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G. Ishii
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MO04 - Lung Cancer Biology I (ID 86)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Biology
- Presentations: 1
- Moderators:G. Sozzi, D.C. Lam
- Coordinates: 10/28/2013, 16:15 - 17:45, Bayside 103, Level 1
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MO04.10 - Identification of biological properties of intralymphatic tumor related to the development of lymph node metastasis in lung adenocarcinoma (ID 1724)
17:10 - 17:15 | Author(s): G. Ishii
- Abstract
- Presentation
Background
Intralymphatic tumors in the extratumoral area are considered to represent the preceding phase of lymph node (LN) metastasis. The aim of this study was to clarify the biological properties of intralymphatic tumors susceptible to the development of LN metastasis, with special reference to the expression of cancer initiating/stem cell (CIC/CSC) markers in cancer cells and the number of infiltrating stromal cells.Methods
A total of 2087 consecutive adenocarcinoma patients underwent complete resections and systematic LN dissections between May 1998 and December 2012 were identified. Among these cases, we selected those that had been diagnosed as having lymphatic permeation in the extratumoral area (n = 107). We examined the expression levels of CIC/CSC related markers including ALDH1, OCT4, NANOG, SOX2 and Caveolin-1 in the intralymphatic and primary tumor cells to evaluate their relationship to LN metastasis. The number of infiltrating stromal cells expressing CD34, α-smooth muscle actin, and CD204 were also evaluated. Moreover, we measured E-cadherin expression to identify a correlation between CIC/CSC related molecules and epithelial - mesenchymal transition (EMT) process.Results
Intrathoracic LN metastases were detected in specimens from 86 patients (80%). Among the intralymphatic tissues, low ALDH1 expression in cancer cells, high SOX2 expression in cancer cells, and a high number of CD204(+) macrophages were independent predictive factors for LN metastasis (odds ratio [95%CI] = 3.25 [1.11 – 9.82], P = 0.031 for ALDH1; 4.09 [1.38 – 13.4], P = 0.011 for SOX2; and 3.45 [1.16 – 11.4], P = 0.026 for CD204(+) macrophages). However, in the primary tumors, only a high SOX2 expression level in the cancer cells within the primary tumor was significantly correlated with LN metastasis (p=0.008); ALDH1 expression in the cancer cells and the number of CD204(+) macrophages were not correlated with LN metastasis (P = 0.230 and P = 0.088, respectively). Among these factors, only low ALDH1 expression in intralymphatic cancer cells was significantly correlated with the farther spreading of LN metastasis (mediastinal LN, pN2) (P = 0.046) and higher metastatic LN ratio (metastatic/resected) (P = 0.028). Intralymphatic cancer cells expressing low ALDH1 levels exhibited lower E-cadherin expression levels than cancer cells with high levels of ALDH1 expression (P = 0.015). The expressions of other CIC/CSC related markers, including OCT4, NANOG, SOX2, and Caveolin-1, were not correlated with the E-cadherin expression.Conclusion
Intralymphatic cancer cells expressing low levels of ALDH1 and infiltrating macrophages expressing CD204 have a critical impact on LN metastasis. Especially, intralymphatic cancer cells expressing low levels of ALDH1 might acquire a metastatic aggressiveness by the EMT process. Our study highlighted the significance of evaluating the biological properties of intralymphatic tumors for tumor metastasis and suggested the possibility of usefulness as a new molecular target, especially as an adjuvant therapy.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO26 - Anatomical Pathology II (ID 129)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Pathology
- Presentations: 2
- Moderators:E. Brambilla, V.L. Capelozzi
- Coordinates: 10/30/2013, 10:30 - 12:00, Bayside 105, Level 1
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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): G. Ishii
- Abstract
- Presentation
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.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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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): G. Ishii
- Abstract
- Presentation
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 Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O13 - Limited Resections (ID 101)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Surgery
- Presentations: 1
- Moderators:G.M. Wright, K. Kernstine
- Coordinates: 10/29/2013, 10:30 - 12:00, Bayside 204 A+B, Level 2
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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): G. Ishii
- Abstract
- Presentation
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.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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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
- Moderators:
- Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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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): G. Ishii
- 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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P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)
- Event: WCLC 2013
- Type: Poster Session
