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Abstract Background Pulmonary carcinoids are rare neuroendocrine tumors accounting for less than 1% of all lung cancers. They are classified into two subcategories; typical and atypical carcinoids with the latter tending to grow faster. Historically, open thoracotomy was the standard approach for pulmonary resection. However, in the recent years, video-assisted thoracoscopy has gained popularity and become the preferred technique for resectioning pulmonary carcinoids. This report details the diagnosis and management of a pleural carcinoid tumor in a patient with recurrent unilateral pleural effusion. Case presentation A 77-year-old African male with a history of hypertension and heart failure with reduced ejection presented with a 6-month history of an irritating non-productive cough, occasional productive episodes and exertional dyspnea but no history of hemoptysis, chest pain, orthopnea, evening fevers, or significant weight loss. Despite multiple interventions, including tube drainage and antituberculosis medications, symptoms persisted. A chest X-ray was performed and it revealed a homogeneous opacity on the left, and a computed tomography scan showed mild pleural thickening especially at the bases. Video-assisted thoracoscopy was performed revealing thickened pleural and biopsies confirmed a diagnosis of malignant carcinoid tumor. The patient underwent successful pleurodesis, resulting in significant improvement. Conclusion This case highlights the pivotal role of video-assisted thoracoscopy in diagnosing and managing rare cases such as pulmonary carcinoids when less invasive methods such as thoracentesis fail.

Abstract Currently, there is no consensus regarding the extent of surgery for stage I pulmonary carcinoid (PC) tumors, which encompass typical carcinoid (TC) and atypical carcinoid (AC) tumors. Sublobar resection includes segmental resection and wedge resection; the former is regarded as a type of anatomical resection that is better suited for tumor treatment. Therefore, it needs to be further verified whether differences exist in the effects of the two surgical methods on the survival time of patients. Propensity score matching (PSM) was used. The primary endpoints were cancer-specific survival (CSS) and overall survival (OS) time. Survival differences were analyzed via the Kaplan–Meier method and the log-rank test. There was no significant difference in survival between the sublobar resection and lobectomy groups after PSM in either the TC or AC tumor groups (all p > 0.05). A total of 1680 patients underwent pulmonary wedge resection (TC: n = 1547, AC: n = 133), and 398 patients underwent segmental resection (TC: n = 365, AC: n = 33). After PSM, there were no statistically significant differences in survival, regardless of whether OS or CSS was considered the primary endpoint (OS: p = 0.337; CSS: p = 0.470). Furthermore, segmental resection did not prolong patient survival time compared with wedge resection in different subgroup analyses on the basis of histology, age, and tumor size (all p > 0.05). Finally, the same results were obtained via multivariate Cox analysis (OS: p = 0.153; HR = 1.21; CSS: p = 0.351, HR = 1.32). Sublobar resection could be considered for patients with early-stage typical or atypical pulmonary carcinoid, provided that a rigorous lymph node evaluation is conducted. If the tumor is distant from the pulmonary hilum, either segmentectomy or wedge resection may be performed depending on the specific location of the tumor and the clinical condition of the patient.

The predictive value of the extent of peri-operative lymph node (LN) sampling in relation to disease relapse in patients with pulmonary carcinoid (PC) is unknown. Furthermore, post-surgery follow-up recommendations rely on institutional retrospective studies with short follow-ups. We aimed to address these shortcomings by examining the relation between LN sampling and relapse in a population-based cohort with long-term follow-up. By combining the Dutch nationwide pathology and cancer registries, all patients with surgically resected PC (2003–2012) were included in this analysis (last update 2020). The extent of surgical LN dissection was scored for the number of LN samples, location (hilar/mediastinal), and completeness of resection according to European Society of Thoracic Surgeons (ESTS) guidelines. Relapse-free interval (RFI) was evaluated using Kaplan Meier and multivariate regression analysis. 662 patients were included. The median follow-up was 87.5 months. Relapse occurred in 10% of patients, mostly liver (51.8%) and locoregional sites (45%). The median RFI was 48.1 months (95% CI 36.8–59.4). Poor prognostic factors were atypical carcinoid, pN1/2, and R1/R2 resection. In 546 patients LN dissection data could be retrieved; at least one N2 LN was examined in 44% and completeness according to ESTS in merely 7%. In 477 cN0 patients, 5.9% had pN1 and 2.5% had pN2 disease. In conclusion, relapse occurred in 10% of PC patients with a median RFI of 48.1 months thereby underscoring the necessity of long-term follow-up. Extended mediastinal LN sampling was rarely performed but systematic nodal evaluation is recommended as it provides prognostic information on distant relapse. [ABSTRACT FROM AUTHOR]

Currently, there is no consensus regarding the extent of surgery for stage I pulmonary carcinoid (PC) tumors, which encompass typical carcinoid (TC) and atypical carcinoid (AC) tumors. Sublobar resection includes segmental resection and wedge resection; the former is regarded as a type of anatomical resection that is better suited for tumor treatment. Therefore, it needs to be further verified whether differences exist in the effects of the two surgical methods on the survival time of patients. Propensity score matching (PSM) was used. The primary endpoints were cancer-specific survival (CSS) and overall survival (OS) time. Survival differences were analyzed via the Kaplan–Meier method and the log-rank test. There was no significant difference in survival between the sublobar resection and lobectomy groups after PSM in either the TC or AC tumor groups (all p > 0.05). A total of 1680 patients underwent pulmonary wedge resection (TC: n = 1547, AC: n = 133), and 398 patients underwent segmental resection (TC: n = 365, AC: n = 33). After PSM, there were no statistically significant differences in survival, regardless of whether OS or CSS was considered the primary endpoint (OS: p = 0.337; CSS: p = 0.470). Furthermore, segmental resection did not prolong patient survival time compared with wedge resection in different subgroup analyses on the basis of histology, age, and tumor size (all p > 0.05). Finally, the same results were obtained via multivariate Cox analysis (OS: p = 0.153; HR = 1.21; CSS: p = 0.351, HR = 1.32). Sublobar resection could be considered for patients with early-stage typical or atypical pulmonary carcinoid, provided that a rigorous lymph node evaluation is conducted. If the tumor is distant from the pulmonary hilum, either segmentectomy or wedge resection may be performed depending on the specific location of the tumor and the clinical condition of the patient. [ABSTRACT FROM AUTHOR]

Purpose: The observation‐based prognosis, rather than resection, for small carcinoid tumors is still unclear. This lack of clarity has important implications for counseling elderly patients or patients for whom surgical resection poses a high risk. This study compared the outcomes of observation and surgical resection in patients with pulmonary carcinoid (PC) tumors ≤3 cm in size without metastasis. Methods: Data of patients with PC tumors with ≤3 cm in diameter and without lymph node and distant metastases were retrieved from Surveillance, Epidemiology, and End Results (SEER) registry. To reduce the inherent bias of retrospective studies, propensity score matching analysis was performed. Overall survival (OS) and lung carcinoid‐specific survival (LCSS) were analyzed using Kaplan–Meier plots. Multivariate analysis was used to determine predictors of LCSS in different size subgroups. Results: In total, 4552 patients with early‐stage PCs ≤3 cm in diameter, including 435 (9.56%) who were observed and 4117 (90.44%) treated by surgery, were recruited. Patients with surgery had significantly better OS and LCSS than those who were observed. However, patients with observation had comparable LCSS to those with surgery for PCs with tumor diameters ≤1 cm. Multivariate analysis indicated that surgical resection was an independent prognostic factor for LCSS in 1 cm < tumors ≤2 cm, and 2 cm < tumors ≤3 cm groups, but not for tumors ≤1 cm in diameter. Conclusion: Surgical resection of small PCs is associated with a survival advantage over observation. However, for early PCs ≤1 cm in diameter, observation may be considered in patients with high risk for surgical resection. [ABSTRACT FROM AUTHOR]

Background: Orthopedia homeobox protein (OTP), highlighted as a sensitive and specific marker for pulmonary carcinoids, may provide a more objective criterion for subclassification. Materials and Methods: A total of 110 patients who underwent surgery for pulmonary carcinoids (2009–2019) were included. Gender, age, application complaint, tumor diameter and location, typical and atypical tumor type, lymph node involvement, stage, recurrence, and survival data were evaluated retrospectively with OTP nuclear staining. Results: The sensitivity of OTP was 66.4%. OTP in subclassifying pulmonary carcinoids was not significant. There was no significant relationship between OTP and lymph node involvement, recurrence, and survival. Conclusion: OTP does not provide significant results in the subclassification of typical and atypical carcinoid tumors and the evaluation of recurrence and survival of carcinoid tumor cases.

