Clinical and Pathologic Differences between Small-Cell Carcinoma and Large-Cell Neuroendocrine Carcinoma of the Lung.

BACKGROUND: Both small-cell carcinoma (SCLC) and large-cell neuroendocrine carcinoma (LCNEC) of the lung are often clinically dealt with as being in the same category as neuroendocrine carcinoma, and their clinical differences have not been adequately assessed. METHODS: The postoperative prognosis was retrospectively analyzed using the data of 196 patients who underwent resection for SCLC or LCNEC. RESULTS: Of the patients included, 99 (50.5%) had SCLC and 97 (49.5%) had LCNEC. The median duration of follow-up was 39 months (interquartile range [IQR] 21-76) and 56 months (IQR 21-87) for SCLC and LCNEC, respectively. The estimated 5-year overall survival (OS) probabilities were 53.7% and 62.7% (p = 0.133) for patients with SCLC and LCNEC, respectively. In the SCLC group, a multivariate analysis showed that adjuvant chemotherapy (hazard ratio 0.54, 95% confidence interval 0.30-0.99, p = 0.04) was the only factor that was significantly associated with OS. In the LCNEC group, univariate analyses demonstrated that pathologic stage I (p = 0.01) was the only factor that was associated with better OS after surgery. CONCLUSIONS: We found different clinical features in SCLC and LCNEC; in patients with SCLC, because OS could be expected to significantly improve with postoperative adjuvant chemotherapy, patients with resected SCLC of any pathologic stage should receive adjuvant chemotherapy. For patients with LCNEC, because pathologic stage I LCNEC is related to better prognosis than any other stages, a thorough clinical staging, including invasive staging, according to present guidelines should be performed to identify clinical stage I LCNEC with the highest certainty.

Impact of 18F-FDG PET on TNM Staging and Prognosis in Thymic Epithelial Tumors.

BACKGROUND: Preoperative fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG PET) of thymic epithelial tumors (TETs) is well known for identifying malignant-grade TETs; however, its predictive power for determining locally advanced tumors, lymph node (LN) metastasis, and prognosis remains unknown. PATIENTS AND METHODS: We retrospectively evaluated patients with resectable TETs who were preoperatively assessed using 18F-FDG PET from January 2012 to January 2023. The receiver operating characteristic curve was used to evaluate the cutoff value of the maximum standardized uptake value (SUVmax) to predict advanced-stage disease. Recurrence/progression-free survival (RFS/PFS) was analyzed using the Kaplan-Meier method. The staging was classified according to the tumor-node-metastasis system. RESULTS: Our study included 177 patients; 145 (81.9%) had pathological early-stage TET (stage I or II), and 32 (19.1%) had advanced stage (stage III or IV). The area under the curve value for predicting the advanced stage was 0.903, and the cutoff value was 5.6 (sensitivity 81.3%, specificity 84.8%). SUVmax > 5.6 was associated with worse prognosis for RFS/PFS. LN metastasis was preoperatively detected by FDG uptake in 30.8% of patients with pathological LN positivity, whereas LN metastasis was not pathologically detected in patients with SUVmax < 5.9. In patients with advanced-stage TETs, LN recurrence was more frequent in patients who were preoperatively detected by 18F-FDG PET than those who were not (75.0% versus 7.1%). CONCLUSIONS: 18F-FDG PET is a potentially valuable tool for predicting advanced stage and poor prognosis of recurrence in patients with TETs. SUVmax can help thoracic surgeons to guide them in selecting appropriate therapeutic strategies for TETs.

Rare but clinically important salivary gland-type tumor of the lung: A review.

