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W.D. Travis



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    MO19 - Lung Cancer Immunobiology (ID 91)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 2
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      MO19.02 - The Tumor Immune Microenvironment in Octogenarians with Stage I Non-Small Cell Lung Cancer: Implications for Immunotherapy (ID 3155)

      10:35 - 10:40  |  Author(s): W.D. Travis

      • Abstract
      • Presentation
      • Slides

      Background
      The elderly have less-robust immune responses to infections, immunizations, and tumors, compared with younger people. Furthermore, preclinical studies have indicated that immunotherapeutic interventions are less effective in older animals. Considering the effects of age-associated changes in immune function, most clinical trials of cancer-related immunotherapy have been conducted in relatively young patients. With the increasing focus on immunotherapy for non-small cell lung cancer (NSCLC), we investigated the relationship between patient age and tumor immune parameters in stage I NSCLC.

      Methods
      Tissue microarrays from patients with stage I NSCLC (n=1371; 1995-2009; median follow-up, 3.5 years) were constructed, and immunohistochemical analyses for immune cell infiltration (CD3, CD4, CD8, CD20, FoxP3) were performed. Patients were categorized into 3 groups: (1) ≤65 years old, (2) 66-79 years old, and (3) ≥80 years old. Stains were analyzed for immune cell infiltration (low vs high) in the tumor nest. The Chi-Square test was used to analyze the association between immune parameters and age group. The Kaplan-Meier method was used to estimate recurrence-free survival (RFS).

      Results
      In total, 1116 patients with stage I lung adenocarcinoma and 255 patients with stage I squamous cell carcinoma were enrolled. Patients aged ≥80 years did not have a significantly poorer prognosis (n=155; 5-year RFS, 76.0%) than the patients in the two younger groups (p=0.65; Figure 1A). There were no statistically significant differences in numbers of tumor-infiltrating lymphocytes in the tumor nest between the three groups (Figure 1B), nor was there a statistically significant difference between the elderly group and the younger patients when effector regulatory immune response ratios were compared (FoxP3/CD3 ratio; high vs low, p=0.85). Figure 1

      Conclusion
      In this large cohort of stage I NSCLC patients selected for surgical resection, the tumor microenvironment among elderly patients resembles other age groups. Our study provides important information while considering immunotherapy in elderly patients with lung cancer.

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      MO19.12 - Prognostic Impact of Tumor-Infiltrating Immune Cells in Lung Squamous Cell Carcinoma (ID 2896)

      11:35 - 11:55  |  Author(s): W.D. Travis

      • Abstract
      • Presentation
      • Slides

      Background
      The prognostic significance of the tumor immune microenvironment in lung adenocarcinoma has been established by us (CCR 2011, JCO 2013, Oncoimmunology 2013) and others. Here, we investigate whether tumor-infiltrating immune cells correlate with prognosis, independent from TNM staging, in lung squamous cell carcinoma (SCC).

      Methods
      All available tumor slides from therapy-naive, surgically resected solitary lung SCCs (n=485; 1999-2009) were reviewed. Tissue microarrays were constructed using 451 cases (stage I, 255; II, 131; III, 65) from 3 representative tumor areas. Immunostaining for CD3 (pan T cell marker), CD45RO (memory T cell), CD8 (cytotoxic T cell), CD4 (helper T cell), FoxP3 (regulatory T cell), CD20 (B cell), CD68 (macrophage), and CD10 (neutrophil) was performed. For each case, the average number of cells positive for T cell markers was recorded as the ratio to CD3+ lymphocytes, and classified as low or high by use of the median. CD20, CD68, and CD10 were classified as low or high by the number of positive cells (≥20, ≥50, and ≥10, respectively) as our recent publication (JCO 2013). Overall survival (OS) was estimated using the Kaplan-Meier method; multivariate analyses were performed using the Cox proportional hazards model.

