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G. Ishii
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OA07 - Lymph Node Metastases and Other Prognostic Factors for Local Spread (ID 376)
- Event: WCLC 2016
- Type: Oral Session
- Track: Surgery
- Presentations: 1
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OA07.05 - Prognostic Impact of Pleural Lavage Cytology (PLC): Significance of PLC after Lung Resection (ID 5801)
15:05 - 15:15 | Author(s): G. Ishii
- Abstract
- Presentation
Background:
We previously reported the prognostic significance of pleural lavage cytology (PLC) in patients undergoing surgery for non-small-cell lung cancer (NSCLC). Based on a larger cohort of more than 3500 NSCLC patients, which is the largest ever reported from a single institution in the literature, we evaluated the prognostic impact of PLC on survival and recurrence.
Methods:
From January 1993 to July 2015, 3671 patients underwent R0 surgical resection for NSCLC at our institution and PLC results before (pre-) and after (post-) lung resection were both available. The cytological evaluation was classified into 3 categories: negative (-), suggestive (±), positive (+). We excluded 77 patients whose PLC results were suggestive, and 3594 patients were analyzed. The impact of PLC results on survival and recurrence was evaluated with conventional clinicopathological factors.
Results:
The overall survival (OS) of pre-PLC (+) patients was significantly inferior to that of pre-PLC (-) patients. However, the 5-year OS rate of pre-PLC (+) patients was 43%, which was significantly better than that of patients with pleural dissemination (11%). In the following analyses, we divided the patients into 3 groups according to pre/post- PLC results as follows: Pre (-)/ post (-), Group A (n=3461); pre (+)/ post (-), Group B (n=43); and post (+), Group C (n=87). Statistically significant difference was not observed between Groups A and B in OS or in recurrence-free survival (RFS) (p=1.00, 0.28, respectively). However, there were significant differences in OS and RFS between Groups B and C (p=0.01 and p=0.02), and between Groups A and C (p<0.01 and p<0.01), respectively. In univariate and multivariate analyses of clinicopathological factors including post-PLC results to identify prognosticators for OS, post-PLC(+) (hazard ratio (HR) =2.20, p<0.01), older age (≥65 years; HR=1.95, p<0.01), smoking history (+) (HR=1.48, p<0.01), elevated serum CEA level (>5.0 mg/dL; HR=1.28, p<0.01), pathological(p)T≥2 (HR=1.28, p<0.01), pN≥1 (HR=1.48, p<0.01), pStage≥II (HR=1.51, p<0.01), pl(+) (HR=1.43, p<0.01), ly(+) (HR=1.32, p<0.01), and v(+) (HR=1.53, p<0.01) were found to be significant independent unfavorable prognosticators.
Conclusion:
The prognostic impact of pre-PLC was moderate and not prohibiting lung resection. Post-PLC was shown to be a strong independent prognostic factor. Its impact on survival of NSCLC patients was very strong, and therefore should be incorporated in the future TNM classification.
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OA15 - Sublobar Resections for Early Stage NSCLC (ID 396)
- Event: WCLC 2016
- Type: Oral Session
- Track: Surgery
- Presentations: 1
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OA15.01 - Limited Resection Trial for Pulmonary Sub-solid Nodules: Case Selection Based on High Resolution CT: Outcome at Median Follow-up of 105 Months (ID 4454)
16:00 - 16:10 | Author(s): G. Ishii
- Abstract
- Presentation
Background:
The objective of this study is to confirm limited resection efficacy as radical surgery in patients with minimally invasive lung cancer as indicated by high-resolution (HR) computed tomography (CT), 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 unfit for lobectomy and systematic lymph node dissection were excluded. We performed a wedge or segmental resection. The used stapling cartridges were washed with saline, which was cytologically evaluated. 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. We aimed at enrolling 100 patients. The primary endpoint is 10-year local recurrence free survival rate.
Results:
This prospective study started in November 2003, and 101 patients were enrolled in 6 years. Of them, 99 were eligible for analysis. The mean age was 62 years (range: 30-75), and 60 were women. There were 11 Noguchi type A tumors, 54 type B tumors, 26 type C tumors, one type D tumor, one malignant lymphoma, 3 hyperplastic lesions, and 3 inflammatory fibroses. None of the 93 malignant nodules showed any 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 105 months (range: 72−129) as of June 2016, there have been no recurrences, but one patient died for unspecified cause.
