In 2004, several groups reported the correlation between EGFR mutations and sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Since then, multiple EGFR-TKIs have been developed, improving the prognosis of advanced EGFR-mutated lung cancer patients. However, most patients with advanced EGFR mutation-positive lung cancer die of lung cancer in less than five years, highlighting the need for the further development of effective therapies. To develop effective inhibitors or treatment strategies, a basic understanding of EGFR-mutated lung cancer is essential. In particular, the knowledge of how EGFR mutations activate EGFR kinase and how sensitivity to EGFR-TKIs is determined is important. In this review, I will summarize the knowledge and propose clinical insight on how to translate this basic knowledge into a clinical setting.

The development of immune-checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced and/or recurrent non-small-cell lung cancer (NSCLC), mainly in the driver gene-negative subset. In stage IV NSCLC, ICIs have been widely applied not only as monotherapy but also in combination with cytotoxic chemotherapeutic agents. Furthermore, in recent years, ICIs combination therapy has also become available. In cases of unresectable stage III locally advanced NSCLC, ICIs have been shown to be effective as maintenance therapy after chemo-radiotherapy and are now available in clinical practice. This trend has led to the expectation of the efficacy of ICIs for earlier-stage resectable NSCLC. A number of phase III trials are now underway for perioperative treatment, mainly for stage II-III NSCLC, and some drugs have already been submitted for approval. However, there are some issues that need to be addressed concerning their use, such as perioperative complications and the emergence of immune-related adverse events.

In most cases, bronchoscopy is the first choice for the diagnosis of lung cancer because of its low rate of complications and low invasiveness compared to other methods. Bronchoscopic procedures can be divided into biopsies for visible airway lesions, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), and biopsies for peripheral pulmonary lesions, all of which have different characteristics. In recent years, cryobiopsies have been introduced in many institutions, and their usefulness in lung cancer has been widely reported. In the recent treatment of lung cancer, there have been many cases that require a molecular analysis and the evaluation of cancer immunity by immunostaining. Therefore, it is indispensable to obtain high-quality specimens in clinical practice. We herein review the advances in bronchoscopic techniques for lung cancer and describe some of the techniques available in clinical practice.

Objective. The Oncomine™ Dx Target Test^® (ODxTT) has emerged as a companion diagnosing system for advanced non-small cell lung cancer (NSCLC) using next generation sequencing. However, the instability of the test results due to the small size of the biopsy samples makes it challenging to use in a clinical setting. Methods. From June 2018 to December 2020, NSCLC samples diagnosed in our hospital were evaluated. Fifty-one NSCLC samples were analyzed for BRAF mutations, and 19 biopsy samples were subjected to a multiplex analyses. The correlation between the clinicopathological factors and success rate was analyzed into integration. Results. The success rates according to procedure were 100% (25/25) for surgical samples, 100% for excisional biopsy samples, 75% for transbronchial biopsy samples, 78% for endobronchial ultrasound-transbronchial needle aspiration, and 57% for computed tomography-guided biopsy samples. The biopsy samples for which the analysis of BRAF mutations was successful showed a larger quantity of DNA than the failed group (median 279 vs. 18 ng, p<0.01). In a multiplex analysis, the quantity of DNA and RNA in the successful analysis samples showed a larger quantity than the failure samples (median quantity of DNA 198 vs. 45.6 ng, p<0.01; median quantity of RNA 180 vs. 34.2 ng, p<0.01). The number of biopsies in successful transbronchial biopsy cases and the tumor nuclei content in successful multiplex analyses cases were also greater than those in the failed samples (median number of biopsies 6.5 vs. 4, p<0.01, median tumor nuclei content 50% vs. 30%, p=0.01). Conclusion. The quantity of nucleic acid was associated with the analysis success rates of ODxTT. The tumor nuclei content and number of punctures for transbronchial biopsies might be associated with analysis success rates for ODxTT.

