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Original Article
SMJ
Suparauk Geanphun, M.D.*, Vilasinee Rerkpichaisuth, M.D.**, Ruchira Ruangchira-urai, M.D.**,
Punnarerk ongcharoen,
M.D.*
*Department of Surgery, **Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.
Survival of Non-Small Cell Lung Cancer Patients
with Unexpected N2 after Complete Resection: Role
of Aggressive Invasive Mediastinal Staging should
be Considered
ABSTRACT
Objective: Mediastinal lymph node (N2) metastasis is one of the poor prognostic factors in non-small cell lung
cancer patients (NSCLC). However, the accuracy of mediastinal lymph node staging in real practice is uncertain
and inadequate. Consequently, the aim of this study was to determine the survival of NSCLC patients with clinically
non-suspicious mediastinal lymph node metastases who underwent complete resection but were pathologically
conrmed as having N2 metastases (unexpected N2).
Materials and Methods: A retrospective review was performed of all pathology-proven N2 metastases NSCLC
patients who underwent curative surgical resection from January 2007 to December 2016. A total of 158 patients
were initially included in the study. Aer the exclusions (known N2, small cell carcinomas, neuroendocrine tumor),
125 unexpected N2 patients who underwent complete resection were analyzed. Survival analysis was determined
using the Kaplan–Meier method and multivariate analysis was determined using the Cox regression method.
Results: e overall 2-year, 3-year, and 5-year survival rates were 40%, 24%, and 20% respectively. Complete
resection was achieved in all patients. Invasive mediastinal staging (IMS) was performed in 47 patients (37.6%),
by endobronchial ultrasonography (EBUS) in 46 (36.8%) patients (82.6% negative and 17.4% inadequate tissue)
while only 1 patient underwent mediastinoscopy. e factors aecting the survival rate upon comparison were
the histology type (p=0.019), dierentiate characteristics (p=0.004), adjuvant therapy (p=0.011), and presence
of distant metastasis by postoperative re-staging (p=0.003). e independent predictive factors for survival were
chemo-radiation therapy (odds ratio 0.367, 95% condence interval 0.176–0.766) and distant metastasis (odds ratio
2.280, 95% condence interval 1.334–3.897). However, a small size, periphery lesion, T staging, and number of N2
lesions were not signicant factors.
Conclusion: e survival rate of unexpected N2 patients was low despite complete resection being achieved in
these patients. Adjuvant therapy seemed to improve survival for those with unexpected N2 metastasis as it is a
systemic disease. However, not all patients received IMS, which was mostly done by EBUS and which had a high
false negative, leading to underestimating the staging. Other modalities, such as cervical mediastinoscopy, video-
assisted mediastinoscopic lymphadenectomy (VAMLA) or open biopsy should be considered for the adequate e
valuation of N2 metastasis, nonetheless further study is still needed.
Keywords: N2 disease, Unexpected N2, Non-small lung cancer (NSCLC), Invasive mediastinal staging (IMS), Stage
3A NSCLC (Siriraj Med J 2022; 74: 161-168)
Corresponding author: Punnarerk ongcharoen
E-mail: punnarerk.tho@mahidol.ac.th
Received 7 September 2021 Revised 30 November 2021 Accepted 25 December 2021
ORCID ID: https://orcid.org/0000-0002-0420-1462
http://dx.doi.org/10.33192/Smj.2022.20
All material is licensed under terms of
the Creative Commons Attribution 4.0
International (CC-BY-NC-ND 4.0)
license unless otherwise stated.
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INTRODUCTION
e prognosis of non-small cell lung cancer (NSCLC)
patients with mediastinal lymph node metastases (N2
disease) is usually poor.
1-3
N2 involvement is one of the
important factors that determine the prognosis and
treatment. Because N2 disease seems to indicate systemic
spreading, systemic therapy, such as chemotherapy,
radiation therapy, or combined chemo-radiation therapy,
has better 5-year survival than surgery alone (38% vs
30%).
