
from distant metastasis (FFDM), and overall survival (OS). Kaplan-
NSCLC may help to further stratify patients into risk groups,
Meier methods were used to generate estimates of LF, FFDM, and
allowing for further refinement of adjuvant treatment recom-
OS in patients with and without LVI.
mendations. For example, lymphovascular space invasion
Results: One thousand five hundred and fifty-nine patients were iden-
(LVI) is an adverse prognostic factor for numerous solid
tified. LVI was independently associated with the presence of regional
tumors. Furthermore, the presence of LVI is an independent
LN involvement (p < 0.001) along with lobar (versus sublobar) resec-
indication for postoperative radiation therapy in several epi-
tions (p < 0.001), and an open thoracotomy (versus video-assisted
thelial malignancies, including cervix,7 endometrial,8 vulvar,9
thoracoscopic surgery). LVI was not independently associated with
and head and neck cancers.10
LF on multivariate analysis (hazard ratio [HR] = 1.23, p = 0.25), but
Several studies have demonstrated that LVI is also a
was associated with a lower FFDM (HR 1.52, p = 0.005) and OS
poor prognostic factor for recurrence-free and overall survival
(HR 1.26, p = 0.015). In addition, multivariate analysis showed that
(OS) in NSCLC.11–15 One recent study has demonstrated that
LVI was strongly associated with increased risk of developing distant
presence of LVI in a biopsy specimen is an independent risk
metastases (HR = 1.75, p = 0.006) and death (HR = 1.53, p = 0.003)
factor for death and metastatic progression for patients treated
in adenocarcinomas but not in squamous carcinomas.
with definitive chemoradiotherapy.16 However, the influence of
Conclusions: LVI is associated with an increased risk of harboring
LVI on adjuvant-treatment recommendations after resection is
regional LN involvement. LVI is also an adverse prognostic factor for
unclear. Current NCCN guidelines are somewhat ambiguous,
the development of distant metastases and long-term survival.
stating that the presence of LVI is considered “high-risk”.17
Key Words: Lymphovascular invasion, Lung cancer, Local failure. Whether LVI increases the risk of local or distant recurrence
(or both) is unknown. In addition to this question, we also
(J Thorac Oncol. 2012;7: 1141–1147)
sought to investigate the association between the presence of
LVI in the primary tumor and the risk of harboring disease in
hilar and/or mediastinal LNs.
*Department of Radiation Oncology, Emory University, Atlanta, Georgia;
†Department of Radiation Oncology, ‡Department of Medicine, Division
of Medical Oncology, §Department of Surgery, Division of Cardiovascular METHODS
and Thoracic Surgery, and ||Department of Pathology, Duke University This Institutional Review Board-approved study identi-
Medical Center, Durham North Carolina; and #National Comprehensive
Cancer Network, US Oncology, Dallas, Texas. fied all patients who underwent surgery for T1-3N0-2 NSCLC
Disclosure: The authors declare no conflicts of interest. at Duke University between 1995 and 2008. Patients were
Address for correspondence: Kristin A. Higgins, MD, Department of excluded if they received preoperative chemotherapy and/or
Radiation Oncology, Emory University, Winship Cancer Institute, Atlanta, preoperative radiation therapy, or had a prior history of lung
GA 30322. E-mail: kristin.higgins@emory.edu
Copyright © 2012 by the International Association for the Study of Lung
cancer. Medical records and pertinent radiological imaging
Cancer were reviewed to characterize each patient’s demographic
ISSN: 1556-0864/12/0707-1141 information, obtain surgical and pathological details, and

