In April 2021, after a five-year interval, the WHO revised the classification system for thoracic tumors. Although there were no major changes in this revision, the information has been updated in detail, and several new diseases have been introduced. In addition, the new format of "Essential and desirable diagnostic criteria" is used throughout the text, which is designed to facilitate the diagnosis and understanding of diseases. This review summarizes the changes made in the 5th edition of the WHO classification of thoracic tumors.

Lung cancer is a cancer for which personalized medicine based on genomic information, including companion diagnostics, such as driver gene mutations, is already available. In addition, after standard treatment is completed, gene panel tests, including liquid biopsies, can be performed under national insurance coverage to seek new treatment methods. However, there is an emerging trend involving the implementation of whole-genome sequencing into cancer care for many intractable cancers, including lung cancer. Given the limited amount of cancer tissue samples available from patients and the fact that the information on genetic alterations required for medical treatment varies greatly among patients, it would be ideal to implement whole-genome sequencing, which has no restrictions on the genes that can be analyzed. However, due to the huge amount of genomic information obtained, the resources and time required to process it, and the need for quality assurance, we are not yet at a stage where this approach can be implemented immediately. Therefore, a national project is set to be launched that will implement whole-genome sequencing of cancer into studies and return results to patients for use in further research and development.

In Japan, predictive biomarker testing for driver mutations as companion diagnostics (CDxs) in lung cancer includes six genes: EGFR, ALK, ROS1, BRAF, MET, and RET (newly added in 2021). As a CDx for cancer immunotherapy, PD-L1 immunohistochemistry testing has been conducted since 2016. We herein review the issues experienced during the clinical introduction of such testing and overview the future development of CDxs expected to be useful as new technologies, such as multiplex assays and liquid biopsies.

Objective. In recent years, many driver gene mutations and their corresponding molecular-targeted drugs have been approved for the treatment of advanced or recurrent non-small cell lung cancer. The Oncomine™ Dx Target Test (ODxTT), a gene panel test using a next-generation sequencer, has been approved for the simultaneous detection of multiple gene mutations. However, its practicality in clinical practice in a general hospital is unclear, so we verified the success rate of the test. Methods. We examined the submission rate of the ODxTT, the analysis success rate, and the detection rate of gene mutations in consecutive cases searched for driver gene mutations at our hospital from June 2020 to March 2021. Results. Fifty-four (65.1%) out of 83 patients underwent the ODxTT, and we successfully analyzed all tests in 52 patients (96.3%). Two cases with surgical specimens of brain metastases failed the RNA analyses, while the DNA analyses were successful. Among the 54 total tested patients, the ODxTT detected genetic mutations in 25 (46.3%). Conclusion. A total of 65.1% of the cases of genetic mutation search could be submitted to the ODxTT. More than 95% of them were successfully analyzed, and about half of them showed genetic mutations, suggesting that the test may be practical for general hospitals.

Background. Epidermal growth factor receptor (EGFR) mutation-positive squamous cell lung cancer is rare, and the effect of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) on these lesions is inferior to that for lung adenocarcinoma. Osimertinib is more effective against central nervous system metastases than gefitinib and afatinib and is expected to be effective against brain metastases of EGFR mutation-positive squamous cell lung cancer. However, no studies have investigated the efficacy of osimertinib against brain metastases of EGFR mutation-positive squamous cell lung cancer. Case. A 72-year-old woman was diagnosed with squamous cell lung cancer (T1bN2M0, stage IIIA) harboring an EGFR mutation (exon19 deletion). Two years after receiving chemoradiotherapy, she visited a nearby medical neurosurgery clinic because of a difficulty speaking. Head contrast-enhanced magnetic resonance imaging (MRI) revealed a mass lesion in the left frontal lobe. She underwent craniotomy at the same hospital and was diagnosed with brain metastasis from squamous cell lung cancer; therefore, she was referred to our hospital. Head MRI on admission showed the recurrence of brain metastasis near the excision cavity, and she was administered osimertinib. After the initiation of osimertinib treatment, the brain metastasis markedly shrank, and she continued to receive osimertinib for 20 months. Conclusion. For EGFR mutation-positive lung cancer with brain metastases, osimertinib may be useful, even in cases of squamous cell carcinoma.