Conclusion:
We have repeatedly warned that delayed cut-end recurrence is possible following limited resection even for small sub-solid lung cancers. So far, however, HRCT scans appear to predict non- or minimally invasive sub-solid 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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P1.07 - Poster Session with Presenters Present (ID 459)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.07-037 - Clinicopathological Significance of Cancer Stem-Like Cell Markers in High-Grade Neuroendocrine Carcinoma of the Lung (ID 4993)
14:30 - 14:30 | Author(s): G. Ishii
- Abstract
Background:
Over the past decade, cancer stem cells or cancer stem-like cells (CSLCs) have been identified in various tumors. However, few studies have examined the significance of CSLC marker expression in high-grade neuroendocrine carcinoma (HGNEC). This study aimed to evaluate the clinicopathological significance of CSLC markers in high-grade neuroendocrine carcinoma (HGNEC) of the lung, including small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC).
Methods:
We retrospectively studied patients who underwent surgical resection of SCLC (n = 60) and LCNEC (n = 45) to analyze their clinicopathological profiles and the immunohistochemical expression of putative CSLC markers (Caveolin, Notch, CD44, CD166, SOX2, ALDH1, and Musashi1). Staining scores for these markers in tumor cells were calculated by multiplying the percentage of positive tumor cells per lesion by the staining intensity level (0, 1, and 2); a score of ≥ 10 represented positive expression.
Results:
There was a difference between SCLC and LCNEC with respect to both SOX2 (55 vs. 27 %, p = 0.003) and CD166 (27 vs. 47 %, p = 0.034) expression. ALDH1 expression was equally observed in SCLC and LCNEC (67 vs. 73 %, p = 0.46), and patients with ALDH1-positive HGNEC had significantly worse recurrence-free survival (RFS) and overall survival (OS) rates than those with ALDH1-negative HGNEC (5-year RFS: 39 vs. 67 %, p = 0.009; 5-year OS: 50 vs. 79 %, p = 0.021). A multivariate analysis revealed that positive ALDH1 expression was an independent unfavorable prognostic factor with respect to both RFS and OS.
Conclusion:
The differences in the expression profiles of CSLC markers might reflect morphological differences between SCLC and LCNEC. Positive ALDH1 expression in lung HGNEC was associated with an unfavorable patient prognosis, which suggested that ALDH1-positive tumor cells might be future therapeutic targets for the treatment of lung HGNEC.
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P3.01 - Poster Session with Presenters Present (ID 469)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 3
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.01-001 - Cancer Cell Invasion Driven by Extracellular Matrix Remodeling is Dependent on the Properties of Cancer‑Associated Fibroblasts (ID 3891)
14:30 - 14:30 | Author(s): G. Ishii
- Abstract
Background:
As one form of tumor invasion, cancer cells can invade the extracellular matrix (ECM) through tracks that have been physically remodeled by cancer-associated fibroblasts (CAFs). However, CAFs are a heterogeneous population with diverse matrix-remodeling capacities. The purpose of this study is to investigate how CAFs with various matrix-remodeling capacities influence cancer cell invasion.
Methods:
We established single-cell derived clones from 3 primary cultures of CAFs from lung adenocarcinoma patients (Case 1, 5 clones; Case 2, 5 clones; Case 3, 7 clones). Using a co-culture model, we evaluated the correlations between the number of invaded cancer cells and the remodeling areas generated by CAF clones in each case.
Results:
When A549 lung adenocarcinoma cells and CAF clones were co-cultured, both the numbers of invaded cancer cells and the remodeling areas generated by the CAF clones varied greatly. The number of invaded cancer cells was moderately and strongly correlated with the remodeling areas generated by each CAF clone originating from Cases 1 and 2 (R[2] value = 0.53 and 0.68, respectively), suggesting that the remodeling areas in the ECM may determine the number of invaded cancer cells. In contrast, the number of invaded cancer cells was not correlated with the remodeling areas generated by CAF clones originating from Case 3, suggesting that factors other than the remodeling areas might determine the number of invading cancer cells.
