Based on a questionnaire survey, the Lung Cancer Screening Committee considers that the aging of doctors involved in lung cancer screening and the high coverage rate of non-specialist doctors are problems; thus, the acquisition of new reading doctors and maintaining and improving the reading ability for doctors who currently perform reading, are considered very important. In 2012, we published Chest X-ray Interpretation Textbook for Lung Cancer Screening with the aim of solving these problems; however, we needed a method to apply the knowledge learned there. In 2018, screening image data were collected from facilities related to the Lung Cancer Screening Committee members, and the image data were evaluated by central judgment. Based on the data and results, we have developed a system that enables interpretation exercises similar to the examination interpretation environment. In May 2019, it started operation as a system that members can practice anytime and anywhere via the internet. It is now stably operated at more than one year after the start of operation. This paper explains the progress of the development of this system and how it is used. It also reports the usage status.

In the pathological diagnosis of lung cancer, the expression of certain transcription factors is important as differentiation markers and for predicting underlying molecular abnormalities. TTF-1 is a master regulator of lung differentiation, and TTF-1-positive lung adenocarcinomas frequently harbor mutually exclusive driver mutations, such as EGFR and ALK. Furthermore, some studies have reported that TTF-1 itself is important for the survival of cancers. HNF4α, which is involved in gastrointestinal epithelial differentiation, is mutually exclusive with TTF-1 in lung cancer, and HNF4α-positive lung adenocarcinomas frequently harbor a TTF-1 gene-inactivating mutation/hypermethylation and KRAS mutation. SALL4, an embryonic tumor marker, is highly expressed in high-grade fetal adenocarcinoma. SALL4 is attracting attention as a new oncogene and a target for molecular therapy. In EMT-type lung cancer, the loss of chromatin remodeling factors, such as SMARCA4 and SMARCA2, has been observed, and in recent years, a new disease concept known as SMARCA4-deficient dedifferentiated tumor has been proposed. It was recently reported that small-cell carcinomas can be classified into four molecular subtypes depending on four transcription factors: ASCL1, NEUROD1, POU2F3, and YAP1. Based on my own pathological research on lung cancer, I will briefly explain these transcription factors and regulators related to the pathological diagnosis.

Until the advent of immune checkpoint inhibitors, first-line treatment of patients with advanced non-small-cell lung cancer (NSCLC) without an EGFR/ALK alteration was platinum-based chemotherapy. The introduction of immune checkpoint inhibitors has altered the treatment paradigm for patients with advanced NSCLC. A phase III trial comparing pembrolizumab with platinum-based chemotherapy was conducted in EGFR/ALK-negative advanced NSCLC patients with a tumor proportion score (TPS) for programmed cell death-ligand 1 (PD-L1) of ≥50%. Pembrolizumab monotherapy significantly improved the progression-free survival (PFS) and overall survival (OS) with tolerability. In addition, several phase III studies showed a higher efficacy of combination treatment with an immune checkpoint inhibitor than platinum-based chemotherapy alone in advanced NSCLC. Immunotherapy is an important treatment modality for driver oncogene-negative NSCLC. It is important to know which regimen is the most useful for each patient, but such details are still unclear, and no biomarkers have yet been established. Therefore, it is necessary to choose a treatment regimen while considering the patient background, PD-L1 expression, characteristics and toxicity profile of each regimen in clinical practice. Establishing predictive markers of long-term clinical benefit with immune checkpoint inhibitor treatment is an important issue.

The standard treatment for non-small-cell lung cancer (NSCLC) with distant metastases is pharmacotherapy, and the survival benefit of additional localized therapy has not been clarified. However, in cases of oligometastatic disease in which metastatic lesions are limited, a long-term prognosis has been observed with localized therapy. In recent years, several randomized controlled trials have reported the effects of additional localized therapy for oligometastatic disease. These trials have targeted cases of synchronous oligometastatic disease, and all have tended to show the extension of the survival period. Treatment of NSCLC is diversifying due to the advent of novel strategies, such as targeted therapy, immune checkpoint inhibitors, and radiotherapeutic technology. Localized therapy for oligometastatic disease might be a new treatment strategy, although the disadvantages of its invasiveness and the risks associated with discontinuation of pharmacotherapy need to be considered.