AbstractObjective To investigate the clinical efficacy of thermal ablation in the treatment of pulmonary carcinoid (PC) tumor.Methods Data of patients with inoperable PC diagnosed from 2000 to 2019 were obtained from the SEER database and analyzed according to different therapeutic modality: thermal ablation vs non-ablation. Propensity score matching (PSM) was used to reduce intergroup differences. Kaplan–Meier curves and the log-rank test were used to compare intergroup differences of overall survival (OS) and lung cancer-specific survival (LCSS). Cox proportional risk models were used to reveal prognostic factors.Results After PSM, the thermal ablation group had better OS (p 3.0 cm. Subgroup analysis by M stage showed that thermal ablation was superior to non-ablation in OS and LCSS for patients with M0 stage, but no significant difference was found in subgroups with distant metastatic disease. Multivariate analysis showed that thermal ablation was an independent prognostic factor for OS (HR: 0.34, 95% CI: 0.25–0.46, p

Background: Prognostic factors and role with chemotherapy (CT) and radiotherapy (RT) remain unclear for patients of pulmonary carcinoid (PC) with positive lymph node after surgery. Methods: PC patients who underwent surgery and with positive lymph node between 2000 and 2016 were identified from the SEER database. Univariate and multivariate cox regression analysis were used to identify independent risk factors for overall survival (OS). Results: A total of 552 patients were identified. Multivariate analysis indicated that age (≤ 70/ > 70) (HR = 0.32, 95% CI 0.21–0.50; P < 0.001), histologic type (typical carcinoid [TC]/atypical carcinoid [AC]) (HR = 0.53, 95% CI 0.36–0.78, P = 0.001), number of positive lymph nodes (n ≥ 3/n = 1–2) (HR = 1.91, 95% CI 1.26–2.90; P = 0.002), and treatment mode (surgery + RT/surgery alone) (HR = 1.75, 95% CI 1.09–2.81; P 0.02) were independent prognostic factors for OS. In subgroup analysis according to histological type, prognostic factors were similar between AC and TC, except surgery + RT being negative prognostic factor for TC but AC. No significant difference in OS was observed between the surgery alone and surgery + CT in any subgroup of patients. Conclusions: Age > 70, histological type of AC, positive lymph nodes ≥ 3, and surgery + RT were likely to be negative prognostic factors for OS. Addition CT to surgery did not appear to provide additional OS benefit. [ABSTRACT FROM AUTHOR]

Pulmonary carcinoids (PCs) are part of a spectrum of well-differentiated neuroendocrine neoplasms (NENs) and are classified as typical carcinoid (TC) and atypical carcinoid (AC). TC differ from AC not only for its histopathological features but also for its "functional imaging pattern" and prognosis. ACs are more undifferentiated and characterized by higher aggressiveness. Positron emission tomography/computed tomography (PET/CT) with somatostatin analogs (SSA) labeled with Gallium-68 (68Ga-DOTA-TOC, 68Ga-DOTA-NOC, 68Ga-DOTA-TATE) has widely replaced conventional imaging with gamma camera using 111In- or 99mTc-labelled compounds and represents now the gold standard for diagnosis and management of NENs. In this setting, as already described for gastro-entero-pancreatic NENs, 18F-Fluorodeoxiglucose ([18F]FDG) in addition to 68Ga-SSA can play an important role in clinical practice, particularly for ACs that show a more aggressive behavior compared to TCs. The aim of this systematic review is to analyze all original studies collected from the PubMed and Scopus databases regarding PCs in which both 68Ga-SSA PET/CT and [18F]FDG PET/CT were performed in order to evaluate the clinical impact of each imaging modality. The following keywords were used for the research: "18F, 68Ga and (bronchial carcinoid or carcinoid lung)". A total of 57 papers were found, of which 17 were duplicates, 8 were reviews, 10 were case reports, and 1 was an editorial. Of the remaining 21 papers, 12 were ineligible because they did not focus on PC or did not compare 68Ga-SSA and [18F]FDG. We finally retrieved and analyzed nine papers (245 patients with TCs and 110 patients with ACs), and the results highlight the importance of the combined use of 68Ga-SSA and [18F]FDG PET/CT for the correct management of these neoplasms. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with low- and intermediate-grade neuroendocrine tumors (NETs) of the lung, also called typical (TC) and atypical carcinoids (AC), are often managed in a very heterogenous way. This lack of standardized procedures, probably due to the rare occurrence of these tumors, was and is unfavorable for the affected patients. In 2015, the European NET society (ENETS) published new guidelines for best practice for TC and AC. Using data from the SwissNET registry, we wanted to check whether there was an impact of these guidelines on the diagnosis and treatment of the affected patients. As we could see, there was an improvement after 2016, in the sense of an increase in functional imaging and the determination of histopathological markers. Additionally, more systemic lymph node resections were conducted. These findings are encouraging; nevertheless there is room for further improvement in the management of these patients. Typical (TC) and atypical carcinoids (AC) are the most common neuroendocrine tumors (NETs) of the lung. Because these tumors are rare, their management varies widely among Swiss centers. Our aim was to compare the management of Swiss patients before and after the publication of the expert consensus of the European Neuroendocrine Tumor Society (ENETS) in 2015. We used data from the Swiss NET registry from 2009 to 2021 with patients with TC and AC. Survival analysis was performed using the Kaplan–Meier method and log-rank test. Overall, 238 patients were included, 76% (180) thereof with TC and 24% (58) with AC, including 155 patients before and 83 patients after 2016. An increase in the use of functional imaging was observed, 16% (25) before and 35% (29) after 2016, p < 0.001. The presence of SST2A-receptors was determined more often: 32% (49 times) before 2016 and 47% (39 times) after, p = 0.019. Concerning therapy, higher removal of lymph nodes after 2016 was observed, 54% (83) before versus 78% (65) after, p < 0.001. Median overall survival for patients with AC was significantly shorter, with 89 months compared to 157 months for patients with TC, p < 0.001. While the implementation of a more standardized approach was observed over the years, there is still room for amelioration in the management of TC and AC in Switzerland. [ABSTRACT FROM AUTHOR]