Salivary gland-type tumor (SGT) of the lung, which arises from the bronchial glands of the tracheobronchial tree, was first recognized in the 1950s. SGT represents less than 1% of all lung tumors and is generally reported to have a good prognosis. Mucoepidermoid carcinoma (MEC) and adenoid cystic carcinoma (ACC) are the two most common subtypes, comprising more than 90% of all SGTs. The reported 5-year survival rate of patients with SGT is 63.4%. Because this type of tumor develops in major bronchi, patients with SGT commonly present with symptoms of bronchial obstruction, including dyspnea, shortness of breath, wheezing, and coughing; thus, the tumor is usually identified at an early stage. Most patients are treated by lobectomy and pneumonectomy, but bronchoplasty or tracheoplasty is often needed to preserve respiratory function. Lymphadenectomy in the surgical resection of SGT is recommended, given that clinical benefit from lymphadenectomy has been reported in patients with MEC. For advanced tumors, appropriate therapy should be considered according to the subtype because of the varying clinicopathologic features. MEC, but not ACC, is less likely to be treated with radiation therapy because of its low response rate. Although previous researchers have learned much from studying SGT over the years, the diagnosis and treatment of SGT remains a complex and challenging problem for thoracic surgeons. In this article, we review the diagnosis, prognosis, and treatment (surgery, chemotherapy, and radiotherapy) of SGT, mainly focusing on MEC and ACC. We also summarize reports of adjuvant and definitive radiation therapy for ACC in the literature.

Tumor microenvironment-mediated immune profiles and efficacy of anti-PD-L1 antibody plus chemotherapy stratified by DLL3 expression in small-cell lung cancer.

BACKGROUND: Delta-like ligand 3 (DLL3) is a therapeutic target in small-cell lung cancer (SCLC). However, how DLL3 expression status affects the tumor microenvironment (TME) and clinical outcomes in SCLC remains unclear. METHODS: This retrospective study included patients with postoperative limited-stage (LS)-SCLC and extensive-stage (ES)-SCLC treated with platinum and etoposide (PE) plus anti-programmed cell death ligand 1 (PD-L1) antibody. We investigated the relationship of DLL3 expression with TME, mutation status, tumor neoantigens, and immunochemotherapy. RESULTS: In the LS-SCLC cohort (n = 59), whole-exome sequencing revealed that DLL3High cases had significantly more neoantigens (P = 0.004) and a significantly higher rate of the signature SBS4 associated with smoking (P = 0.02) than DLL3Low cases. Transcriptome analysis in the LS-SCLC cohort revealed that DLL3High cases had significantly suppressed immune-related pathways and dendritic cell (DC) function. SCLC with DLL3High had significantly lower proportions of T cells, macrophages, and DCs than those with DLL3Low. In the ES-SCLC cohort (n = 30), the progression-free survival associated with PE plus anti-PD-L1 antibody was significantly worse in DLL3High cases than in DLL3Low cases (4.7 vs. 7.4 months, P = 0.01). CONCLUSIONS: Although SCLC with DLL3High had a higher neoantigen load, these tumors were resistant to immunochemotherapy due to suppressed tumor immunity by inhibiting antigen-presenting functions.

Long-Term Prognosis and Prognostic Indicators of Stage IA Lung Adenocarcinoma.

BACKGROUND: The 8th edition of the TNM stage classification of lung cancer was developed based on an evaluation of the 5-year prognosis using an international database. Since recurrence after 5 years postoperatively is known to develop, the applicability of the stage classification beyond 5 years after treatment needs to be evaluated. PATIENTS AND METHODS: Postoperative prognosis and prognostic indicators were analyzed using data for 648 patients of pathological stage IA adenocarcinoma, who underwent complete resection between 2007 and 2012. RESULTS: The median age was 66 years (interquartile range 60-73 years), and the median follow-up duration was 100 months (interquartile range 70-116 months). Overall survival probabilities for pathological stage IA1, IA2, and IA3 patients were 100%, 96.3%, and 91.5% at 5 postoperative years, and 94.2%, 89.8%, and 83.5% at 10 postoperative years, respectively (IA1 vs IA2: p = 0.05; IA2 vs IA3: p = 0.05). Multivariate analysis for overall survival of patients who survived without recurrence for 5 postoperative years revealed that age (hazard ratio 3.21, p = 0.02) was the only factor that was significantly associated with long-term survival. Stage classification (IA1, IA2, or IA3) was not an associated factor. The incidence of secondary primary lung cancer continued to increase, resulting in an estimated probability of 8.6% at 10 postoperative years. CONCLUSIONS: For patients who survived without recurrence for 5 postoperative years, age, not stage classification, was associated with survival thereafter. The long-term follow-up strategy does not need to be modified according to the stage classification, and screening for secondary primary lung cancer should be considered.

Dynamics of recurrence after curative resection of nonsmall cell lung cancer.

