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Lymphovascular Invasion in Non-Small-Cell Lung Cancer: Implications For Staging and Adjuvant Therapy
Lymphovascular Invasion in Non-Small-Cell Lung Cancer: Implications For Staging and Adjuvant Therapy
score patterns of failure after surgery. The pathologic stag- intervals, and comparisons were made via the log-rank test.
ing of patients in this cohort reflects the updated tumor, node, When generating survival curves for patients with LVI versus
metastasis staging for NSCLC.1 no LVI, the patients with unknown LVI status were grouped
Between 1995 and 1997, lung tumor specimens were into the “no LVI” category. Progression-free survival was cal-
interpreted by multiple pathologists at Duke University culated from the date of surgery to date of treatment failure
Medical Center. After 1998, all specimens were interpreted (defined as local and/or distant recurrence, development of a
by a single pathologist with a special interest in pulmonary second primary lung cancer, or death from any cause). Time
pathology (TAS). Hematoxylin and eosin stains were per- to LF and time to distant failure (DF) were calculated from the
formed on all specimens. LVI was reported when tumor cells date of surgery to date of local or distant recurrence, respec-
were demonstrated on histologic examination within lym- tively. For these analyses, patients developing what was felt to
phatic channels, veins/venules, and/or arteries/arterioles. be a second primary lung cancer were censored on the date the
Patterns of failure were assessed by means of follow-up second primary malignancy was diagnosed. Local and distant
imaging studies and information obtained from procedures such recurrences were scored independently (i.e., patients develop-
as computed-tomography (CT)–guided transthoracic biopsies, ing a distant recurrence were not censored for LF, but were
bronchoscopy, endobronchial ultrasound, and mediastinoscopy, assessed for LF until the date of last follow-up or death).
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 RESULTS
mediastinum were defined as a new or enlarging LN of 1 cm or Between 1995 and 2008, 1559 patients met the inclu-
more on short axis on CT, and/or hypermetabolic on positron sion criteria. Median follow-up for all patients was 34 months
emission tomography imaging, which in the patient’s subse- and for survivors it was 40 months. Patient characteristics are
quent clinical follow-up was consistent with disease progres- reported in Table 1. The majority (98%) had hilar and/or medi-
sion. All cases of possible local and distant recurrence were astinal LN sampling/dissection at the time of surgery. The
reviewed by two authors (CK and JB/KH) to ensure accuracy. majority of patients were stage I, with 41% of patients with
All patients had routine postsurgical surveillance with imaging pathologic stage IA disease and 26% of patients with stage IB
studies, including chest CT, but the frequency and choice of disease. Presence of LVI was noted in 23% of the patients.
imaging modality was not standardized.
LVI and Regional LN Involvement
Patients with no regional LN sampling were excluded
Statistical Analysis
from this analysis (n = 33). Of the remaining 1526 patients,
The Mann-Whitney U test was used to test for an asso- 1219 were pathologic N0, 235 patients were pathologic N1,
ciation between LVI and the presence of involved regional and 72 patients were pathologic N2.
LNs. Primary tumor size, type of surgery (wedge/segment- Factors associated with regional LN involvement on uni-
ectomy versus lobectomy/pneumonectomy), thoractomy ver- variate analysis included LVI, increasing size of the primary
sus a video-assisted thoracoscopic surgical (VATS) approach, tumor, lobar versus sublobar resection, thoracotomy versus
histology, visceral pleural invasion, grade, and primary tumor VATS approach, visceral pleural invasion, and squamous/large-
location (right versus left, upper/middle versus lower) were cell histology. On multivariate ordinal regression, the pres-
also included in this assessment. Factors with a p value of ence of LVI (p < 0.001), thoracotomy (p < 0.001), and lobar
0.1 or less were included in a multivariate ordinal regres- resections (p < 0.001) continued to be significant predictors of
sion. Patients without regional LN sampling/dissection were harboring pathologically involved regional LNs (Table 2).
excluded from this part of the analysis. In patients who underwent lobectomy or pneumonec-
Univariate and multivariate analyses were also per- tomy (n = 696), the risk of harboring ipsilateral hilar LN dis-
formed to examine clinical and pathological factors associated ease was 36% versus 21% (p < 0.001) and the risk of harboring
with LF, development of distant metastases (DM), and OS, mediastinal LN disease was 12% versus 5% (p < 0.001), for
including LVI, type of surgical resection (thoracotomy versus patients with and without LVI, respectively. Furthermore,
VATS), size of primary tumor, number of hilar LNs sampled, LVI was associated with increasing number of positive LNs
number of hilar LNs involved, number of mediastinal LN sta- (p < 0.001), with the median number of positive LNs equal to
tions sampled, number of mediastinal LNs involved, tumor one (interquartile range 1–2) for patients without LVI and two
histology (squamous/large-cell versus others),18 tumor grade, (interquartile range 1–4) for patients with LVI.