Abstract Background Although most guidelines suggest performing a positron emission tomography/computed tomography (PET/CT) with somatostatin receptor (SSTR) ligands for staging of pulmonary carcinoid tumours (PC), only a limited number of studies have evaluated the role of this imaging tool in this specific patient population. The preoperative differentiation between typical carcinoid (TC) and atypical carcinoid (AC) and the extent of dissemination (N/M status) are crucial factors for treatment allocation and prognosis of these patients. Therefore, we performed a pathology-based retrospective analysis of the value of SSTR PET/CT in tumour grading and detection of nodal and metastatic involvement of PC and compared this with the previous literature and with [18F]FDG PET/CT in a subgroup of patients. Methods SSTR PET/CT scans performed between January 2007 and May 2020 in the context of PC were included. If available, [18F]FDG PET/CT images were also evaluated. The maximum standardized uptake (SUVmax) values of the primary tumour, of the pathologically examined hilar and mediastinal lymph node stations, as well as of the distant metastases, were recorded. Tumoural SUVmax values were related to the tumour type (TC versus AC) for both SSTR and [18F]FDG PET/CT in diagnosing and differentiating both tumour types. Nodal SUVmax values were compared to the pathological status (N+ versus N−) to evaluate the diagnostic accuracy of SSTR PET/CT in detecting lymph node involvement. Finally, a mixed model analysis of all pathologically proven distant metastatic lesions was performed. Results A total of 86 SSTR PET/CT scans performed in 86 patients with PC were retrospectively analysed. [18F]FDG PET/CT was available in 46 patients. Analysis of the SUVmax values in the primary tumour showed significantly higher SSTR uptake in TC compared with AC (median SUVmax 18.4 vs 3.8; p = 0.003) and significantly higher [18F]FDG uptake in AC compared to TC (median SUVmax 5.4 vs 3.5; p = 0.038). Receiver operating characteristic (ROC) curve analysis resulted in an area under the curve (AUC) of 0.78 for the detection of TC on SSTR PET/CT and of 0.73 for the detection of AC on [18F]FDG PET/CT. A total of 267 pathologically evaluated hilar and mediastinal lymph node stations were analysed. ROC analysis of paired SSTR/[18F]FDG SUVmax values for the detection of metastasis of TC in 83 lymph node stations revealed an AUC of 0.91 for SSTR PET/CT and of 0.74 for [18F]FDG PET/CT (difference 0.17; 95% confidence interval − 0.03 to 0.38; p = 0.10). In a sub-cohort of 10 patients with 12 distant lesions that were pathologically examined due to a suspicious aspect on SSTR PET/CT, a positive predictive value (PPV) of 100% was observed. Conclusion Our findings confirm the higher SSTR ligand uptake in TC compared to AC and vice versa for [18F]FDG uptake. More importantly, we found a good diagnostic performance of SSTR PET/CT for the detection of hilar and mediastinal lymph node metastases of TC. Finally, a PPV of 100% for SSTR PET/CT was found in a small sub-cohort of patients with pathologically investigated distant metastatic lesions. Taken together, SSTR PET/CT has a very high diagnostic value in the TNM assessment of pulmonary carcinoids, particularly in TC, which underscores its position in European guidelines.

Background: The optimal number of examined lymph nodes (ELNs) for older early-stage pulmonary carcinoid tumour (PC) patients is unknown. Aims: To explore the prognostic effect of the ELN count in older patients with stage T1N0M0 PC resection. Methods: Clinical data from the Surveillance, Epidemiology, and End Results database on stage T1N0M0 PC older patients (age ≥ 65 years) who underwent sublobar resection and lobectomy between 2000 and 2018 were retrospectively analysed for two ELNs-stratified (≥ 7 vs. < 7 ELNs) propensity score-matched (PSM) groups. Overall survival (OS) was calculated and compared with Kaplan–Meier analysis and log-rank test, respectively, and the independent prognostic factors were estimated using a Cox proportional hazard model. Results: Among 1077 participants (median dissected LN 4; mean ELNs 6.19 ± 7.04), 393 (36.49%) in the ≥ 7 ELNs group had better 5- and 10-year OS than the < 7 ELNs group (before PSM: 5-year OS = 93.01 vs. 85.22%, 10-year OS = 72.38 vs. 58.99%, p < 0.001; after PSM: 5-year OS = 93.12 vs. 85.97%, 10-year OS = 75.25 vs. 60.03%, p = 0.001). Subgroup analysis stratified by histologic type and surgical method showed a similar survival trend. Age-stratified analysis showed that, compared with the < 7 ELNs group, the ≥ 7 ELNs group had better 5- and 10-year OS but only better 5-year OS in participants > 75 years. Compared with the < 7 ELNs group, subgroup analysis by tumour size showed superior OS with 1.1–3.0 cm tumours in the ≥ 7 ELNs group, but no significant intergroup difference with tumours < 1.0 cm. Multivariate Cox analysis showed ≥ 7 ELNs was associated with improved OS. Conclusion: Higher ELNs correlated with increased long-term survival in older early‑stage PC patients, and a minimum of 7 ELNs are recommended for prognostication in these patients (especially those aged 65–75 years, with tumour size 1.1–3.0 cm). [ABSTRACT FROM AUTHOR]

To investigate the clinical efficacy of thermal ablation in the treatment of pulmonary carcinoid (PC) tumor. Data of patients with inoperable PC diagnosed from 2000 to 2019 were obtained from the SEER database and analyzed according to different therapeutic modality: thermal ablation vs non-ablation. Propensity score matching (PSM) was used to reduce intergroup differences. Kaplan–Meier curves and the log-rank test were used to compare intergroup differences of overall survival (OS) and lung cancer-specific survival (LCSS). Cox proportional risk models were used to reveal prognostic factors. After PSM, the thermal ablation group had better OS (p <.001) and LCSS (p <.001) than the non-ablation group. Subgroup analysis stratified by age, sex, histologic type and lymph node status subgroups showed similar survival profile. In the subgroup analysis stratified by tumor size, the thermal ablation group showed better OS and LCSS than those of the non-ablation group for tumors ≤3.0 cm, not statistically significant for tumors >3.0 cm. Subgroup analysis by M stage showed that thermal ablation was superior to non-ablation in OS and LCSS for patients with M0 stage, but no significant difference was found in subgroups with distant metastatic disease. Multivariate analysis showed that thermal ablation was an independent prognostic factor for OS (HR: 0.34, 95% CI: 0.25–0.46, p <.001) and LCSS (HR: 0.23, 95%CI: 0.12–0.43, p <.001). For patients with inoperable PC, thermal ablation might be a potential treatment option, especially in M0-stage with tumor size ≤3 cm. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to determine the optimal surgical procedure for early-stage pulmonary carcinoids (PCs). Background: PCs, comprising typical carcinoids (TCs) and atypical carcinoids (ACs), are rare low-grade malignant tumors. We determine the optimal surgical management for early-stage PCs using data from the Surveillance, Epidemiology, and End Results registry. Methods: Clinical and survival data of patients with early-stage PC tumors with a diameter ≤3 cm were retrieved. The Kaplan-Meier method and logrank tests were used to assess the differences in overall survival (OS). Subgroup analyses were also performed. To reduce the inherent bias of retrospective studies, two propensity score matching (PSM) analysis with (PSM2) or without (PSM1) consideration of lymph node assessment were performed. Results: In total, 2934 patients with PCs, including 2741 (93.42%) with TCs and 193 (6.58%) with ACs, were recruited. After PSM1 analysis, TC patients in the lobectomy group had a significantly better OS than those in the sublobar resection group (P = 0.0067), which is more remarkable for patients with a tumor diameter of 2 cm

Simple Summary: Chemotherapy administration after surgical resection of pulmonary carcinoid is not well studied. While guidelines state adjuvant therapy may be appropriate in some scenarios, this is not observed clinically. We reviewed the literature to examine if adjuvant chemotherapy in patients with resected pulmonary carcinoid provided any survival benefit. The aim of this review is to aid clinicians when deciding on next steps for these patients after resection. Pulmonary carcinoid tumors are a rare subtype of neuroendocrine cell tumor found in approximately 1–2% of lung cancers. Management is primarily through surgical resection, with limited benefit of adjuvant therapy in the clinical setting. Genomic profiling is in the nascent stages to molecularly classify these tumors, but there are promising insights for future targeted therapy. A total of 80 abstracts were analyzed for further review with 11 included in our final analysis. Only 4 of the 11 reviewed in depth provided statistical analysis. We evaluated PFS, OS, 1- and 5-year survival as mentioned in the studies. Nodal and KI67 status were also analyzed. Based on the current literature, there is no definitive evidence that adjuvant chemotherapy after resection confers a survival benefit in typical or atypical carcinoids. [ABSTRACT FROM AUTHOR]

Pulmonary neuroendocrine cells (PNECs) are sensory epithelial cells that transmit airway status to the brain via sensory neurons and locally via calcitonin gene-related peptide (CGRP) and γ- aminobutyric acid (GABA). Several other neuropeptides and neurotransmitters have been detected in various species, but the number, targets, functions, and conservation of PNEC signals are largely unknown. We used scRNAseq to profile hundreds of the rare mouse and human PNECs. This revealed over 40 PNEC neuropeptide and peptide hormone genes, most cells expressing unique combinations of 5–18 genes. Peptides are packaged in separate vesicles, their release presumably regulated by the distinct, multimodal combinations of sensors we show are expressed by each PNEC. Expression of the peptide receptors predicts an array of local cell targets, and we show the new PNEC signal angiotensin directly activates one subtype of innervating sensory neuron. Many signals lack lung targets so may have endocrine activity like those of PNEC-derived carcinoid tumors. PNECs are an extraordinarily rich and diverse signaling hub rivaling the enteroendocrine system.

