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K. Tsuta
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P1.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 224)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 2
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.08-026 - First Case of SMARCB1(INI1)- Deficient Squamous Cell Carcinoma of the Pleura (ID 978)
09:30 - 09:30 | Author(s): K. Tsuta
- Abstract
Background:
SMARCB1(INI1) is a tumor-suppressor gene located at 22q11.2. It is considered an integral component of the chromatin remodeling complex SW1/SNF. Loss of SMARCB1 expression has been reported to be associated with atypical teratoid/rhabdoid tumors and malignant rhabdoid tumors of the kidney and extrarenal tissues. In addition, sinonasal basaloid carcinomas and neoplasms arising from the gastrointestinal tract, pancreas and uterus with SMARCB1 deficiency have been reported.To date, however, SMARCB1-deficient carcinoma of the pleura has not been reported.
Methods:
We report the first case of SMARCB1-deficient squamous cell carcinoma of the pleura in a patient, and describe the clinical course from initial presentation to diagnosis with pathological findings.
Results:
The case was a 33-year-old female never smoker with no previous medical or family history of malignant disease. She visited a previous hospital with a one-month history of worsening cough and dyspnea. Chest X-ray and computed tomography (CT) showed left pleural tumors with a large amount of pleural effusion. She underwent the diagnostic thoracoscopy to obtain sufficient tumor tissue from the parietal pleura. Systemic work-up including CT identified no other lesions apart from those in the left thoracic cavity. Pathological diagnosis in the previous hospital was squamous cell carcinoma of the pleura. She received six cycles of cisplatin plus gemcitabine therapy and achieved stable disease an overall best response. After progression, she transferred to our institution for expected further treatment. Although she received TS-1 therapy as second-line treatment, her disease progressed rapidly with worsening chest pain and dyspnea, and she died at 10 months after diagnosis. On pathological review of formalin-fixed, paraffin-embedded tissues of parietal pleura obtained in the previous hospital, primary tumors were composed of morphologically poorly differentiated cancer cells with characteristics of squamous cell carcinoma. Tumor cells were completely negative for INI1 protein expression by immunohistochemistry. Malignant pleural mesothelioma, thymic carcinoma and NUT midline carcinoma were ruled out. Claudin4 and MOC31 were positive, and C-kit and NUT were negative by immunohistochemistry suggesting that the tumor was primary squamous cell carcinoma of the pleura with SMARCB1 deficiency. Genome analysis using next-generation sequence data revealed no oncogene mutations, such as EGFR mutation, ALK, RET or ROS1 rearrangement.
Conclusion:
To our knowledge, this is the first report of SMARCB1-deficient squamous cell carcinoma of pleura. The tumor was highly aggressive and carried a poor prognosis with short survival. The existence of other SMARCB1- deficient tumors is likely, such as atypical teratoid/rhabdoid tumors and malignant rhabdoid tumors of the kidney and extrarenal tissues. The clinical features and treatments of this tumor are not clear, and additional cases wiii assist the establishment of treatments and improve the poor prognosis.
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P1.08-028 - PD-L1 Expression in Neuroendocrine Tumors of the Lung (ID 2217)
09:30 - 09:30 | Author(s): K. Tsuta
- Abstract
Background:
The World Health Organization (WHO) classification recognizes four major types of neuroendocrine tumors of the lung: typical carcinoid, atypical carcinoid, small cell lung cancer (SCLC), and large-cell neuroendocrine carcinoma (LCNEC). These diagnostic categories have different prognostic implications and require distinct treatment strategies. The PD-1/PD-L1 pathway is a major target of anti-tumor immunotherapy. PD-L1 expression has been reported to cause local immune suppression and is considered as a predictive marker of immune checkpoint therapeutics. In order to clarify any differences in the expression of PD-L1 according to the type of neuroendocrine tumor in the lung, we investigated the expression levels of PD-L1 by immunohistochemistry in neuroendocrine tumors of the lung.
Methods:
The subjects of this study were patients who were diagnosed as having lung neuroendocrine tumors and were treated at the National Cancer Center Hospital from 1982 to 2010. A tissue microarray (TMA) made from the surgical specimens was analyzed. After the rabbit monoclonal PD-L1 antibody was validated (clone E1L3N, Cell Signaling Technology, Danvers, MA), the TMA was stained and the tumor PD-L1 expression score was calculated by a semiquantitative method (by multiplying the intensity [0–3] by the staining area [0–100%]). To determine the PD-L1 expression, 3 (1%) was used as the cutoff score.
Results:
A total of 227 patients were included in this study. The characteristics of the entire patient population were as follows; median age, 65 years (range: 19-84 years); gender, male 168 (74.0%) / female 59 (26.0%); smoking status, smokers 191 (84.1%)/non-smokers 36 (15.9%); pStage: IA 79 (34.8%)/IB 36 (15.9%)/IIA 25 (11.0%)/IIB 29 (12.8%)/IIIA 47 (20.7%)/IIIB 6 (2.6%)/IV 5 (2.2%); histology, typical carcinoid 46 (20.3%)/atypical carcinoid 6 (2.6%)/SCLC 69 (30.4%)/LCNEC 106 (46.7%). Of the 227, samples from 15 (6.6%) showed positive staining for PD-L1. The characteristics of the patients showing positive staining for PD-L1 were as follows; median age, 71 years (range: 37-84 years); gender, males 12 (7.1%)/females 3 (5.1%); smoking status, smokers 13 (6.8%)/non-smokers 2 (5.6%); pStage, IA 3 (3.8%)/IB 2 (5.6%)/IIA 2 (8.0%)/IIB 5 (17.2%)/IIIA 2 (4.3%)/IIIB 0 (0%)/IV 1 (20.0%); histology, typical carcinoid 0 (0%)/atypical carcinoid 0 (0%)/SCLC 4 (5.8%)/LCNEC 11 (10.4%). In 31 of the 69 cases of SCLC who were treated by surgery, the disease recurred; of these 31 patients who developed disease recurrence, positive expression for PD-L1 was noted in 2 patients (6.5%). Furthermore, the disease recurred in 33 of the 106 cases of LCNEC treated by surgery; of the 33, 2 (6.1%) showed expression of PD-L1.