Objective. A second opinion has potential advantages of leading to the appropriate diagnosis and treatment plan for patients with cancer and medical oncologist. However, whether or not the second opinion influences the diagnosis and treatment policy of patients with thoracic malignancies remains unclear. Methods. We retrospectively investigated patients with thoracic malignancies who asked for a second opinion at the National Cancer Center Hospital in 2019. Results. A total of 540 patients asked for a second opinion, including 341 (63.1%) patients with non-small-cell lung cancer, 38 (7.0%) patients with small-cell lung cancer, 68 (12.6%) patients with thymic epithelial tumor, 16 (3.0%) patients with pleural mesothelioma, and 77 (14.3%) patients with other thoracic malignancies. Different treatment advice from that received at the referring hospital was received by 147 (27.2%) patients at the second opinion. The details concerning the proposed treatment policies included a change in the chemotherapy regimen in 51 (34.7%) patients, a change to best supportive care (BSC) in 28 (19.0%) patients, a change from BSC to chemotherapy in 24 (16.3%) patients, and a change to surgery in 12 (8.2%) patients. Conclusion. The second opinion can result in different treatment advice, including curable treatments, such as surgery, for patients with thoracic malignancies.

Background. Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI), is a first-line drug for EGFR mutation-positive advanced non-small cell lung carcinoma in patients with a good Performance Status (PS). However, there are few reports of the administration of osimertinib as a first-line treatment for patients with a poor PS. We herein report a case in which osimertinib was effective as a first-line treatment for advanced lung adenocarcinoma with a decreased PS due to carcinomatous meningitis. Case. A 79-year-old man was diagnosed with right middle lobe lung adenocarcinoma (cT4N0M1b cStage IVA) with carcinomatous meningitis. The patient was positive for the EGFR L858R mutation. Cognitive decline and ataxia due to carcinomatous meningitis were observed, and the patient had a PS of 3, which is classified as poor. However, the administration of osimertinib was started in consideration of the efficacy of the medicine for central nervous system lesions. After administration, the primary lesion shrank rapidly, and the patient's cognitive and motor functions improved. Conclusion. Osimertinib may a treatment option in first-line treatment of EGFR mutation-positive advanced non-small cell lung cancer in patients with a decreased PS due to paraneoplastic symptoms.

Background. Immune checkpoint inhibitors (ICIs), such as pembrolizumab, rarely cause sclerosing cholangitis as an immune-related adverse event (irAE). We herein report a patient with pembrolizumab-related sclerosing cholangitis who was successfully treated with prednisolone. Case. An 80-year-old woman with stage IV non-small cell lung cancer received pembrolizumab as first-line chemotherapy. After three cycles of pembrolizumab, she complained of a slight fever and appetite loss; her hepatic and biliary enzymes were elevated on a laboratory examination (CTCAE Grade 3). Abdominal ultrasonography and magnetic resonance imaging revealed dilated common bile duct, edema around the intrahepatic bile ducts, and irregularly narrowed intrahepatic bile ducts. We established a diagnosis of ICI-induced secondary sclerosing cholangitis bases on these findings and the clinical course. Oral ursodeoxycholic acid (UDCA) improved the levels of hepatobiliary enzymes; however, relapse was noted after UDCA discontinuation. After prednisolone was added, there was an immediate reduction in the hepatobiliary enzyme levels and improvement in the biliary dilation. Conclusion. Our patient showed a good response to prednisolone. However, irAE sclerosing cholangitis with extrahepatic bile duct may not respond to steroid therapy, conversely becoming exacerbated. We should therefore investigate additional factors in addition to the spread of the lesion of cholangitis regarding the response to the treatment.

Background. A pulmonary tumorlet is a rare tumor-like lesion, recognized as hyperplasia of neuroendocrine cells. Most tumorlets are incidentally found in resected lung specimens with chronic respiratory diseases. The association of pulmonary tumorlets with primary lung carcinoma is extremely rare. Cases. Case 1: Computed tomography (CT) showed a 50-mm tumor in the right lower lobe and swelling of the ipsilateral hilar lymph node. The tumor was diagnosed as non-small cell carcinoma by a bronchoscopic biopsy, and then the right lower lobe was resected. The histological diagnosis based on the surgical specimen was adenocarcinoma with some squamous cell carcinoma. A tumorlet was found near the carcinoma tissue. Case 2: CT showed a 40×30-mm mass in S⁵ of the right middle lobe with a 3-mm nodular shadow. The right middle lobe was resected, and a histopathological examination revealed adenocarcinoma and a tumorlet 3×1.5 mm in size near the carcinoma tissue. Conclusion. Although it is important to differentiate lung tumorlets from malignant tumors, the number of reports is small because of their rarity. We experienced two cases of pulmonary tumorlets complicated by primary lung cancer.