      Results
      Five-year OS was 59% for the entire cohort and 68% for stage I patients. Analysis of single immune cell infiltration revealed that high CD10+ neutrophil count was correlated with lower OS (5-year OS, 53%; n=160) than low CD10+ count (5-year OS, 61%; n=286; p=0.006). Analysis of biologically relevant immune cell combinations identified 2 significant factors of prognosis: (1) patients with high CD4+ and high FoxP3+ T cell ratios had worse prognosis (5-year OS, 52%; n=140) than the other groups (5-year OS, 62%; n=304; p=0.008), and (2) patients with high CD10+ neutrophil and low CD20+ B lymphocyte counts had worse prognosis (5-year OS, 43%; n=102) than the other groups (5-year OS, 63%; n=340; p<0.001). These results were confirmed in a subgroup analysis limited to stage I patients (p=0.020 for high CD4/high FoxP3+ ratios; p=0.007 for high CD10+/low CD20+ counts). In multivariate analysis, high CD4+/high FoxP3+ ratios (HR=1.58; p=0.001) and high CD10+/low CD20+ counts (HR=1.71; p<0.001) remained significantly associated with poorer survival (Table).

      Table. Multivariate analysis for overall survival
      Variable HR 95% CI p
      High CD4+/high FoxP3+ ratios 1.58 1.21–2.06 0.001
      High CD10+/low CD20+ counts 1.71 1.28–2.27 <0.001
      Age (>65 years old) 1.51 1.09–2.09 0.014
      Sex (male vs. female) 1.31 1.01–1.69 0.043
      Smoking pack years (>90) 1.01 1.00–1.01 0.003
      Stage (II and III vs. I) 1.53 1.16–2.02 0.002
      Lymphovascular invasion 1.38 1.02–1.88 0.040

      Conclusion
      High CD4+/high FoxP3+ ratios and high CD10+/low CD20+ counts are significant factors of prognosis for lung SCC, independent of TNM staging. Targeting regulatory T cells or enhancing tumor-specific B-cell responses may thus have applicability for the treatment of lung SCC.

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    MO25 - NSCLC - Combined Modality Therapy II (ID 112)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
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      MO25.09 - A Phase II study of <sup>18</sup>F-FDG PET guided optimization of neoadjuvant chemotherapy for resectable non-small cell lung cancer (ID 2442)

      11:20 - 11:25  |  Author(s): W.D. Travis

      • Abstract
      • Presentation
      • Slides

      Background
      Perioperative chemotherapy improves overall survival in patients with resectable non-small cell lung cancers. In contrast to adjuvant chemotherapy, neoadjuvant chemotherapy enables radiographic assessment of chemotherapy effect and hence, the option to switch non-responding patients to a potentially more effective regimen. Responses to neoadjuvant chemotherapy assessed by PET imaging correlate better with clinical outcomes than does CT imaging. We have initiated a Phase II trial of PET response guided chemotherapy, where chemotherapy administration decisions are based on comparisons of baseline PET imaging, imaging after 2 cycles of platinum-based chemotherapy, and imaging after ‘switch’ chemotherapy in patients with an initial suboptimal response.

      Methods
      This Phase II trial (NCT01443078) is enrolling patients with clinical Stage IB-IIIA non-small cell lung cancers deemed operable by a thoracic surgeon. To be eligible, the primary lung mass must be >2 cm with a SUV ≥4.5. Patients with diabetes requiring insulin are excluded. Patients are initially treated with cisplatin (or carboplatin if cisplatin ineligible) + gemcitabine (squamous cell) or pemetrexed (non-squamous). After 2 cycles, if repeat PET imaging shows less than a 35% decrease in SUV of the primary tumor, patients are switched to vinorelbine + docetaxel every 2 weeks with pegylated filgrastim support (2 doses = 1 cycle). The primary endpoint of this study is partial metabolic response after 2 cycles of switch vinorelbine + docetaxel as assessed by PERCIST (SUV decrease of ≥30% using the pre-switch scan as the new baseline). We considered a >20% partial metabolic response rate in those who received vinorelbine + docetaxel worthy of further study. Therefore this study was powered to see at least 6 of 25 partial metabolic responses to vinorelbine + docetaxel, estimating a total patient accrual of 100 patients.

      Results
      27 patients have been enrolled. 5 are undergoing platinum-based chemotherapy and have not yet been reassessed. 22 patients have been reimaged after 2 cycles of platinum-based chemotherapy, 13 (59%) have had a > 35% decrease in SUV and continued on platinum-based chemotherapy. 9 (41%) patients have had a <35% decrease in SUV after platinum-based therapy and were assigned to switch chemotherapy. 7 received vinorelbine + docetaxel, and 5 (71%, 95% CI 29-96%) have had a PERCIST partial metabolic response after 2 cycles, 1 progressive disease and 1 is pending reassessment. 17 patients have been surgically explored with 13 (76%) R~0~ resections.

