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T. Hishida



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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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      MO26.09 - Prognostic impact of CD204-positive macrophages in lung squamous cell carcinoma (ID 2023)

      11:15 - 11:20  |  Author(s): T. Hishida

      • Abstract
      • Presentation
      • Slides

      Background
      Stromal cells, including macrophages, lymphocytes and fibroblasts, are known to interact with cancer cells and to produce a specific microenvironment capable of influencing tumor progression. Tumor-associated macrophages (TAMs) are recruited into cancer-induced stroma and produce a specific microenvironment for cancer progression. CD204 positive TAMs are reportedly related to tumor progression and clinical outcome in some tumors. The aim of this study was to clarify the correlation between CD204 positive TAMs and the clinicopathological features of lung squamous cell carcinoma.

      Methods
      We investigated the relationships between the numbers of CD204 positive TAMs and clinicopathological factors, microvessel density (MVD), and the numbers of Foxp3 positive lymphocytes in 208 consecutively resected cases. We also examined the relationships between the numbers of CD204 positive TAMs and the expression levels of cytokines involved in the migration and differentiation of CD204 positive TAMs.

      Results
      A high number of CD204 positive TAMs in the stroma was significantly correlated with an advanced p-stage, T factor, N factor, and the presence of vascular and pleural invasion. A high number of CD204 positive TAMs in the stroma was also a significant prognostic factor for all p-stages and p-stage I. Moreover, the numbers of CD204 positive TAMs were correlated with the MVD and the numbers of Foxp3 positive lymphocytes. A high number of CD204 positive TAMs was strongly correlated with the tissue expression level of MCP-1. CD204 positive TAMs were shown to be significant independent prognostic factors in a multivariate analysis.

      Conclusion
      CD204 positive TAMs were an independent prognostic factor in lung squamous cell carcinoma. CD204 positive TAMs, along with other tumor-promoting stromal cells such as regulatory T cells and endothelial cells, may create tumor-promoting microenvironments.

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      MO26.12 - Prognostic Impact of Microscopic Vessel Invasion and Visceral Pleural Invasion in Non-small Cell Lung Cancer (ID 2480)

      11:35 - 11:40  |  Author(s): T. Hishida

      • Abstract
      • Presentation
      • Slides

      Background
      In non-small cell lung cancer (NSCLC), visceral pleural invasion (VPI) is incorporated as a staging factor in the current TNM classification. Microscopic vessel invasion (MVI: defined collectively as histological blood vessel invasion and lymphatic permeation) has been reported to be a strong independent predictor of poor prognosis, but it has not been incorporated in the TNM classification. We assessed the prognostic significance of MVI as well as VPI.

      Methods
      Between August 1992 to December 2009, 2657 consecutive patients with pathological T1-4N0-2M0 NSCLC underwent complete resection at our institution. We analyzed the prognostic significance of MVI for recurrence in addition to the conventional prognostic factors. The recurrence-free proportion was estimated using the Kaplan-Meier method and differences were analyzed by the log-rank test. Cox regression analyses were used to identify independent risk factors for recurrence.

      Results
      The 5-year recurrence-free proportion for patients with or without MVI was 52.6% and 87.5%, respectively (p < 0.001). On multivariate analysis, MVI, similarly to VPI, was found to be an independently significant predictor of recurrence (HR 2.78). In 1601 patients with pathological stage I disease without adjuvant chemotherapy, MVI and VPI were the two strongest independent predictors of recurrence on multivariate analysis (HR 2.74 and 1.84, respectively). Evident and significant separation of the recurrence-free proportion curves among the following 3 groups according to the number of the two risk factors (VPI and MVI) was observed; both VPI and MVI absent (0), either VPI or MVI present (1), and both VPI and MVI present (2). We compared the recurrence-free proportion of patients stratified by tumor size and the number of the risk factors (0/1/2) (Table 1). The groups of small tumor size without PL and MVI showed the best recurrence-free proportions (T1a_0, T1b_0, and T2a_0). The T1a_1, T1b_1, and T2a_1 subgroups showed poorer outcomes which were comparable with the T2b_0 subgroup. The groups with both PL and MVI, even in small tumor size groups, resulted in poor outcomes equivalent to that of T3_0/1 groups. The T3_2 group showed the poorest outcome equivalent to the T4 group.

