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J. Nitadori



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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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      O17.05 - Accuracy and Interobserver Agreement in Identifying Histologic Subtypes in Stage I Lung Adenocarcinomas ≤3 cm Using Frozen Section (ID 2590)

      10:30 - 12:00  |  Author(s): J. Nitadori

      • Abstract
      • Presentation
      • Slides

      Background
      The new IASLC/ATS/ERS classification of lung adenocarcinoma (ADC) histologic subtypes is now recommended for prognostic stratification. The ability to determine histologic subtype accurately by frozen section (FS) may help surgeons to choose limited resection versus anatomic resection in the management of lung ADC. The aim of this study is to investigate the accuracy and interobserver agreement of FS for predicting histologic subtype.

      Methods
      FS and permanent section slides from 361 surgically resected stage I lung ADCs ≤3 cm were reviewed for predominant histologic subtype and presence or absence of lepidic, acinar, papillary, micropapillary, and solid patterns. To determine interobserver agreement, 50 cases were additionally reviewed by 3 pathologists. To test the accuracy of FS in determining degree of invasion in cases with predominantly lepidic growth pattern, 5 pathologists reviewed FS slides from 35 patients and attempted to discriminate between adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic predominant adenocarcinoma (LPA).

      Results

      Parameter Accuracy, % (95% CI) Sensitivity, % (95% CI) Specificity, % (95% CI) κ
      Predominant histologic subtype
      Overall 68 (63–73) Not applicable Not applicable 0.565
      Lepidic 90 (86–92) 75 (64–84) 93 (90–96) 0.681
      Acinar 76 (71-80) 70 (61–77) 79 (73–84) 0.481
      Papillary 85 (81-88) 62 (50–72) 91 (87–94) 0.527
      Micropapillary 94 (91-96) 21 (9–40) 99 (97–100) 0.277
      Solid 91 (88-94) 79 (67–87) 94 (90–96) 0.700
      Presence or absence of each histologic pattern
      Lepidic 80 (76–84) 75 (69–80) 91 (84–96) 0.588
      Acinar 89 (85–92) 90 (86–93) 67 (35–90) 0.252
      Papillary 72 (67–77) 70 (64–75) 79 (69–87) 0.397
      Micropapillary 67 (62–72) 37 (30–45) 94 (89–97) 0.321
      Solid 84 (80–88) 69 (61–76) 96 (92–98) 0.670
      The accuracy of FS for predicting histologic subtype is shown in the Table. There was moderate agreement on the predominant histologic subtype between FS diagnosis and final diagnosis (κ=0.565). FS had high specificity for micropapillary and solid patterns (94% and 96%, respectively), but sensitivity was low (37% and 69%, respectively). The interobserver agreement was satisfactory (κ > 0.6, except for acinar pattern). All cases of AIS were correctly diagnosed using FS. For MIA, only 41.3% of FS diagnoses were correct, and 52% were overdiagnosed as LPA; for cases of LPA, 79% of FS diagnoses were correct.

      Conclusion
      FS can provide information on the presence of aggressive histologic patterns—micropapillary and solid—with high specificity but low sensitivity. FS is not suitable for determining the predominant pattern or degree of invasion. Although FS can be helpful in diagnosing AIS, it has poor accuracy in distinguishing MIA from LPA.

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    O22 - Mesothelioma III (ID 122)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
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      O22.02 - CD8 T-cell Infiltration and Tumor IL-7R Expression are Independent Prognostic Factors in Epithelioid Malignant Pleural Mesothelioma (ID 2935)

      16:15 - 17:45  |  Author(s): J. Nitadori

      • Abstract
      • Presentation
      • Slides

      Background
      Following our publication (Cancer Immunol Immunother 2011) demonstrating the prognostic importance of chronic inflammatory cell infiltration in epithelioid malignant pleural mesothelioma (MPM), we investigated the prognostic significance of the immune microenvironment in the tumor nest and the tumor-associated stroma in epithelioid MPM.