Conclusion:
None of the tumors in the patients with typical or atypical carcinoid in our study showed expression of PD-L1. Only the tumors in 4 of the 69 patients (5.8%) with SCLC and 11 of the 106 patients (10.4%) with LCNEC showed positive staining results for PD-L1. The data suggest that drugs directed against PD-1/PD-L1 might be potentially useful in the immunotherapy of SCLC and LCNEC.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 2
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-037 - Prevalence of NRG1 Fusions in Caucasian NSCLC Patients Determined by Fluorescence in Situ Hybridisation (ID 1553)
09:30 - 09:30 | Author(s): K. Tsuta
- Abstract
Background:
Fusions of the gene Neuregulin1 (NRG1) have been described to activate PI3K-AKT signaling in NSCLC via NRG1 overexpression and binding to Her2/Neu-Her3. NRG1 fusions were detected in pulmonary mucinous adenocarcinoma of Asian non-smokers lacking other known oncogenic driver mutations. The incidence in such patients has been described to be between 17.6% (6/34) and 44.4% (4/9). NRG1 fusions might be targeted by Her2/Her3-inhibitors and clinical trials are planned. Here we describe for the first time the systematic analysis of NRG1 in Caucasian patients by Fluorescence in situ hybridization (FISH).
Methods:
A ZytoLight®-based FISH assay (ZytoVision, Bremerhaven, Germany) was developed and verified on nine published clinical cases with known NRG1 fusions. A total of 160 Caucasian NSCLC patients were screened. 25 of the cases were mucinous adenocarcinoma lacking a known oncogenic driver mutation as determined by deep-sequencing and FISH tests. 135 cases were pulmonary adenocarcinoma of various subtypes including 35 cases that lacked a driver mutation and 100 cases that were EGFR, ALK and ROS1 wildtype. The smoking-status was not evaluated. Statistics were calculated using R 3.1.0 .
Results:
The NRG1 fusions in the published cases were easily detected by the FISH assay. However, none of the screened cases harbored a NRG1 fusion. The result is significant compared to published reference values of 17.6% (p=0.041) and 44.4% (p<0.001). The theoretical maximum incidence of NRG1 fusions among Caucasian NSCLC patients not stratified by smoking-status was calculated to be <16.6% for mucinous adenocarcinomas lacking driver mutations, <7.5% for adenocarcinoma of all morphological subtypes lacking driver mutations and <3% for EGFR, ALK, ROS1 negative pulmonary adenocarcinoma (95% confidence intervals).
Conclusion:
FISH is a suitable technique to screen for NRG1 fusions in pulmonary adenocarcinoma. Among 160 Caucasian patients including 25 mucinous carcinomas lacking a driver mutation none were NRG1 positive. Thus, the incidence among Caucasian patients appears to be low and should be evaluated in studies of large NSCLC cohorts.
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P3.04-110 - PTPRH Hypomethylation as a Prognostic Factor in Non-Small Cell Lung Cancer (ID 759)
09:30 - 09:30 | Author(s): K. Tsuta
- Abstract
Background:
Tyrosine phosphorylation is an important signaling mechanism in cancer. PTPRH is a receptor-type protein tyrosine phosphatase thought to be a potential regulator of tumorigenesis. The aim of this study is to clarify the significance of PTPRH expression and its regulation by DNA methylation in non-small cell lung cancer (NSCLC), especially in lung adenocarcinoma.
Methods:
PTPRH mRNA expression was examined in 89 NSCLC and corresponding non-cancerous tissues. The correlation between DNA methylation and PTPRH gene expression was investigated in another cohort that consisted of 145 patients with lung adnocarcinoma. Gene regulation by DNA methylation was assessed using a DNA methylation inhibitor. Statistic analysis was performed to clarify whether the DNA methylation status of PTPRH is a prognostic factor for patients with lung adenocarcinoma.
Results:
PTPRH mRNA expression was significantly up-regulated in NSCLC. PTPRH DNA methylation was reduced in lung ademocarcinomas and inversely correlated with mRNA expression. 5-aza-2'-deoxycytidine treatment of lung cancer cell lines with low PTPRH expression, restored mRNA PTPRH expression levels. Furthermore, low PTPRH methylation was associated with shorter recurrence-free survival (P < 0.0002) and overall survival (P < 0.0001). Multivariate analysis revealed that PTPRH DNA methylation was an independent prognostic factor (P < 0.01).
Conclusion:
We confirmed that PTPRH is overexpressed in NSCLC. In addition, we determined that hypomethylation of PTPRH is a poor prognostic factor in lung adenocarcinoma.