• Resected TC patients at 30y or younger had an additional lifetime cancer risk up to 3.1 % (ENETS) at 40y. • Less extensive radiological follow-up for young TC patients is worth exploring. • Implementation of predictive biomarkers in order to personalize follow-up is warranted. After primary resection of pulmonary carcinoids, the recurrence rate is low (approximately 10 %). However, long-term radiological follow-up is generally recommended due to the risk of late recurrence. This must be weighed against risk of radiation-induced cancer, particularly in young patients. The frequency and modality of radiological follow-up according to the ENETS, ESMO, and CommNETs-NANETS guidelines were assessed. Cumulative radiation exposure per guideline and subsequent increased lifetime cancer risk were estimated using sex- and age-dependent risk factors. Data from the Netherlands Cancer Registry (2003–2012) of adults with resected pulmonary carcinoids were used as a reference. Of 706 reference patients, 32 (4.5 %) were 18–30 years (y). After median follow-up of 127 months, none of the patients aged 18-30y at diagnosis developed recurrence. For these patients, the additional radiation exposure at the age of 40y due to follow-up ranges from 140-308 mSv following ENETS and 35–42 mSv following ESMO guidelines. The additional risk of death due to carcinogenic effects ranged from 0.7 % (male 30y) to 3.1 % (female 18y) following ENETS and 0.2 % (male) to 0.4 % (female) following ESMO guidelines. Individualised, less extensive follow-up for young patients with resected carcinoids and a low risk of recurrence are worth exploring to decrease radiation exposure and the corresponding risk of cancer induction. The use of predictive biomarkers to personalise follow-up is warranted. [ABSTRACT FROM AUTHOR]

Background: The optimal extent of surgery for older patients with early-stage pulmonary carcinoid tumour (PC) remains controversial. Aims: To compare prognostic differences between sublobar resection versus lobectomy in older patients with early-stage PC. Methods: The SEER database was searched for stage T1N0M0 PC patients aged ≥ 65 years who underwent lobectomy or sublobar resection from 2000 to 2017. Propensity score matching (PSM) was used to determine intergroup covariate differences. Kaplan–Meier curves and the log-rank test were used for intergroup comparison of overall survival (OS). A Cox proportional hazard model was used to evaluate independent risk factors. Results: Among 1023 participants, 650 and 373 underwent lobectomy and sublobar resection, respectively. Before PSM, the 5- and 10-year OS in the sublobar resection group were lower than that of the lobectomy group (5-year OS 84.12% vs. 91.16%; 10-year OS 57.43% vs. 64.77%; p = 0.014); after PSM, no significant prognostic difference existed between lobectomy and sublobar resection (5-year OS 88.17% vs. 89.23%; 10-year OS 58.32% vs. 62.75%; p = 0.811). Subgroup analysis included tumour size, age, number of lymph nodes examined and histological type, and showed no statistically significant survival differences between the lobectomy and sublobar resection groups. Multivariable Cox analysis indicated that age ≥ 77 years, male sex, inadequate lymph node assessment (< 7), and atypical carcinoid were associated with reduced OS. Conclusion: Sublobar resection showed a similar long-term survival rate for early-stage PC patients aged ≥ 65 years as with lobectomy, thereby providing a basis for the selection of surgical methods for PC. [ABSTRACT FROM AUTHOR]

Simple Summary: Evidence of prediction of disease recurrence after curative surgery in bronchial carcinoid is still limited. The aim of this study was to retrospectively investigate a set of markers as potential predictors of dissemination. This study confirmed that adding OTP, CD44, and Ki-67 to the carcinoid classification improved the identification of patients who are at risk for metastatic disease. Patients who did not develop metastasis in follow-up had typical carcinoids with proliferation index <5% and positive OTP and CD44. Atypical carcinoids with proliferation index ≥5% and loss of OTP and/or CD44 were at high risk for distant metastases. Such patients should be screened for metastatic disease at diagnosis and during follow up. Background: Curatively treated bronchial carcinoid tumors have a relatively low metastatic potential. Gradation into typical (TC) and atypical carcinoid (AC) is limited in terms of prognostic value, resulting in yearly follow-up of all patients. We examined the additional prognostic value of novel immunohistochemical (IHC) markers to current gradation of carcinoids. Methods: A retrospective single-institution cohort study was performed on 171 patients with pathologically diagnosed bronchial carcinoid (median follow-up: 66 months). The risk of developing distant metastases based on histopathological characteristics (Ki-67, p16, Rb, OTP, CD44, and tumor diameter) was evaluated using multivariate regression analysis and the Kaplan–Meier method. Results: Of 171 patients, seven (4%) had disseminated disease at presentation, and 164 (96%) received curative-intent treatment with either endobronchial treatment (EBT) (n = 61, 36%) or surgery (n = 103, 60%). Among the 164 patients, 13 developed metastases at follow-up of 81 months (IQR 45–162). Univariate analysis showed that Ki-67, mitotic index, OTP, CD44, and tumor diameter were associated with development of distant metastases. Multivariate analysis showed that mitotic count, Ki-67, and OTP were independent risk factors for development of distant metastases. Using a 5% cutoff for Ki-67, Kaplan–Meier analysis showed that the risk of distant metastasis development was significantly associated with the number of risk predictors (AC, Ki-67 ≥ 5%, and loss of OTP or CD44) (p < 0.0001). Six out of seven patients (86%) with all three positive risk factors developed distant metastasis. Conclusions: Mitotic count, proliferation index, and OTP IHC were independent predictors of dissemination at follow-up. In addition to the widely used carcinoid classification, a comprehensive analysis of histopathological variables including Ki-67, OTP, and CD44 could assist in the determination of distant metastasis risks of bronchial carcinoids. [ABSTRACT FROM AUTHOR]

Limited number of tumor types have been examined for Orthopedia Homeobox (OTP) expression. In pulmonary carcinoids, loss of expression is a strong indicator of poor prognosis. Here, we investigated OTP expression in 37 different tumor types, and the association between OTP expression and DNA methylation levels in lung neuroendocrine neoplasms. We analyzed publicly available multi‐omics data (whole‐exome‐, whole‐genome‐, RNA sequencing and Epic 850K‐methylation array) of 58 typical carcinoids, 27 atypical carcinoids, 69 large cell neuroendocrine carcinoma and 51 small cell lung cancer patients and TCGA (The Cancer Genome Atlas) data of 33 tumor types. 850K‐methylation analysis was cross‐validated using targeted pyrosequencing on 35 carcinoids. We report bimodality of OTP expression in carcinoids (OTPhigh vs OTPlow group, likelihood‐ratio test P = 1.5 × 10−2), with the OTPhigh group specific to pulmonary carcinoids while absent from all other cohorts analyzed. Significantly different DNA methylation levels were observed between OTPhigh and OTPlow carcinoids in 12/34 OTP infinium probes (FDR < 0.05 and β‐value effect size >.2). OTPlow carcinoids harbor high DNA methylation levels as compared to OTPhigh carcinoids. OTPlow carcinoids showed a significantly worse overall survival (log‐rank test P =.0052). Gene set enrichment analysis for somatically mutated genes associated with hallmarks of cancer showed robust enrichment of three hallmarks in the OTPlow group, that is, sustaining proliferative signaling, evading growth suppressor and genome instability and mutation. Together our data suggest that high OTP expression is a unique feature of pulmonary carcinoids with a favorable prognosis and that in poor prognostic patients, OTP expression is lost, most likely due to changes in DNA methylation levels. [ABSTRACT FROM AUTHOR]

