The Committee for Lung Cancer Screening of the Japan Lung Cancer Society revised the "Lung Cancer Screening Guidelines" in 2022. We herein report the background and outline of this revision. The "Recommendation" concerning "Current population-based lung cancer screening in Japan" remains the same as in the 2010 Guidelines. Nationwide quality control and evaluations of the contribution of the effect to the reduction in lung cancer mortality as well as sensitivity and specificity are required. Evidence that low-dose computed tomography (CT) screening for heavy smokers is effective at reducing lung cancer mortality has been obtained in Europe and the United States. However, the associated disadvantages cannot be ignored, including the risk of false positives, overdiagnosis, and radiation exposure. To avoid the potential chaos that might be caused by the careless introduction of CT screening into Japanese society, appropriate "implementation research" should be conducted. However, there is currently insufficient evidence concerning the efficacy of low-dose CT screening for non-/light smokers, so it is of primary importance to accumulate such evidence.

With the advent of immune checkpoint inhibitors, long-term survival can now be expected, even in patients who present with advanced non-small-cell lung cancer. While these drugs are used for many lung cancer patients and are expected to be more effective when used in combination with cytotoxic anticancer agents than when administered alone, the cost and toxicity of immune checkpoint inhibitors are also a major concern. It is therefore necessary to urgently identify the predictors of effectiveness that can reduce the risk of additional toxicities and cost by accurately identifying the patients who should and should not be using these drugs in advance. With regard to predictors of the efficacy of immune checkpoint inhibitors, factors such as the tumor PD-L1 expression and tumor mutational burden have attracted attention, and some predictive factors are already widely used in clinical practice. Unfortunately, however, none of these factors alone can sufficiently predict the effects of immune checkpoint inhibitors. We herein review the current status and future issues concerning predictive factors for the efficacy of immune checkpoint inhibitors.

Although a great deal of research on cancer immunotherapy has been conducted using mice, there are many differences between humans and mice, which is associated with some limitations. Therefore, the analysis of human clinical specimens is important for elucidating the essence of cancer immunology. Recently, advances in technology have made it possible to perform comprehensive gene analyses of various clinical specimens. While such analyses are often performed in bulk, we believe that it is important to analyze clinical specimens at the single-cell level in order to understand the role of each cell, including various immune cells, in detail. Various novel findings have been obtained from such analyses.

Objective. In Japan, few cases of asbestos lung cancer, which is predicted to be more prevalent than mesothelioma, have been certified by the Industrial Accident Compensation Insurance Program. We suspect this to be due to the lack of asbestos exposure interviews. Study Design. A web-based survey was performed among physicians who conduct asbestos exposure-related interviews in their lung cancer practices to determine the current status of and challenges associated with their practice systems. Results. Regarding knowledge about asbestos, physicians are mainly aware of the details concerning direct exposure, and providing information to patients is a similar task. Patients with possible indirect exposure may therefore be difficult to diagnose. Conclusion. Doctors must study more about the health hazards of indirect exposure to asbestos, and a system of cooperation should be established with the consultation and support departments in hospitals.

Background. Takotsubo cardiomyopathy (TCM) is characterized by Takotsubo-shaped apical akinesis and hyperkinesis in the basal segment of left ventricle, which was first described by Dote et al. in 1991. There have been many case reports on TCM associated with surgery, chemotherapy, and seizure; however, TCM associated with seizure due to brain metastasis from lung cancer is extremely rare. Case. A 72-year-old man underwent left upper lobectomy with lymph node dissection in February 20XX, (pT2aN0M0, stage IB, pleomorphic carcinoma). In September 20XX, he was referred to the emergency unit due to seizure and respiratory failure. Gadolinium-enhanced magnetic resonance imaging (MRI) of the brain showed a metastatic tumor accompanied by brain edema. Based on the Takotsubo-shaped left ventricle and low ejection fraction on echocardiography, we diagnosed him with TCM associated with brain metastasis of lung cancer. After treatment with anticonvulsant and anticoagulant drugs, his cardiac function soon improved, and he was discharged from the hospital on day 14 from emergent admission. Unfortunately, however, despite stereotactic body radiotherapy for the metastatic brain tumor, he died of cancer in October 20XX+1. Conclusion. To our knowledge, this is an extremely rare case of TCM related to physical stress from seizure due to brain metastasis of lung cancer. An immediate diagnosis and treatment are essential, as TCM is sometimes misdiagnosed as ischemic heart disease.