      Conclusion
      Preliminary results from this ongoing trial suggest that patients with resectable non-small cell lung cancers who have a suboptimal PET-assessed response to standard histology-selected, platinum-doublet neoadjuvant chemotherapy can be effectively treated with vinorelbine and docetaxel followed by surgery. This study is on-going. Assessment of pathologic response in resected patients and clinical follow-up in all patients will be available by the time of presentation.

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    MO26 - Anatomical Pathology II (ID 129)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 2
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      MO26.03 - In Patients with Stage I Lung Adenocarcinoma, Tumor Budding Is a Significant Prognostic Factor for Recurrence, Independent of the IASLC/ATS/ERS Classification, and Correlates with a Protumor Immune Microenvironment (ID 2917)

      10:40 - 10:45  |  Author(s): W.D. Travis

      • Abstract
      • Presentation
      • Slides

      Background
      In 2011, the IASLC/ATS/ERS proposed a new classification for lung adenocarcinoma (ADC) that has powerful prognostic value. However, tumors in each subtype may still include heterogeneous prognostic subgroups - especially in the acinar, papillary, and solid subtypes, in which the majority of tumors are classified. Recently, immune markers such as CD markers and cytokines have been identified as prognostic factors in lung cancer. In this study, we investigate whether tumor budding further stratifies prognosis for stage I lung ADC, independent of the IASLC/ATS/ERS classification, and whether it correlates with prognostic immune markers.

      Methods
      All available tumor slides from patients with therapy-naive, surgically resected solitary stage I lung ADC (1995-2009) were reviewed (n=1038). Tumors were classified according to the IASLC/ATS/ERS classification. Mitoses were counted at 10 high-power fields (HPFs) (x400 magnification). Tumor budding (tumor nest composed of <5 cells) was assessed, at 10 HPFs (x200 magnification), in areas with the smallest tumor nests and was graded by the maximum number of budding : 0, 0/HPF; 1, 1-4/HPF; 2, 5-9/HPF, and 3, ≥10/HPF. Tissue microarrays were constructed from tumoral and stromal cores, and immunostaining for CD3, FoxP3, IL-7R, and IL-12Rβ2 was performed. Lymphocytes positive for CD3 and FoxP3 were scored in tumor and stroma, and tumors were classified using our recently reported FoxP3/CD3 risk index (JCO 2013). Tumoral expression of IL-7R and IL-12Rβ2 was dichotomized by the sum of intensity (0-3) and distribution (1, 1%-50%; 2, >50%) scores: negative (total score <1) and positive (≥1). Recurrence-free probability (RFP) was estimated using the Kaplan-Meier method; multivariate analyses were performed using the Cox proportional hazards model.

      Results
      RFP was lowest for patients with budding grade 3 (n=180; 5-year RFP, 69%; p<0.001), followed by grade 2 (n=139; 75%), 1 (n=189; 81%), and 0 (n=530; 89%). Budding grade was dichotomized into negative (grades 0-1) or positive (grades 2-3) using colorectal cancer criteria. The RFP for patients with positive budding (n=319; 5-year RFP, 72%) was significantly lower than that for patients with negative budding (n=719; 87%; p<0.001), which was confirmed in a subgroup analysis limited to stage IA (p=0.004) and IB (p<0.001) patients. Tumor budding further stratified RFP in patients with acinar (p<0.001), papillary (p=0.027), and solid (p=0.015) tumors. Budding was more frequently observed in tumors with high-grade histology (solid and micropapillary; p<0.001), lymphovascular invasion (p<0.001), and high mitotic count (p<0.001). Tumor budding was positively correlated with stromal CD3+ lymphocytes (p<0.001), stromal FoxP3+ (p<0.001), FoxP3/CD3 risk index (high FoxP3, low CD3) in stroma (p<0.001), and tumoral IL-7R expression (p<0.001). In multivariate analysis, tumor budding was an independent prognostic factor for recurrence (HR=1.13; p=0.002).

      Conclusion
      Tumor budding was a significant prognostic factor in stage I lung ADC, independent of IASLC/ATS/ERS classification, and it correlated with a protumor immune microenvironment (high FoxP3+ lymphocyte infiltration and high IL-7R expression). These findings may inform therapeutic decisions and stratify patients for additional therapy, including immunotherapy.