Conclusion:
These findings showed two types of fibroblast-dependent cancer cell invasion that are dependent on and independent of the remodeling areas generated by CAFs.
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P3.01-016 - Factors Influencing the Concordance of Histological Subtype Diagnosis by Biopsy and Resected Specimens of Lung Adenocarcinoma (ID 5018)
14:30 - 14:30 | Author(s): G. Ishii
- Abstract
Background:
Lung adenocarcinoma is heterogeneous, characterized by various histological subtypes. Determination of the predominant histological subtype (lepidic, papillary, acinar or solid-predominant) has been shown to correlate with genetic abnormalities and clinicopathological features. Although subtyping using small biopsy samples is important for tailored approaches to clinical management, limited data exist on the concordance of predominant subtype between resected specimens and biopsy specimens.
Methods:
We compared the diagnosed predominant subtypes in resected specimens and matched biopsy specimens in a series of 327 lung adenocarcinomas. Histological subtyping of preoperative material was made by review of archived hematoxylin and eosin stain slides that had originally been prepared for diagnosis before surgery. The histological subtype of surgically resected tumors was obtained from the pathological case records for each surgical resection specimen. The accuracy of preoperative diagnosis by biopsy and the factors that influence concordance with resected specimen analysis were examined.
Results:
In 211 of the 326 patients (66.0%), the predominant adenocarcinoma subtype diagnosed from biopsy matched the findings of resection analysis. Concordance rate was highest in papillary pattern (82%), followed by lepidic pattern (75%), solid pattern (66%), and acinar pattern (39%). Overall, the concordance rate in biopsy samples with larger tumor areas (≥0.7 mm[2]) was significantly higher than in those with smaller tumor area (<0.7 mm[2]; 71% vs 58%, respectively; p = 0.02). Other factors in biopsy samples, such as number of biopsies, or the small biopsy type, did not have significant influence on the concordance between preoperative and postoperative diagnosis. In the biopsy samples with smaller tumor areas, the concordance rate was 77% in lepidic subtype, 71% in papillary subtype, 60% in solid subtype, and 40% in acinar subtype. Concordance rate in the biopsy samples with larger tumor area was higher in papillary and solid subtypes (88% and 76%, respectively), but remained low in acinar subtype (37%).
Conclusion:
These results indicate that accuracy of adenocarcinoma subtyping based on small biopsy samples is influenced by tumor area. Our study also suggests that subtyping of acinar histology using biopsy specimen is particularly error-prone.
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P3.01-024 - Drastic Morphological and Molecular Differences between Lymph Node Micrometastatic Tumors and Macrometastatic Tumors of Lung Adenocarcinoma (ID 5894)
14:30 - 14:30 | Author(s): G. Ishii
- Abstract
Background:
The expansion of micrometastatic tumors to macrometastatic ones is thought to be tightly regulated by several microenvironmental factors. The aim of this study was to elucidate the morphological and phenotypical differences between micrometastatic and macrometastatic tumors.
Methods:
We first examined the morphological characteristics of 66 lymph node (LN) micrometastatic tumors (less than 2 mm in size) and 51 macrometastatic tumors (more than 10 mm in size) in 42 lung adenocarcinoma cases. Then, we evaluated the expression level of E-cadherin, S100A4, ALDH1, and Geminin in cancer cells and the number of smooth muscle actin (SMA), CD34, and CD204 (+) stromal cells in the primary tumors, matched micrometastatic tumors, and macrometastatic tumors (n = 34, each).
Results:
Tumor budding reflects the process of EMT, and stromal reactions were observed more frequently in macrometastatic tumors (P < 0.001). E-cadherin staining score for the micrometastatic tumors was significantly higher than that for the primary tumors (P < 0.001). In contrast, the E-cadherin staining score for the macrometastatic tumors was significantly lower than that for the micrometastatic tumors (P = 0.017). As for the stromal cells, the numbers of SMA (+) fibroblasts, CD34 (+) microvessels, and CD204 (+) macrophages were significantly higher for the macrometastatic tumors and primary tumors than for the micrometastatic tumors (P < 0.001, all).
Conclusion:
The present study clearly showed that dynamic microenvironmental changes (e.g., EMT-related changes incancer cells and structural changes in stromal cells) occur during the growth of micrometastases into macrometastases.