Background. Hilar and/or mediastinal lymph node (LN) cancer without a primary tumor is rare. Case. A 50-year-old man underwent distal gastrectomy for gastric cancer in year X. Although preoperative fluorodeoxyglucose (FDG)-positron emission tomography (PET) showed an LN of 11 mm in diameter with the abnormal uptake of FDG in the subaortic region (LN#5), a biopsy was not requested. In year X+1, LN#5 shrank to 3 mm, and the carcinoembryonic antigen (CEA) concentration decreased from 56.6 ng/ml to 8.6 ng/ml after gastric cancer surgery. However, the mediastinal LN slowly enlarged from year X+2, increasing to 24 mm at year X+11; the CEA concentration increased to 1760.4 ng/ml and a nodule appeared in the S¹⁺² segment of the left lung. Surgery was performed. Thoracoscopic resection of LN#5 and left upper division segmentectomy was performed. The postoperative pathological diagnosis was adenocarcinoma in both the pulmonary nodule and LN#5, and immunostaining was positive for thyroid transcription factor-1 and napsin A. Eleven years later, the primary lesion appeared in the lung and was diagnosed as lung cancer and mediastinal LN metastasis, pT1bN2M0 stage IIIA. Conclusion. Patients with lymph node carcinoma of unknown origin may develop a primary lesion after a long period of time. This case is instructive in suggesting the importance of long-term follow-up in such cases.

Background. In 2017, the General Rules for the Clinical and Pathological Classification of Lung Cancer were revised, and the classification of minimally invasive adenocarcinoma was added. We herein report a case in which lymph node metastasis was detected despite the tumor being diagnosed as a minimally invasive adenocarcinoma. Case. An 80-year-old woman was referred to our department after computed tomography (CT) revealed a suspected lung cancer nodule in the upper right lung lobe. CT showed a solid 2.3-cm nodule with an air bronchogram and a pleural indentation in the upper lobe (S³) of the right lung. Positron emission tomography (PET)-CT revealed the accumulation of fluorodeoxyglucose in the nodule (maximum standardized uptake value=4.5). No obvious lymph node enlargement was observed on CT, and no abnormal fluorodeoxyglucose accumulation suspected as distant metastasis was observed on PET-CT. Despite the lack of a histological diagnosis, we strongly suspected lung cancer and made a preoperative diagnosis of c-T1cN0M0 c-stage IA3. We therefore performed thoracoscopic right upper lobectomy and ND2a-1 lymph node dissection and obtained a rapid intraoperative diagnosis of lung adenocarcinoma. A histopathological examination also revealed lung adenocarcinoma. The 1.8-cm tumor had a predominantly lepidic pattern and an infiltrative diameter of <5 mm and was therefore diagnosed as pT1mi. Lobar lymph node #12u was positive for metastasis. We thus made a diagnosis of pN1. As there is no stage that corresponds to T1miN1M0 in the 8th edition of the General Rules for the Clinical and Pathological Classification of Lung Cancer, postoperative adjuvant chemotherapy was performed for T1aN1M0 stage IIA in accordance with the 7th edition. At the time of writing this report, the patient was alive at 51 months after surgery without recurrence. Conclusion. We experienced a very rare case of minimally invasive adenocarcinoma accompanied by a lymph node metastasis.

Background. Pulmonary enteric adenocarcinoma is a rare histological type and is solid in most reports. Case. A 69-year-old man had been diagnosed as interstitial pneumonia at 55 years old. Follow-up computed tomography (CT) performed four years later showed a new reticular shadow in the right lower lobe. The shadow was enlarged on follow-up CT, so we performed wedge resection of the right lower lobe at 63 years old, but no malignancy was detected. Follow-up CT performed at 69 years old showed consolidation near the resected area, so he underwent right lower lobectomy. The histological findings of the tumor showed papillotubular adenocarcinoma that was suspected to be colorectal carcinoma. He underwent a thorough checkup of colorectal carcinoma, but no malignancy was detected. We ultimately diagnosed him with pulmonary enteric adenocarcinoma. Conclusion. An enlarging non-solid consolidation is difficult to distinguish from neoplastic disease and sometimes indicates the presence of pulmonary enteric adenocarcinoma, although this is rare.

