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Lobectomy Is Associated with Better Outcomes than Sublobar Resection in Spread through Air Spaces (STAS)-Positive T1 Lung Adenocarcinoma: A Propensity Score–Matched Analysis

Open ArchivePublished:September 19, 2018DOI:https://doi.org/10.1016/j.jtho.2018.09.005

      Abstract

      Introduction

      Spread through air spaces (STAS) is a form of invasion wherein tumor cells extend beyond the tumor edge within the lung parenchyma. In lung adenocarcinoma (ADC), we investigated the (1) association between STAS and procedure-specific outcomes (sublobar resection and lobectomy), (2) effect of surgical margin-to-tumor diameter ratio in STAS-positive patients, and (3) potential utility of frozen sections (FSs) for detecting STAS intraoperatively.

      Methods

      We investigated 1497 patients who underwent lobectomy (n = 970) or sublobar resection (n = 527) for T1N0M0 lung ADC after propensity score matching. Outcomes were analyzed by using a competing risks approach. The effect of margin-to-tumor ratio on recurrence pattern (locoregional and distant) was investigated in patients who underwent sublobar resection. Five pathologists evaluated the feasibility of intraoperatively identifying STAS by using FSs (sensitivity, specificity, and interrater reliability).

      Results

      On multivariable analysis after propensity score matching (349 pairs/procedure), sublobar resection was significantly associated with recurrence (subhazard ratio = 2.84 [p < 0.001]) and lung cancer–specific death (subhazard ratio = 2.63 [p = 0.021]) in patients with STAS but not in those without STAS. Patients with STAS who underwent sublobar resection had a higher risk of locoregional recurrence regardless of margin-to-tumor ratio (for a margin-to-tumor ratio of ≥1 versus <1, the 5-year cumulative incidence of recurrence rates were 16% and 25%, respectively); among patients without STAS, locoregional recurrences occurred in patients with margin-to-tumor ratio lower than 1 (a 5-year cumulative incidence of recurrence rate of 7%). The sensitivity and specificity for detecting STAS by use of FSs were 71% and 92%, with substantial interrater reliability (Gwet’s AC1, 0.67).

      Conclusions

      In patients with T1 lung ADC with STAS, lobectomy was associated with better outcomes than sublobar resection was. Pathologists can recognize STAS on FSs.

      Keywords

      Introduction

      Anatomical surgical resection by lobectomy is the standard of care for the management of early-stage lung adenocarcinoma (ADC), the most common histologic subtype of NSCLC.
      U.S. Department of Health and Human Services
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      This practice is influenced by the Lung Cancer Study Group 821 randomized trial,
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      which showed that sublobar resection was associated with a higher risk of recurrence than lobectomy for patients with T1N0M0 NSCLC.

      National Comprehensive Cancer Centers. NCCN clinical practice guidelines in oncology: non-small cell lung cancer v5. 2017. http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed July 16, 2018.

      Despite ongoing concerns about the adequacy of sublobar resection for cure,
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      An analysis of patients with stage I NSCLC from the Surveillance, Epidemiology, and End Results database (1998–2009) showed that both the incidence of small (≤2 cm) NSCLC tumors (most of which are lung ADCs) and the use of sublobar resection are increasing.
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      More importantly, we found that presence of the micropapillary (MIP) histologic subtype predisposes patients undergoing sublobar resection for small lung ADC to a higher risk of locoregional recurrence
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      despite a negative surgical margin. This observation led us to investigate the resected lung beyond the edge of the tumor. We thereby identified a previously unrecognized pattern of invasion: tumor spread through air spaces (STAS), which is defined as tumor cells existing within air spaces in the lung parenchyma beyond the tumor edge. STAS is present in 38% of T1a lung ADCs.
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      Tumor spread through air spaces is an important pattern of invasion and impacts the frequency and location of recurrences after limited resection for small stage I lung adenocarcinomas.
      We were the first to report that STAS is significantly associated with a higher risk of locoregional recurrence after sublobar resection.
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      • et al.
      Tumor spread through air spaces is an important pattern of invasion and impacts the frequency and location of recurrences after limited resection for small stage I lung adenocarcinomas.
      The prognostic importance of STAS has been validated in cohorts from multiple institutional databases
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      Tumor islands in resected early-stage lung adenocarcinomas are associated with unique clinicopathologic and molecular characteristics and worse prognosis.
      and for other NSCLC histologic subtypes.
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      Spread through air spaces (STAS) is an independent predictor of recurrence and lung cancer-specific death in squamous cell carcinoma.
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      Tumor spread through air spaces is an independent predictor of recurrence-free survival in patients with resected lung squamous cell carcinoma.
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      • et al.
      High frequency of spread through air spaces in resected small cell lung cancer.
      Achieving a surgical margin greater than the diameter of the tumor has been recommended as a strategy to decrease the incidence of recurrence after sublobar resection.

      National Comprehensive Cancer Centers. NCCN clinical practice guidelines in oncology: non-small cell lung cancer v5. 2017. http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed July 16, 2018.

      • Schuchert M.J.
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      Anatomic segmentectomy in the treatment of stage I non-small cell lung cancer.
      A recent study reported that among 31 STAS-positive tumors, the distance between the farthest STAS lesion and the tumor edge did not exceed the tumor diameter.
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      Impact of free tumor clusters on prognosis after resection of pulmonary adenocarcinoma.
      We hypothesized that in STAS-positive T1N0M0 lung ADCs, achieving a surgical margin greater than the tumor diameter may reduce the incidence of recurrence after sublobar resection. The aim of this study was to investigate the effect of STAS and surgical margin on procedure-specific outcomes (recurrence and lung cancer–specific death) in patients with early-stage lung ADC. Propensity score matching between patients who underwent lobectomy and sublobar resection was performed with the use of clinical and pathologic factors to address selection bias and differential outcomes between patients who undergo lobectomy versus sublobar resection.
      Although histologic subtype can affect outcomes in a procedure-specific manner (lobectomy versus sublobar resection), preoperative imaging and frozen sections (FSs) are unable to accurately identify the predominant or presence of histologic subtype, which would aid in determining the most appropriate resection to perform.
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      • Nitadori J.
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      • et al.
      Using frozen section to identify histological patterns in stage I lung adenocarcinoma of </= 3 cm: accuracy and interobserver agreement.
      In this study, we assessed the potential utility of FS analysis for detecting STAS intraoperatively by investigating the sensitivity, specificity, and interrater reliability of identifying STAS on FSs across five pathologists.