BACKGROUND AND OBJECTIVES: This study examined the trend of hazards for postoperative recurrence of lung cancer according to pathologic stages. METHODS: We reviewed the records of 1987 patients who underwent resection for lung cancer between 2007 and 2012. Postoperative recurrence and development of second primary lung cancer were analyzed to evaluate the trend of hazard rate. RESULTS: Recurrence-free survival (RFS) probabilities at 5 postoperative years in patients with stage I/II/III disease were 87.8%/54.7%,/33.4%, respectively. The hazard rate of RFS was consistently low (<0.005) for stage I patients for 5 years after surgery. The hazard rate of RFS for stage II patients showed a peak of 0.016 at 12.4 months after surgery, and that for stage III patients had a higher peak of 0.029 at 13.7 months after surgery, after which they showed a gradual decrease. The hazard rate for the development of second primary lung cancer exceeded that of recurrence of first primary lung cancer after 72 months postoperatively. CONCLUSIONS: Short-interval postoperative surveillance might be unnecessary for stage I patients but should be considered in stage II/III patients. Screening of second primary lung cancer rather than surveillance of recurrence might be beneficial after more than 6 years postoperatively.

Utility of the endobronchial Watanabe spigot for intractable cancer-related pneumothorax: a retrospective observational study.

BACKGROUND: The use of endobronchial Watanabe spigots for intractable secondary pneumothorax in patients with cancer has not been adequate. This study aimed to investigate the use of endobronchial Watanabe spigots for intractable pneumothorax in patients with malignant tumors. METHODS: Consecutive patients with malignant tumors who underwent occlusion with an endobronchial Watanabe spigot for intractable pneumothorax associated with perioperative treatment or drug therapy at our institution between January 2014 and February 2022 were reviewed. RESULTS: Of the 32 cases in which an endobronchial Watanabe spigot was used, six were excluded; we thus evaluated 26 cases in which the chest tube was removed. Chest tubes were removed in 19 cases (73.1%) and could not be removed and required surgical treatment under general anesthesia in seven patients (26.9%), of which four (14.8%) underwent open-window thoracostomy. Half of the patients were treated with both an endobronchial Watanabe spigot and pleurodesis. Although thin-slice chest computed tomography revealed a fistula in 15 patients, the chest tube was removed in 11 (57.9%) patients. A significant difference was only observed in patients with a history of heavy smoking. CONCLUSIONS: The chest tube removal rate was comparable to those reported in previous studies. An endobronchial Watanabe spigot may be a useful treatment option for intractable cancer-related pneumothorax.

Clinicopathological characteristics and molecular analysis of lung cancer associated with ciliated muconodular papillary tumor/bronchiolar adenoma.

Ciliated muconodular papillary tumor/bronchiolar adenoma (CMPT/BA) is a recently introduced benign lung tumor. It remains unclear whether CMPT/BA is associated with a specific type of lung cancer (LC). We studied the clinicopathological characteristics and genetic profiles of the coexisting primary LC and CMPT/BA (LCCM) cases. We identified eight LCCM (0.4%) from the resected Stage 0-III primary LC (n = 1945). The LCCM cohort was male-dominant (n = 8), elderly (median 72 years old), and most were smokers (n = 6). In addition to the adenocarcinoma (n = 8), we detected two squamous cell carcinomas and one small cell carcinoma-in some cases, multiple cancer. The target sequence/whole exome sequence (WES) revealed no shared mutations between CMPT/BA and LC. One exceptional case was invasive mucinous adenocarcinoma harboring an HRAS mutation (I46N, c.137T>A), but it was likely to be a single nucleotide polymorphism based on variant allele frequency (VAF). Other driver mutations in LC included EGFR (InDel, n = 2), BRAF(V600E) (n = 1), KRAS (n = 2), GNAS (n = 1), and TP53 (n = 2). BRAF(V600E) was the most frequent mutation in CMPT/BA (60%). In contrast, LC showed no specific trend in driver gene mutations. In conclusion, our study revealed differences in the gene mutation profiles of CMPT/BA and LC in coexisting cases, suggesting mostly independent clonal tumorigenesis of CMPT/BA from LC.