Background. To clarify the current status of re-biopsies for lung cancer in daily clinical practice, we conducted a multicenter prospective observational registry study in Chiba prefecture. Method. Between September 2017 and March 2019, we prospectively enrolled 73 patients who underwent a re-biopsy as a second biopsy during treatment for primary lung cancer at 7 registered centers in Chiba Prefecture and analyzed the clinicopathological characteristics of the patients. Results. The biopsy sites were 39 lungs, 21 regional lymph nodes, 4 bones, 3 pleural effusion samples, 3 livers, and 1 each of the brain, skin, and axillary lymph node. The biopsy modalities were 55 bronchoscopies, 12 percutaneous needle biopsies, 4 surgical biopsies and 2 computed tomography-guided biopsies. A pathological diagnosis was possible in 87.6% (64/73 biopsies). Driver gene mutation re-assessment was successfully performed in 98.2% (55/56 biopsies, only for adenocarcinoma). Among the molecular target therapy-resistant cases, T790M was detected in 47.7% (21/44 biopsies), and histological transformation was observed in 8.6% (5/58 cases). The Tumor Proportion Score (TPS) was assessed for 32 patients, and the TPS was 0% in 37.5%, 1-49% in 34.4%, and ≥50% in 28.1%. Conclusion. This consortium, which was formed through the cooperation of multiple departments at multiple centers, revealed the current status of re-biopsies for lung cancer in Chiba Prefecture. We believe that re-biopsies will continue to play an important role in determining treatment policies for lung cancer.

Background. The abscopal effect is a phenomenon in which tumor shrinkage occurs outside the radiation field. It usually occurs between the primary tumor and metastatic lesions of the same cancer or between metastatic lesions, and there have been no reports on the abscopal effect occurring after irradiation of other cancer types. Case. A woman in her 50s was diagnosed with double primary cancer of lung and oropharyngeal cancer. After the administration of nivolumab as second-line treatment for lung cancer, the lung cancer did not show any increase in size for six months (stable disease). However, the pharyngeal cancer showed progression, so irradiation was started for it. After radiotherapy, shrinkage of the primary lung cancer (outside the irradiation field) was observed. Conclusion. We experienced a case in which primary lung cancer shrank after irradiation for primary pharyngeal cancer. This case suggests that abscopal-like effects may occur between different cancer types.

Background. The cause of paraneoplastic neurological syndrome (PNS) in about 80% of cases is small-cell lung cancer. However, PNS is difficult to diagnose, and there is no established standard therapy for it.Case. A 78-year-old man was admitted to the hospital with acutely progressive symptoms of cerebellar ataxia. Chest computed tomography performed on his clavicle when he broke it had shown a pulmonary nodule in the right upper lobe and mediastinal lymph node swelling 6 months before the admission, but these nodules had spontaneous regressed by admission. After treating the patient with high dose intravenous immunoglobulin (IVIG), the neurological symptoms improved. However, mediastinal lymph node showed re-swelling. The mediastinal lymph node was diagnosed as metastatic small-cell lung cancer by mediastinoscopy. In addition, anti-voltage gated calcium channel antibody, which is an anti-neural antibody, was positive. Therefore, the patient was diagnosed with paraneoplastic cerebellar degeneration due to small-cell lung cancer. The patient underwent chemoradiation and achieved a complete response, ultimately obtaining a long-term survival. Conclusion. IVIG and chemoradiation for PNS improve the neurological symptoms and prognosis.

Background. Standard therapy for unresectable cases of mediastinal lymph node carcinoma of unknown primary site has not been established. Cases. Case 1. A 59-year-old man underwent computed tomography (CT) that showed right paratracheal lymphadenopathy. The lymphadenopathy was diagnosed as adenocarcinoma by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). He was treated with chemoradiotherapy successfully, but squamous cell carcinoma appeared in the lower lobe of the right lung 10 years later. Case 2. A 70-year-old man was found to have left paratracheal lymphadenopathy. The lymphadenopathy was diagnosed as adenosquamous carcinoma by mediastinoscopy. Chemoradiotherapy was successful, but squamous cell carcinoma appeared in the lower lobe of the left lung 7 years later and was resected. Case 3. A 71-year-old man was found to have swelling of the right paratracheal lymph node during follow-up of combined pulmonary fibrosis and emphysema. The lymphadenopathy was diagnosed as adenocarcinoma by EBUS-TBNA. He was treated with chemoradiotherapy and has been alive without recurrence for 10 years. Case 4. A 64-year-old man was found to have subcarinal lymph node swelling. The lymphadenopathy was diagnosed as squamous cell carcinoma by EBUS-TBNA. He received chemoradiotherapy and has been relapse-free for 5 years. Conclusion. Chemoradiotherapy with paclitaxel (PTX) and carboplatin (CBDCA) seems to be a promising treatment for unresectable cases of mediastinal lymph node carcinoma of unknown primary site. Lung cancer is likely to occur during the course, and careful follow-up is required.