      Methods

      Study Cohort

      This retrospective study was approved by the institutional review board at Memorial Sloan Kettering Cancer Center (WA0269-08). The prospectively maintained lung cancer database of the Memorial Sloan Kettering Cancer Center's Thoracic Service was reviewed to identify consecutive patients who had been surgically treated for 3-cm or smaller pathologic stage (p-Stage) I lung ADC between January 1, 1995, and December 31, 2014. p-Stage was based on the eighth edition of the American Joint Committee on Cancer Staging Manual.
      Exclusion criteria are shown in Figure 1. In total, 1497 patients met the inclusion criteria. Additional information on pathologic lymph node evaluation and data collection is available in Supplementary Method 1, Supplementary Method 2, and Supplementary Table 1.
      Figure thumbnail gr1
      Figure 1CONSORT diagram. Abbreviation: ADC, adenocarcinoma.

      Recurrence and Lung Cancer–Specific Death as End Points

      The study end points were recurrence and lung cancer–specific death. All recurrences were confirmed by clinical, radiologic, and pathologic assessment and were classified as locoregional or distant.
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      • Ferguson M.
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      • et al.
      American College of Chest Physicians and Society of Thoracic Surgeons consensus statement for evaluation and management for high-risk patients with stage I non-small cell lung cancer.
      Lung cancer–specific death was defined as death due to recurrent disease associated with resected lung cancer (Supplementary Method 3).
      • Eguchi T.
      • Bains S.
      • Lee M.C.
      • et al.
      Impact of increasing age on cause-specific mortality and morbidity in patients with stage I non-small-cell lung cancer: a competing risks analysis.

      Histologic Evaluation

      Tumor slides were reviewed by two experienced thoracic pathologists (S. L. and W. D. T. [Supplementary Methods 4]) who were blinded to patient clinical outcomes. Tumor STAS was defined as tumor cells either in clusters, solid nests, or aggregates of single cells within air spaces beyond the edge of the main tumor.
      • Kadota K.
      • Nitadori J.
      • Sima C.S.
      • et al.
      Tumor spread through air spaces is an important pattern of invasion and impacts the frequency and location of recurrences after limited resection for small stage I lung adenocarcinomas.
      Artifacts were excluded on the basis of previously described criteria.
      • Kadota K.
      • Nitadori J.
      • Sima C.S.
      • et al.
      Tumor spread through air spaces is an important pattern of invasion and impacts the frequency and location of recurrences after limited resection for small stage I lung adenocarcinomas.

      Assessment of Surgical Margin Distance and Effect of Margin-to-Tumor Diameter on Recurrence Pattern

      Surgical margin distance was defined as the distance between the surgical staple margin and the nearest tumor edge, which was assessed by gross measurement using a ruler placed along the tumor and surrounding lung parenchyma in the gross specimen after cross-section of the tumor.
      • Nitadori J.
      • Bograd A.J.
      • Kadota K.
      • et al.
      Impact of micropapillary histologic subtype in selecting limited resection vs lobectomy for lung adenocarcinoma of 2cm or smaller.
      The relationship between surgical margin distance, tumor diameter, and recurrence patterns was evaluated by use of the ratio of surgical margin distance to tumor diameter (margin-to-tumor ratio).
      • Schuchert M.J.
      • Pettiford B.L.
      • Keeley S.
      • et al.
      Anatomic segmentectomy in the treatment of stage I non-small cell lung cancer.
      Cumulative incidence of each type of recurrence at 5 years (only locoregional recurrence, or distant recurrence including both locoregional and distant) was summarized separately in patients with or without STAS and compared between margin-to-tumor ratios of 1 or higher (surgical margin ≥ tumor diameter) and less than 1 (surgical margin < tumor diameter) by using the Gray test.

      Propensity Score Matching

      To reduce potential selection bias related to using a nonrandomized cohort to generate two groups (lobectomy and sublobar resection) with comparable characteristics, we performed propensity score–matched analyses. Year of surgery, age at surgery, sex, smoking status, chronic obstructive pulmonary disease (COPD), cardiovascular disease, diabetes mellitus, prior lung cancer, prior other malignancies, body mass index, forced expiratory volume in one second (FEV1, predicted), diffusion capacity of the lungs for carbon monoxide (DLCO, predicted), p-Stage, pathologic tumor size, invasive tumor size, lymphovascular invasion (LVI), visceral pleural invasion (VPI), necrosis, and STAS were used to achieve balance in covariates between the two groups. Balance of covariates between the groups was assessed by the absolute standardized mean difference (ASMD) before and after the matching procedure. An ASMD of 0.1 or less indicates balance in the covariate between the two groups.
      • Austin P.C.
      Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples.
      Additional information is available in Supplementary Method 5.

