Identification of a Gene Expression Signature to Predict the Risk of Early Recurrence and the Degree of Immune Cell Infiltration in Triple-negative Breast Cancer.

BACKGROUND/AIM: Patients with triple-negative breast cancer (TNBC) have a high rate of recurrence within 3 years of diagnosis and a high rate of death within 5 years compared to other subtypes. The number of clinical trials investigating various new agents and combination therapies has recently increased; however, current strategies benefit only a minority of patients. This study aimed to identify specific genes that predict patients at high risk of recurrence and the immune status of the tumor microenvironment at an early stage, thereby providing insight into potential therapeutic targets to improve clinical outcomes in TNBC patients. MATERIALS AND METHODS: We evaluated the prognostic significance of microarray mRNA expression of 20,603 genes in 233 TNBC patients from the METABRIC dataset and further validated the results using RNA-seq mRNA expression data in 143 TNBC patients from the GSE96058 dataset. RESULTS: Eighteen differentially expressed genes (AKNA, ARHGAP30, CA9, CD3D, CD3G, CD6, CXCR6, CYSLTR1, DOCK10, ENO1, FLT3LG, IFNG, IL2RB, LPXN, PRKCB, PVRIG, RASSF5, and STAT4) identified in both datasets were found to be reliable biomarkers for predicting TNBC recurrence and progression. Notably, the genes whose low expression was associated with increased risk of recurrence and death were immune-related genes, with significant differences in levels of immune cell infiltration in the tumor microenvironment between high- and low- expression groups. CONCLUSION: Genes reported herein may be effective biomarkers to identify TNBC patients who will and will not benefit from immunotherapy and may be particularly important genes for developing future treatment strategies, including immunotherapy.

Sublobar resection or lobectomy and postoperative respiratory complications in emphysematous lungs.

OBJECTIVES: Pulmonary resection in patients with severe emphysema may impact postoperative respiratory complications. Low-attenuation areas evaluated using three-dimensional computed tomography to assess emphysematous changes are strongly associated with postoperative respiratory complications. Herein, we investigated the relationship between low-attenuation area, the surgical procedure and resected lung volume, which has not been explored in previous studies. METHODS: We retrospectively evaluated patients with primary or metastatic lung cancer who underwent surgical resection. The low-attenuation area percentage (low-attenuation area/total lung area × 100) and resected lung volume were calculated using three-dimensional computed tomography software, and the relationship with postoperative respiratory complications was analysed. RESULTS: Postoperative respiratory complications occurred in 66 patients (17%) in the total cohort (n = 383). We set the median value of 1.1% as the cut-off value for low-attenuation area percentage to predict postoperative respiratory complications, which occurred in 24% and 10% of patients with low-attenuation area >1.1% and <1.1%, respectively (P < 0.001). Postoperative respiratory complications occurred in approximately one-third of the patients with low-attenuation area >1.1%, whose resected lung volume was ≥15.8% or ≥5 resected subsegments. Multivariable analysis revealed that sublobar resection was associated with a significantly lower risk of postoperative respiratory complications in patients with low-attenuation area >1.1% (odds ratio 0.4, 95% confidence interval 0.183-0.875). CONCLUSIONS: Emphysema is a risk factor for postoperative respiratory complications, and lobectomy is an independent predictive risk factor. Preserving more lung parenchyma may yield better short-term prognoses in patients with emphysematous lungs.

Saving Lives in Thoracic Surgery: Balancing Oncological Radicality and Functional Preservation, Transitioning from Standard Pneumonectomy to Targeted Sublobar Resection.

This review chronicles the evolution of thoracic surgical interventions, from the standardized pneumonectomy to the precise approach of sublobar resections. It discusses the emergence and acceptance of minimally invasive and robot-assisted surgical techniques, highlighting their impact on improving outcomes beyond cancer and their influence on the surgical management of early-stage lung cancer. Evaluating historical developments alongside present methodologies, this review underscores the critical need for meticulous surgical planning and execution to optimize both oncological radicality and functional preservation. This evolution portrayed not only technical advancements but also a shift in the clinical approach towards tailored, organ-preserving methodologies, culminating in a contemporary framework promoting sublobar resections as the standard for specific patient profiles, signifying a new era of precision in thoracic surgery.

Segmentectomy-oriented anatomical model for enhanced precision surgery of the left upper lobe.