Background. The frequency of pseudo-progression caused by immune-checkpoint inhibitors in non-small cell lung cancer (NSCLC) is approximately 5%. Thus far, most reports of pseudo-progression in NSCLC have been due to immune-checkpoint inhibitor monotherapy. We report a case of pseudo-progression-like pleurisy after combined treatment with nivolumab and ipilimumab for lung adenocarcinoma. Case. A 70-year-old man with adenocarcinoma (pT3N0M1a, stage IVA) with pleural dissemination received combination therapy consisting of carboplatin, pemetrexed, nivolumab, and ipilimumab as first-line treatment. After treatment, he had fever, dyspnea, elevated CRP, and developed pleural effusion on the affected side. Thoracic drainage was subsequently performed. Abundant T lymphocytes with predominant CD4-positive cells infiltration were observed in pleural fluid cell-block specimens. Afterwards, his symptoms improved. No further accumulation of pleural effusion was observed, even though he continued receiving chemotherapy. Hence, he was diagnosed with pseudo-progression rather than an immune-related adverse event (irAE). Conclusion. This is the first report of pseudo-progression-like pleurisy in a lung cancer patient after combined nivolumab and ipilimumab treatment. It is important to distinguish pseudo-progression from irAE-induced pleurisy.

Background. Histiocytic sarcoma (HS) is extremely rare, and few studies have reported paraneoplastic syndromes with HS. We encountered a case of lung HS expressing granulocyte colony-stimulating factor (G-CSF). Case. A 50-year-old woman who presented with fatigue was referred to our hospital for a further examination of leukocytosis. Chest computed tomography (CT) revealed a 28×22×43-mm nodule in the left upper lung, and positron emission tomography (PET)/CT showed an abnormally high uptake of fluorodeoxyglucose (FDG) in the nodule. The level of serum G-CSF was abnormally high (183.2 pg/ml), so we suspected a G-CSF-producing tumor of the lung and performed left upper lobectomy with mediastinal lymph node dissection for the diagnosis and treatment. An immunohistochemical evaluation indicated HS of the lung, and the tumor cells were partly positive for anti-human G-CSF antibody. The final pathological diagnosis was lung HS expressing G-CSF. Postoperatively, the patient has remained relapse-free for 12 months without adjuvant chemotherapy. Conclusion. We experienced an extremely rare case of lung HS with the expression of G-CSF. Currently, the patient is still alive with no recurrence, although further close follow-up is essential.

Background. Pleural mesothelioma is difficult to diagnose at an early stage and has a poor prognosis. This tumor may occasionally metastasize to other organs in the terminal stage. However, intrapulmonary miliary metastases are rare. We herein report a case of epithelioid pleural mesothelioma that presented with miliary metastases during chest imaging and an autopsy. Case. The patient was a 92-year-old woman without a history of asbestos exposure. The initial sign of mesothelioma was left pleural effusion. The patient lived for one year after the definitive diagnosis without specific treatment other than pleurodesis. Two months prior to death, chest radiography and computed tomography showed intrapulmonary miliary metastases. An autopsy confirmed this pattern of metastasis. The reason for the occurrence of miliary metastases remains unclear. However, the invasive characteristics of the tumor were speculated based on the histological and immunohistochemical findings. For example, a homozygous deletion of p16, which is related to a poor prognosis, was noted. In addition, the mesothelioma possessed micropapillary components, which indicated its aggressive characteristic. Thus, we speculated that these invasive characteristics contributed to hematogenous metastasis and lymphangitic spread and ultimately resulted in miliary metastases. Conclusion. We presented a case of epithelioid pleural mesothelioma with a rare metastatic pattern. We speculate that the pathogenesis of intrapulmonary miliary metastasis was related to the aggressive behavior, characterized by p16 deletion or micropapillary components.