      Prognostic Analyses

      The outcomes of interest were recurrence and lung cancer–specific death, both of which were analyzed in the competing risk framework. For recurrence, death from any cause without recurrence was considered a competing event. For lung cancer–specific death, death from causes other than lung cancer or from unknown causes was considered a competing event. Cumulative incidence of recurrence (CIR) and lung cancer–specific cumulative incidence of death (LC-CID) were used to estimate the probability of recurrence or lung cancer–specific death after surgical resection with curative intent.
      • Dignam J.J.
      • Zhang Q.
      • Kocherginsky M.
      The use and interpretation of competing risks regression models.
      Patients who did not experience recurrence or die during the study period were censored at the time of the last available follow-up. Differences in CIR or LC-CID between groups were tested by using the Gray method.
      • Gray R.J.
      A Class of K-sample tests for comparing the cumulative incidence of a competing risk.
      Associations between variables and CIR or LC-CID were estimated by using Gray and Fine models.
      • Fine J.P.
      • Gray R.J.
      A proportional hazards model for the subdistribution of a competing risk.
      Multivariable models were constructed in a backwards selection approach starting with variables with a p value less than 0.1 from the univariable analyses. Statistical analyses were performed by using R software (version 3.1.1, R Foundation for Statistical Computing, Vienna, Austria); the survival and cmprsk software packages were used in the analyses. All p values were two sided; significance was set at 5%.

      FS Analysis for Detection of STAS

      To evaluate the feasibility of using FSs for intraoperative detection of STAS, we assessed the performance of FS slide reporting. FS slides were selected to identify cases that had substantial nonneoplastic lung parenchyma to allow for evaluation of STAS. Performance was quantified by sensitivity, specificity, and interrater reliability (agreement). FS analysis was performed on 48 lung ADC tumors for which complete FS slides, FS control slides, and permanent tumor slides were available with adequate adjacent lung parenchyma. The FS slides were independently reviewed for STAS status by five pathologists (S. L., J. C. C., J. M., N. R., and W. D. T.) who were blinded to patient clinicopathologic data. This FS slide review to identify STAS was performed specifically for the purposes of this study after reporting of the final pathologic results. Gwet's AC1 statistic,
      • Gwet K.L.
      Computing inter-rater reliability and its variance in the presence of high agreement.
      which is an alternative to the kappa statistic
      • Fleiss J.L.
      Measuring nominal scale agreement among many raters.
      when there is potential extreme distribution across categories, was applied to evaluate interrater reliability. The degree of agreement was interpreted as follows: slight agreement, AC1 from 0.00 to 0.20; fair agreement, AC1 from 0.21 to 0.40; moderate agreement, AC1 from 0.41 to 0.60; substantial agreement, AC1 from 0.61 to 0.80; and almost perfect agreement, AC1 of 0.81 or higher. Additional information is available in Supplementary Method 6.

      Results

      Patient Characteristics: Lobectomy versus Sublobar Resection before and after Propensity Score Matching

      Table 1 lists patient clinicopathologic characteristics and the differences between the lobectomy and sublobar cohorts before and after propensity score matching. Before matching, 18 of 25 covariates were unbalanced (ASMD ≥ 0.1) between lobectomy and sublobar resection. The 1:1 matching for lobectomy versus sublobar resection resulted in 349 matched pairs (n = 698) with balanced covariates (ASMD ≤ 0.1) except for prior lung cancer (ASMD = 0.105).
      Table 1Patient Demographic Characteristics and Difference between Lobar and Sublobar Resection before and after Propensity Score Matching
      CharacteristicBefore Matching (n = 1497)After Matching (n = 698)
      Lobectomy (n = 970)Sublobar (n = 527)ASMD
      ASMD of 0.1 or lower indicates balance in the covariate between the two groups.
      Lobectomy (n = 349)Sublobar (n = 349)ASMD
      ASMD of 0.1 or lower indicates balance in the covariate between the two groups.
      Clinicopathologic variables
       Period of surgery
      1995–199968 (7)22 (4)0.43515 (4)15 (4)0.030
      2000–2004244 (25)63 (12)45 (13)46 (13)
      2005–2009341 (35)179 (34)117 (34)121 (35)
      2010–2014317 (33)263 (50)172 (49)167 (48)
       Age at surgery, y69 (61–75)70 (64–76)0.20369 (64–75)70 (63–76)0.045
       Sex
      Female601 (62)337 (64)0.041222 (64)222 (64)<0.001
      Male369 (38)190 (36)127 (36)127 (36)
       Smoking
      Never181 (19)87 (17)0.06664 (18)59 (17)0.085
      Former669 (69)379 (72)236 (68)249 (71)
      Current120 (12)61 (12)49 (14)41 (12)
       COPD positive157 (16)135 (26)0.23473 (21)78 (22)0.035
       CVD positive175 (18)141 (27)0.21084 (24)84 (24)<0.001
       DM positive90 (9)75 (14)0.15443 (12)54 (15)0.091
       Prior LC positive24 (2)105 (20)0.57618 (5)27 (8)0.105
       Prior malignancy positive240 (25)199 (38)0.280120 (34)129 (37)0.054
       BMI (n = 1495)26 (23–30)27 (24–30)0.09827 (23–30)27 (24–30)0.054
       FEV1, % (n = 1435)92 (80–105)86 (69–101)0.32389 (78–101)90 (71–104)0.071
       DLCO, % (n = 1377)84 (70–97)79 (64–92)0.32882 (67–95)82 (66–94)0.097
       Serum creatinine level (mg/dL) (n = 1450)1.0 (0.8–1.2)1.0 (0.8–1.2)0.0441.0 (0.8–1.2)1.0 (0.8–1.2)0.038
       SUVmax (n = 1226)2.5 (1.4–4.7)2.1 (1.0–3.6)0.2592.1 (1.1–4.0)2.2 (1.2–3.9)0.062
       Pathologic tumor size, cm1.8 (1.3–2.3)1.4 (1.0–1.8)0.6701.5 (1.1–1.9)1.5 (1.1–1.9)0.037
       Invasive tumor size, cm1.4 (1.0–2.0)1.0 (0.6–1.5)0.6781.1 (0.7–1.5)1.1 (0.7–1.5)0.017
       p-Stage
      IA1144 (15)172 (33)0.57396 (28)96 (28)0.019
      IA2453 (47)223 (42)158 (45)160 (46)
      IA3252 (26)49 (9)43 (12)41 (12)
      IB121 (12)83 (16)52 (15)52 (15)
       LVI positive384 (40)165 (31)0.174108 (31)111 (32)0.019
       VPI positive120 (12)83 (16)0.09752 (15)52 (15)<0.001
       Necrosis (n = 1478) positive121 (13)35 (7)0.20134 (10)28 (8)0.060
       Histologic grade
      Low132 (14)129 (24)0.28173 (21)78 (22)0.066
      Intermediate604 (62)292 (55)197 (56)201 (58)
      High234 (24)106 (20)79 (23)70 (20)
       Presence (≥5%) of LEP pattern616 (64)366 (69)0.126242 (69)241 (69)0.006
       Presence (≥5%) of MIP pattern473 (49)231 (44)0.099160 (46)143 (41)0.098
       Presence (≥5%) of SOL pattern386 (40)194 (37)0.061122 (35)128 (37)0.036
       STAS positive389 (40)218 (41)0.026141 (40)135 (39)0.035
       Mutation status (n = 1306)
      Wild type440 (51)230 (52)0.117161 (50)151 (52)0.057
      EGFR181 (21)75 (17)61 (19)49 (17)
      KRAS240 (28)140 (31)99 (31)91 (31)
      OutcomesP
       Any recurrence991023063
      Only locoregional recurrence2457634
      Distant recurrence75452429
       Any death2121556896
      Lung cancer–specific death57581634
      Other cause/unknown death155975262
       5-y CIR, %12 (10–14)21 (18–26)10 (7–14)20 (16–25)<0.001
       5-y LC-CID, %6 (4–7)11 (8–15)6 (4–10)9 (6–13)0.013
       5-y overall survival, %84 (82–87)74 (69–78)82 (77–87)78 (74–83)0.015
      Note: Data are number (%), median (25th and 75th percentiles), or 5-year cumulative incidence or survival rate (95% confidence interval [lower-upper]). Boldface indicates statistical significance.
      ASMD, absolute standardized mean difference; BMI, body mass index; CIR, cumulative incidence of recurrence; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular disease; DLCO, diffusion capacity of the lung for carbon monoxide; DM, diabetes mellitus; FEV1, forced expiratory volume in one second; LC, lung cancer; LC-CID, lung cancer–specific cumulative incidence of death; LEP, lepidic; LVI, lymphovascular invasion; MIP, micropapillary; p-Stage, pathologic stage; SOL, solid; STAS, spread through air spaces; SUVmax, maximum standardized uptake value; VPI, visceral pleural invasion.
      a ASMD of 0.1 or lower indicates balance in the covariate between the two groups.