Objective: To optimize surgical outcomes and minimize complications in complex segmentectomy of the left upper lobe, we investigated the topographical anatomy of the left upper lobe and developed a segmentectomy-oriented anatomical model. Methods: A state-of-the-art 3-dimensional computed tomography workstation was used to visualize the intersegmental planes and associated veins to categorize the anatomical patterns influencing surgical procedures during left upper lobe segmentectomy. This included the central vein affecting S1+2 (apicoposterior segment) segmentectomy, the transverse S3 (anterior segment) affecting S3 segmentectomy, and other venous branching patterns in 395 patients who underwent thoracic surgery at our institution. Results: The central vein was observed in 32% of the patients, necessitating access from the interlobar area after segmental artery and bronchus division. Transverse S3 incidence was 27%, revealing that only one-third of the patients required complete left upper lobe transection between S4 and S3 during S3 segmentectomy. A significant negative correlation was observed between the presence of transverse S3 and the central vein (<10% of patients with the central vein had transverse S3 and vice versa). In 6% of patients, the lingular segmental veins partially or entirely drained into the inferior pulmonary vein, potentially causing excessive or insufficient resection during surgery. Conclusions: This study offers valuable insights into the topographic anatomy of the left upper lobe and presents a segmentectomy-oriented anatomical model for complex segmentectomies. Our approach enables a more precise and individualized surgical planning for patients undergoing segmentectomy based on their unique anatomy, which could thereby lead to improved patient outcomes.

Predicting 1-year non-cancer-related adverse events after lung resection.

OBJECTIVES: Assessing the risk for non-cancer-related outcomes following lung cancer surgery is crucial for high-risk patients. This study examined non-cancer-related adverse events within 1 year after lung resection, emphasizing the role of resected lung volume and postoperative atrial fibrillation (POAF). METHODS: We conducted a retrospective analysis of 460 patients who underwent anatomical lung resection for malignant lung tumours. We assessed perioperative factors, such as the number of resected subsegments and POAF, as potential predictors of 1-year non-cancer-related adverse events. Additionally, we validated a previously published nomogram for predicting POAF. RESULTS: One-year non-cancer-related adverse events occurred in 20% of patients. Multivariable analysis identified higher age, lower percentage-predicted forced expiratory volume in 1 second, greater number of resected subsegments and POAF as independent predictors of these adverse events. The incidence of POAF was 8.5%, with higher age, history of atrial fibrillation, and open thoracotomy as independent predictors. A temporal link between POAF and other severe postoperative complications was observed, as 71% of POAF cases preceded other complications. The nomogram's predicted risk for POAF was associated well with the actual incidence. CONCLUSIONS: Resected lung volume and POAF are statistically significant factors associated with non-cancer-related outcomes after lung resection. Minimizing resected lung volume when oncologically and technically feasible, along with identifying patients at risk for POAF, may contribute to improved postoperative outcomes. Our results have implications for risk stratification and preoperative decision-making in lung cancer surgery.

Harnessing 3D-CT Simulation and Planning for Enhanced Precision Surgery: A Review of Applications and Advancements in Lung Cancer Treatment.

The clinical application of three-dimensional computed tomography (3D-CT) technology has rapidly expanded in the last decade and has been applied to lung cancer surgery. Two consecutive reports of large-scale prospective clinical trials from Japan and the United States have brought a paradigm shift in lung cancer surgery and may have led to a rapid increase in sublobar lung resections. Sublobar resection, especially segmentectomy, requires a more precise understanding of the anatomy than lobectomy, and preoperative 3D simulation and intraoperative navigation support it. The latest 3D simulation software packages are user-friendly. Therefore, in this narrative review, we focus on recent attempts to apply 3D imaging technologies, particularly in the sublobar resection of the lung, and review respective research and outcomes. Improvements in CT accuracy and the use of 3D technology have advanced lung segmental anatomy. Clinical applications have enabled the safe execution of complex sublobar resection through a minimally invasive approach, such as video-assisted thoracoscopic surgery and robotic surgery. However, currently, many facilities still render 3D images on two-dimensional monitors for usage. In the future, it will be challenging to further spread and advance intraoperative navigation through the application of 3D output technologies such as extended reality.

Bronchial branching patterns and volumetry in the right upper lobe: impact on segmentectomy planning.