Background: Although most guidelines suggest performing a positron emission tomography/computed tomography (PET/CT) with somatostatin receptor (SSTR) ligands for staging of pulmonary carcinoid tumours (PC), only a limited number of studies have evaluated the role of this imaging tool in this specific patient population. The preoperative differentiation between typical carcinoid (TC) and atypical carcinoid (AC) and the extent of dissemination (N/M status) are crucial factors for treatment allocation and prognosis of these patients. Therefore, we performed a pathology-based retrospective analysis of the value of SSTR PET/CT in tumour grading and detection of nodal and metastatic involvement of PC and compared this with the previous literature and with [18F]FDG PET/CT in a subgroup of patients. Methods: SSTR PET/CT scans performed between January 2007 and May 2020 in the context of PC were included. If available, [18F]FDG PET/CT images were also evaluated. The maximum standardized uptake (SUVmax) values of the primary tumour, of the pathologically examined hilar and mediastinal lymph node stations, as well as of the distant metastases, were recorded. Tumoural SUVmax values were related to the tumour type (TC versus AC) for both SSTR and [18F]FDG PET/CT in diagnosing and differentiating both tumour types. Nodal SUVmax values were compared to the pathological status (N+ versus N−) to evaluate the diagnostic accuracy of SSTR PET/CT in detecting lymph node involvement. Finally, a mixed model analysis of all pathologically proven distant metastatic lesions was performed. Results: A total of 86 SSTR PET/CT scans performed in 86 patients with PC were retrospectively analysed. [18F]FDG PET/CT was available in 46 patients. Analysis of the SUVmax values in the primary tumour showed significantly higher SSTR uptake in TC compared with AC (median SUVmax 18.4 vs 3.8; p = 0.003) and significantly higher [18F]FDG uptake in AC compared to TC (median SUVmax 5.4 vs 3.5; p = 0.038). Receiver operating characteristic (ROC) curve analysis resulted in an area under the curve (AUC) of 0.78 for the detection of TC on SSTR PET/CT and of 0.73 for the detection of AC on [18F]FDG PET/CT. A total of 267 pathologically evaluated hilar and mediastinal lymph node stations were analysed. ROC analysis of paired SSTR/[18F]FDG SUVmax values for the detection of metastasis of TC in 83 lymph node stations revealed an AUC of 0.91 for SSTR PET/CT and of 0.74 for [18F]FDG PET/CT (difference 0.17; 95% confidence interval − 0.03 to 0.38; p = 0.10). In a sub-cohort of 10 patients with 12 distant lesions that were pathologically examined due to a suspicious aspect on SSTR PET/CT, a positive predictive value (PPV) of 100% was observed. Conclusion: Our findings confirm the higher SSTR ligand uptake in TC compared to AC and vice versa for [18F]FDG uptake. More importantly, we found a good diagnostic performance of SSTR PET/CT for the detection of hilar and mediastinal lymph node metastases of TC. Finally, a PPV of 100% for SSTR PET/CT was found in a small sub-cohort of patients with pathologically investigated distant metastatic lesions. Taken together, SSTR PET/CT has a very high diagnostic value in the TNM assessment of pulmonary carcinoids, particularly in TC, which underscores its position in European guidelines. [ABSTRACT FROM AUTHOR]

Abstract Background The abscopal effect was described as early as the 1950s, when untreated tumors demonstrated a response after radiation therapy was delivered to an untreated, distant site. The mechanisms underlying this global response to otherwise localized therapy remain unknown, though there is increasing evidence that increased antigen expression following ablative radiotherapy may play a role. Case presentation We report a case of a 69-year-old African American woman with a history of metastatic typical pulmonary carcinoid with multiple lung nodules who had a significant decrease in size of an untreated left upper lobe nodule after stereotactic body radiation therapy to an oligoprogressive left lower lobe lesion. Conclusions To our knowledge, this report describes the first case of an abscopal effect in a typical pulmonary carcinoid. Further research is needed regarding the mechanisms responsible for this finding and the role of combining radiation therapy and cancer immunotherapy in patients with pulmonary carcinoid tumors.

Introduction: Multi-omic studies have identified three molecular separated pulmonary carcinoid (PC) subgroups (A1, A2, B) with distinctive mRNA expression profiles (e.g., orthopedia homeobox protein [OTP], achaete-scute homolog [ASCL1], and hepatocyte nuclear factor 1 homeobox A [HNF1A]). We aimed to establish an immunohistochemical (IHC) biomarker panel that enables subgroup identification, and assessment of its potential clinical relevance., Methods: All patients with resected pulmonary carcinoids (2003-2012) were identified from the Dutch Cancer/Pathology Registry, and tumors were revised. The IHC expression of OTP, ASCL1, and HNF1A was scored in a blinded fashion in a mRNA-profiled (n = 5 per subgroup) and national carcinoid cohort (N = 478). The expression of potential therapeutic targets (somatostatin receptor type 2a [SSTR2A] and delta-like canonical Notch ligand 3 [DLL3]) was assessed. Immunohistochemistry was assessed using H-scoring., Results: OTP, ASCL1, and HNF1A reported similar IHC and mRNA expression patterns in the matched primary samples. In the national cohort, IHC separated PCs into subgroups A1 (n = 224 [53%], OTP high -ASCL1 high -HNF1A low ), A2 (n = 161 [38%], OTP high -ASCL1 low -HNF1A high ), and B (n = 37 [9%], OTP low -ASCL1 low -HNF1A high ). In 12% of PCs, no distinct classification could be provided. Patients with A1 were enriched for older age (83% > 50 y), female individuals (83%), and peripheral location (55%) with low SSTR2A (median = 10) and high DLL3 (median = 52) expression. A2 included younger patients (34% < 40 y) and endobronchial/central (87%) tumors with high SSTR2A (median = 160), but low DLL3 (median 0) expression. Group B included more male individuals (59%) and recurrence was more frequent (19%) than in groups A1 (8%) and A2 (6%). Neuroendocrine cell hyperplasia was enriched in A1 (25%) compared with A2 (3%) and B (0%)., Conclusions: An OTP, ASCL1, and HNF1A IHC panel enables the identification of molecular-defined pulmonary carcinoid subgroups with distinct clinical phenotypes and diverging therapeutic vulnerabilities that require further prospective evaluation., Competing Interests: Disclosure Dr. Speel reports grants from the Dutch Cancer Society, AstraZeneca, and Bayer, and participated in the advisory board of AstraZeneca, GSK, Janssen-Cilag, and Merck, outside the submitted work. Dr. Dingemans reports grants from Dutch Cancer Society, HANARTH, and Amgen, consulting fees from Sanofi, Amgen, Bayer, Roche, Janssen, AstraZeneca, Boehringer-Ingelheim, Honoraria from Eli Lilly, Pfizer, Janssen, Takeda and AstraZeneca, participated in the advisory board of Roche and Takeda, and is chair of the EORTC lung cancer group, outside the submitted work. Although authors are identified as personnel of the International Agency for Research on Cancer/WHO, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policies, or views of the International Agency for Research on Cancer/WHO. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction and Importance: Surgeons often need to make intraoperative decisions regarding resection of lung tumors without a preoperative pathological diagnosis. Although intraoperative fine-needle aspiration cytology (FNAC) often provides useful diagnostic information, literatures on its usefulness in pulmonary carcinoids is limited., Case Presentation: A medical chest radiograph revealed an abnormal shadow in the right upper lung field of a 45-year-old Japanese man. Chest computed tomography (CT) revealed a solid 2.5-cm nodule in the right upper lobe. Follow-up CT for one year showed that the tumor size had increased. In case of lung cancer, it was clinically detected to be resectable at stage IA3 with clinical T1cN0M0. Intraoperative FNAC confirmed a specific appearance, and a diagnosis of carcinoid was made. Right upper lobectomy and mediastinal lymph node dissection were performed via video-assisted thoracic surgery. The final histopathological diagnosis was a typical carcinoid with positive chromogranin A, synaptophysin, and CD56, a Ki-67 labeling index of 5 %, and pathological stage IA3 with T1cN0M0, which was consistent with the intraoperative diagnosis., Clinical Discussion: This is the first report describing the diagnosis of pulmonary carcinoid by intraoperative FNAC with the publication of characteristic pathological images, demonstrating the usefulness of intraoperative FNAC., Conclusion: Intraoperative FNAC may be a low-risk and short-duration procedure for diagnosing pulmonary carcinoids., Competing Interests: Conflict of interest statement The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Current guidelines recommend anatomic lung resection of typical bronchopulmonary carcinoids. Typical carcinoid tumors have excellent prognosis and sublobar resection has been associated with noninferior long-term survival. It's unclear whether wedge resection is acceptable for small typical carcinoid tumors. We hypothesize there is no difference in survival between wedge resection and segmentectomy for Stage I typical bronchopulmonary carcinoid tumors. Using the National Cancer Database from 2010 to 2016, we identified clinical T1N0M0 typical bronchopulmonary carcinoid tumors by wedge resection or segmentectomy. Short-term outcomes included length of stay, lymph nodes evaluated, pathologic node status, positive margin status, and 90-day mortality. Primary outcome was overall survival and estimated using Kaplan-Meier survival analysis. 821 patients were identified: 677 receiving wedge resection, 144 receiving segmentectomy. Segmentectomy was more commonly performed in an academic setting (70.0% vs 57.3%, P = 0.005). The mean tumor size for segmentectomy was 1.7 cm versus 1.4 cm for wedge resection (P < 0.001). There was no difference in LOS, positive margin status, and 90-day mortality between groups. There were significantly more lymph nodes evaluated in segmentectomy patients (median 4 vs 0, P < 0.001), but there was no difference in positive lymph node status (5.3% vs 2.6%, P = 0.165). The OS was similar between wedge and segmental resection (P = 0.613): 3-year survival (93.5% vs 92.8%) and 5-year survival (83.8% vs 84.9%). Wedge resection and segmentectomy have similar survival for Stage I typical bronchopulmonary carcinoids in a large national database. This analysis suggests nonanatomic, parenchymal-sparing resection should be considered an appropriate alternative for Stage I typical bronchopulmonary carcinoids. [ABSTRACT FROM AUTHOR]