4
Despite the recommendation for mediastinal lymph
node tissue conrmation when there is a high suspicion
of N2 by imaging, such as enlarged lymph nodes seen
by computed tomography (CT) or an increased uptake
in the mediastinum by positron-emission tomography
(PET)
5
, the accuracy of the clinical staging still has a high
false negative rate ranging from 25% to 40%
6
; therefore,
some patients undergo surgery as the rst course of
treatment. Previous reports showed that unexpected
N2 disease patients had a poor prognosis and a survival
rate ranging from only 10%-35%.
7-10
Consequently, the objective of this study is to determine
survival rate in ai population of the clinical N0 NSCLC
patients who underwent complete pulmonary resection
with systematic mediastinal lymph nodes dissection and
who had unexpected N2 as a nal pathological result.
MATERIALS AND METHODS
Patients and staging
is study is a retrospective review of all the pathology-
proven N2 metastases NSCLC patients included in the
data registry of the Division of Cardio-oracic Surgery
and in reports from the Department of Pathology, Siriraj
Hospital, Bangkok, ailand, between January 2007 and
December 2016. Among all the patients aged 18 years old
and older who received complete pulmonary resection
with systematic mediastinal lymphadenectomy (n = 158),
we excluded patients (n = 33) who had a diagnosis of N2
disease as either highly suspicious (14 patients whose
CT shows enlarged N2 lymph node more than 1 cm in
short axis) or conrmed from preoperative imaging
(2 patients whose N2 uptake in PET-CT), small cell
carcinoma (10 patients), and neuroendocrine tumor (7
patients). Following the exclusions, the remaining patients
(n = 125) were proven to be NSCLC preoperatively or
at the time of surgery, and had been clinically staged
as N0 or N1 from an imaging study (CT or FDG-PET
scan) and from invasive mediastinal staging if done. All
of the included patients had not received neoadjuvant
systemic chemotherapy nor radiation therapy before
surgical resection. e Siriraj Ethic and Clinical Research
Institutional Review Board approved this study as well
as the electronic database used. e need for individual
patient consent was waived due to the nature of the
retrospective study design.
Staging was primarily performed by chest computed
tomography (CT). Only a small number of patients
received positron-emission tomography (PET-CT scan)
due to the cost and availability. Invasive mediastinal
staging, such as endobronchial ultrasound ne needle
aspiration (EUS-FNA) or cervical mediastinoscopy, were
performed in cases with a mediastinal lymph node larger
than 1 cm in short axis as determined by the imaging
and when all the results were negative for N2 disease.
Nevertheless, there is no specic criteria in the institution
for selecting patients to receive particular preoperative
invasive mediastinal staging, the decision depends on
experienced pulmonologists or surgeons.
Surgery was performed by both standard thoracotomy
and video-assisted thoracoscopic surgery (VATS).
Anatomical complete resection (R0 resection) was
achieved by lobectomy, bi-lobectomy, or pneumonectomy.
Systematic lymphadenectomy was performed in all
patients and included lymph node stations 2R, 4R,
7-9
for
the right-sided lesions, and stations
5-9
for the le-sided
lesions. e pathological review was done using the
standard technique for both the primary lung lesions
and mediastinal lymph nodes.
All the patients received routine follow-up examination
in the thoracic out-patient unit and were referred to an
oncologist and radiotherapist for appropriate adjuvant
chemotherapy or radiation therapy.
Statistical analysis
Data analysis was performed using SPSS statistical
soware (SPSS version 25, 2017, IBM Corporation).
Categorial data are presented as the percentage and
continuous variables are expressed as the mean. Continuous
variables between groups were compared using the
t test and discrete variables using Pearson’s chi square
test. Survival rates were calculated using the Kaplan–
Meier method and log-rank test for adjusting for the
dierences between subgroups. Univariate analysis for
the prognostic factors was performed using the log-rank
test and multivariate analysis using multiple logistic
regression analysis method. A p-value of less than 0.05
was dened as statistically signicant.