OBJECTIVES: The use of segmentectomy is expected to increase. However, understanding of the segmental bronchial branching is limited. Herein, we aimed to investigate bronchial branching pattern complexity and segmental volumetry of the right upper lung lobe to develop an accurate understanding of segmental anatomy and contribute to the advancement of safe and efficient lung segmentectomy. METHODS: We evaluated chest computed tomography scans of 303 patients and categorized the branching of segmental bronchi (segment 1, apical; segment 2, posterior; and segment 3, anterior) into 4 major types (typical trifurcated, bifurcated non-defective, bifurcated defective and atypical trifurcated) and 11 subtypes. Segmental volumetry was performed to determine the predominant segment in each case (volume difference <5% was considered equal). Branching complexity was evaluated separately for volumetry-predominant and volumetry-non-predominant segments. RESULTS: Trifurcated non-defective was the most frequent branching type (64.4%), followed by bifurcated non-defective (22.1%), bifurcated defective (8.6%) and trifurcated half-defective (4.0%). In terms of segmental volumetry, most cases had a one-segment-predominant distribution (71%) and only 5% of cases had equal distribution (segment 1 = segment 2 = segment 3). More than half of the cases had a segment 3-predominant distribution (52%). Branching complexity analysis revealed that the volumetry-non-predominant segment was associated with a higher risk of complex branching patterns compared with the volumetry-predominant segment (37% vs 19%, respectively; P < 0.005). CONCLUSIONS: Volumetric assessment of the right upper lobe showed a heterogeneous segmental volume distribution. Care should be taken during lung segmentectomy of the volumetry-non-predominant segments because of the high risk associated with complex bronchial branching patterns. CLINICAL TRIAL REGISTRATION: No. 4840.

Successful resection after first-line lenvatinib therapy in an advanced thymic carcinoma.

Thymic carcinoma is a highly malignant tumor and treatment options are limited. Lenvatinib, a novel multitargeted kinase inhibitor, has recently been approved for the treatment of unresectable thymic carcinoma. There are no reports of complete surgical resection after the administration of first-line lenvatinib in advanced thymic carcinoma. A 50-year-old man visited our hospital because a computed tomography (CT) scan of the chest showed a large thymic squamous cell carcinoma. We suspected malignant pericardial effusion, invasion of the left upper lobe of the lung, and left mediastinal lymph node metastases. The patient was diagnosed with WHO classification stage IVb disease. Lenvatinib therapy was started at 24 mg/day as first-line therapy. Gradual dose reduction to 16 mg/day was required because of hypertension, diarrhea, and palmar-plantar erythrodysesthesia syndrome as side effects. Chest CT findings after 6 months of lenvatinib therapy showed reduction of the main tumor, disappearance of the mediastinal lymph node metastases, and pericardial effusion. Complete salvage resection was successfully performed a month after discontinuation of lenvatinib. The patient has been disease-free for 1 year without adjuvant therapy. Lenvatinib therapy is one of the promising therapeutic options for thymic carcinoma and may make salvage surgery increasingly useful for advanced thymic carcinoma.

Anatomical resection for right B3 downwards-shifting malformation.

The right B3 downwards-shifting malformation is rare. This malformation often leads to the following complications: abnormal pulmonary arteries that accompany the downward-displaced B3, and complete fusion of the upper and middle lobes into one lobe, with no horizonal fissure. When performing pulmonary anatomical resection in the right upper or middle lobes in patients with this malformation, careful preoperative planning and surgical technique are required, with which the surgeon should be familiar. Herein, we present the anatomical features necessary for anatomical resection of the right B3 downwards-shifting malformation based on our technical experiences with anatomic segmentectomy and lobectomy techniques.

Significance of the evaluation of tracheal length using a three-dimensional imaging workstation.