Assessment of Resectability of Mediastinal Germ Cell Tumor Using Preoperative Computed Tomography.

BACKGROUND AND OBJECTIVES: Mediastinal germ cell tumor (MGCT) is a relatively rare tumor. Complete resection after chemotherapy is a standard treatment against this disease. However, the risk factors of incomplete resection are unclear. Therefore, we analyzed survival rates and risk factors for incomplete resection based on preoperative imaging. METHODS: We retrospectively reviewed the medical records of patients (n = 56) with MGCT operated at National Cancer Center Hospital, and analyzed preoperative computed tomography (CT) data in terms of relationship of the tumor and vessels, and investigated survival rate and risk factors for incomplete resection. RESULTS: A total of 56 patients underwent resection of MGCT. The 5-y progression-free survival (PFS) and overall survival (OS) were 79% and 83%. In multivariate analysis, complete resection was the only significant prognostic factor for better PFS (hazard ratio (HR) = 9.083, P= 0.00021) and OS (HR = 5.519, P= 0.0445). The preoperative CT finding of arteries (including the aorta, right brachiocephalic artery, left common carotid artery, and left subclavian artery) surrounded by the tumor was a predictor of incomplete resection (odds ratio = 10.089, P= 0.049). CONCLUSIONS: Complete resection is essential for improving the survival of MGCT, and the risk stratification using preoperative CT imaging brings important information to achieve the complete resection.

Aggressive histological component in subsolid lung adenocarcinoma: priority for resection without delay.

INTRODUCTION: This study explored the predictors of a histological aggressive component in ground glass opacity-containing lung adenocarcinoma. METHODS: Of the 2388 patients who underwent resection for lung cancer at our institute between 2017 and 2020, we collected data on the 501 patients with ground glass opacity-containing adenocarcinoma with a total diameter of ≤2 cm. Using a historical cohort, we identified histological aggressive components that were related to a poor prognosis in early-stage adenocarcinoma. A multivariable analysis was conducted to identify predictors for the presence of a histological aggressive component. RESULTS: Lymphovascular invasion and predominant micropapillary or solid patterns were identified as histological aggressive components by a prognostic analysis using a historical cohort. Of the 501 patients included, 36 (7.2%) had at least one histological aggressive component. A multivariate analysis showed that a consolidation/tumour ratio > 0.5 (P < 0.01), maximum standardized uptake value on positron emission tomography ≥1.5 (P = 0.01) and smoking index >20 pack-years (P = 0.01) were predictors of the presence of a histological aggressive component. A total of 98% of cases without any of the above factors did not have a histological aggressive component. CONCLUSIONS: Approximately 7% of ground glass opacity-containing small adenocarcinomas contained histological aggressive component. A consolidation/tumour ratio > 0.5, maximum standardized uptake value ≥ 1.5 and smoking index >20 pack-years were predictors for such cases. These predictors may be useful for screening patients with a potentially high risk of a poor prognosis and for prioritizing resection without delay.

Minimally invasive open surgery (MIOS) for clinical stage I lung cancer: diversity in minimally invasive procedures.

BACKGROUND: Many thoracic surgeons have tried to make lung cancer surgery less invasive. Among the minimally invasive approaches that are currently available, it is controversial which is optimal. Minimally invasive open surgery, i.e. hybrid video-assisted thoracic surgery, has been adopted for lung cancer surgery at our institute. The objective of this study was to evaluate minimally invasive open surgery in terms of perioperative outcomes over the most recent 5 years. METHODS: Between 2015 and 2019, 2738 patients underwent pulmonary resection for lung cancer at National Cancer Center Hospital, Japan. Among them, 2174 patients with clinical stage I lung cancer who underwent minimally invasive open surgery were included. Several perioperative parameters were evaluated. RESULTS: The patients consisted of 1092 men (50.2%) and 1082 women (49.8%). Lobectomy was performed in 1255 patients (57.7%), segmentectomy in 603 (27.7%) and wide wedge resection in 316 (14.5%). Median blood loss was 30 ml (interquartile range: 15-57 ml) for lobectomy, 17 ml (interquartile range: 10-31 ml) for segmentectomy and 5 ml (interquartile range: 2-10 ml) for wide wedge resection. Median operative time was 120 min (interquartile range: 104-139 min) for lobectomy, 109 min (interquartile range: 98-123 min) for segmentectomy and 59 min (interquartile range: 48-76 min) for wide wedge resection. Median length of postoperative hospital stay was 4 days (interquartile range: 3-5 days). The 30-day mortality rate was 0.08% for lobectomy, 0.17% for segmentectomy and 0.00% for wide wedge resection. CONCLUSIONS: Minimally invasive open surgery for clinical stage I lung cancer is a feasible approach with a low mortality and a short hospital stay. Oncological outcomes need to be investigated.