RESULTS
In total, 125 patients were included in this study.
Complete surgical lung resection and systematic mediastinal
lymphadenectomy were achieved in every patient. As
shown in Table 1, male and female in age group of 60 is
Geanphun et al.
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TABLE 1. Patients’ characteristics (n = 125).
*EBUS endobronchial ultrasonography.
Gender
Male 60 (48%)
Female 65 (52%)
Median age (years, range) 62 (31-82)
Clinical presentation
Abnormal chest radiograph 66 (52.8%)
Chest discomfort 4 (3.2%)
Prolong cough 34 (27.2%)
Hemoptysis 16 (12.8%)
Dyspnea 3 (2.4%)
Weight loss 1 (0.8%)
Pneumonia 1 (0.8%)
Site of primary tumor
Right upper lobe 32 (25.6%)
Right middle lobe 14 (11.2%)
Right lower lobe 30 (24%)
Left upper lobe 33 (26.4%)
Left lower lobe 16 (12.8%)
Invasive mediastinal staging (IMS) 47 (37.6%)
EBUS*(negative result) 38 (30.4%)
EBUS (inadequate tissue) 8 (6.4%)
Mediastinoscopic biopsy 1 (0.8%)
(negative result)
Mean time to surgery (months) 1.29 (±0.875)
Extent of surgery
Segmental resection 2 (1.6%)
Lobectomy 104 (83.2%)
Bilobectomy 11 (8.8%)
Pneumonectomy 8 (6.4%)
Adjuvant therapy 102 (81.6%)
Chemotherapy 45 (36%)
Radiation therapy 4 (3.2%)
Chemo-radiation therapy 53 (42.4%)
Distant metastases (restaging) 71 (56.8%)
not dierent for the lung cancer characteristics. e most
common presentation was an abnormal chest radiography
on annual check-up followings with prolong cough
and hemoptysis. One-third of the patients received an
invasive mediastinal staging procedure by endobronchial
ultrasonography (EBUS), for which the results were all
negative or there was inadequate tissue for evaluation,
and only 1 patient received mediastinoscopy with lymph
node biopsy. e mean time from diagnosis to surgery
was less than 60 days. Lobectomy was performed most
oen, which was equally performed in the right upper lobe,
right lower lobe, and le upper lobe. Among the study,
almost patients received adjuvant therapy, comprising
chemotherapy alone, radiation therapy alone, or combined
chemo-radiation therapy.
For the tumor characteristics (Table 2), the most
common T staging was still early (T2a). Adenocarcinoma
was the predominant histologic subtype along with
moderate dierentiation. ere was a rather high incidence
of visceral pleural invasion and lymphovascular invasion.
e most common site of mediastinal nodal metastasis
for unexpected N2 disease was station 7 followed by
stations 4R and 4L, while three quarters of patients had
multiple N2 station metastases.
e overall 2-year, 3-year, and 5-year Kaplan–Meier
survival rates were 40%, 24%, and 20%, respectively (Fig 1).
For the pathological characteristics, the histologic subtype
and dierentiation had signicant dierences in their
eect on the survival rates (Fig 2). e adenocarcinoma
group had a better 5-year survival rate compared to the
squamous cell carcinoma group (24% vs. 14%, p = 0.019),
whereas good dierentiation had a better 5-year survival
rate than moderate and poor dierentiation (45%, 24%,
and 13%, p = 0.004). ere was no signicant dierence
among the T staging classes (p = 0.282, Fig 2). e presence
of visceral pleural invasion of the tumor had a 5-year
survival rate of 16% compared to the absence group,
but this was not signicantly dierent (p = 0.199, Fig 3).
Lymphovascular invasion also showed no signicant
dierence (p = 0.097, Fig 3), and the 5-year survival rate
was 15% in the presence of lymphovascular invasion.