Rationale and Objective: To assess the possibility of differentiating pulmonary carcinoids from hamartomas and typical from atypical carcinoids by means of 18F-FDG PET/CT.Materials and Methods: We retrospectively reviewed 139 patients with pathologically proven pulmonary carcinoids and hamartomas who underwent 18F-FDG PET/CT before surgical resection. Receiver operating characteristics curves were calculated to determine the potential of SUVmax to discriminate between pulmonary carcinoids and hamartomas, typical and atypical carcinoids. The correlation between SUVmax and tumor size was analyzed by Spearman correlation analysis.Results: SUVmax was significantly higher in pulmonary carcinoids than in hamartomas (p<0.001), and also higher in atypical carcinoids than in typical carcinoids (p = 0.034). With a SUVmax of 2.0 as a cutoff, the sensitivity, specificity, positive predictive value, and negative predictive value for 18F-FDG PET/CT to differentiate pulmonary carcinoids from hamartomas were 85.3%, 82.9%, 61.7%, and 94.6%, respectively. The cutoff value of SUVmax for differentiating atypical carcinoids from typical carcinoids was 4.1. The area under the receiver operating characteristics curve of SUVmax was 0.900 for carcinoids and hamartomas, and 0.722 for typical and atypical carcinoids. SUVmax was correlated with maximum tumor size in pulmonary carcinoids (r = 0.658, p <0.001) and in pulmonary hamartomas (r = 0.672, p <0.001).Conclusion: 18F-FDG PET/CT might be a useful tool in the differential diagnosis of carcinoids and hamartomas, and can also distinguish atypical from typical carcinoids. This may facilitate improved selection of patients for surgical resection and radiological follow-up. [ABSTRACT FROM AUTHOR]

BackgroundEctopic adrenocorticotropic syndrome (EAS) is a rare cause of endogenous ACTH-dependent Cushing’s syndrome, usually associated with severe hypercortisolism as well as comorbidities. Tumor detection is still a challenge and often requires several imaging procedures. In this report, we describe a case of an ectopic ACTH secretion with a misleading localization of the responsible tumor due to a concomitant rectal carcinoma.Case presentationA 49-year-old man was referred to our Endocrinology Unit due to suspicion of Cushing’s syndrome. His medical history included metastatic rectal adenocarcinoma, diagnosed 5 years ago and treated with adjuvant chemotherapy, radiotherapy and surgical resection. During follow-up, a thoracic computed tomography scan revealed two pulmonary nodules located in the superior and middle lobes of the right lung with a diameter of 5 and 10 mm, respectively. However, these nodules remained radiologically stable thereafter and were not considered relevant. All biochemical tests were suggestive of EAS (basal ACTH levels: 88.2 ng/L, nv 0–46; basal cortisol levels: 44.2 µg/dl, nv 4.8–19.5; negative response to CRH test and high dose dexamethasone suppression test) and radiological localization of the ectopic ACTH-secreting tumor was scheduled. The CT scan revealed a dimensional increase of the right superior lung nodule (from 5 to 12 mm). [68Ga]-DOTA-TOC PET/CT scan was negative, while [18F]-FDG-PET/CT showed a tracer accumulation in the superior nodule. After a multidisciplinary consultation, the patient underwent thoracic surgery that started with two atypical wedge resections of nodules. Frozen section analyses showed a neuroendocrine tumor on the right middle lobe nodule and a metastatic colorectal adenocarcinoma on the superior lesion. Then, a right superior nodulectomy and a right middle lobectomy with mediastinal lymphadenectomy were performed. The final histopathological examination confirmed a typical carcinoid tumor, strongly positive for ACTH. A post-surgical follow-up showed a persistent remission of Cushing’s syndrome.ConclusionsThe present report describes a case of severe hypercortisolism due to EAS not detected by functional imaging methods, in which the localization of ACTH ectopic origin was puzzled by a concomitant metastatic rectal carcinoma. The multidisciplinary approach was crucial for the management of this rare disease.