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 LVI and Risk of Local Recurrence
analysis, patients with positive margins and/or those receiving For this analysis, patients with positive surgical margins
postoperative radiation were excluded. Univariate and multi- and those receiving postoperative radiation were excluded,
variate analyses were also performed based on histology, with leaving 1458 evaluable patients. On univariate analysis, LVI
LF, DM, and OS examined separately in squamous-cell carci- was associated with statistically significant increased risk of
nomas and adenocarcinomas. LF with Kaplan-Meier estimates of 5-year local control of
The Kaplan-Meier product-limit method19,20 was used 79% versus 71% (p = 0.001) (Fig. 1). However, on multivari-
to estimate 5-year recurrence probabilities and confidence ate analysis this association was lost (Table 4).
1142 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
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
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
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.
1146 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
for erlotinib and crizotinib.21,22 Interestingly, when patients were 3. Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP,
analyzed according to histology, the association of LVI with Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative
Group. Cisplatin-based adjuvant chemotherapy in patients with completely
increased risk of DM and death was only found in adenocarcino- resected non-small-cell lung cancer. N Engl J Med 2004;350:351–360.
mas. Currently, the presence of LVI is rarely reported in pathol- 4. Winton T, Livingston R, Johnson D, et al.; National Cancer Institute of
ogy reports from core needle biopsies of lung masses, as tumor Canada Clinical Trials Group; National Cancer Institute of the United
stroma containing vessels and lymphatics must be present to make States Intergroup JBR.10 Trial Investigators. Vinorelbine plus cisplatin
such a determination. Improving biopsy techniques to allow for vs. observation in resected non-small-cell lung cancer. N Engl J Med
2005;352:2589–2597.
more adequate tumor sampling is necessary to routinely report 5. Pignon JP, Tribodet H, Scagliotti GV, et al.; LACE Collaborative Group.
presence or absence of LVI and determine tumor histology and Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE
molecular status. Although the present study demonstrates LVI to Collaborative Group. J Clin Oncol 2008;26:3552–3559.
be a poor prognostic factor in resected lung specimens, a recently 6. Strauss GM, Herndon JE 2nd, Maddaus MA, et al. Adjuvant paclitaxel
published study has also demonstrated that LVI in core needle plus carboplatin compared with observation in stage IB non-small-cell
lung cancer: CALGB 9633 with the Cancer and Leukemia Group B,
biopsies is associated with poor outcome in patients undergoing Radiation Therapy Oncology Group, and North Central Cancer Treatment
chemoradiation.16 We believe that refining tumor characterization Group Study Groups. J Clin Oncol 2008;26:5043–5051.
at core needle biopsy is an important step forward. 7. Sedlis A, Bundy BN, Rotman MZ, Lentz SS, Muderspach LI, Zaino RJ.
The presence of LVI was associated with a higher risk of LF A randomized trial of pelvic radiation therapy versus no further therapy
on univariate analysis. This distinction was most evident in stage in selected patients with stage IB carcinoma of the cervix after radical
hysterectomy and pelvic lymphadenectomy: A Gynecologic Oncology
IB patients (i.e., those with larger primary tumors but no evidence Group Study. Gynecol Oncol 1999;73:177–183.
of regional LN involvement). In this patient population, LVI has 8. Keys HM, Roberts JA, Brunetto VL, et al.; Gynecologic Oncology Group.
been associated with inferior OS in multiple studies,11,14 but the A phase III trial of surgery with or without adjunctive external pelvic
impact of LVI on LF was not evaluated. Although significant on radiation therapy in intermediate risk endometrial adenocarcinoma: a
univariate analysis, LVI did not remain statistically significant for Gynecologic Oncology Group study. Gynecol Oncol 2004;92:744–751.