Journal of Thoracic Oncology • Volume 7, Number 7, July 2012 1141

Higgins et al.
score patterns of failure after surgery. The pathologic stag-
ing of patients in this cohort reflects the updated tumor, node,
metastasis staging for NSCLC.1
Between 1995 and 1997, lung tumor specimens were
interpreted by multiple pathologists at Duke University
Medical Center. After 1998, all specimens were interpreted
by a single pathologist with a special interest in pulmonary
pathology (TAS). Hematoxylin and eosin stains were per-
formed on all specimens. LVI was reported when tumor cells
were demonstrated on histologic examination within lym-
phatic channels, veins/venules, and/or arteries/arterioles.
Patterns of failure were assessed by means of follow-up
imaging studies and information obtained from procedures such
as computed-tomography (CT)–guided transthoracic biopsies,
bronchoscopy, endobronchial ultrasound, and mediastinoscopy,
etc. A local failure (LF) was scored when disease recurred at
the surgical resection margin or regional LNs (ipsilateral hilum
and/or mediastinum). Nodal failures in the ipsilateral hilum or
mediastinum were defined as a new or enlarging LN of 1 cm or
more on short axis on CT, and/or hypermetabolic on positron
emission tomography imaging, which in the patient’s subse-
quent clinical follow-up was consistent with disease progres-
sion. All cases of possible local and distant recurrence were
reviewed by two authors (CK and JB/KH) to ensure accuracy.
All patients had routine postsurgical surveillance with imaging
studies, including chest CT, but the frequency and choice of
imaging modality was not standardized.
Statistical Analysis
The Mann-Whitney U test was used to test for an asso-
ciation between LVI and the presence of involved regional
LNs. Primary tumor size, type of surgery (wedge/segment-
ectomy versus lobectomy/pneumonectomy), thoractomy ver-
sus a video-assisted thoracoscopic surgical (VATS) approach,
histology, visceral pleural invasion, grade, and primary tumor
location (right versus left, upper/middle versus lower) were
also included in this assessment. Factors with a p value of
0.1 or less were included in a multivariate ordinal regres-
sion. Patients without regional LN sampling/dissection were
excluded from this part of the analysis.
Univariate and multivariate analyses were also per-
formed to examine clinical and pathological factors associated
with LF, development of distant metastases (DM), and OS,
including LVI, type of surgical resection (thoracotomy versus
VATS), size of primary tumor, number of hilar LNs sampled,
number of hilar LNs involved, number of mediastinal LN sta-
tions sampled, number of mediastinal LNs involved, tumor
histology (squamous/large-cell versus others),18 tumor grade,
visceral pleural invasion, stage, adjuvant chemotherapy, age,
and sex. Factors with a p value of 0.1 or less on univariate
analysis were included in the multivariate model. For the LF
analysis, patients with positive margins and/or those receiving
postoperative radiation were excluded. Univariate and multi-
variate analyses were also performed based on histology, with
LF, DM, and OS examined separately in squamous-cell carci-
nomas and adenocarcinomas.
The Kaplan-Meier product-limit method19,20 was used
to estimate 5-year recurrence probabilities and confidence
1142 Copyright © 2012 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 7, Number 7, July 2012
intervals, and comparisons were made via the log-rank test.
When generating survival curves for patients with LVI versus
no LVI, the patients with unknown LVI status were grouped
into the “no LVI” category. Progression-free survival was cal-
culated from the date of surgery to date of treatment failure
(defined as local and/or distant recurrence, development of a
second primary lung cancer, or death from any cause). Time
to LF and time to distant failure (DF) were calculated from the
date of surgery to date of local or distant recurrence, respec-
tively. For these analyses, patients developing what was felt to
be a second primary lung cancer were censored on the date the
second primary malignancy was diagnosed. Local and distant
recurrences were scored independently (i.e., patients develop-
ing a distant recurrence were not censored for LF, but were
assessed for LF until the date of last follow-up or death).
RESULTS
Between 1995 and 2008, 1559 patients met the inclu-
sion criteria. Median follow-up for all patients was 34 months
and for survivors it was 40 months. Patient characteristics are
reported in Table 1. The majority (98%) had hilar and/or medi-
astinal LN sampling/dissection at the time of surgery. The
majority of patients were stage I, with 41% of patients with
pathologic stage IA disease and 26% of patients with stage IB
disease. Presence of LVI was noted in 23% of the patients.
LVI and Regional LN Involvement
Patients with no regional LN sampling were excluded
from this analysis (n = 33). Of the remaining 1526 patients,
1219 were pathologic N0, 235 patients were pathologic N1,
and 72 patients were pathologic N2.
Factors associated with regional LN involvement on uni-
variate analysis included LVI, increasing size of the primary
tumor, lobar versus sublobar resection, thoracotomy versus
VATS approach, visceral pleural invasion, and squamous/large-
cell histology. On multivariate ordinal regression, the pres-
ence of LVI (p < 0.001), thoracotomy (p < 0.001), and lobar
resections (p < 0.001) continued to be significant predictors of
harboring pathologically involved regional LNs (Table 2).
In patients who underwent lobectomy or pneumonec-
tomy (n = 696), the risk of harboring ipsilateral hilar LN dis-
ease was 36% versus 21% (p < 0.001) and the risk of harboring
mediastinal LN disease was 12% versus 5% (p < 0.001), for
patients with and without LVI, respectively. Furthermore,
LVI was associated with increasing number of positive LNs
(p < 0.001), with the median number of positive LNs equal to
one (interquartile range 1–2) for patients without LVI and two
(interquartile range 1–4) for patients with LVI.
LVI and Risk of Local Recurrence
For this analysis, patients with positive surgical margins
and those receiving postoperative radiation were excluded,
leaving 1458 evaluable patients. On univariate analysis, LVI
was associated with statistically significant increased risk of
LF with Kaplan-Meier estimates of 5-year local control of
79% versus 71% (p = 0.001) (Fig. 1). However, on multivari-
ate analysis this association was lost (Table 4).
Journal of Thoracic Oncology • Volume 7, Number 7, July 2012 Lymphovascular Invasion and Non–Small-Cell Lung Cancer