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P3.06-050 - Characteristic Immunophenotype of Solid Subtype Component<br /> in Lung Adenocarcinoma (ID 3289)
09:30 - 09:30 | Author(s): G. Ishii
- Abstract
Background
Lung adenocarcinomas represent a morphologically heterogeneous tumor composed of an admixture of different histologic subtypes (lepidic, papillary, acinar, and solid subtype). The presence of a solid subtype component is reported to be associated with a poorer prognosis. The aim of this study was to evaluate the characteristic immunophenotype of the solid subtype component compared with the immunophenotypes of other components.Methods
We analyzed the clinicopathological characteristics of stage I adenocarcinoma patients with predominant solid subtype disease. Furthermore, we immunostained adenocarcinomas with predominant lepidic, papillary, acinar, and solid subtype components (n = 23 each) for 10 molecular markers of tumor invasiveness and scored the results.Results
Patients showing predominance of the solid subtype component (solid subtype adenocarcinoma) had a poorer prognosis than those showing predominance of the lepidic, papillary, or acinar component. Lymphovascular invasion was more often detected in solid subtype tumors than in others. The solid subtype component showed a significantly stronger staining intensity of laminin-5 expression than the lepidic, papillary, and acinar components (P\\0.001, P\\0.001, and P = 0.016, respectively). The fibronectin and vimentin expression levels were also significantly higher in the solid subtype component than in other components. This immunostaining character was validated by using mixed-subtype adenocarcinomas containing all four components in the same tumor.Conclusion
This study concluded that the solid subtype component in lung adenocarcinomas exhibit the invasive immunophenotype, including increased laminin-5 expression, compared with the other components, which may be associated with a poorer prognosis.
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P3.07 - Poster Session 3 - Surgery (ID 193)
- Event: WCLC 2013
- Type: Poster Session
- Track: Surgery
- Presentations: 1
- Moderators:
- Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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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): G. Ishii
- 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.
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P3.10 - Poster Session 3 - Chemotherapy (ID 210)
- Event: WCLC 2013
- Type: Poster Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:
- Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P3.10-035 - Usefulness of IHC for detection of the ALK-fusion gene in non-small cell lung cancer (ID 2122)
09:30 - 09:30 | Author(s): G. Ishii
- Abstract
Background
Diagnostic guidelines on CAP-IASLC-AMP recommend the use of the ALK fluorescence in situ hybridization (FISH) assay for selecting suitable patients for ALK-TKI therapy. However, based on some reports of the usefulness of immunohistochemistry (IHC) for the detection of ALK, it was considered that it may be possible to use IHC instead of FISH, which is more time-consuming and technically difficult, for the select suitable patients for ALK-TKI therapy in FFPE specimens. The purpose of this study was to investigate the usefulness of IHC as compared to FISH for the diagnosis of ALK-fusion gene-positive NSCLC in clinical practice.Methods
A total of 52 patients with NSCLC who were examined for the ALK-fusion gene by both IHC (Envision Flex+, Dako) and FISH (break-apart probe) at the National Cancer Center Hospital East from March 2012 to March 2013 were included in this study. The reliability and usefulness of IHC as compared to those of FISH were examined for the diagnosis of ALK-fusion gene-positive NSCLC.Results
There were 26 men and 26 women, with a median age 63 years (range, 25-78 years). The pathological diagnosis, based on the examination of 20 resected specimens and 32 biopsy specimens, was adenocarcinoma in 47 cases and poorly-differentiated NSCLC in the remaining 5 cases. ALK protein overexpression was detected by IHC in 11 patients, in contrast, ALK rearrangement was detected by FISH in 9 patients. When the results of the FISH assay were considered as true-positive, the sensitivity, specificity, accuracy, positive predictive value and negative predictive value of IHC were 78%, 100%, 74%, 64%, and 93%, respectively. There were 7 patients with discordant ALK status, consisting of 2 patients who were IHC-negative/ FISH-positive, 4 patients who were IHC-positive/ FISH-indeterminate and 1 patient who was IHC-negative/FISH-indeterminate. Of these patients with discordant ALK status, three received ALK-TKI (crizotinib) therapy. The best response rate according to assessment by the RECIST was SD in the patient who was IHC-negative/ FISH-positive, and PR in both the patients who were IHC-positive / FISH-indeterminate. Figure 1Conclusion
Although the ALK-true positive result remained unclear, based on the responses to crizotinib, it might be judged that the result was true-positive in the patients who were IHC-positive/ FISH-indeterminate and true-negative in the patient who was IHC-negative/ FISH-positive. Thus, it appeared that FISH could not determine the ALK status in approximately 10% of the patients, and it can therefore not be considered an absolute diagnostic method.