Background. Drug-induced lung injury, skin rashes, and diarrhea are known adverse effects of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Corneal epithelial disorder and herpes simplex are rarely encountered in association with EGFR-TKIs. Case. A 69-year-old woman was admitted to our hospital for further evaluation of an abnormal shadow on chest radiography. Chest computed tomography (CT) showed a nodule on the right S⁸. Adenocarcinoma with the EGFR L858R mutation was diagnosed via transbronchial lung biopsy. We made a diagnosis of cT1bN0M1b stage IV with brain metastasis and administered erlotinib. On the 5th day, she developed herpes simplex on the left lower jaw area. She was treated with valacyclovir. On the 11th day, her visual acuity deteriorated, and she was diagnosed with bicorneal epithelitis and bikeratitis. A detailed history confirmed a history of corneal detachment of unknown cause, suggesting corneal fragility. After the discontinuation of erlotinib, her corneal epithelial opacity gradually improved. When gefitinib was administered, her visual acuity deteriorated again in the afternoon of the same day. Herpes simplex recurred on her lips. On the next day, the ophthalmology department diagnosed a relapse of corneal epithelial opacity. After the discontinuation of gefitinib, her corneal epithelial opacity gradually improved. Conclusion. Corneal epithelial disorder and herpes simplex were considered to be adverse effects of EGFR-TKIs since re-administration caused the same disorder.

Background. Malignant pleural mesothelioma is a disease with a poor prognosis and limited therapeutic options. With only a few reports available, spontaneous regression of malignancy is very rare, and the mechanism underlying spontaneous regression of malignancy is unknown. Case. A 68-year-old man was referred to our hospital because of dyspnea on exertion, anorexia, and weight loss. Chest computed tomography (CT) revealed multiple tumors in the pleura and interlobar pleura at the right side along with right pleural effusion. We performed a percutaneous needle biopsy of a pleural mass and thoracentesis. We finally diagnosed the patient with epithelioid malignant pleural mesothelioma, pathological T3N0M0 stage III. However, the patient's performance status was 3, so we concluded that chemotherapy would be difficult and suggested best supportive care instead. One year later, he was referred to our hospital again. Chest CT indicated that multiple tumor shadows on the pleura and interlobar pleura had been reduced and decreased despite no medical treatment, such as radiotherapy, chemotherapy, or immunotherapy. Thus, spontaneous regression of malignant pleural mesothelioma was considered to have occurred. Conclusion. Spontaneous regression of malignant pleural mesothelioma is very rare. CD8⁺ T cells are known to play a critical role in antitumor immunity. In our case, we performed immunohistochemical anti-CD8 antibody staining, and many tumor-infiltrating lymphocytes were stained. There was a significantly greater increase of CD8⁺ than CD4⁺ tumor-infiltrating lymphocytes. This significant increase in CD8⁺ tumor-infiltrating lymphocytes further supported the possibility that the spontaneous regression of the malignant pleural mesothelioma had been caused by the antitumor effect of CD8⁺ tumor-infiltrating lymphocytes. These findings suggest that the spontaneous regression of malignant pleural mesothelioma may have been caused by CD8⁺ tumor-infiltrating lymphocytes. The presence of CD8⁺ tumor-infiltrating lymphocytes may correlate with spontaneous regression and an improved clinical outcome.

Background. An emphysematous bulla is considered a risk factor of lung cancer. Case. A man in his 40s had a history of video-assisted thoracoscopic surgery for right spontaneous pneumothorax in his 20s but had continued to smoke. After an abnormal shadow was noted on chest X-ray during a medical examination, he was referred to us. Computed tomography (CT) showed a right emphysematous cystic lesion 9.0×5.0×10.0 cm in size and a 2.4 cm solid nodule on a part of the cyst wall. Although lung cancer originating near the bulla wall was suspected, a postoperative foreign body and chest wall tumor could not be ruled out. After a CT-guided core needle biopsy was performed, pneumothorax occurred. Because a histopathological study revealed adenocarcinoma, he was diagnosed with primary lung cancer originating near the emphysematous bulla wall. Subsequently, right upper lobectomy was performed. The postoperative course was uneventful. Conclusion. We experienced a case of lung cancer originating near the bulla wall with atypical findings of clinical imaging.