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J. Nitadori



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    MO19 - Lung Cancer Immunobiology (ID 91)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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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): J. Nitadori

      • 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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    MO26 - Anatomical Pathology II (ID 129)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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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): J. Nitadori

      • 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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    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): J. Nitadori

      • 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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    O20 - Staging and Advanced Disease (ID 102)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Surgery
    • Presentations: 1
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      O20.02 - A novel nodal classification for resected non-small cell lung cancer: comparison between location-based and number-based systems (ID 881)

      16:25 - 16:35  |  Author(s): J. Nitadori

      • Abstract
      • Presentation
      • Slides

      Background
      The current UICC/WHO nodal classification system is based on the location of metastatic lymph nodes, while some studies have revealed that the number or ratio of metastatic lymph nodes may work as more effective prognostic indicators. The Japan Lung Cancer Society proposed a new tumor site-based classification for mediastinal nodal metastases according to the tumor-bearing lobe. This study aimed to compare the prognostic power of location-based and number-based classification systems and elucidate the optimal classification.

      Methods
      Of 511 patients with non-small cell lung cancer (NSCLC) who underwent lung lobectomy and complete hilar and mediastinal lymph node dissection with curative intent at our institute between 1998 and 2009, 119 with confirmed lymph node metastases were retrospectively analyzed. Ten classifications were compared using a log-rank test. Four classifications were location-based: the current system, the tumor site-based classification, the classification based on presence or absence of clinical N2 disease, and the classification based on presence or absence of non-skip N2 disease. The other 6 classifications were number-based: the classifications based on the number or ratio of metastatic lymph nodes, the classifications based on that of metastatic stations, and the classifications based on that of metastatic mediastinal lymph nodes.

      Results
      Compared with the current system [hazard ratio (HR), 1.4; p = 0.29], the tumor site-based classification (HR, 2.8; p = 3.0E-4), the classification based on the number of metastatic lymph nodes (HR, 2.8; p = 1.7E-4), and the classification based on the number of metastatic mediastinal lymph nodes (HR, 2.3; p = 3.3E-3) were considered to be stronger predictors of overall survival. Similar results were obtained in terms of disease-free survival (current system: HR, 1.6; p = 0.047; tumor site-based classification: HR, 2.7; p = 2.3E-5; number of metastatic lymph nodes, HR, 2.3; p = 4.0E-4; number of metastatic mediastinal lymph nodes: HR, 2.4; p = 1.4E-4). A combination of the tumor site-based classification with the classification based on the number of metastatic lymph nodes (p = 9.0E-4) or the classification based on the number of metastatic mediastinal lymph nodes (p = 9.5E-4) further increased predictive efficiency.

      Conclusion
      The tumor site-based classification as well as the classifications based on the number of metastatic lymph nodes and the number of metastatic mediastinal lymph nodes was more predictive of surgical outcomes compared with the current nodal system. The results need to be further validated in a new set of patients. Figure 1

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    P2.21 - Poster Session 2 - Diagnosis and Staging (ID 170)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P2.21-001 - Solitary pulmonary squamous cell carcinoma in patients with a history of squamous cell carcinoma: metastasis or second primary tumour? (ID 315)

      09:30 - 09:30  |  Author(s): J. Nitadori

      • Abstract

      Background
      Primary and metastatic squamous cell carcinomas (SCC) in the lung are often histologically indistinguishable, and the differential diagnosis between them is primarily dependent on clinical information such as the location of the lung lesion, the tumour stage, and the disease-free interval, particularly when the pulmonary nodule is solitary. The management of solitary pulmonary SCC in patients with a history of SCC may pose diagnostic and therapeutic challenges.

      Methods
      A retrospective chart review analysis was conducted. The study included 244 consecutive patients with antecedent cancer histories who subsequently underwent pulmonary resections for newly discovered solitary pulmonary nodules (new SPNs) from January 1998 to December 2007 at our institute.

      Results
      Of the 244 patients, 36 had a history of SCC (neck: 14, oesophagus: 9, neck and oesophagus: 3, lung: 5, anal canal: 1, unknown: 1, uterine cervix: 3), and 208 had no history of SCC. A history of SCC was significantly associated with the squamous pathology of new SPNs (22 of 36, p < 0.0001). Of the 22 new SPNs with a squamous pathology, 14 of them were diagnosed as metastatic (mSCC), and 8 were diagnosed as primary carcinomas (pSCC). The mSCC showed a more advanced initial disease (p = 0.0109) and a marginally shorter disease-free interval (p= 0.0818) than the pSCC. The overall survival (OS) and recurrence-free survival (RFS) of patients with pSCC were superior to those of patients with mSCC (OS: p = 0.0413, RFS: p = 0.0282) (Figure 1). Notably, 6 intra-thoracic recurrences were observed in the mSCC group.Figure 1

      Conclusion
      The current policy for differentiation between mSCC and pSCC, which is based on clinical information, appears to be acceptable. In cases in which the origin of the pulmonary lesion is unclear, it might be better to treat solitary lung SCC as a primary lung cancer because it might offer the best chance for a cure.