      Conclusion
      This study demonstrated that MVI was a significantly independent risk factor for recurrence in resected T1-4N0-2M0 NSCLC patients. We propose the T-classification of tumors with either MVI or VPI (1) should be upgraded to the next T level and that with both MVI and VPI (2) to the second T level (Table 1).

      Table 1. Incorporation of PL and MVI into T classification
      Current (7th) T Classification Tumor Size (cm) No. of VPI and MVI Risk Factors Recurrence-free Proportion at 5 Years (%) OurProposalT
      T1a ≤ 2 0 92.2 T1
      ≤ 2 1 72.2 T2
      ≤ 2 2 58.2 T3
      T1b > 2, ≤ 3 0 89.6 T1
      > 2, ≤ 3 1 64.8 T2
      > 2, ≤ 3 2 50.9 T3
      T2a > 3, ≤ 5 0 87.8 T1
      > 3, ≤ 5 1 61.9 T2
      > 3, ≤ 5 2 44.8 T3
      T2b > 5, ≤ 7 0 75.9 T2
      > 5, ≤ 7 1 49.4 T3
      > 5, ≤ 7 2 47.5 T3
      T3 > 7 0 58.2 T3
      > 7 1 50.6 T3
      > 7 2 38.8 T4

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    O13 - Limited Resections (ID 101)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Surgery
    • Presentations: 1
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      O13.01 - Limited Resection Trial for Pulmonary Ground-glass Opacity Nodules: Case Selection Based on High Resolution Computed Tomography: Interim Results (ID 1233)

      10:30 - 10:40  |  Author(s): T. Hishida

      • Abstract
      • Presentation
      • Slides

      Background
      Japanese researchers have reported good correlation between radiologic and pathologic findings in early lung adenocarcinomas. For negative margin confirmation, we found a technique using lavage and cytological examination. The objective of this study is to confirm limited resection efficacy as radical surgery in patients with high-resolution (HR) computed tomography (CT) indicated minimally invasive lung cancer, and to confirm intraoperative cytology as a negative margin indicator and reliable margin non-recurrence predictor.

      Methods
      Enrollment required patients with a tumor ≤ 2 cm in diameter, diagnosed or suspected as a clinical T1N0M0 carcinoma in the lung periphery based on a CT scan. They had to have a HRCT scan indicating a sub-solid nodule with tumor disappearance ratio; TDR ≥ 0.5. (TDR = 1- DM/DL; DM: maximum tumor diameter on mediastinal settings, DL: maximum tumor diameter on lung settings). Patients with a malignancy history within the past 5 years or those unfit for lobectomy and systematic lymph node dissection were excluded. We performed a wedge or segmental resection. The used stapling cartridges were washed with 50 ml saline. Washing saline was centrifuged and sediment stained using Papanicolaou’s method and examined for cancer cells. If cytology was cancer positive, additional margin was resected, and cytologic examination repeated. If the second exam was positive, a routine lobectomy and systematic lymph node dissection was performed. Patients are followed up every 6 months by chest CT for the first 3 years, and annually thereafter for at least 5 years. The initial endpoint was 5-year local recurrence free survival rate, but we are now looking at 10-year rate.