For unexpected N2 metastasis, the numbers of nodal
stations were analyzed. Fig 4 shows the Kaplan–Meier
5-year survival for 39 patients with single nodal station
metastasis compared to 86 patients with multiple nodal
stations metastases (25% vs. 18% respectively), but the
dierence was not statistically signicant (p = 0.103). In
terms of the patient follow-ups, 23 patients declined the
adjuvant therapy. Here, all the patients with or without
adjuvant therapy were compared, and the best prognosis
was found in the adjuvant chemo-radiation therapy
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TABLE 2. Tumors’ characteristics (n = 125).
For the tumor characteristics (Table 2), the most common T staging
was T2a (55.2%) with the median size of 4.31 cm. Adenocarcinoma
was the predominant histologic subtype (83.2%) along with moderate
dierentiation (67.2%). ere was a rather high incidence of visceral
pleural invasion (69.6%) and lymphovascular invasion (75.2%). e
most common site of mediastinal nodal metastasis for unexpected
N2 disease was station 7 (49.6%) followed by stations 4R and 4L
(44%), while 68.8% of patients had multiple N2 station metastases.
Size of primary tumor (cm) 4.31 ± 1.921
Histology
Adenocarcinoma 104 (83.2%)
Squamous cell carcinoma 16 (12.8%)
Other 5 (4%)
Differentiation
Well 6 (4.8%)
Moderate 84 (67.2%)
Poor 27 (21.6%)
Not evaluated 8 (6.4%)
Visceral pleural invasion 87 (69.6%)
Lymphovascular invasion 94 (75.2%)
Adjacent structure invasion 16 (12.8%)
T staging (from pathology)
T1a 5 (4%)
T1b 10 (8%)
T2a 69 (55.2%)
T2b 20 (16%)
T3 16 (12.8%)
T4 5 (4%)
N1 station involvement
10R, 10L 45 (36%)
11R, 11L 71 (56.8%)
N2 station
3 6 (4.8%)
4R,4L 55 (44%)
5 33 (26.4%)
6 3 (2.4%)
7 62 (49.6%)
8R,8L 2 (1.6%)
9R,9L 10 (8%)
Number of N2
Single 39 (31.2%)
Multiple 86 (68.8%)
Fig 1. Overall 2-, 3-, and 5-year survival rates, which were 40%, 24%,
and 20%, respectively.
group, which had a 5-year survival rate of 30%, while
the 5-year survival rates of the radiation therapy alone
group, chemotherapy alone group, and did not receive
adjuvant therapy group were 25%, 15%, and 10%, and
the dierence was statistically signicant (p = 0.011,
Fig 4).
Post-treatment re-staging data were also collected
and analyzed. The survival graph demonstrated the
5-year survival rate of patients with a presentation of
distant metastasis in any organ was 10%; while for the
group with no distant metastasis, it was 40%, and there
was a highly signicant dierence in statistical terms as
the p-value was 0.003 (Fig 4). e univariate analysis
was insignicant. e multivariate analysis results in
Table 3 depict that the independent predictive factors
for survival were receiving adjuvant chemo-radiation
therapy and a distant metastasis on re-staging.
DISCUSSION
Recently, Krantz and colleagues
11
did a study based
on e Society of oracic Surgeons General oracic
Surgery Database (STS-GTSD) participants in the United
States (US) and reported that 34% of lung cancer patients
staged by computed tomography and positron-emission
tomography and rst treated with anatomical resection
underwent invasive mediastinal staging (IMS). Compatible
with our study, which found that in all 125 “unexpected
N2” disease patients, only 47 patients (37.6%) received
IMS, which included 46 EBUS and only 1 who underwent
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Fig 2. Survival rates according to histologic subtype (le upper)
with signicant dierence between the subgroups (p = 0.019),
where it can be seen the ve-year survival rate in the adenocarcinoma
group was 24% and 14% in the squamous cell carcinoma group.