      CIR and LC-CID Analysis after Matching: Sublobar Resection versus Lobectomy

      There was no significant difference in CIR between lobectomy and sublobar resection in patients without STAS (Fig. 2A); however, in patients with STAS, sublobar resection was associated with a significantly higher risk of recurrence than lobectomy was (Fig. 2B) (5-year CIR, 39% versus 16%; p < 0.001). Similar results were observed in LC-CID analyses (Fig. 2C and D). Further analyses to validate the significance of STAS demonstrated that (1) there were no unbalanced clinicopathologic covariates between lobectomy and sublobar resection in both the STAS-positive and STAS-negative cohorts (Supplementary Table 2) and (2) the magnitude of difference in survival outcomes between lobectomy and sublobar resection by STAS status was not influenced by p-Stage, LVI, necrosis, or MIP and solid (SOL) patterns (Supplementary Figs. 1 and 2). For example, sublobar resection had a worse prognosis than lobectomy did regardless of necrosis status (see Supplementary Fig. 2B).
      Figure thumbnail gr2
      Figure 2Cumulative incidence of recurrence (CIR) and lung cancer–specific cumulative incidence of death (LC-CID) curves for lobectomy and sublobar resection. CIR (A and B) and LC-CID (C and D) curves comparing lobectomy with sublobar resection in patients with spread through air spaces (STAS)-negative tumors and patients with STAS-positive tumors are shown. In patients with STAS-negative tumors, risk of recurrence (A) and lung cancer–specific death (C) did not differ significantly between lobectomy and sublobar resection; however, in patients with STAS-positive tumors, sublobar resection was associated with a significantly higher risk of recurrence (B) and lung cancer–specific death (D) (sublobar resection versus lobectomy: a 5-year CIR of 39% versus 16% [p < 0.001]; 5-year CID, 16% versus. 8% [p = 0.005]). CI, confidence interval.
      In the present study, owing to the small number of patients undergoing segmentectomy, segmentectomy and wedge resection were treated as one group. However, we include a CIR and LC-CID analysis that compared three procedures (lobectomy, segmentectomy, and wedge resection) in Supplementary Figure S3. In patients with STAS, both segmentectomy and wedge resection had higher CIR and LC-CID than lobectomy.