Background. Sialadenoma papilliferum is a benign epithelial tumor that primarily occurs in the palate and floor of the mouth. We herein report a rare case of sialadenoma papilliferum originating from the bronchus. Case. A 66-year-old man presented with simple chest radiographic findings of a well-defined nodule in the right lower lung. Chest computed tomography (CT) revealed a 28-mm dendritic nodule in the right lower lobe of B⁸, and positron emission tomography-CT revealed fluorodeoxyglucose hyperaccumulation with a maximum standardized uptake value of 30.6, coinciding with the nodule. Bronchoscopy revealed a polypoid tumor in B⁸b, diagnosed as a papillary epithelial proliferating lesion on a biopsy, but bronchial lavage cytology indicated adenocarcinoma. The patient underwent right lower lobectomy and lymph node dissection. The histopathological findings showed that the tumor comprised a collection of many branched papillary structures protruding into the lumen of the B⁸b bronchus, with a biphasic structure of atypical basal and luminal cells. Based on the immunohistochemical features, the patient was diagnosed with primary bronchial sialadenoma papilliferum. Conclusion. Sialadenoma papilliferum is considered a benign disease. Only 9 cases of primary bronchial sialadenoma have been reported. We summarized the clinical, histopathological, and prognostic features of previously reported cases.

Background. Immune checkpoint inhibitors are drugs that exert anti-tumor effects by activating tumor immunity, but it is sometimes difficult to differentiate between hyperprogressive disease, which causes rapid growth of the target lesion immediately after the start of treatment, and pseudoprogression, which causes transient growth followed by shrinkage. Case. A 54-year-old man with lung adenocarcinoma cT1bN3M1c (brain), cStage IVB, experienced rapid tumor progression after the administration of pembrolizumab as second-line treatment; however, tumor shrinkage followed with third-line treatment of ramucirumab and docetaxel. Although chemotherapy was stopped due to the development of watery diarrhea and systemic scleroderma, the anti-tumor effect was maintained for about one and a half years. Conclusion. The combination of ramucirumab and docetaxel may have enhanced the anti-tumor effect after the administration of immune checkpoint inhibitors and influenced tumor immunity.

Background. Autoimmune hemolytic anemia is reported to be associated with the use of immune checkpoint inhibitors, and steroid therapy is recommended as the first choice of treatment. Case. A 61-year-old woman was treated with carboplatin+pemetrexed+pembrolizumab as first-line treatment for postoperative recurrence of lung adenocarcinoma. Anemia was detected at the start of the third-line treatment, and the patient was diagnosed with autoimmune hemolytic anemia based on the clinical course and increased peripheral blood reticulocyte count, increased serum levels of bilirubin and LDH, and a decreased serum level of haptoglobin. Treatment with prednisolone showed limited efficacy. She was started on rituximab in addition to steroid therapy, but died of progression of lung cancer 3 days after the initiation of rituximab therapy. Conclusion. The accumulation of cases of autoimmune hemolytic anemia associated with the use of immune checkpoint inhibitors is desired.

Background. Pulmonary enteric-type adenocarcinoma is a rare type of non-small-cell lung cancer showing a histological pattern mimicking metastatic colorectal cancer. Case. A man in his 60s was referred to our hospital because of an abnormal shadow on a chest radiograph during follow-up for prostate cancer. Chest computed tomography (CT) showed a 55-mm mass with multiple small calcifications in the left upper lobe. The peripheral area of the left upper lobe showed obstructive atelectasis. Fluorodeoxyglucose (FDG)-positron emission tomography (PET) showed an increased FDG uptake in the mass of the left upper lobe (maximum standardized uptake value [SUV_max] 12.7), mediastinal lymphadenopathy, and left supraclavicular lymphadenopathy. A bronchoscopy specimen showed tumors that formed ducts composed of tall columnar cells. Immunohistochemical staining demonstrated CK7 (-), CK20 (focally+), TTF-1 (-), CDX2 (+), and Napsin A (-) expression. The findings indicated pulmonary enteric-type adenocarcinoma or metastatic colorectal carcinoma. The tumor was diagnosed as adenocarcinoma with enteric features (cT2bN3M0, cStage IIIB), as no evidence of a tumor was found elsewhere by colonoscopy. He underwent chemoradiotherapy. Subsequent CT revealed shrinkage of the tumor. Conclusion. We encountered a case of lung adenocarcinoma with enteric features which showed calcification on CT. The CT findings of pulmonary enteric-type adenocarcinoma are similar to the imaging findings for invasive pulmonary adenocarcinoma and metastatic colorectal cancer. Distinguishing between these two entities by imaging alone is difficult.