Background: Limited information is available on the total tracheal length and its other characteristics for tracheal surgery. This study aimed to investigate the reference value of tracheal length and assess its relationship with physiological variables. Methods: We measured the tracheal length of 215 patients (107 men and 108 women) who underwent contrast-enhanced computed tomography before thoracic surgery using a three-dimensional imaging workstation. Pearson correlation analysis and multiple linear regression analysis were performed to investigate the relationship between the total tracheal length (cervical and thoracic) and common physiological parameters. Results: The mean total tracheal length was 11.5±1 cm (range, 8.8-14.4 cm); 8% of the patients had a total tracheal length <10 cm. The cervical trachea was significantly shorter in men than in women (2.9±1.3 vs. 3.8±1.3 cm, P<0.001), whereas the thoracic trachea was significantly longer in men than in women (8.9±1.1 vs. 7.4±1.1 cm, P<0.001). Correlation analysis showed that the total tracheal length was positively associated with height in both sexes, while the height was positively associated with only cervical tracheal length. In the multiple linear regression analysis, the total tracheal length was influenced most by height, while cervical and thoracic tracheal lengths were influenced most by sex. Older age was also an independent contributor to a shorter cervical trachea and longer thoracic trachea in both sexes. Conclusions: The total tracheal length ranged from short to long in individuals, and characteristics of tracheal length varied with height, age, sex, and part of the trachea. We should thus be aware of the tracheal length of each patient for appropriate tracheal management.

Is using a consolidation tumor ratio 0.5 as criterion feasible in daily practice? Evaluation of interobserver measurement variability of consolidation tumor ratio of lung cancer less than 3 cm in size.

BACKGROUND: Consolidation tumor ratio (CTR) calculated as the ratio of the tumor consolidation diameter to the tumor maximum diameter on thin-section computed tomography (CT) of lung cancer has been reported as an important prognostic factor. It has also been used for treatment decision-making. This study aimed to investigate the interobserver variability of CTR measurements on preoperative CT and propose a clinically useful CTR-based classification criterion. METHODS: We enrolled 119 patients who underwent surgery for suspected or diagnosed small-sized lung cancer (≤3.0 cm in diameter). Nine doctors reviewed preoperative CT scans to measure CTR. Interobserver variability of CTR measurements was evaluated using the coefficient of variation (CV) and Fleiss' κ. The prognostic effect of the CTR-based classification was assessed using the Kaplan-Meier method. RESULTS: Interobserver variability of CTR measurement was the highest for tumors with the lowest CTR (CTR = 0); it decreased as CTR increased and reached a plateaued level of low variability (CV <0.5) at CTR of 0.5. We proposed a three-group classification based on the findings of CTR interobserver variability (CTR < 0.5, 0.5 ≤ CTR < 1, and CTR = 1). Interobserver agreement of the judgment of the CTR-based classification was excellent (Fleiss' κ = 0.81). The classification significantly stratified patient prognosis (p < 0.001, 5-year overall survival rates with CTR < 0.5, 0.5 ≤ CTR < 1, and CTR = 1 were 100, 88, and 73.8%, respectively). CONCLUSIONS: CTR 0.5 is a clinically relevant and helpful cutoff for treatment decision-making in patients with early-stage lung cancer based on high interobserver agreement and good prognostic stratification.

Adoption of Robotic Core Technology in Minimally Invasive Lung Segmentectomy: Review.

A recent randomized trial demonstrated the survival superiority of lung segmentectomy over lobectomy in patients with early stage, small-sized lung cancer. Hence, there is a pressing need for thoracic surgeons to gain familiarity with lung segmentectomy. However, lung segmentectomy, especially via minimally invasive surgery, is a technically challenging thoracic surgical procedure. The robotic surgery platform helps surgeons to improve their operative performance based on its core technological features: improved dexterity, precision, and visualization. Herein, we have discussed the key issues related to robotic lung segmentectomy, explicitly focusing on the technical features of complex segmentectomy under difficult conditions. We have also introduced our preferred surgical strategy for robotic lung segmentectomy with specific maneuvers.

Three-step strategy for robotic lung segmentectomy.

Lung segmentectomy is a technically challenging procedure when deep hilar dissection and multiple intersegmental plane divisions are required. We demonstrate a 3-step strategy for robotic lung segmentectomy to overcome these challenges.

Syndrome of Inappropriate Antidiuretic Hormone Secretion as the Initial Presentation in a Patient with Stage I Small-cell Lung Cancer.

A 67-year-old man with a history of esophageal cancer resection was referred to our hospital because of nausea and appetite loss. Laboratory findings showed severe hyponatremia and were compatible with syndrome of inappropriate antidiuretic hormone (SIADH) secretion. Chest computed tomography (CT) revealed a nodule measuring 13 mm in the lower lobe of the right lung. Right thoracotomy was performed, and the histopathological diagnosis was small-cell lung cancer (T1bN0M0; Stage 1b). Although SIADH is frequently associated with small-cell lung cancer, it is extremely rare as the initial clinical feature in stage I small-cell lung cancer.