      Results
      This prospective study started in November 2003, and 101 patients were enrolled as of November 2009. This was 4.5% of all resected lung cancer patients during this period, and 99 of them were eligible for analysis. There were 39 men and 60 women, aged 30-75, with an average 62 years. Tumor sizes ranged from 7 to 20 mm on high-resolution CT, averaging 15 mm. There were 11 Noguchi type A tumors, 54 type B tumors, 26 type C tumors, one type D tumor, one malignant lymphoma, one atypical adenomatous hyperplasia, one atypical cuboidal cell hyperplasia, one alveolar hyperplasia, and 3 inflammatory fibroses. All cancers showed no vessel invasion. Although no positive cytology results were obtained, pathologically positive margin was reported after surgery in one type C patient. He later underwent a routine lobectomy and systematic lymph node dissection. There was no clear correlation between tumor size, TDR, and Noguchi subtype. No mortality occurred, but one patient developed postoperative pneumothorax and pneumonia, and another hemorrhagic gastric ulcer. With a median follow-up period of 69 months, there have been no recurrences.

      Conclusion
      So far, HRCT scans appear to predict non- or minimally invasive GGO lung cancers with high reliability, warranting limited resection as curative surgery in this cohort. Intraoperative cytology reliably indicated negative margins and seems to predict freedom from local recurrence.

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    P1.12 - Poster Session 1 - NSCLC Early Stage (ID 203)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.12-007 - The Predictors of Early Recurrence in Patients with Completely Resected p-stage I Non-Small Cell Lung Cancer (ID 1256)

      09:30 - 09:30  |  Author(s): T. Hishida

      • Abstract

      Background
      The objective of this study was to identify the risk factors for early (within 2 years after surgery) recurrence in patients with completely resected pathological stage I (p-stage I) non-small cell lung cancer (NSCLC).

      Methods
      We reviewed retrospectively 864 consecutive patients with p-stage I NSCLC who underwent complete resection between 1992 and 2012 at our institution. The correlation between clinicopathologic factors (sex, age, preoperative CEA level, tumor laterality, primary lobe, smoking history, histological type, histological differentiation, p-T status, lymphatic permeation, vascular invasion, pleural invasion) and early recurrence was evaluated using chi-square test and multivariate analysis.

      Results
      There were 498 men and 366 women, with an average age of 67 years. (range: 33-87). The median follow up period was 78 months. Histologically, 659 patients had adenocarcinomas, 189 squamous cell carcinomas, and 16 other types. T status was 1a in 230 patients, 1b in 274, and 2a in 360. Vascular invasion was observed in 326 patients, and lymphatic permeation in 169. Recurrence developed in 208 patients (24.1%), and 64 (7.4%) of them developed within 2 years after surgery. By multivariate analysis, vascular invasion (hazard ratio 3.441, 95% confidence interval 1.892-6.428) and moderate to poor differentiation (hazard ratio 3.252, 95% confidence interval 1.242-8.512) were shown to be independently significant risk factors for early recurrence. In patients with vascular invasion, distant failure occurred significantly more frequently than locoregional recurrence. The early recurrences were distant failure in 46 patients (72%). Of the 18 patients with locoregional recurrence only, 13 had malignant pleural effusion or pleural dissemination.

      Conclusion
      Moderate to poor differentiation and vascular invasion were the significant predictors of early recurrence within 2 years after complete resection of p-stage I NSCLC. More than 90% of the early recurrences were disseminated diseases. Therefore, adjuvant chemotherapy after complete resection may be beneficial for p-stage I NSCLC patients with vascular invasion or moderately to poorly differentiated tumors.

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    P1.19 - Poster Session 1 - Imaging (ID 179)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Imaging, Staging & Screening
    • Presentations: 1
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      P1.19-005 - Computer-aided lung nodule analysis focused on ground glass opacity and consolidation on thin-section computed tomography. (ID 1447)

      09:30 - 09:30  |  Author(s): T. Hishida

      • Abstract

      Background
      Ground-glass opacity (GGO) component in a nodule on thin-section computed tomography (TSCT) often corresponds to a lepidic growth pattern of adenocarcinoma. In contrast, solid attenuation or consolidation on TSCT corresponds to invasive components. Many researchers reported consolidation tumor ratio (CTR; defined as the ratio of the size of solid attenuation to the maximum tumor dimension) was a reliable parameter in predicting tumor invasiveness. However, it has been pointed out that inter-/intra-observer variability in CTR measurement is a major problem in precise and reproducible evaluation of tumor characteristics. The aim of this study was to determine the optimal CT settings to reproducibly diagnose GGO and consolidation areas on TSCT by using an imaging software.