Recent advances and future perspectives in adjuvant and neoadjuvant immunotherapies for lung cancer.

The superior efficacy of immune checkpoint inhibitors for the treatment of advanced non-small cell lung cancer has inspired many clinical trials to use immune checkpoint inhibitors in earlier stages of lung cancer worldwide. Based on the theoretical feasibility that neoantigens derived from a tumor tissue are present in vivo, some clinical trials have recently evaluated the neoadjuvant, rather than the adjuvant, use of immune checkpoint inhibitors. Some of these trials have already produced evidence on the safety and efficacy of immune checkpoint inhibitors in a neoadjuvant setting, with a favorable major pathologic response and few adverse events. In the most impactful report from Johns Hopkins University and the Memorial Sloan Kettering Cancer Center, the programed death-1 inhibitor nivolumab was administered to 21 patients in a neoadjuvant setting. The authors reported a major pathologic response rate of 45%, with no unexpected delay of surgery related to the adverse effects of nivolumab. The adjuvant as well as the neoadjuvant administration of immune checkpoint inhibitors has also been considered in various clinical trials, with or without the combined use of chemotherapy or radiotherapy. The development of appropriate biomarkers to predict the efficacy of immune checkpoint inhibitors is also underway. The expression of programed death ligand-1 and the tumor mutation burden are promising biomarkers that have been evaluated in many settings. To establish an appropriate method for using immune checkpoint inhibitors in combination with surgery, the Lung Cancer Surgical Study Group of the Japan Clinical Oncology Group will manage clinical trials using a multimodality treatment, including immune checkpoint inhibitors and surgery.

Factors Associated with Unexpected Readmission Following Lung Resection.

BACKGROUND: Identification of the predictors of readmission can facilitate appropriate perioperative management. The current study aimed to investigate the potential predictors of unexpected readmission after lung resection for primary lung cancers. METHODS: This retrospective study enrolled 1000 patients who underwent pulmonary resection for lung cancer at our institution between January 2016 and December 2017. Unexpected readmission was defined as unscheduled readmission to our hospital within 30 days after discharge. Univariate and multivariate analyses were performed for identification of perioperative factors associated with readmission. RESULTS: Forty-three patients (4.3%) required unexpected readmission, and the median interval between the day of discharge and readmission was 10 days (range 1-29 days). The reasons for readmission included empyema and pleural effusion (n = 11), acute exacerbation of idiopathic pulmonary fibrosis (n = 7), pneumothorax (n = 7), and others (n = 18). The median hospitalization length after readmission was 14 days (range 2-90 days). Four patients (9.3%) died in the hospital because of acute exacerbation of idiopathic pulmonary fibrosis after readmission. In multivariate logistic regression analysis, postoperative refractory air leakage, defined as prolonged air leakage lasting > 5 days or requiring reoperation, was identified as a significant predictor associated with an increased risk of readmission (odds ratio 2.87; 95% confidence interval 1.22-6.72; p = 0.015). CONCLUSIONS: Unexpected readmission was an inevitable event following lung resection. Patients with readmission had an increased risk of death. Refractory air leakage after lung resection for primary lung cancer was strongly associated with unexpected readmission.

Squamous differentiation in surgically resected malignant pleural mesothelioma with neoadjuvant chemotherapy.