TABLE 1.  Patient Characteristics TABLE 2.  Factors Associated with Regional Lymph Node
Involvement
Characteristic
Age (yrs) Factors p Valuea
 Median 67 Lobectomy versus wedge/ segmentectomy <0.01
 Range 20–91 Lymphovascular invasion <0.01
Race Tumor size 0.094
 African-American 202 (13%) Squamous/large cell versus adenocarcinoma 0.80
 White 1328 (85%) Moderate/high grade versus low grade 0.12
 Other 29 (2%) Open resection versus VATS approach <0.01
Sex Visceral pleural invasion 0.08
 Male 833 (53%) Multivariate ordinal regression analysis.
a

 Female 726 (47%) VATS, video-assisted thoracoscopic surgical.

Pathologic stage (TNM 7)
 IA 638 (41%)
 IB 411 (26%)
 IIA 272 (17%) LVI and DM, Recurrence-Free Survival, and OS
 IIB 124 (10%) The presence of LVI was found to be significantly asso-
 IIIA 112 (7%) ciated with a detriment in freedom from DM as depicted in
 IIIB 2 (0.1%) Figure 2 (57% versus 73% at 5 years, p < 0.001). This remained
Histology significant on multivariate analysis (Table 4).
 Adenocarcinoma 734 (47%) The presence of LVI was also associated with increased
  Squamous cell 561 (36%)
risk of death (5-year OS 31% versus 56%, p < 0.001)
  Large cell 93 (6%)
(Fig. 3), which remained significant on multivariate analysis
 Bronchioloalveolar 40 (3%)
(Table 4). Adjuvant chemotherapy was also associated with
 Adenosquamous 21 (1%)
improved OS on multivariate analysis (p < 0.001), and seemed
  NSCLC NOS 110 (7%)
to improve the 5-year survival for patients with LVI (32% ver-
Surgical Approach
sus 60%, p = 0.001) and for patients without LVI (49% versus
 Open 795 (51%)
69%, p < 0.001). In addition, when examined by histology,
 VATS 764 (49%)
LVI was strongly associated with increased risk of developing
Surgical Procedure
DM (hazard ratio [HR] = 1.75, p = 0.006) and death (HR =
 Wedge/Segmentectomy 305 (20%)
1.53, p = 0.003) on multivariate analysis in adenocarcinomas.
 Lobectomya 1154 (74%)
Multivariate analysis did not find LVI to be statistically sig-
 Pneumonectomy 100 (6%)
nificant for DM (HR = 1.08, p = 0.75) or death (HR = 1.23,
Mediastinal sampling/dissection
p = 0.11) in squamous-cell carcinoma.
 Yes 1361 (87%)
 No 198 (13%) DISCUSSION
Lymphovascular space invasion LVI is an adverse prognostic factor in many other solid
 Yes 352 (23%) tumors and its presence is an independent indication for post-
 No 1107 (71%) operative radiotherapy in head and neck and multiple gyneco-
 Unknown 100 (6%) logical malignancies. The presence of LVI does not currently
Visceral Pleural Invasion influence treatment recommendations in NSCLC.
 Yes 366 (24%) In the present study, the presence of LVI within the pri-
 No 1128 (72%) mary tumor was independently associated with a higher risk
 Unknown 65 (4%) that regional LNs were pathologically involved. Such infor-
Chemotherapy mation could be useful when determining treatment recom-
 Yes 184 (12%) mendations for patients who do not undergo regional LN
 No 1375 (88%) sampling/dissection at the time of surgery or in patients with-
out LN sampling before undergoing definitive radiotherapy.
NSCLC NOS, non–small-cell carcinoma not otherwise specified; VATS, video-
assisted thoracoscopic surgery; TNM, tumor, node, metastasis. Not surprisingly, increased risk of regional node involvement
a
Including bilobectomy and sleeve lobectomy. was also associated with lobectomy compared with sublobar
resection, likely because of the absence of LN dissection or
a limited number of LNs retrieved with most sublobar resec-
tions. In addition, open thoracotomy was also associated with
When examining the effect of LVI on a stage-by-stage increased risk of regional node involvement, perhaps because
basis, a statistically significant detriment in local control was seen patients not eligible for a VATS procedure had a greater extent
in patients with stage IB disease with LVI versus stage IB without of the disease.
LVI (61% versus 81%, p < 0.01). Presence of LVI was not statisti- The therapy of NSCLC is now being driven by histology,
cally significant for LF in the other stage groups (Table 3). along with the presence of validated predictive biomarkers
Copyright © 2012 by the International Association for the Study of Lung Cancer 1143
Higgins et al. Journal of Thoracic Oncology • Volume 7, Number 7, July 2012