      Methods
      We reviewed preoperative TSCT images of the patients undergoing surgical resection for T1 lung adenocarcinoma in our institution between 2005 and 2009. The TSCT images were obtained without contrast enhancement and reconstructed in 1.0 or 2 mm thickness, using several CT systems. The imaging software colored GGO areas with cut-off CT levels of -800, -700 and -600 HU. Consolidation areas were colored with cut-off CT levels of -300, -200 and -100 HU. These GGO/consolidations identified by the software were compared with those visually determined by the consensus of the 4 authors (EY, KA, YM, HO). The 4 authors scored the correspondence between visual evaluation and software identification according to the cut-off levels. The scores were summarized to determine the optimal cut-off CT levels.

      Results
      We have reviewed 20 patients so far. Figure 1 shows a TSCT image and software-yielded image showing good correspondence with each other of GGO and consolidation areas. The best score was obtained when the cut-off level was -700 HU for GGO and -200 HU for consolidation. Figure1. Figure 1

      Conclusion
      Although based on a small cohort, we found optimal cut-off CT levels to identify GGO and consolidation areas using an imaging software. We need to analyze more cases, but this image analysis method is promising in determining CTR reproducibly.

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    P3.07 - Poster Session 3 - Surgery (ID 193)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Surgery
    • Presentations: 1
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      P3.07-014 - Post-recurrence survival of surgically resected non-small cell lung cancer patients in the era of EGFR-TKI (ID 1450)

      09:30 - 09:30  |  Author(s): T. Hishida

      • Abstract

      Background
      Although surgical resection is the standard treatment of choice for early stage non-mall-cell lung cancer (NSCLC), not a small percentage of patients recur even after complete resection, and post-recurrence survival (PRS) is dismal. Since epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) was approved for patients with advanced or recurrent NSCLC in 2002 in Japan, the number of long-term survivors after recurrence seems to be increasing. There have been few reports on post-recurrence survival in the era of EGFR-TKI. In the present study, we analyzed PRS in patients with completely resected NSCLC after EGFR-TKI was introduced in clinical practice.

      Methods
      From 1992 to 2010, 3058 NSCLC patients underwent complete resection in our hospital. Among them, 938 (31%) patients recurred. Of them, 503 patients, who recurred in 2002 or later and received anticancerous treatment, were the subject of this analysis. We retrospectively analyzed their clinicopathological characteristics, PRS, and identified favorable prognostic factors.

      Results
      The median age at recurrence was 68 years (range: 23-91), and 332 (58%) of them were men. There were 347 (69%) adenocarcinoma patients and 101 (20%) squamous cell carcinoma patients. The pathological stages of the primary cancers were I in 183 patients (36%), II in 120 (24%), and III in 200 (40%), respectively. Fifty-six patients (11%) underwent reoperation for recurrent lesions. Of the 216 patients whose EGFR mutation was examined, mutation was positive in 97 patients (45%). The median period of follow-up after recurrence was 49 months (range: 7-124). The overall 3- and 5-year PRS were 27% and 16%, respectively and their median PRS length was 19 months. The multivariate analysis revealed that adenocarcinoma, negative pleural invasion, locoregional recurrence, surgical resection of recurrent lesion, positive EGFR mutation were independent favorable prognostic factors. The 3-year PRS rate and median PRS length of the patients undergoing surgery and those with EGFR mutation were 60% (55 month) and 46% (35 month), respectively.

      Conclusion
      The PRS was still poor, but longer survival can be expected in selected patients, who have resectable recurrence or EGFR mutation.