Background: Lung cancer is the leading cause of cancer-related deaths and pulmonary carcinoids (PCs) account for almost 2% of all pulmonary malignancies. However, few published articles have reported prognosis and related factors of pulmonary carcinoid patients. Material and Method: The Surveillance, Epidemiology, and End Results (SEER) database was used to collect data of patients diagnosed with metastatic PCs from 2010 to 2016. The prognosis and survival of these patients were compared by employing Cox proportional hazards and the Kaplan-Meier survival analysis. Results: A total of 1763 patients were analyzed. The liver (668, 25.6%) was shown to be the most common metastatic site in the isolated organ metastasis cohort, followed by the lung (636, 24.4%), bone (562, 21.6%), and brain (460, 17.6%). Among the patients, the tumor metastasized to a single distant site included the liver, bone, lung, and brain. Cancer-specific survival (CSS) in metastatic PCs is determined by the site of metastasis and the total number of such sites. Pulmonary carcinoid patients with isolated liver metastasis manifested more favorable survival rates in comparison to patients having isolated metastasis in the lung, brain, or bone. The median CSS was 45, 7, 6, 5 months (P = 0.011). The number of distant metastatic sites and the location of distant metastasis were found to be independent risk factors for CSS. For patients with distant isolated metastasis, liver metastasis (P < 0.0001) had better CSS in comparison to those with bone metastasis. When compared to patients whose carcinoids had metastasized to the bones, patients with a brain (P = 0.273) or lung (P = 0.483) metastasis had the same CSS. Conclusion: Cancer-specific survival in metastatic PCs depends on the site of metastasis and the total number of such locations. PC patients with isolated liver metastasis manifested more favorable survival in comparison to patients with isolated metastasis in the lung, brain, or bone. [ABSTRACT FROM AUTHOR]

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Background: Ectopic adrenocorticotropic syndrome (EAS) is a rare cause of endogenous ACTH-dependent Cushing's syndrome, usually associated with severe hypercortisolism as well as comorbidities. Tumor detection is still a challenge and often requires several imaging procedures. In this report, we describe a case of an ectopic ACTH secretion with a misleading localization of the responsible tumor due to a concomitant rectal carcinoma. Case presentation: A 49-year-old man was referred to our Endocrinology Unit due to suspicion of Cushing's syndrome. His medical history included metastatic rectal adenocarcinoma, diagnosed 5 years ago and treated with adjuvant chemotherapy, radiotherapy and surgical resection. During follow-up, a thoracic computed tomography scan revealed two pulmonary nodules located in the superior and middle lobes of the right lung with a diameter of 5 and 10 mm, respectively. However, these nodules remained radiologically stable thereafter and were not considered relevant. All biochemical tests were suggestive of EAS (basal ACTH levels: 88.2 ng/L, nv 0–46; basal cortisol levels: 44.2 µg/dl, nv 4.8–19.5; negative response to CRH test and high dose dexamethasone suppression test) and radiological localization of the ectopic ACTH-secreting tumor was scheduled. The CT scan revealed a dimensional increase of the right superior lung nodule (from 5 to 12 mm). [68Ga]-DOTA-TOC PET/CT scan was negative, while [18F]-FDG-PET/CT showed a tracer accumulation in the superior nodule. After a multidisciplinary consultation, the patient underwent thoracic surgery that started with two atypical wedge resections of nodules. Frozen section analyses showed a neuroendocrine tumor on the right middle lobe nodule and a metastatic colorectal adenocarcinoma on the superior lesion. Then, a right superior nodulectomy and a right middle lobectomy with mediastinal lymphadenectomy were performed. The final histopathological examination confirmed a typical carcinoid tumor, strongly positive for ACTH. A post-surgical follow-up showed a persistent remission of Cushing's syndrome. Conclusions: The present report describes a case of severe hypercortisolism due to EAS not detected by functional imaging methods, in which the localization of ACTH ectopic origin was puzzled by a concomitant metastatic rectal carcinoma. The multidisciplinary approach was crucial for the management of this rare disease. [ABSTRACT FROM AUTHOR]

Background: Pulmonary carcinoids are rare neoplasms, accounting for approximately 1%–2% of all lung malignancies. A retrospective analysis was undertaken of all patients who underwent surgical resection of pulmonary carcinoid tumours across multiple institutions in Melbourne, Australia. Methods: From May 2000 through April 2020, 241 patients who underwent surgical resection of pulmonary carcinoid tumours were retrospectively reviewed. Patient demographics, pathologic data, and long-term outcomes were recorded. Results: Median age was 57.7 years and the majority of patients were female (58.9% vs. 41.1%). Typical carcinoid was present in 77.1%. Histological subtype was associated with several factors. Atypical carcinoid was more likely to have larger tumour size and nodal involvement. Overall survival for typical carcinoid at 5, 10, and 15 years was 98%, 95%, and 84%, and for atypical carcinoid was 88%, 82%, and 62%, respectively. Histological subtype and age were found to be independent predictors of overall survival, with worse outcomes for atypical and those above 60 years of age. Disease-free survival was related to sublobar resection (p < 0.001, sub-hazard ratio (SHR): 6.89), lymph node involvement (p = 0.022, SHR: 3.18), and atypical histology (p < 0.001, SHR: 9.89). Conclusion: Excellent long-term outcomes can be achieved following surgical resection of pulmonary carcinoids. Atypical histology and lymph node involvement are significant prognostic factors, and sublobar resection should not be considered in patients with either of the above features. Typical carcinoid tumour without nodal involvement may be appropriate for sublobar resection. Typical and atypical carcinoid tumours should be considered distinct disease entities, and as such treated accordingly. [ABSTRACT FROM AUTHOR]

Pulmonary carcinoids, particularly the typical variant, are low-grade neuroendocrine tumors (NETs) known for their often indolent behavior. Their rare and atypical presentations can pose significant diagnostic challenges. We present a case of a 39-year-old female with no significant past medical history who presented with high-grade intermittent fever, chills, rigors, and breathlessness, with symptoms persisting for approximately 20 days. Initial investigations, including chest X-ray and contrast-enhanced computed tomography scans, revealed a homogenously enhancing lesion in the left lower lobe, raising concerns of a malignant process. A percutaneous lung biopsy was performed to further evaluate the lesion. Histopathological examination confirmed a diagnosis of Grade 1 NET (typical carcinoid), supported by elevated levels of Synaptophysin and Chromogranin A on immunohistochemistry. This case highlights the varied clinical presentations of pulmonary carcinoid tumors and underscores the importance of comprehensive radiological and histopathological assessments for accurate diagnosis and effective management., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Kannadasan et al.)

Abstract Background The response to temozolomide (TMZ) treatment in small-cell lung cancer (SCLC) correlated with O(6)-methylguanine -DNA methyltransferase (MGMT) promoter methylation. 1p/19q co-deletion within oligodendroglioma is a responsive predictor for TMZ. Currently, the status of MGMT promoter methylation and 1p/19q co-deletion in pulmonary carcinoid (PC) and large-cell neuroendocrine carcinoma (LCNEC) is not reported. Methods Nine PC [two atypical carcinoids (AC), seven typical carcinoids (TC)] and six LCNEC patients were collected retrospectively. The pyrosequencing and fluorescence in situ hybridization were used to detect the MGMT promoter methylation and 1p/19q co-deletion in surgically resected specimens. Kaplan–Meier analysis was used to assess the rate of disease-free survival (DFS). Results MGMT promoter methylation was found in two (2/6, 15.3%) LCNEC patients but not in any PC patients. Three (3/6, 50%) 1p and two (2/6, 33.3%) 19q single deletions were found in LCNEC patients. One 1p single deletion was found in AC patients. One (1/7, 14.3%) 1p and two (2/7, 28.6%) 19q single deletions were found in TC patients. After a median follow-up of 38 months, three LCNEC patients developed distant metastasis and one patient died of LCNEC disease. The DFS of PC patients was much longer than LCNEC patients (χ 2 = 7.565, P = 0.006). Conclusions MGMT promoter methylation and 1p/19q co-deletion might not be the ideal biomarkers for TMZ treatment in TC/AC patients. Thus, the detection of MGMT promoter methylation and whether it can be used as a medication for TMZ in LCNEC patients necessitates investigation. Furthermore, 1p deletion could be a negative prognostic factor for LCNEC patients.

The article describes a clinical case of ectopic Cu­shing’s syndrome in a man aged 39 years. Characteristic signs of hypercorticism (obesity, arterial hypertension, striae, thinning of the extremities, myasthenia, diabetes mellitus, hypokalemia) developed over a period of 1.5 years. However, the diagnosis of Cushing’s syndrome was established after hospitalization for arterial hypertension. Hormones: adrenocorticotropic hormone (ACTH) — 110 pg/ml (7–69), daily urinary cortisol excretion — 3,400 μg/24 h (28.5–213.7). Magnetic resonance imaging of the pituitary gland, multislice helical computed tomography (MHCT) of the abdominal cavity organs and [111In-DTPA-D-Phe1]-octreotide scintigraphy have not revealed a tumor. Only after the MHCT of the thoracic organs, carcinoid of the left lung was found. The patient was operated, and then during 2 months he almost recovered. Pathohistological conclusion: well-differentiated neuroendocrine tumor. Level of cell expression of cytoplasmic markers of neuroendocrine differentiation: synaptophysin (+), chromogranin A (+), CD56 (–), CD68 (–). The proliferation index Ki 67 was 1 %. Hormones: ACTH — 34 pg/ml, serum cortisol — 13.69 μg/dl (6.2–19).