Background. Thoracic SMARCA4-deficient undifferentiated tumors are malignancies with an extremely poor prognosis, characterized by a loss of SMARCA4 expression and undifferentiated round cell or rhabdoid morphology. Case. We encountered a case of a thoracic SMARCA4-deficient undifferentiated tumor in a 63-year-old man who presented with hemoptysis and died following rapid progression. He was suspected of having left lower lobe lung cancer (cT2bN0M0: cStage IIA) by computed tomography. Therefore, we performed left lower lobectomy and lymph node dissection for the diagnosis and treatment via thoracoscopic surgery. Based on the histopathological findings, the excised tumor was diagnosed as thoracic SMARCA4-deficient undifferentiated tumor with intrapulmonary metastases [pT3 (pm1) N0M0: pStage IIB]. The patient's immediate postoperative course was good, and he was discharged on the eighth postoperative day. However, at an outpatient visit two weeks after discharge, the patient showed left pleural effusion. Thoracic drainage revealed hemorrhagic pleural effusion, and computed tomography showed bone destruction of the right second rib and swelling of the left adrenal gland, findings suggestive of metastases, although these had not been detected preoperatively. We performed diagnostic thoracoscopy and found left pleural dissemination. The patient ultimately died of respiratory failure 49 days after the initial surgery without effective therapeutic intervention for the rapidly progressing disease. Conclusion. Thoracic SMARCA4-deficient undifferentiated tumor should be considered in the differential diagnosis of tumors with undifferentiated rhabdoid morphology.

Background. Bronchogenic cysts are commonly found in the mediastinum but also occasionally in the lung parenchyma. We herein report a rare case of lung cancer arising in an intrapulmonary bronchogenic cyst. Case. A 58-year-old woman with a smoking history developed a cough and hemosputum in April 2021. On an examination at a local hospital, no abnormal shadow was found on her chest radiograph, but computed tomography of the chest revealed a 6.4-cm pulmonary cyst with irregular wall thickness in the right lower lobe. Fluorodeoxyglucose-positron emission tomography showed abnormal accumulation in the thickened wall of the pulmonary cyst (maximum standardized uptake value: 4.22). The diagnosis based on sputum cytology was class IIIA, but lung cancer with cystic lesion could not be excluded. In September 2021, the patient underwent resection of the cystic lesion under thoracoscopic surgery. A frozen section obtained during surgery revealed adenocarcinoma, and video-assisted thoracoscopic right lower lobectomy was performed. Microscopic findings showed bronchogenic lung cysts and the proliferation of malignant cells along the cyst' inner walls (pT3N0M0). The patient was alive nine months after surgery without recurrence. Conclusion. Only 10 cases of lung cancer arising from intrapulmonary bronchogenic cyst have been reported in Japan. When carcinoma is suspected in the bronchogenic cyst, appropriate surgical procedures should be considered.

Background. The BRAF mutation is a rare driver mutation in lung cancer. Case. A 73-year-old man was treated with antibacterial agents for bacterial pneumonia, but his symptoms and chest computed tomography findings did not improve. Therefore, he was referred to our hospital. He had respiratory failure at the initial visit, and bronchoscopy showed massive hemorrhaging in the left lower lobe. The biopsy specimens showed adenocarcinoma. He underwent left lower lobectomy because of control of hemostasis. As a result, his respiratory failure improved. The presence of the BRAF-V600E mutation was identified. With combination therapy of dabrafenib and trametinib, his lung tumor dramatically decreased in size. Conclusion. We reported a case of BRAF-V600E mutation-positive lung adenocarcinoma complicated by hemorrhaging and respiratory failure that was successfully treated with palliative surgery and combination therapy of dabrafenib and trametinib.

Background. We experienced a case of acute sialadenitis that occurred during immune checkpoint therapy. Case. The patient was a 69-year-old male who had received pembrolizumab (an anti-PD-1 antibody) monotherapy as first-line treatment for advanced non-small cell lung cancer. Forty-two days after the start of pembrolizumab monotherapy, he complained of severe xerostomia, fever, and swelling of the bilateral parotid glands. Based on these symptoms, we diagnosed the patient with immune-related acute sialadenitis and administered systemic steroid therapy. These symptoms were resolved by treatment. Conclusion. Sicca syndrome is recognized as a relatively common immune-related adverse event; however, acute sialadenitis is rare. It should be noted as a potential immune-related adverse event in patients treated with immune checkpoint inhibitors in the clinical setting.