FIGURE 1.  Local control based on

the presence or absence of LVI. LVI,
lymphovascular space invasion.

TABLE 3.  Local Control Stage by Stage Stratified by Lymphovascular Invasion

5-Year Local
Stage Control (%) 95% CI (%) p Value
IA 86 82–90 0.43
  Lymphovascular invasion 92 85–99
  No lymphovascular invasion 85 81–89%
IB 77 71–84 <0.01
  Lymphovascular invasion  61 43–79
  No lymphovascular invasion 81 74–87
IIA 63 54–72 0.22
  Lymphovascular invasion 59 44–74
  No lymphovascular invasion 65 54–76
IIB 63 48–77 0.45
  Lymphovascular invasion 60 32–89
  No lymphovascular invasion 62 46–79
IIIA 69 51–86 0.94
  Lymphovascular invasion 67 38–97
  No lymphovascular invasion 70 48–91
CI, confidence interval.

1144 Copyright © 2012 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 7, Number 7, July 2012 Lymphovascular Invasion and Non–Small-Cell Lung Cancer

FIGURE 2.  Freedom from distant

metastasis based on the presence
or absence of LVI. LVI, lymphovas-
cular space invasion.

TABLE 4.  Multivariate Analyses for Local Recurrence, Distant Metastases, and Overall Survival
Local Failure Distant Metastases Overall Survival
Hazard Hazard Hazard
Factorsa Ratio 95% CI p Value Ratio 95% CI p Value Ratio 95% CI p Value
Surgical procedure
  Wedge/ segmentectomy 1.78 1.23–2.58 <0.01 1.56 1.30–1.88 <0.01
  ≥Lobectomy
Lymphovascular invasion
 Yes 1.23 0.87–1.76 0.25 1.52 1.13–2.02 <0.01 1.25 1.05–1.51 0.02
 No
Age (per yr) 0.99 0.97–0.99 0.03 1.02 1.01–1.03 <0.01
Tumor size (per cm) 1.13 1.05–1.22 <0.01 1.16 1.10–1.23 <0.01 1.08 1.04–1.13 <0.01
Visceral pleural invasion
 Yes 2.07 1.48–2.89 <0.01 1.30 0.96–1.76 0.09 1.12 0.93–1.36 0.24
 No
Grade
 Moderate/high 1.66 0.86–3.21 0.13 1.42 0.86–2.35 0.17 1.33 1.00–1.77 0.05
 Low
Histology
  Squamous or large cell 1.48 1.07–2.04 0.02 1.13 0.96–1.32 0.15
 Non-squamous
VATS approach
 Yes 0.91 0.65–0.91 <0.01 0.84 0.63–1.11 0.22 0.89 0.75–1.05 0.16
 No (Continued)