      Univariable and Multivariable Competing Risk Regression Analysis after Matching

      Table 2 shows the results of univariable analyses for both survival end points of interest. Factors significantly associated with a higher risk of recurrence were sublobar resection, COPD, prior lung cancer, lower FEV1, lower DLCO, higher creatinine level, higher maximum standardized uptake value, larger tumor size, larger invasive tumor size, higher stages, LVI, VPI, necrosis, higher histologic grade, absence of lepidic pattern, presence of MIP, presence of SOL, and absence of EGFR mutation. Factors significantly associated with a higher risk of lung cancer–specific death were sublobar resection, smoking, COPD, lower FEV1, lower DLCO, larger invasive tumor size, higher stages, LVI, VPI, necrosis, higher histologic grade, presence of MIP, presence of SOL, and absence of EGFR mutation.
      Table 2Univariable Competing Risk Regression for Recurrence and Lung Cancer–Specific Death after Propensity Score Matching
      RecurrenceLung Cancer–Specific Death
      SHR95% CIp ValueSHR95% CIp Value
      Sublobar resection (vs. lobectomy)2.19(1.42–3.37)<0.0012.10(1.16–3.80)0.014
      Age at surgery (per 1-y increase)1.01(0.99–1.03)0.41.02(0.99–1.05)0.2
      Male sex (vs. female)1.38(0.92–2.08)0.121.60(0.92–2.77)0.094
      Smoking (vs. never)
       Former1.29(0.71–2.34)0.49.42(1.29–68.85)0.027
       Current1.25(0.57–2.77)0.611.34(1.42–90.56)0.022
      COPD history (vs. no COPD)1.75(1.12–2.71)0.0132.25(1.27–3.98)0.005
      CVD history (vs. no CVD)0.86(0.52–1.41)0.51.02(0.53–1.94)1
      DM history (vs. no DM)0.78(0.40–1.51)0.50.80(0.32–2.01)0.6
      Prior LC (vs. no prior LC)2.96(1.67–5.23)<0.0011.67(0.66–4.23)0.3
      Prior malignancy (vs. no prior malignancy)0.80(0.52–1.24)0.30.69(0.38–1.25)0.2
      BMI (per 1 index)0.99(0.95–1.02)0.50.96(0.92–1.00)0.076
      FEV1 (per 1%)0.99(0.98–1.00)0.0090.99(0.97–1.00)0.039
      DLCO (per 1%)0.99(0.98–1.00)0.0140.99(0.97–1.00)0.021
      Serum creatinine level (per 1 mg/dL increase)1.93(1.15–3.24)0.0132.84(1.37–5.89)0.005
      SUVmax (per 1 SUV increase)1.07(1.03–1.12)0.0011.07(1.01–1.14)0.025
      Pathologic tumor size (per 1 cm increase)1.44(1.00–2.06)0.0481.24(0.73–2.12)0.4
      Invasive tumor size (per 1 cm increase)2.27(1.71–3.01)<0.0011.95(1.33–2.87)<0.001
      p-Stage (vs. IA1)
       IA22.83(1.43–5.57)0.0031.98(0.80–4.88)0.14
       IA32.37(0.96–5.85)0.0621.90(0.53–6.78)0.3
       IB6.15(2.98–12.67)<0.0016.12(2.47–15.43)<0.001
      LVI (vs. no LVI)4.10(2.70–6.24)<0.0014.68(2.59–8.46)<0.001
      VPI (vs. no VPI)2.84(1.82–4.45)<0.0013.73(2.11–6.58)<0.001
      Necrosis (vs. no necrosis)3.35(2.02–5.57)<0.0013.94(2.05–7.55)<0.001
      Histologic grade (vs. low)
       Intermediate8.76(2.77–27.71)<0.00111.71(1.61–85.13)0.015
       High9.12(2.76–30.18)<0.00116.37(2.19–122.59)0.007
      Presence of LEP pattern (vs. no LEP pattern)0.59(0.39–0.89)0.0120.59(0.34–1.02)0.060
      Presence of MIP pattern (vs. no MIP pattern)3.14(2.01–4.89)<0.0012.11(1.19–3.74)0.010
      Presence of SOL pattern (vs. no SOL pattern)3.05(2.02–4.62)<0.0014.47(2.45–8.15)<0.001
      STAS (vs. no STAS)3.80(2.45–5.90)<0.0013.31(1.85–5.95)<0.001
      Note: Boldface indicates statistical significance.
      BMI, body mass index; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular disease; DLCO, diffusion capacity of the lung for carbon monoxide; DM, diabetes mellitus; FEV1, forced expiratory volume in one second; LC, lung cancer; LEP, lepidic; LVI, lymphovascular invasion; MIP, micropapillary; p-Stage, pathologic stage; SHR, subhazard ratio; SOL, solid; STAS, spread through air spaces; SUVmax, maximum standardized uptake value; VPI, visceral pleural invasion.
      Table 3 shows the results of the final multivariable competing risk regression model. In all patients after matching (n = 698), sublobar resection, resection type, prior lung cancer, p-Stage IB (versus IA1) disease, LVI, necrosis, presence of MIP, presence of SOL, and STAS were independent risk factors for recurrence. Sublobar resection, LVI, presence of SOL, and STAS were independent risk factors for lung cancer–specific death (see Table 3 [top]).
      Table 3Final Multivariable Competing Risk Regression Model for Recurrence and Lung Cancer–Specific Death after Propensity Score Matching in All Patients, Patients with STAS, and Patients without STAS
      PatientsRecurrenceLung Cancer–Specific Death
      SHR95% CIp ValueSHR95% CIp Value
      All patients after matching (n = 698)
       Sublobar resection (vs. lobectomy)2.33(1.46–3.70)<0.0011.95(1.07–3.58)0.030
       Prior LC (vs. no prior LC)2.96(1.67–5.26)<0.001
       p-Stage (vs. IA1)
      IA21.60(0.79–3.25)0.191.14(0.43–3.00)0.8
      IA31.74(0.70–4.34)0.21.58(0.47–5.34)0.5
      IB2.30(1.02–5.19)0.0442.46(0.89–6.80)0.082
       LVI (vs. no LVI)2.00(1.18–3.29)0.0092.16(1.03–4.18)0.042
       Necrosis (vs. no necrosis)2.17(1.20–3.91)0.0101.70(0.84–3.41)0.14
       Presence of MIP pattern (vs. no MIP pattern)1.86(1.10–3.15)0.021
       Presence of SOL pattern (vs. no SOL pattern)1.51(0.93–2.45)0.0982.07(1.03–4.18)0.042
       STAS (vs. no STAS)1.88(1.07–3.30)0.0282.03(1.05 -3.94)0.035
      Patients with STAS after matching (n = 276)
       Sublobar resection (vs. lobectomy)2.84(1.59–5.08)<0.0012.63(1.16–5.95)0.021
       Prior LC (vs. no prior LC)2.64(1.30–5.33)0.007
       p-Stage (vs. IA1)
      IA21.34(0.58–3.06)0.50.90(0.29–2.84)0.9
      IA31.86(0.65–5.35)0.21.29(0.25–6.56)0.8
      IB1.62(0.63–4.18)0.32.15(0.66–7.08)0.2
       LVI (vs. no LVI)1.48(0.85–2.59)0.171.54(0.68–3.50)0.3
       Necrosis (vs. no necrosis)2.22(1.11–4.43)0.0231.52(0.68–3.44)0.3
       Presence of MIP pattern (vs. no MIP pattern)1.34(0.73–2.47)0.3
       Presence of SOL pattern (vs. no SOL pattern)1.08(0.60–1.92)0.81.38(0.62–3.08)0.4
      Patients without STAS after matching (n = 422)
       Sublobar resection (vs. lobectomy)1.93(0.88–4.21)0.101.56(0.56–4.30)0.4
       Prior LC (vs. no prior LC)4.60(1.65–12.8)0.004
       p-Stage (vs. IA1)
      IA21.97(0.59–6.56)0.31.30(0.22–7.84)0.8
      IA31.53(0.23–9.96)0.72.20(0.27–18.0)0.5
      IB4.19(1.06–16.46)0.0402.27(0.35–14.9)0.4
       LVI (vs. no LVI)4.23(1.60–11.2)0.0043.32(0.70–15.76)0.13
       Necrosis (vs. no necrosis)1.74(0.55–5.54)0.32.12(0.48–9.28)0.3
       Presence of MIP pattern (vs. no MIP pattern)2.29(1.04–5.03)0.040
       Presence of SOL pattern (vs. no SOL pattern)2.06(0.76–5.54)0.153.79(0.88–16.2)0.073
      Note: Boldface indicates statistical significance.
      CI, confidence interval; LC, lung cancer; LVI, lymphovascular invasion; MIP, micropapillary; p-Stage, pathologic stage; SHR, subhazard ratio; SOL, solid; STAS, spread through air spaces.
      Given that the impact of lobectomy and sublobar resection on recurrence and lung cancer–specific death varied significantly by STAS status (see Fig. 2), we conducted further multivariable analyses by using the same variables in two separate cohorts that were stratified by STAS status. In this analysis, sublobar resection was independently associated with both recurrence and lung cancer–specific death in patients with STAS (see Table 3 [middle]) (subhazard ratio for recurrence = 2.84 [p < 0.001] and subhazard ratio for lung cancer–specific death = 2.63 [p = 0.021) but not in patients without STAS (see Table 3 [bottom]).