      Methods
      A tissue microarray (TMA) was constructed from 170 epithelioid MPM cases, with 6 representative tumor cores and 3 representative stromal areas. Immunohistochemical analyses for immune cell infiltration (CD3, CD4, CD8, CD20, FoxP3) and interleukin receptors (IL-7R and IL-12Rβ2) were performed. TMA slides were analyzed for immune cell infiltration of tumor and stroma (low vs high, divided by use of the median), as well as for immune marker expression (sum of intensity and distribution). Overall survival (OS) was estimated using Kaplan-Meier analysis, and log-rank tests and Cox proportional hazards models were used to analyze the association between each marker and OS.

      Results
      Analysis of single immune cell infiltration for all patients revealed that high tumor CD8+ T-cell infiltration, high CD20+ B-cell infiltration, and low tumor IL-7R expression correlated with higher OS (Figure). Combined tumor CD8+ and CD4+ cell infiltration significantly correlated with better OS (5-year OS, 36% [n=61] vs. 20% [n=96]; p=0.008). In a multivariate analysis including age, stage, lymph node metastases, lymphatic invasion, and vascular invasion, high CD8+ T-cell infiltration and low tumor IL-7R expression were independent predictors of OS (Table). Figure 1Figure 2

      Conclusion
      Tumor CD8+ T-cell infiltration and tumor IL-7R expression are independently associated with survival, which highlights the biologic and prognostic significance of the immune microenvironment for patients with epithelioid MPM.

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    P1.18 - Poster Session 1 - Pathology (ID 175)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P1.18-019 - Micropapillary Histology Is Associated with Occult Lymph Node Metastasis (pN2) in Patients with Clinically N2-Negative (cN0/N1) Lung Adenocarcinoma (ID 3232)

      09:30 - 16:30  |  Author(s): J. Nitadori

      • Abstract

      Background
      Among patients with lung adenocarcinoma staged as N2-negative in the mediastinum by PET/CT scan, up to 16% will have occult N2 metastasis (pN2) detected on mediastinoscopy or surgical resection. We investigated the association between histologic subtyping (according to the newly proposed IASLC/ATS/ERS classification) and occult lymph node metastasis in patients with unsuspected N2 disease.

      Methods
      We performed a retrospective review of 297 patients with lung adenocarcinoma (≤2 cm, 51%; >2 cm, 49%) who underwent surgical resection and mediastinal nodal dissection from 2007 to 2009. Mediastinal lymph node disease was assessed preoperatively by FDG-PET/CT scan. Histologic subtyping was performed according to the newly proposed IASLC/ATS/ERS classification.

      Results
      Ninety-three percent of patients had N0 disease, and 7% had N1 disease, as detected by preoperative PET/CT scan. Of the 297 patients, 32 (10.8%) had occult N2 metastasis identified by pathologic examination (9.7% of patients with cN0 disease, 25% of patients with cN1 disease). On univariate analysis, SUVmax of the primary tumor >4 (p=0.001), predominant histologic subtype (p=0.001), presence or absence of lepidic pattern (p<0.001), micropapillary pattern (p=0.009), and solid pattern (p=0.011) were associated with pN2 disease. On multivariate analysis, presence of lepidic pattern (odds ratio [OR], 0.33; 95% confidence interval [CI], 0.14-0.77; p=0.011), presence of micropapillary pattern (OR, 2.58; 95% CI, 1.13-5.92; p=0.025), and SUVmax of the primary tumor >4 (OR, 2.44; 95% CI, 1.03-5.79; p=0.042) were significantly associated with occult N2 metastasis.

      Conclusion
      Micropapillary histology and primary tumor SUVmax >4 on FDG-PET/CT were independently associated with occult N2 metastasis.

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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 - 16:30  |  Author(s): J. Nitadori

      • 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.