Copyright © 2012 by the International Association for the Study of Lung Cancer 1145
Higgins et al. Journal of Thoracic Oncology • Volume 7, Number 7, July 2012

TABLE 4. (Continued)
Local Failure Distant Metastases Overall Survival
Hazard Hazard Hazard
Factorsa Ratio 95% CI p Value Ratio 95% CI p Value Ratio 95% CI p Value
Adjuvant chemotherapy
 Yes 0.66 0.41–1.06 0.09 0.67 0.46–0.98 0.04 0.35 0.24–0.50 <0.01
 No
Male sex
 Yes 1.13 0.83–1.55 0.44 1.32 1.13–1.55 <0.01
 No
Number of N1 LNs sampled (per node) 0.99 0.96–1.03 0.69
Number of involved N1 LNs (per node) 1.12 0.98–1.29 0.10 1.12 1.00–1.25 0.05 1.12 1.04–1.21 <0.01
Number of involved N2 LNs (per node) 1.31 0.91–1.88 0.15 1.37 1.06–1.77 0.02 1.31 1.09–1.57 <0.01
Only factors with a p value less than 0.1 on univariate analysis were included in the multivariate model. The second factor listed is the reference set.
a

LN, lymph node; CI, confidence interval; VATS, video-assisted thoracoscopic surgical.

FIGURE 3.  Overall survival

based on the presence or
absence of LVI. LVI, lymphovas-
cular space invasion.

1146 Copyright © 2012 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 7, Number 7, July 2012
for erlotinib and crizotinib.21,22 Interestingly, when patients were
analyzed according to histology, the association of LVI with
increased risk of DM and death was only found in adenocarcino-
mas. Currently, the presence of LVI is rarely reported in pathol-
ogy reports from core needle biopsies of lung masses, as tumor
stroma containing vessels and lymphatics must be present to make
such a determination. Improving biopsy techniques to allow for
more adequate tumor sampling is necessary to routinely report
presence or absence of LVI and determine tumor histology and
molecular status. Although the present study demonstrates LVI to
be a poor prognostic factor in resected lung specimens, a recently
published study has also demonstrated that LVI in core needle
biopsies is associated with poor outcome in patients undergoing
chemoradiation.16 We believe that refining tumor characterization
at core needle biopsy is an important step forward.
The presence of LVI was associated with a higher risk of LF
on univariate analysis. This distinction was most evident in stage
IB patients (i.e., those with larger primary tumors but no evidence
of regional LN involvement). In this patient population, LVI has
been associated with inferior OS in multiple studies,11,14 but the
impact of LVI on LF was not evaluated. Although significant on
univariate analysis, LVI did not remain statistically significant for
LF for the entire cohort on multivariate analysis. In contrast, other
pathologic factors were strongly associated with LF, including
visceral pleural invasion and squamous/large-cell histology.
Our data indicate that LVI is more strongly associ-
ated with DF as opposed to LF. Patients with LVI had sig-
nificantly increased risk of developing DM and a lower rate
of survival. Other studies have demonstrated an association
between LVI and decreased recurrence-free survival and OS
in NSCLC.12–14 The present study is the first to evaluate LF
and DF as distinct entities in association with LVI. Why LVI
is more strongly associated with DF and death in adenocarci-
nomas is unknown.
Limitations to the present study do exist. First, given its ret-
rospective nature, no centralized confirmatory pathologic review
was possible. However, the vast majority of specimens were
analyzed by a single pathologist who specializes in pulmonary
pathology. Second, lymphatic invasion and vascular invasion
were analyzed together and not independent of one another. It is
not known if one is of greater importance than the other. Finally,
although the sample cohort was large, the majority of patients
had stage I disease. Statistical power may be limited in stage II
and III patients, the subset of patients with the highest risk of LF.
In conclusion, the presence of LVI is associated with an
increased risk of developing DM and death after surgery for
early-stage NSCLC. LVI alone does not seem to be a strong
enough risk factor for LF alone to warrant postoperative radi-
ation therapy in NSCLC. The presence of LVI is associated
with an increased risk of developing DM and may be helpful
in the decision paradigm for adjuvant chemotherapy.
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