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      MO26.04 - Reclassification of Resected Non-Small Cell Lung Carcinomas Originally Diagnosed as Squamous Cell Carcinoma, after Reevaluation Using Immunohistochemical Analysis (p40, p63, TTF-1, and Napsin A): Memorial Sloan-Kettering Cancer Center Experience (ID 2905)

      10:45 - 10:50  |  Author(s): W.D. Travis

      • Abstract
      • Presentation
      • Slides

      Background
      Currently, non-small cell lung carcinomas (NSCLCs) are mainly classified by histologic analysis and mucin staining: (1) squamous cell carcinoma (SCC) shows keratinization and intercellular bridges; (2) adenocarcinoma shows lepidic, acinar, papillary, micropapillary, or solid pattern, with mucin production; and (3) large cell carcinoma lacks these findings. However, recent studies have shown promising improvements in the classification of NSCLC with immunostain-based markers, including p40 and thyroid transcription factor–1 (TTF-1). In this study, we investigate the use of immunohistochemical analysis in reclassifying NSCLCs originally diagnosed as SCCs.

      Methods
      All available tumor slides from patients with therapy-naive, surgically resected solitary NSCLCs originally diagnosed as SCC (1999-2009) were reviewed. Tissue microarrays were constructed with 3 cores (n=480), and immunostaining for p40, p63, TTF-1 (clone 8G7G3/1), TTF-1 (SPT24), napsin A, chromogranin A, synaptophysin, and CD56 was performed. Immunoreactivity was scored semiquantitatively by staining intensity (weak, moderate, or strong) and percentage of positive tumor cells (diffuse, ≥50%; focal, <50%). Tumors were first grouped by p40 and TTF-1 (8G7G3/1) status: (1) group A (favor SCC): p40 (+) and TTF-1 (8G7G3/1) (-); (2) group B (favor adenocarcinoma): p40 (- or +) and TTF-1 (8G7G3/1) (+); and (3) group C (favor large cell carcinoma): p40 (-) and TTF-1 (8G7G3/1) (-). Immunostain-based tumor classification was then confirmed with histologic findings and other markers.

      Results
      In group A (n=448), 1 tumor was reclassified as adenosquamous carcinoma by histologic findings and focal immunoreactivity for p40, p63, and TTF-1 (SPT24). In group B (n=15), 2 tumors were reclassified as large cell neuroendocrine carcinoma (LCNEC) by neuroendocrine morphologic findings and differentiation (1 as pure LCNEC and the other as combined LCNEC with SCC). In group C (n=17), 6 tumors were confirmed as large cell carcinoma because they lacked adenocarcinoma morphology and TTF-1 [SPT24] expression (2 of these showed focal p63 reactivity without keratinization); 4 were reclassified as large cell carcinoma (favor adenocarcinoma) because they were focally positive for TTF-1 (SPT24) but negative for TTF-1 (8G7G3/1) and napsin A; 2 were reclassified as adenocarcinoma because they were diffusely and strongly positive for TTF-1 (SPT24) but focally (<10%) positive for p63, without keratinization; 3 were reclassified as LCNEC by neuroendocrine morphologic findings and differentiation; and 2 were reclassified as small cell carcinoma by morphologic findings. All tumors finally diagnosed as SCC (n=447) using histologic findings and immunohistochemical analysis were positive for p40 and p63. Among them, 27 tumors were positive for TTF-1 (SPT24) (19 focally and 8 diffusely) but negative for TTF-1 (8G7G3/1), with all showing clear squamous morphologic pattern, thus verifying the greater specificity of the TTF-1 8G7G3/1 clone in SCC.

      Conclusion
      After immunohistochemical reevaluation of 480 NSCLCs originally diagnosed as SCC by classical morphologic analysis, 33 (7%) were reclassified as other histologic types. Immunohistochemical analysis may provide additional valuable information to achieve an accurate diagnosis, particularly in poorly differentiated NSCLCs and in tumors for which the diagnosis of nonkeratinizing SCC is considered.

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    O02 - NSCLC - Combined Modality Therapy I (ID 111)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Combined Modality
    • Presentations: 1
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      O02.05 - Major pathologic response (≤10% viable tumor) following neoadjuvant chemotherapy as a surrogate for overall survival in patients with pathologically documented stage IIIA (N2) lung adenocarcinomas (ID 2345)

      11:15 - 11:25  |  Author(s): W.D. Travis

      • Abstract
      • Presentation
      • Slides

      Background
      Neoadjuvant chemotherapy improves overall survival in patients with resectable stage IIIA lung adenocarcinomas. The gold-standard endpoint for clinical trials evaluating curative therapies is overall survival. Unfortunately, these trials take nearly a decade to complete and this prolonged timeline hinders the approval of promising therapies in the curative realm. Alternative endpoints that can act as a surrogate for overall survival have been evaluated, including nodal downstaging, nodal clearance, and pathologic response. We evaluated the degree to which these endpoints associate with overall survival in patients with pathologically proven stage IIIA(N2) lung adenocarcinoma treated with neoadjuvant chemotherapy.