Epidemiological analysis of lung and mediastinal neuroendocrine neoplasms in Japan based on the national database.

BACKGROUND: Neuroendocrine neoplasms (NENs) are rare and can originate from any body part. However, there are only few epidemiological studies, especially on lung and mediastinal NENs. This study investigated the epidemiological trends and differences between lung and mediastinal NENs in Japan. METHODS: Patients with lung and mediastinal NENs were identified in a national hospital-based cancer registry between 2009 and 2015 in Japan. NENs were subclassified into neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). NECs were further subdivided into large neuroendocrine carcinomas (LCNECs) and small cell carcinomas (SCCs). We examined the patient characteristics: sex, age, histology, year of diagnosis, diagnostic opportunity, and initial treatment. RESULTS: We identified 48,433 patients with 47,888 lung (98.9%) and 545 mediastinal (1.1%) NENs. The commonest subtype of lung NENs was SCCs (87%), followed by LCNECs (10%) and NETs (3%). In the mediastinum, SCCs were also the commonest (48%), followed by NETs (38%) and LCNECs (14%). The number of lung NEN annually increased; however, that of mediastinal NENs did not change over time. The mean age of patients with lung NETs was lower than that of patients with lung LCNECs and SCCs (NETs, 62 ± 14 years; LCNECs, 70 ± 9 years; SCCs, 71 ± 9 years; p < .001). The lung and mediastinal NENs were mainly detected based on symptoms, except for lung NETs. Surgical intervention, including multimodal therapy, was performed for 89.3% of lung NETs (surgery alone: 83.6%), while only 15.6% of lung NECs were treated with surgery. For the mediastinum, 75.9% of NETs were treated with surgery, with 27.1% of cases treated with surgery plus multimodal therapy. Surgery was performed more frequently for mediastinal NECs (37%) than for lung NECs (15.6%). CONCLUSIONS: This study highlights differences in trends of lung and mediastinal NENs. This study's findings support the importance of epidemiological evaluations based on the primary sites and histological subtypes.

Prediction of Pulmonary Artery-Adherent Lymph Nodes for Minimally Invasive Lung Resection.

BACKGROUND: During minimally invasive surgery (MIS), pulmonary artery (PA)-adherent lymph nodes (LNs) may increase the risk of conversion to thoracotomy and/or PA injury. The aims of this study were to investigate (1) preoperative workups as predictors of PA-adherent LNs and (2) predictors of conversion/PA injury during MIS. METHODS: We investigated 1210 patients who underwent anatomical lung resection (MIS: 772, thoracotomy: 438) and determined the PA-adherent LN status by reviewing the operation video/record. The size and calcification of the hilar LNs on computed tomography, bilateral high metabolic activity on positron emission tomography, and mucosal dark pigmentation on bronchoscopy were evaluated as potential predictors for PA-adherent LNs. RESULTS: Among patients who underwent all 3 workups (n = 594), both bronchoscopy and computed tomography were independent predictors for PA-adherent LNs; the combination of dark pigmentation and LN size ≥8 mm stratified patients according to the risk of PA-adherent LNs (lowest to highest risk, 3%-65%). Among the patients who underwent MIS (n = 772), conversion and PA injuries were observed in 32 (4%) and 25 (3%) patients, respectively. Multivariate analysis revealed that the presence of PA-adherent LNs was an independent predictor of both conversion and PA injury (both P < .001). The effect of PA-adherent LNs on conversion risk was significantly modified by the resected lobe (P = .008). CONCLUSIONS: The presence of PA-adherent LNs is associated with a high risk of conversion/PA injury during MIS. Bronchial dark pigmentation, size of hilar LNs, and their combination are useful for predicting PA-adherent LNs; this finding may help in achieving safer MIS.

Preemptive Intercostal Nerve Block as an Alternative to Epidural Analgesia.