We describe a rare case of malignant pleural mesothelioma (MPM) that developed squamous differentiation. MPM can present various patterns of histology, but squamous differentiation has not been reported in any surgically resected cases to date. The patient was a 50-year-old female without smoking habit who had right MPM and underwent pleurectomy/decortication after chemotherapy. Pathological examination of the surgical specimen found that the MPM contained squamous cancer cells with apparent keratinization close to the tubulopapillary epithelioid tumor cells. Squamous differentiation was recognized close to the mesothelial proliferation, and the topographical origin of the tumor could not be recognized in the lung. The tubulopapillary tumor cells were positive for cytokeratin 5/6, Wilms tumor-1, and calretinin, and negative for thyroid transcription factor-1 (TTF-1), claudin-4, and p40. Squamous cells were positive for cytokeratin 5/6 and p40, and negative for Wilms tumor-1, calretinin, and TTF-1. Loss of BRCA1 associated protein-1 (BAP1) was observed in both the tubulopapillary and squamous tumor cells. Based on the loss of BAP1 and no history of smoking, we diagnosed this case as a rare differentiation of biphasic-type MPM into squamous cell carcinoma.

Surgical Results in Pathological N1 Nonsmall Cell Lung Cancer.

BACKGROUND: This retrospective study investigated the prognosis of patients with pathological N1 (pN1) nonsmall cell lung cancer (NSCLC). METHODS: We included patients with pN1 NSCLC who underwent lobectomy or pneumonectomy with mediastinal lymph node dissection and achieved complete resection (R0) between January 2000 and December 2012. Patients who received neoadjuvant therapy were excluded. RESULTS: A total of 249 patients were included. The mean age was 63.2 years, and 172 patients were males. Of the 249 patients, 200, 20, and 29 underwent lobectomy, bilobectomy, and pneumonectomy, respectively. The median observation period was 5.5 years. The 5-year overall survival (OS) rate was 64.6% (95% confidence interval: 58.3-70.4). Five-year OS rates were 79.8% for positive lymph nodes at station 13 or 14 (n = 57), 59.6% at station 12 (n = 72), 62.7% at station 11 (n = 69), and 56.9% at station 10 (n = 51) (log-rank test; p = 0.016); furthermore, the 5-year OS rate was 75.2% for patients with positive lymph nodes at a single station (n = 160) and 45.4% for patients with positive lymph nodes at multiple stations (n = 89) (log-rank test; p < 0.001). Five-year cumulative incidences of recurrence were equivalent between patients who received adjuvant chemotherapy and patients who did not (45.9 vs. 55.1%; Gray's test; p = 0.366). Distant recurrence was the most frequent mode of recurrence in both groups (70.8 and 67.3%). CONCLUSION: The locations and the number of stations of the positive lymph nodes were identified as prognostic factors in patients with pN1 NSCLC. The primary mode of recurrence was distant recurrence irrespective of postoperative adjuvant chemotherapy.

[Surgery for Recurrent Lung Cancer].

Treatment strategies for oligo-recurrence of lung cancer have recently been discussed well. Some studies have reported a favorable prognosis after the definitive local treatment for oligo-recurrent lung cancer. The definitive local treatment, including surgery, may be effective for recurrent lung cancer in selected patients. The time to recurrence and number of recurrence regions should be considered when selecting appropriate candidates for surgery. Thoracic surgeons will likely have more opportunities to perform surgery for recurrent lung cancer in the near future. Surgery for recurrent lung cancer requires a high level of skill owing to the difficulty in dissecting the pulmonary artery because of intrathoracic adhesions and the risk of major bleeding. To perform safe surgery, securing the central portion of the pulmonary artery is necessary. By reaching the pericardial cavity, the central portion of the pulmonary artery can be secured relatively safely.

[Current Status of Perioperative Chemotherapy for Lung Cancer].

Clinical trials have been conducted to evaluate the efficacy of perioperative chemotherapy. The results of trials on preoperative chemotherapy or chemoradiotherapy have not clearly shown an improved prognosis, although potential benefits have been noted in selected cases. As for adjuvant treatment, cisplatin-containing regimens have been shown to have prognostic benefit in cases of stage Ⅱ and ⅢA(N2)disease. In Japan, the adjuvant use of tegafur/uracil has been recommended for stage Ⅰ and Ⅱ adenocarcinoma with a tumor diameter of more than 2 cm. The efficacy of the perioperative use of molecular- targeted agents has been evaluated in some clinical trials, but the results to date have not shown any significant improvement in prognosis. Immune checkpoint inhibitors have also been assessed in some trials, and these may change the strategy for the perioperative management of lung cancer.