      Impact of Margin-to-tumor Ratio on Recurrence after Sublobar Resection in STAS-Positive Tumors

      The relationship between margin-to-tumor ratio and recurrence patterns is shown in Figure 3. Among patients with STAS-negative tumors, if the margin-to-tumor ratio was 1 or higher (surgical margin ≥ tumor diameter), recurrence was rare and no locoregional recurrence was observed. In STAS-negative tumors, a margin-to-tumor ratio of 1 or higher was associated with a significantly lower risk of recurrence (particularly locoregional recurrence) than was a margin-to-tumor ratio less than 1 (for a margin-to-tumor ratio of ≥1 versus <1, the 5-year CIR for any recurrence was 5% versus 12% [p = 0.038], the 5-year CIR for locoregional recurrence only was 0% versus 7% [p = 0.008], and the 5-year CIR for distant recurrence was 5% versus 5% [p = 0.7]).
      Figure thumbnail gr3
      Figure 3Relationship between margin-to-tumor ratio and recurrence pattern after sublobar resection by tumor spread through air spaces (STAS) status. Margin-to-tumor ratio was defined as the ratio of surgical margin distance to tumor diameter. Patients who underwent sublobar resection with available surgical margin assessment were divided into two groups on the basis of STAS status: STAS-negative (A) and STAS-positive (B) status. Each dot represents a patient and is plotted on the basis of tumor size (x axis) and surgical margin (y axis). Each patient (dot) is categorized into one of four groups on the basis of recurrence pattern: gray dot, no recurrence; red dot, locoregional recurrence; blue dot, distant recurrence; and purple dot, both locoregional and distant recurrence. A dot located in the area under the dotted diagonal line represents a patient whose surgical margin was smaller than his or her tumor diameter. The number of cases and 5-year cumulative incidence of recurrence (CIR) for each recurrence type are shown in the bottom table. Recurrence was rare (n = 4, no locoregional recurrence) in patients with STAS-negative tumors (A) with a margin-to-tumor ratio of 1 or higher (surgical margin ≥ tumor size, above the dotted diagonal line); in contrast, 14 patients with STAS-negative tumors with a margin-to-tumor ratio less than 1 (surgical margin < tumor size, under the dotted diagonal line) had recurrence, of which eight were locoregional. Of the patients with STAS (B), more than 25% had recurrence at 5 years after surgery regardless of margin-to-tumor ratio (for a margin-to-tumor ratio of ≥1 versus <1, the 5-year CIR for any recurrence was 29% versus 36% [P = 0.3] and the 5-year CIR for locoregional recurrence only was 16% versus 25% [P = 0.3]).
      Among patients with STAS-positive tumors, the risk of recurrence was high regardless of margin-to-tumor ratio (for a margin-to-tumor ratio of ≥1 versus <1, the 5-year CIR 5-year CIR for any recurrence was 29% versus 36% [p = 0.3], the 5-year CIR for locoregional recurrence only was 16% versus 25% [p = 0.3], and the 5-year CIR for distant recurrence was 13% versus 12% [p = 0.3]).