Right upperpicture shows the survival rates according to cell
dierentiation; where the ve-year survival rates of well, moderate
and poor dierentiation were 45%, 24%, and 13%, respectively.
Dierence between the subgroup was signicant (p = 0.004).
Survival rates according to T-staging of the tumor characteristic
(right lower). ere was no signicant dierence between T1,
T2, T3, and T4 (p = 0.282).
Fig 3. Survival rate according to visceral plural invasion (le) and lymphovascular invasion (right). e 5-year survival rate of patients with
pleural invasion was 16%, while it was 26% in the absence group, with no signicant dierence (p = 0.199). For the lymphovascular invasion,
the presence group had a 5-year survival of 15%, while the absence group it was 38%; however, there was no signicant dierence (p =
0.097).
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Fig 4. Survival rate according to number of N2 station metastasis
(le upper); the 5-year survival rate of single station metastasis was
25% while the multiple station metastasis was 18%. However, there
was no statistically signicant dierence (p = 0.103). Survival rate
according to receiving adjuvant therapy (Right upper); the 5-year
survival rate of patients who had received CMT/RT was 30%, while
for radiation therapy alone, chemotherapy alone or had not received
adjuvant therapy, the rates were 25%, 15%, and 10%, and the dierence
was statistically signicant. e le lower gure showed survival
rate according to post-treatment re-staging; the 5-year survival of
patients with the presentation of distant metastasis in any organ was
10% while the group with no distant metastasis was 40%. e signicant
dierence was high, p = 0.003.
TABLE 3. Multivariate analysis of the risk factors of mortality.
Variables Number of patients Adjusted OR (95%CI) p-value
Adenocarcinoma 103 1.378 (0.655–2.902) 0.398
Poor differentiation 27 2.345 (0.734–7.489) 0.150
Visceral pleural invasion 81 0.838 (0.477–1.474) 0.541
Lymphovascular invasion 88 0.725 (0.421–1.247) 0.245
Multiple N2 82 1.429 (0.819–2.494) 0.209
Adjuvant therapy
52 0.367 (0.176–0.766) 0.008
(CMT/RT)
Distant metastasis 66 2.280 (1.334–3.897) 0.003
Adjusted OR, adjusted odds ratio; CI, condence interval.
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mediastinoscopy; all the invasive study results were
either negative for malignancy or had inadequate tissue
for evaluation. Although our population was based on
a clinical non-N2 group with pathological N2 disease
conrmed by the nal pathological report, the rate of
patients who received IMS was not dierent. Whereas
numerous population-based studies have shown low
rates of lung cancer patients who have underwent IMS,
ranging from 21%-27%,
12-18
our result showed higher
rates of IMS.
e information suggests that preoperative non-
invasive image staging only revealing a low suspicion of
N2 metastasis is not adequate. For patients who had a
preoperative PET/CT done, the information provided was
also inadequate. Further prospective randomized trials
on the role of PET/CT are needed. All the patients who
received IMS staging, such as by EBUS, had many false
negatives, leading to a dispute over inadequate tissue.
is was similar to a previous study by Sawhney,
19
which
showed a very low incidence of unexpected N2 disease
by EBUS (3%) when only a CT scan was performed for
preoperative staging, which, when compared to other
modalities, such as mediastinoscopy, video-assisted
mediastinoscopic lymphadenectomy (VAMLA), or
open biopsy of mediastinal lymph node, might play an
important role in the preoperative staging consensus
with previous studies. Further, Bendzsak et al,
20
showed
85% of patients used IMS, which concorded with the
guidelines,
6,21-23
Call et al,
24
concluded that VAMLA is
a feasible and highly accurate technique, with a rate of
unexpected N2–3 of 18%.