Background. Even in cases of stage IVB lung cancer, if metastatic lesions are limited (so-called oligometastatic disease), the prognosis can be improved by local therapy. Case. We experienced a case of a man in his 50s with oligometastatic stage IVB non-small cell lung cancer (NSCLC) who had undergone metastasectomy for small intestine and left adrenal metastases. He subsequently received anti-cancer agents for three and a half years, but only the primary lesion had increased to 130 mm in size. Since, no other metastatic lesions were detected, we resected the primary lesion as a residual lesion of oligometastatic disease. Six months after the operation, recurrence was observed in the right chest wall and left subclavian lymph node as relapse of oligometastatic disease. However, since the lesions were only located in two sites as oligometastatic disease, we performed resection a second time for the lesion on the right chest wall and radiation therapy for the lesion on the left subclavian lymph node. No obvious recurrence has been detected in the 18 months after the second surgery. The patient has survived for five and a half years since the diagnosis of stage IVB lung cancer, and returned to work. Conclusion. Even in cases of stage IVB lung cancer, aggressive local therapy should be effective for oligometastatic disease.

Background. Malignant peripheral nerve sheath tumor (MPNST) is an uncommon malignant schwannoma, and some rare cases of MPNST in the mediastinum have been reported. Case. The patient was a woman in her 60s. An abnormal shadow was incidentally detected on chest X-ray, and the patient was referred to our institution. The tumor was located in the area between the right upper lobe of the lung and the right brachiocephalic vein, with a diameter of 53 mm, and positron emission tomography-computed tomography (PET-CT) showed a fluorodeoxyglucose (FDG) uptake with a maximum standardized uptake value of 32.9 in the tumor. A transbronchial biopsy was performed. A pathological examination of the biopsy specimen showed no evidence of an epithelial tumor. We diagnosed the patient with a malignant tumor suspected to be MPNST or lung sarcoma. We decided to perform surgery. We resected the tumor via open thoracotomy. Due to the involvement of the right phrenic nerve, the right phrenic nerve was resected. The permanent pathological specimen showed dense proliferation of spindle cells with atypical mitoses, and immunohistochemistry was weakly positive for S100 and positive for SOX10. The pathological diagnosis was MPNST of mediastinal origin. The postoperative course was uneventful. The patient was alive without recurrence at one year after surgery. Conclusion. We experienced a case of resection of an MPNST of visceral mediastinal primary origin. In cases where a tumor suspected of being an MPNST on a preoperative examination is adjacent to a great vessel, thorough preoperative preparation, including vessel replacement with synthetic graft, should be performed to ensure complete resection of the tumor.

Background. The number of long-term survivors after radiotherapy for primary cancers is increasing, leading to an increase in radiation-induced cancers. We herein report three cases of radiation-induced lung cancer after chemoradiotherapy. Cases. Case 1 was an 86-year-old man who had received chemotherapy (cisplatin and 5-fluorouracil) and concurrent radiotherapy (60 Gy) for esophageal cancer 9 years previously. Case 2 was a 76-year-old man who had received chemotherapy (cisplatin and 5-fluorouracil) and concurrent radiotherapy (54 Gy) for esophageal cancer 2 years previously. Case 3 was a 73-year-old woman who had received chemotherapy (carboplatin and paclitaxel) and sequential radiotherapy (60 Gy) for squamous cell lung cancer. All patients had a history of smoking and evidence of radiation fibrosis. Since all three lung cancers developed within the irradiated field, we determined them to be radiation-induced. Conclusion. After radiotherapy for primary cancer, radiation-induced lung cancer can develop regardless of the radiation dose. The risk for radiation-induced lung cancer is increased in patients exposed to multiple carcinogenic risk factors.

Background. Immune checkpoint inhibitors (ICIs) are important agents in pharmacotherapy of lung cancer. However, patients treated with ICIs may develop immune-related adverse events that may lead to critical conditions. Therefore, caution should be exercised when using these drugs. Case. A 77-year-old man with relapse after surgery for pT2aN0M0, stage IB pulmonary pleomorphic carcinoma received combination therapy of ipilimumab and nivolumab on March, year X. Although the pulmonary carcinoma responded to the therapy, a variety of immune-related adverse events, such as infiltration in the lung field, relapse of herpes labialis, diarrhea, myocarditis, and myasthenia gravis, were observed. In particular, the myocarditis and myasthenia gravis were critical and challenging to manage. However, the patient survived with intensive care, including steroid pulse therapy and noninvasive positive pressure ventilation by early intensive care in collaboration with specialized departments. Conclusion. Although the pulmonary pleomorphic carcinoma responded to the combination therapy of ipilimumab and nivolumab in this patient, he developed a critical condition due to immune-related adverse events. Myasthenia gravis and myocarditis are serious adverse events associated with ICIs and often occur concomitantly. Therefore, caution should be exercised. Myasthenia gravis and myocarditis are relatively uncommon immune-related adverse events, but they can be severe and are often associated with each other.