LF for the entire cohort on multivariate analysis. In contrast, other 9. Heaps JM, Fu YS, Montz FJ, Hacker NF, Berek JS. Surgical-pathologic
variables predictive of local recurrence in squamous cell carcinoma of the
pathologic factors were strongly associated with LF, including vulva. Gynecol Oncol 1990;38:309–314.
visceral pleural invasion and squamous/large-cell histology. 10. Huang TY, Hsu LP, Wen YH, et al. Predictors of locoregional recurrence
Our data indicate that LVI is more strongly associ- in early stage oral cavity cancer with free surgical margins. Oral Oncol
ated with DF as opposed to LF. Patients with LVI had sig- 2010;46:49–55.
nificantly increased risk of developing DM and a lower rate 11. Hsu CP, Hsia JY, Chang GC, et al. Surgical-pathologic factors affect long-
term outcomes in stage IB (pT2 N0 M0) non-small cell lung cancer: a
of survival. Other studies have demonstrated an association heterogeneous disease. J Thorac Cardiovasc Surg 2009;138:426–433.
between LVI and decreased recurrence-free survival and OS 12. Giraud P, Antoine M, Larrouy A, et al. Evaluation of microscopic
in NSCLC.12–14 The present study is the first to evaluate LF tumor extension in non-small-cell lung cancer for three-dimensional
and DF as distinct entities in association with LVI. Why LVI conformal radiotherapy planning. Int J Radiat Oncol Biol Phys
is more strongly associated with DF and death in adenocarci- 2000;48:1015–1024.
13. Krauss S, Perez C, Lowenbraun S, Sonoda T, Bartolucci A, Buchanan R.
nomas is unknown. Combined modality treatment of localized small-cell lung carcinoma.
Limitations to the present study do exist. First, given its ret- A randomized prospective study of the Southeastern Cancer Study Group.
rospective nature, no centralized confirmatory pathologic review Cancer Clin Trials 1980;3:297–305.
was possible. However, the vast majority of specimens were 14. Meyskens FL Jr, Berglund EB, Saxe DF, et al. Biological and biochemical
analyzed by a single pathologist who specializes in pulmonary properties of a human uveal melanocyte-derived cell line. In Vitro
1980;16:775–780.
pathology. Second, lymphatic invasion and vascular invasion
15. Shiono S, Abiko M, Sato T. Positron emission tomography/computed
were analyzed together and not independent of one another. It is tomography and lymphovascular invasion predict recurrence in stage I
not known if one is of greater importance than the other. Finally, lung cancers. J Thorac Oncol 2011;6:43–47.
although the sample cohort was large, the majority of patients 16. Massabeau C, Filleron T, Wakil G, et al. The prognostic significance of
had stage I disease. Statistical power may be limited in stage II lymphovascular invasion on biopsy specimens in lung cancer treated with
and III patients, the subset of patients with the highest risk of LF. definitive chemoradiotherapy. Clin Lung Cancer 2012;13:59–67.
17. Ettinger DS, Akerley W, Borghaei H, et al. NCCN Clinical Practice
In conclusion, the presence of LVI is associated with an Guidelines in Oncology, Non-Small Cell Lung Cancer, (ed Version
increased risk of developing DM and death after surgery for 2.2012). Fort Washington, PA: National Comprehensive Cancer Network,
early-stage NSCLC. LVI alone does not seem to be a strong 2012.
enough risk factor for LF alone to warrant postoperative radi- 18. Kelsey CR, Marks LB, Hollis D, et al. Local recurrence after surgery for
ation therapy in NSCLC. The presence of LVI is associated early stage lung cancer: an 11-year experience with 975 patients. Cancer
2009;115:5218–5227.
with an increased risk of developing DM and may be helpful 19. Collett D. Modeling Survival Data in Medical Research, 2 nd Ed. London:
in the decision paradigm for adjuvant chemotherapy. Chapman & Hall, 2003.
20. Therneau TM, Grambsch PM. Modeling Survival Data. New York:
Springer, 2000.
REFERENCES 21. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma
1. AJCC. Cancer Staging Manual- Lung ,7 th Ed. New York, Springer, 2010. kinase inhibition in non-small-cell lung cancer. N Engl J Med
Pp. 253–270. 2010;363:1693–1703.
2. Douillard JY, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus cisplatin 22. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are
versus observation in patients with completely resected stage IB-IIIA non- common in lung cancers from “never smokers” and are associated with
small-cell lung cancer (Adjuvant Navelbine International Trialist Association sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA
[ANITA]): a randomised controlled trial. Lancet Oncol 2006;7:719–727. 2004;101:13306–13311.
Copyright © 2012 by the International Association for the Study of Lung Cancer 1147