      FS Analysis

      Tumor cells were observed in the lung parenchyma beyond the edge of the main tumor in both FSs and FS control slides (Supplementary Figure 4; for the demographic characteristics of the 48 patients, see Supplementary Table 3). Across the five pathologists, sensitivity ranged from 59% to 86% and specificity ranged from 74% to 100% (Supplementary Table 4). The overall sensitivity and specificity across the five pathologists, which was derived from the generalized estimating equation logistic regression model, were 71% (95% confidence interval [CI]: 63%–78%) and 92% (95% CI: 84%–96%). The observed percent agreement was 75.4%. Interrater reliability across the five pathologists was substantial on the basis of Gwet’s AC1 (coefficient, 0.67 [95% CI: 0.57–0.77]).

      Discussion

      Our study has demonstrated that in lung ADC the presence of STAS is associated with higher CIR and LC-CID in patients with sublobar resection (both segmentectomy and wedge) than in those undergoing lobectomy and that a benefit of surgical margin wider than the tumor diameter in sublobar resections in protecting against recurrence, especially locoregional recurrence, is found in patients without STAS but not in those with STAS. On multivariable analysis after propensity score matching, sublobar resection was an independent risk factor for recurrence and lung cancer–specific death only in patients with STAS. Most recurrences in patients with STAS who underwent sublobar resection were locoregional, suggesting that a wider resection margin per se may not provide protection against recurrence in these patients.
      Our study provides important insight and identifies a factor, namely, STAS, that should be investigated in prospective studies comparing the impact of lobectomy and sublobar resection, in addition to tumor size, on recurrence and survival. On the basis of our literature review comparing survival outcomes between sublobar resection and lobectomy (Supplementary Table 5),
      • Veluswamy R.R.
      • Ezer N.
      • Mhango G.
      • et al.
      Limited resection versus lobectomy for older patients with early-stage lung cancer: impact of histology.
      • Kates M.
      • Swanson S.
      • Wisnivesky J.P.
      Survival following lobectomy and limited resection for the treatment of stage I non-small cell lung cancer<=1 cm in size: a review of SEER data.
      • Fiorelli A.
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      • Koike T.
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      • Kodama K.
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      Oncologic outcomes of segmentectomy versus lobectomy for clinical T1a N0 M0 non-small cell lung cancer.
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      Limited resection as a cure for early lung cancer: time to challenge the gold standard?.
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      • Normolle D.P.
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      Recurrence and survival outcomes after anatomic segmentectomy versus lobectomy for clinical stage I non-small-cell lung cancer: a propensity-matched analysis.
      • Tsutani Y.
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      Oncologic outcomes of segmentectomy compared with lobectomy for clinical stage IA lung adenocarcinoma: propensity score-matched analysis in a multicenter study.
      • Zhao Z.R.
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      • et al.
      Comparison of segmentectomy and lobectomy in stage IA adenocarcinomas.
      • Qu X.
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      Long-term outcomes of stage I NSCLC (</=3 cm) patients following segmentectomy are equivalent to lobectomy under analogous extent of lymph node removal: a PSM based analysis.
      • Zhang Y.
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      Survival following segmentectomy or lobectomy in elderly patients with early-stage lung cancer.
      • Khullar O.V.
      • Liu Y.
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      Survival After sublobar resection versus lobectomy for clinical stage IA lung cancer: an analysis from the National Cancer Data Base.
      • Shirvani S.M.
      • Jiang J.
      • Chang J.Y.
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      no study had demonstrated factors that significantly change the magnitude of difference in survival outcomes between sublobar resection and lobectomy, such as STAS in the present study. In addition, no study investigated histologic subtypes of lung ADC and STAS. Although our study confirms that lobectomy should remain the standard of care for early-stage lung ADC, especially for STAS-positive patients, it also raises awareness for investigations or considerations of alternate therapies, such as stereotactic body radiation therapy (SBRT) or other ablative therapies. Our group, in collaboration with radiation oncologists and intervention radiologists, has already reported that MIP and SOL histologic subtypes in core biopsy specimens are associated with a high risk of locoregional failure and metastasis after SBRT
      • Leeman J.E.
      • Rimner A.
      • Montecalvo J.
      • et al.
      Histologic subtype in core lung biopsies of early-stage lung adenocarcinoma is a prognostic factor for treatment response and failure patterns after stereotactic body radiation therapy.
      or ablation.
      • Gao S.
      • Stein S.
      • Petre E.N.
      • et al.
      Erratum to: Micropapillary and/or solid histologic subtype based on pre-treatment biopsy predicts local recurrence after thermal ablation of lung adenocarcinoma.
      The present study highlights the significance of STAS in the normal lung surrounding the tumor; without adequate tissue to analyze STAS, alternate therapies such as SBRT or ablation remain a suboptimal alternative to lobectomy.
      Recent studies have suggested that the phenomenon of STAS might be the manifestation of an ex vivo artifact caused by mechanical spread of “dissociated” tumor cells by the knife surface during slide preparation.
      • Thunnissen E.
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      • Borczuk A.C.
      • et al.
      Reproducibility of histopathological subtypes and invasion in pulmonary adenocarcinoma. An international interobserver study.
      However, our findings confirm that STAS is not an ex vivo artifact but is instead a clinically significant biologic phenomenon. We base this conclusion on the multiple independent studies that have shown STAS to be an important prognostic factor in all major histologic types of lung cancer,
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      Tumor spread through air spaces is an important pattern of invasion and impacts the frequency and location of recurrences after limited resection for small stage I lung adenocarcinomas.
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      Impact of free tumor clusters on prognosis after resection of pulmonary adenocarcinoma.
      • Dai C.