Compared to previous reports
3,4,25
, we considered the
dierent results about which adenocarcinoma cell type
and cell dierentiation were factors impacting the survival
rate in the comparisons; however, not T staging (T2),
visceral pleural invasion, and lymphovascular invasion,
which had insignicant dierences in the survival rates
in comparison, even though we found this coincident
with the N2 metastasis (71.2%, 69.6%, and 75.2%). e
number of N2 stations and associated N1 did not show
a statistical relation with unexpected N2, although the
coincidence of multiple N2 stations was rather high
(68.8%). Mediastinal lymph node station 7 was the most
common position for nding unexpected N2 (49.6%),
which was compatible with Eckardt and colleagues
26
,
who reported subcarinal lymph node metastases were
common in NSCLC regardless of the primary location
and should be considered an IMS modality or routinely
dissected during operation.
e present study reported an overall 5-year survival
of only 20% for patients with unexpected N2 disease
despite complete pulmonary resection and systematic
mediastinal lymphadenectomy being achieved, which
correlated with previous studies that reported 5-year
survival rates varying from 10%–38%.
7-10
Surgery is
benecial in early stage NSCLC
27
but still controversial
in stage IIIA-N2, reecting the general trend away from
surgery.
28,29
Pneumonectomy for lung cancer also results
in poor prognosis and followed by several post operative
complication
30
, since then this operation is less performed.
Comparison of the survival rate showed that in our series,
patients who had received adjuvant chemo-radiation
therapy had a better survival rate than the others (p
= 0.011). Pathological N2 disease indicates a systemic
spreading, and like in a previous study, it was found
that systemic therapy tends to play a more important
role and improve survival more than surgery alone
31-33
,
whereby we found a correlation to distant metastases
in 71 patients (56.8%), with a signicant dierence in
the survival comparison (p = 0.003). e multivariate
analysis results also supported that CMT/RT and distant
metastases are independent factors for survival.
ere are several limitations of this study to note.
First, the study population only involved a single group
of clinical N0/N1 patients with unexpected N2 disease,
and we did not compare the overall survival rates of early
stage (stage I–II) patients. Second, as a result of the limited
population, IMS results showing false negatives were
analyzed with the unexpected N2 base patients, and so
the overall IMS information was inadequate. Other than
that, in general, adjuvant chemotherapy is considered in
all patients with N2 disease, despite complete resection
previously being performed. However, in our study, it
depended on the patient preference. In particular, some
patients who were diagnosed distant metastases aer
complete re-staging declined receiving adjuvant therapy,
which might have resulted in a dierent survival rate.
CONCLUSION
e overall 5-year survival rate of unexpected N2
patients was low despite complete pulmonary resection and
mediastinal lymphadenectomy being achieved. Adjuvant
chemo-radiation therapy seems to improve survival for
those with unexpected N2 metastasis as it is a systemic
disease. However, not all patients received IMS, and those
who did it was mostly by EBUS and which had a high
false negative, leading to underestimating the staging.
Other modalities, such as cervical mediastinoscopy, video-
assisted mediastinoscopic lymphadenectomy (VAMLA)
or open biopsy should be considered for the adequate
evaluation of N2 metastasis, nonetheless further study
is still needed to compare each methods.
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REFERENCES
1. Friedel G, Steger V, Kyriss T, Zoller J, Toomes H. Prognosis
in N2 NSCLC. Lung Cancer 2004;45(Suppl):45-53.
2. Goya T, Asamura H, Yoshimura H, Kato H,Shimokata K,
Tsuchiya R, et al. Prognosis of 6644 resected non-small cell
lung cancers in Japan: a Japanese lung cancer registry study.
Lung Cancer 2005;50:227–34.
3. Kang CH, Ra YJ, Kim YT, Jheon SH, Sung SW,Kim JH. e
impact of multiple metastatic nodal stations on survival in
patients with resectable N1 and N2 nonsmall-cell lung cancer.
Ann orac Surg 2008;86:1092–7.
4. Hancock J, Rosen J, Moreno A, Kim AW, Detterbeck FC, Boa
DJ. Management of clinical stage IIIA primary lung cancers in
the national cancer database. Ann oracic Surg. 2014;98:424-
432.