      Methods
      An electronic database search engine was used to identify all patients with resectable stage IIIA(N2) lung adenocarcinoma treated with neoadjuvant chemotherapy at Memorial Sloan-Kettering Cancer Center between 1/2007-8/2012. Nodal downstaging was defined as no residual tumor tissue in the N2 nodes. Nodal clearance was defined as no residual tumor tissue in N1 and N2 nodes. Pathologic response was systemically assessed by a dedicated thoracic pathologist (WDT) who reviewed at least 1 section per centimeter of greatest gross tumor diameter. The percent viable tumor tissue in each slide was estimated to the nearest 10%. Major pathologic response (MPR) was defined as ≤10% viable tumor tissue. All pathologic analyses were performed by a dedicated thoracic pathologist (WDT). Patients with residual N2 disease at resection were offered post-operative radiation and routinely monitored thereafter. Survival proportions were estimated by the Kaplan-Meier method and compared using the log-rank test.

      Results
      69 patients with pathologically confirmed IIIA(N2) disease were identified and 46 (67%) ultimately underwent R0 resection. Among these patients, 16 had nodal downstaging, 14 had nodal clearance and 5 had a MPR. In both intention to treat analyses (N=69) and including only those who underwent resection, only MPR significantly associated with overall survival. The table below details findings from the population who had complete cancer resection.

      Endpoint (N=46) Yes (A) No (B) NA (C) HR (95% CI) ITT (A vs B+C) HR (95% CI) Resected(A vs B)
      Nodal downstaging 16 30 23 0.68 (0.32-1.56) 0.73 (0.24-2.10)
      Nodal clearance 14 32 23 0.57 (0.27-1.36) 0.96 (0.32-2.81)
      MPR 5 41 23 0.28 (0.1-0.78) 0.26 (0.07-0.95)
      NA = not assessable; ITT = intention to treat

      Conclusion
      MPR (≤10% viable tumor) effectively identifies patients with good clinical outcomes after neoadjuvant chemotherapy and can serve as a surrogate endpoint for overall survival. Furthermore, lack of MPR identifies a patient population at high risk of recurrence. Neither nodal downstaging nor nodal clearance effectively discriminated those with improved survival. Adaptive clinical trials designed to target those not achieving MPR are encouraged in attempt to improve the rate of cure in this disease.

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    O17 - Anatomical Pathology I (ID 128)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      O17.06 - Tumor Budding and Nuclear Grade, but not Histologic Subtype, Are Significant Prognostic Factors, Independent of TNM Stage, in Patients with Lung Squamous Cell Carcinoma (ID 2910)

      11:25 - 11:35  |  Author(s): W.D. Travis

      • Abstract
      • Presentation
      • Slides

      Background
      The new IASLC/ATS/ERS lung adenocarcinoma classification, proposed in 2011, has significant prognostic value. For lung squamous cell carcinoma (SCC), however, no pathologic findings have been widely accepted to predict patient outcomes with the exception of TNM stage. Tumor budding has been recognized as a factor of poor prognosis in colorectal cancer, and nuclear grading has been widely accepted as a prognostic indicator in breast cancer. In this study, we determine whether histologic findings can independently predict prognosis in lung SCC.

      Methods
      All available tumor slides from patients with therapy-naive, surgically resected solitary lung SCC (1999-2009) were reviewed (n=485; stage I/II/III, 281/136/68). Tumors were graded by means of tumor differentiation. Tumors were classified as keratinizing, nonkeratinizing, and basaloid subtypes by presence (≥5%) or absence of keratinization and by predominant (≥50%) basaloid pattern. Tumor budding (tumor nests composed of <5 cells) and presence of single tumor-cell invasion were assessed using 10 high-power fields (HPFs) (x200 magnification) in the areas with the smallest tumor nests. Tumor budding was considered positive when the maximum number of budding was ≥10/HPF. Single tumor-cell invasion was considered positive when it was identified at 10 HPFs. Nuclear diameter was evaluated, at ≥3 HPFs in the largest nuclei, using nearby small lymphocytes as reference and was classified as either large (>4 small lymphocytes) or small (≤4). Overall survival (OS) was estimated using the Kaplan-Meier method, and multivariate analyses were performed using the Cox proportional hazards model.