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      Tumor spread through air spaces affects the recurrence and overall survival in patients with lung adenocarcinoma >2 to 3 cm.
      • Shiono S.
      • Yanagawa N.
      Spread through air spaces is a predictive factor of recurrence and a prognostic factor in stage I lung adenocarcinoma.
      • Onozato M.L.
      • Kovach A.E.
      • Yeap B.Y.
      • et al.
      Tumor islands in resected early-stage lung adenocarcinomas are associated with unique clinicopathologic and molecular characteristics and worse prognosis.
      • Lu S.
      • Tan K.S.
      • Kadota K.
      • et al.
      Spread through air spaces (STAS) is an independent predictor of recurrence and lung cancer-specific death in squamous cell carcinoma.
      • Kadota K.
      • Kushida Y.
      • Katsuki N.
      • et al.
      Tumor spread through air spaces is an independent predictor of recurrence-free survival in patients with resected lung squamous cell carcinoma.
      • Aly R.G.
      • Eguchi T.
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      Spread through air spaces (STAS) correlates with prognosis in lung neuroendocrine tumors (LNET) [abstact].
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      as well as on the following observations in this study: (1) STAS was an independent risk factor for both recurrence and lung cancer-specific death in multivariable analysis that included high-grade histologic subtypes and p-Stages and (2) the difference in survival outcomes between sublobar resection and lobectomy was significant according to STAS status but not according to other factors such as p-Stage and presence of high-grade histologic subtype (MIP or SOL).
      Because the impact of STAS on recurrence and lung cancer–specific death appears to be significantly reduced by lobectomy versus by sublobar resection, we investigated whether pathologists can reliably recognize STAS on an intraoperative FS to guide thoracic surgeons in cases in which there is an option for limited resection vs lobectomy. Walts et al. reported a study evaluating FSs from resected lung ADC and found a low sensitivity of 50% but a high specificity of 100% and 100% positive predictive value.
      • Walts A.E.
      • Marchevsky A.M.
      Current evidence does not warrant frozen section evaluation for the presence of tumor spread through alveolar spaces.
      This confirms our finding of high specificity for STAS in FSs. In the study by Walts et al., it is possible that the lower sensitivity may be due to more limited sampling of adjacent lung parenchyma in their cases, whereas in our study, we specifically selected cases in which sufficient nonneoplastic lung parenchyma was present to optimize evaluation for STAS. In clinical practice, it may be important to sample the nonneoplastic lung surrounding the main tumor to evaluate for STAS.
      In our previous study, FS analysis had high specificity (94%) but low sensitivity (37%) for detecting the presence of the MIP pattern.
      • Yeh Y.C.
      • Nitadori J.
      • Kadota K.
      • et al.
      Using frozen section to identify histological patterns in stage I lung adenocarcinoma of </= 3 cm: accuracy and interobserver agreement.
      In the present study, we found that FS analysis has relatively better sensitivity (71%) and similar specificity (92%) for detecting STAS. One of the reasons for higher sensitivity for detection of STAS could be that the tumor cells are readily distinguished from benign inflammatory cells such as macrophages within alveolar spaces whereas recognizing the MIP pattern within the main tumor is more difficult owing to the challenge in distinguishing it from the other lung ADC histologic subtypes. The finding that STAS can be detected by FS analysis with good sensitivity and specificity and substantial interpathologist agreement is promising and provides a rationale to investigate FS analysis in a prospective study. It is important both in prospective studies and in clinical practice to include appropriate and adequate normal lung parenchyma surrounding the tumor and, furthermore, to avoid various forms of FS-related artifacts (e.g., floaters, tangential sections, and rugged or folded tissue).
      One of the limitations of this study is its retrospective nature. Although we performed propensity score matching, preoperative selection bias between lobectomy and sublobar resection remains (for example, in tumors located close to the hilum or in an intersegmental plane). Another limitation of our study is that our cohort included patients who did not undergo pathologic lymph node evaluation (see Study Cohort in Methods and Supplementary Table 1). The inclusion of these patients may have affected our outcomes. Nevertheless, that the incidence of locoregional recurrence in patients with T1 lung ADC remains high despite negative resection margins is an important issue that requires attention.
      In conclusion, our propensity score–matched analysis demonstrates that compared with lobectomy, sublobar resection is associated with a significantly higher risk of recurrence and subsequent lung cancer–specific death in patients with STAS. Our data confirm that lobectomy should remain the standard treatment option for patients with early-stage lung ADC, especially those with STAS-positive tumors. FS analysis may be useful to intraoperatively detect STAS and aid intraoperative decisions regarding the most appropriate type of resection for patients with early-stage lung ADC.

      Acknowledgments

      The authors' laboratory work is supported by grants from the National Institutes of Health (R01 CA236615, R01 217169, and P30 CA008748); U.S. Department of Defense (LC160212, CA170630, and BC132124), the Joanne and John DallePezze Foundation, the Derfner Foundation, Mr. William H. Goodwin and Alice Goodwin and the Commonwealth Foundation for Cancer Research, and the Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center. We thank David B. Sewell of the Memorial Sloan Kettering Thoracic Surgery Service for editorial assistance.

      Supplementary Data

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      Linked Article

      • Sublobar or Suboptimal: Does Tumor Spread through Air Spaces Signify the End of Sublobar Resections for T1N0 Adenocarcinomas?
        Journal of Thoracic OncologyVol. 14Issue 1
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          Since the 1980s, the thoracic surgery and thoracic oncology communities have been debating whether there is an oncologic advantage to lobectomy over sublobar resection for patients with early-stage NSCLC. The question persisted even after results of the Lung Cancer Study Group 821 trial showed a higher risk of recurrence for sublobar resections as compared to lobectomy.1 Fast-forward to 2018, and we are still having the same debate. As timely as ever, Eguchi et al.2 have added some compelling arguments to the data favoring lobectomy and its oncologic superiority.
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