5. De Leyn P, Lardinois D, Van Schil PE, Porta RR,Passlick B,
Zielinski M, et al. ESTS guidelines for preoperative lymph
node staging for non-small cell lung cancer. Eur J Cardiothorac
Surg 2007;32:1-8.
6. Silvestri GA, Gonzalez AV, Jantz MA, Margolis ML,Gould MK,
Tanoue LT, et al. Methods for staging non-small cell lung
cancer: Diagnosis and management of lung cancer, 3rd ed:
American College of Chest Physicians evidence-based clinical
practice guidelines. Chest 2013;143(5 Suppl):e211S-50S.
7. Van Klaveren RJ, Festen J, Otten HJ, Cox AL, de Graaf R,
Lacquet LK. Prognosis of unsuspected but completely resectable
N2 non-small cell lung cancer. Ann orac Surg 1993;56:300-4.
8. Goldstraw P, Mannam GC, Kaplan DK, Michail P. Surgical
management of non-small-cell lung cancer with ipsilateral
mediastinal node metastasis (N2 disease). J orac Cardiovasc
Surg 1994;107:19-27.
9. De Leyn P, Schoonooghe P, Denee G, Van Raemdonck D,
Coosemans W,Vansteenkiste J, et al. Surgery for non-small cell
lung cancer with unsuspected metastasis to ipsilateral mediastinal
or subcarinal nodes (N2 disease). Eur J Cardiothorac Surg 1996;
10:649-54.
10. Cerfolio RJ, Bryant AS. Survival of patients with unsuspected N2
(stage IIIA) nonsmall-cell lung cancer. Ann orac Surg 2008;
86:362–7.
11. Krantz SB, Howington JA, Wood DE, Kim KW,Kosinski AS,
Cox ML, et al. Invasive mediastinal staging for lung cancer
by Society of oracic Surgeons Database participants. Ann
orac Surg. 2018;106:1055-62.
12. Little AG, Rusch VW, Bonner JA, Gaspar LE,Green MR,Webb
WR, et al. Patterns of surgical care of lung cancer patients.
Ann orac Surg. 2005;80:2051-6.
13. Little AG, Gay EG, Gaspar LE, Stewart AK. National survey
of non-small cell lung cancer in the United States: epidemiology,
pathology and patterns of care. Lung Cancer. 2007;57:253-60.
14. Farjah F, Flum DR, Ramsey SD, Heagerty PJ, Symons RG,
Wood DE. Multi-modality mediastinal staging for lung cancer
among Medicare beneciaries. Jorac Oncol. 2009;4:355–363.
15. Vest MT, Tanoue L, Soulos PR, Kim AW,Detterbeck F,
Morgensztern D, et al. oroughness of mediastinal staging in
stage IIIA non-small cell lung cancer. Jorac Oncol. 2012;7:188-
95.
16. Ost DE, Niu J, Elting LS, Buchholz TA, Giordano SH.
Determinantsof practice patterns and quality gaps in lungcancer
staging and diagnosis. Chest. 2014;145:1097-113.
17. Ost DE, Niu J, Elting LS, Buchholz TA, Giordano SH. Quality
gaps and comparative eectiveness in lung cancer staging and
diagnosis. Chest. 2014;145:331-45.
18. Faris N, Yu X, Sareen S, Signore RS,McHugh LM,Roark K,
et al. Preoperative evaluation of lung cancer in a community
health care setting. Ann orac Surg. 2015;100:394-400.
19. Sawhney MS, Bakman Y, Holmstrom AM, Nelson DB,Lederle
FA,Kelly RF. Impact of pre-operative endoscopic ultrasound
on non-small cell lung cancer staging. Chest. 2007;132:916-21.
20. Bendzsak A, Waddell TK, Yasufuku K, Keshavjee S,Perrot
M,Cypel M, et al. Invasive Mediastinal Staging Guideline
Concordance. Ann orac Surg. 2017;103:1736-41.