      Results
      Basaloid subtype correlated with better OS than nonbasaloid subtype (p=0.046). Tumor budding (p<0.001), single tumor-cell invasion (p<0.001), and large nuclei (p=0.005) correlated with worse OS (Table). However, tumor differentiation and presence of keratinization did not correlate with prognosis. The prognostic significance of tumor budding was confirmed in a subgroup analysis limited to stage I (p=0.028) and stage II/III (p=0.008) patients. In addition, basaloid subtype correlated with favorable prognosis (p=0.042), and both single tumor-cell invasion (p=0.014) and large nuclei (p=0.021) were associated with poor prognosis in a subgroup analysis limited to stage I patients. In multivariate analysis, tumor budding (HR=1.04; p=0.024) and large nuclei (HR=1.09; p=0.035) were independent prognostic factors for survival.

      Table. Overall survival by histologic findings
      Histologic finding 5-year OS p
      Subtype Basaloid 69% (n=33) 0.046
      Nonbasaloid 58% (n=452)
      Tumor budding + 39% (n=76) <0.001
      - 62% (n=409)
      Single cell invasion + 47% (n=197) <0.001
      - 67% (n=288)
      Nuclei Large 50% (n=153) 0.005
      Small 63% (n=332)

      Conclusion
      Tumor budding and large nuclei, but not histologic subtype, were significant prognostic factors, independent of TNM stage, for lung SCC. These findings may help to make therapeutic decisions and stratify patients for additional therapy.

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    P2.18 - Poster Session 2 - Pathology (ID 176)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P2.18-003 - Spread Through Alveolar Spaces (STAS): A Newly Recognized Pattern of Invasion in Lung Adenocarcinoma Associated with Increased Recurrence in Patients Undergoing Limited Resection for ≤2cm Tumors (ID 295)

      09:30 - 09:30  |  Author(s): W.D. Travis

      • Abstract

      Background
      We have recently demonstrated that presence of the micropapillary pattern increases the risk of local recurrence after limited resection for ≤2 cm lung adenocarcinoma (ADC). In cases of tumors with the micropapillary pattern, a detached collection of tumor cells is frequently identified within an alveolar space separate from the main tumor, which we have named “Spread Through Alveolar Spaces” (STAS). However, the prognostic significance of this finding is not known. The purpose of this study is to investigate whether the presence of STAS correlates with an increased risk of recurrence after limited resection versus lobectomy.

      Methods
      All available tumor slides from patients with therapy-naive, surgically resected solitary lung ADC ≤2 cm in size (1995-2009) were reviewed (n=697; stage IA/IB, 600/97; limited resection/lobectomy, 226/471). Comprehensive histologic subtyping was performed according to the IASLC/ATS/ERS classification. STAS was defined as isolated tumor islands (morphologically solid or micropapillary pattern) or single cells within alveolar spaces separate from the main tumor. The distance between the tumor surface and the STAS was measured by a ruler (mm) and by the number of alveolar spaces. Recurrence-free probability (RFP) was estimated using the Kaplan-Meier method.

      Results
      STAS was identified in 224 cases (32%). The morphologic types of STAS were as follows: 119 micropapillary, 91 solid, and 14 single cell. Presence of the micropapillary or solid pattern (>5%) in the main tumor and presence of lymphatic invasion were significantly associated with presence of STAS (p<0.001 for each). Presence of STAS correlated with an increased risk of recurrence (5-year RFP, 75.6%), compared with absence of STAS (5-year RFP, 83.5%; p=0.022). In the limited resection group, tumors with STAS were associated with an increased risk of recurrence, compared with those without STAS (5-year RFP, 58.3% vs 81.9%; p=0.004); this did not follow in the lobectomy group (5-year RFP, 84.1% vs 84.2%; p=0.658) (Figure). The distance between the tumor surface and the STAS did not correlate with risk of recurrence (p=0.992). Figure 1

      Conclusion
      Presence of STAS correlated with an increased risk of recurrence in patients treated with limited resection for ≤2 cm lung ADC. This finding may guide surgeons to choose lobectomy over limited resection for the treatment of these patients.