BACKGROUND: The necessity of thoracic epidural analgesia (TEA) during minimally invasive surgery (MIS) remains unclear. We investigated TEA efficacy in MIS versus thoracotomy and the noninferiority of a preemptive intercostal nerve block (ICNB) to TEA in MIS. METHODS: We investigated 393 patients who underwent lung resection, with and without TEA, between 2014 and 2019 (242 MIS, 151 thoracotomy) and 93 patients who underwent MIS with ICNB between 2019 and 2020. To address selection bias 70 TEA and 70 ICNB patients were propensity score matched. Endpoints were pain score during hospitalization, postoperative complications, duration of operating room use, analgesia-related adverse effects, and use of supplemental pain medication. RESULTS: One-third of patients with MIS discontinued TEA on postoperative day 1 or earlier; those with early TEA discontinuation reported worse pain the next day. TEA was associated with lower pain scores compared with non-TEA, regardless of surgical invasiveness, and a lower complication risk in patients with thoracotomy but not MIS. For MIS, ICNB was associated with an equivalent pain score on postoperative day 1, lower average pain score during hospitalization, shorter duration of operation room use, less frequent use of supplemental pain medication, and similar risk of postoperative complication and analgesia-related adverse effects compared with TEA after matching. CONCLUSIONS: Given early TEA discontinuation after MIS and ICNB's noninferior pain relief, preemptive ICNB can be an alternative for TEA in patients undergoing MIS.

Non-incisional pleurectomy/decortication for malignant mesothelioma after cardiac surgery.

A 70-year-old man diagnosed with right-sided malignant epithelial pleural mesothelioma, underwent pleurectomy/decortication after three courses of neoadjuvant chemotherapy. He had a history of mitral valve replacement and maze procedure with median sternotomy, and the procedures resulted in strong adhesion from the apex to the mediastinal side. In particular, the peeling of the area where the tumor invaded the pericardium required the most attention; however, the involved pericardium could be partially resected without damaging the right atrium. Finally, en bloc macroscopic complete resection with the entire pleura was successfully performed without conversion to extrapleural pneumonectomy.

Impact of counterclockwise rotation of the right middle lobe following right upper lobectomy.

OBJECTIVES: Following right upper lobectomy, the right middle lobe may shift towards the apex and rotate in a counterclockwise direction with respect to the hilum. This study aimed to investigate the incidence and clinical impact of middle lobe rotation in patients undergoing right upper lobectomy. METHODS: From January 2014 to November 2018, 82 patients underwent right upper lobectomy at our institution for lung cancer using a surgical stapler to divide the minor fissure. Postoperative computed tomography scans evaluated the counterclockwise rotation of the middle lobe, in which the staple lines placed on the minor fissure were in contact with the major fissure of the right lower lobe (120° counterclockwise rotation). Clinicoradiological factors were evaluated and compared between patients with and without middle lobe rotation. We also reviewed surgical videos in patients with middle lobe rotation to evaluate the position of the middle lobe at the end of surgery. RESULTS: Nine patients had a middle lobe rotation (11%), where 1 patient required surgical derotation. Patients with middle lobe rotation were significantly associated with more frequent right middle lobe atelectasis and severe postoperative complications compared with those without rotation. A surgical video review detected potential middle lobe rotation at the end of the surgery. CONCLUSIONS: Middle lobe rotation without torsion following right upper lobectomy is not rare, and it is associated with adverse postoperative courses. Careful positioning of the right middle lobe at the end of surgery is warranted to improve postoperative outcomes.

A Novel Strategy for the Diagnosis of Pulmonary High-Grade Neuroendocrine Tumor.

Correctly diagnosing a histologic type of lung cancer is important for selecting the appropriate treatment because the aggressiveness, chemotherapy regimen, surgical approach, and prognosis vary significantly among histologic types. Pulmonary NETs, which are characterized by neuroendocrine morphologies, represent approximately 20% of all lung cancers. In particular, high-grade neuroendocrine tumors (small cell lung cancer and large cell neuroendocrine tumor) are highly proliferative cancers that have a poorer prognosis than other non-small cell lung cancers. The combination of hematoxylin and eosin staining, Ki-67, and immunostaining of classic neuroendocrine markers, such as chromogranin A, CD56, and synaptophysin, are normally used to diagnose high-grade neuroendocrine tumors; however, they are frequently heterogeneous. This article reviews the diagnostic methods of lung cancer diagnosis focused on immunostaining. In particular, we describe the usefulness of immunostaining by Stathmin-1, which is a cytosolic phosphoprotein and a key regulator of cell division due to its microtubule depolymerization in a phosphorylation-dependent manner, for the diagnosis of high-grade neuroendocrine tumors.