21. Darling G, Dickie J, Malthaner R, Kennedy E, Tey R. Invasive
mediastinal staging of non-small cell lung cancer. A Quality
Initiative of the Program in Evidence-Based Care (PEBC),
Cancer Care Ontario [Internet]. 2010; Evidence-Based Series
17-6. Accessed September 21, 2016.
22. Darling GE, Dickie AJ, Malthaner RA, Kennedy EB, Tey R.
Invasive mediastinal staging of non-small-cell lung cancer: a
clinical practice guideline. Curr Oncol. 2011;18:e304-10.
23. De Leyn P, Dooms C, Kuzdzal J, Lardinois D,Passlick B,Rami-
Porta R, et al. Revised ESTS guide- lines for preoperative
mediastinal lymph node staging for non-small-cell lung cancer.
Eur J Cardiothorac Surg. 2014;45:787-98.
24. Call S, Obiols C, Rami-Porta R, Trujillo-Reyes JC,Iglesias M,
Saumench R, et al. Video-Assisted Mediastinoscopic
Lymphadenectomy for Staging Non-Small Cell Lung Cancer.
Ann orac Surg. 2016;101:1326-33.
25. Riquet M, Bagan P, Barthes FL, Banu E, Scotte F, Foucault C,
et al. Completely resected non-small cell lung cancer: reconsidering
prognostic value and signicance of N2 metastases. Ann orac
Surg. 2007;84(6):1818-24.
26. Eckardt J, Jakobsen E, Licht PB. Subcarinal Lymph Nodes
Should be Dissected in All Lobectomies for Non-Small Cell
Lung Cancer-Regardless of Primary Tumor Location. Ann
orac Surg. 2017;103:1121-5.
27. Howington JA, Blum MG, Chang AC, Balekian AA, Murthy
SC. Treatment of stage I and II non-small cell lung cancer:
Diagnosis and management of lung cancer. 3rd ed. American
College of Chest Physicians evidence- based clinical practice
guidelines. Chest. 2013;143(5 Suppl): e278S-313S.
28. Ramnath N, Dilling TJ, Harris LJ, Kim AW,Michaud GC,Balekian
AA, et al. Treatment of stage III non-small cell lung cancer:
Diagnosis and management of lung cancer. 3rd ed. American
College of Chest Physicians evidence-based clinical practice
guidelines. Chest. 2013;143(5 Suppl):e314S-40S.
29. Cerfolio RJ, Maniscalco L, Bryant AS. e treatment of patients
with stage IIIA non-small cell lung cancer from N2 disease:
who returns to the surgical arena and who survives. Ann
orac Surg. 2008;86:912-20.
30. Wongkornrat W, Sriyoscharti S, Phanchaipetch T, Subtaweesin
T, ongchareon P, Sakiyalak P, et al. Long-Term Outcome aer
Pneumonectomy at Siriraj Hospital.Siriraj Med J. 2020;64(1):11-14.
31. Rosell R, Gomez-Codina J, Camps C, Sánchez JJ,Maestre J,
Padilla J,et al. Preresectional chemotherapy in stage IIIA
non-small-cell lung cancer: a 7-year assessment of a randomized
controlled trial. Lung Cancer. 1999;26:7-14.
32. Roth J, Fossella F, Komaki R, Ryan MB,Putnam Jr JB,Lee JS,
et al. A randomized trial comparing perioperative chemotherapy
and surgery with surgery alone in resectable stage IIIA non-
small-cell lung cancer. J Natl Cancer Inst. 1994;86:673-80.
33. Vansteenkiste JF, De Leyn PR, Denee GJ, Lerut TE,Demedts
MG. Clinical prognostic factors in surgical treated stage IIIA-N2
non- small cell lung cancer: analysis of the literature. Lung
Cancer. 1998;19:3-13.
Geanphun et al.