Purpose: This study aimed to analyse the molecular imaging (MI) phenotype of typical carcinoid (TC) and atypical carcinoid (AC) by 68Ga-DOTATATE (GaTATE) and 18F-FDG (FDG) PET/CT with the emphasis on its potential theranostic implications for peptide receptor radionuclide therapy (PRRT). Methods: Retrospective review of patients with biopsy-proven TC or AC undergoing both GaTATE and FDG PET/CT at presentation. Based on correlative CT or MRI, positive lesions on either scan were defined by uptake above liver parenchyma. Per patient MI phenotypic pattern was classified as score 1, if all lesions were negative on both scans; score 2, if all were GaTATE positive/FDG negative; score 3, if all lesions were GaTATE positive but some or all were also FDG positive and score 4, if there were any GaTATE negative/FDG positive lesions. Scores 1 and 4 were deemed unsuitable for PRRT. Results: Of 56 patients (median age 66.5 years, 32 female), 22 had TC, and 34 had AC. Distant metastases were seen in 32% of TC and 94% of AC. At a median follow-up of 37 months for TC and 38 months for AC, 100% and 63% were alive, respectively. Median OS for AC was 56 months (95% CI 43, not reached [NR]), and TC was NR. On inter-patient dual-tracer analysis, scores 1, 2, 3 and 4 were 23%, 18%, 36% and 23% in TC and 3%, 15%, 32% and 50% in AC, respectively. In 16 patients (score 2, N = 3; score 3, N = 12; score 4, N = 1) who were treated with PRRT, disease control rate at 3 months and OS were, 85% and 54.6 months (95% CI 44–70), respectively. Conclusions: TC and AC showed a wide inter-patient phenotypic heterogeneity on GaTATE and FDG with around half of patients (46% TC and 53% AC) having an unsuitable phenotype for PRRT. Dual-tracer MI phenotype can be used to select the most suitable patients for PRRT. [ABSTRACT FROM AUTHOR]

• We identified novel somatic mutations and chromosomal rearrangements in PC. • Mucin (MUC) genes were mutated in a mutually exclusive manner in 36% of PCs. • The MAPK and TGF-β signaling pathways were associated with somatic mutations. • A chromosomal rearrangement producing the TRIBE2-PRKCE fusion gene was identified. • All 8 fusion genes were detected in PCs that had developed postsurgical metastasis. The majority of pulmonary carcinoid (PC) tumors can be cured by surgical resection alone, but a significant proportion of patients experience recurrence. As PC is insensitive to conventional chemotherapy, further clarification of the molecular mechanisms of metastasis is needed in order to develop targeted therapeutics. We performed comprehensive whole-exome sequencing (WES) of primary tumors and corresponding normal lung tissues from 14 PC patients (including 4 patients who developed postsurgical distant metastasis) and RNA sequencing of primary tumors from 6 PC patients (including 4 patients who developed postsurgical distant metastasis). Exon array-based gene expression analysis was performed in 25 cases of PC. We identified a total of 139 alterations in 136 genes. MUC6 and SPTA1 were recurrently mutated at a frequency of 21% (3/14) and 14% (2/14), respectively. Mucin protein family genes including MUC2 , MUC4 and MUC6 were mutated in a mutually exclusive manner in 36% (5/14). Pathway analysis of the mutated genes revealed enrichment of genes involved in mitogen-activated protein kinase (MAPK) signaling, regulation of the actin cytoskeleton and focal adhesion, and transforming growth factor (TGF)-β signaling. RNA sequencing revealed a total of 8 novel fusion transcripts including one derived from a chromosomal translocation between the TRIB2 and PRKCE genes. All of the 8 fusion genes were detected in primary PCs that had developed metastasis after surgical resection. We identified 14 genes (DENND1B , GRID1 , CLMN , DENND1B , NRP1 , SEL1L3 , C5orf13 , TNFRSF21 , TES , STK39 , MTHFD2 , OPN3 , MET , and HIST1H3C) up-regulated in 5 PCs that had relapsed after surgical resection. In this study we identified novel somatic mutations and chromosomal rearrangements in PC by examining clinically aggressive cases that had developed postsurgical metastasis. It will be essential to validate the clinical significance of these genetic changes in a larger independent patient cohort. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine whether the computed tomography (CT) features might be used in distinguishing pulmonary carcinoids from hamartomas. Ninety solid pulmonary nodules (43 carcinoids and 47 hamartomas) in 90 patients were evaluated. The following CT scan features were evaluated: size, location (peripheral/central), contour (lobulated/nodular), number of lobulation, attenuation, calcification, endobronchial status, bronchial extension and involvement, parenchymal abnormalities distal to the lesion e.g. hyperlucency, atelectasis, and nodularity. The final pathologic diagnosis of the lesions and bronchial extension were confirmed by review of histopathological specimens. Out of 43 carcinoids, 37 (86%) were typical. Twenty-three carcinoids and four hamartomas were central (p < 0.001). Ten carcinoids and one hamartoma were endobronchial. The majority of tumors had lobulated contours (65% of carcinoids, 44% of hamartomas) and carcinoids tended to have more lobulations (p = 0.052). Distal nodularity (p = 0.001), distal hyperlucency (p < 0.001), and atelectasis (p = 0.005) were significantly more common in carcinoids. Carcinoids had significantly more bronchial extension and involvement (p < 0.001; respectively). In addition, a new sign that we call "bronchial triangle sign" differentiated carcinoids with a sensitivity and specificity of 84.9% (95% CI: 69,1%–93.4%) and 91% (95% CI: 79.7%–96.6%). To the best of our knowledge this is the first study on discrimination of carcinoids and hamartomas. A new CT sign called "bronchial triangle sign" might be used to differentiate carcinoids from hamartomas. Distal parenchymal abnormalities are more common in carcinoids than in hamartomas. • Pulmonary carcinoids are neuroendocrine tumors and are the second most common primary malignant pulmonary neoplasm. • Differentiation of peripheral carcinoid tumors from the more common benign nodules (hamartomas) might be performed by CT • A high attenuation on enhanced CT with lobulated contours and post-obstructive features favor a diagnosis of carcinoid • A new sign called as 'bronchial triangle sign' might suggest the diagnosis of carcinoid. [ABSTRACT FROM AUTHOR]

• The prognosis of atypical pulmonary carcinoid with liver metastases is poor, and the patients are often treated using non-surgical therapies. • We successfully treated multiple liver metastases from atypical pulmonary carcinoid by using two-stage hepatectomy combined with embolization of portal vein branches. • Two-stage hepatectomy may be a good option for bilobar multiple liver metastases of atypical pulmonary carcinoid. The prognosis of atypical pulmonary carcinoid with liver metastases is extremely poor, and patients with multiple liver metastases are often treated using non-surgical therapies. We report a case with multiple liver metastases from atypical pulmonary carcinoid that was successfully treated using two-stage hepatectomy combined with embolization of portal vein branches. A 48-year-old man was referred to our department after multiple liver tumors were detected in both liver lobes on computed tomography. He had undergone right upper lobectomy of the lung for atypical pulmonary carcinoid (T2a, N0, M0; Stage IB) 2 years previously. Positron emission tomography-computed tomography showed no extrahepatic tumor manifestations. The tumors were located in segment 2, 3, 5/8 and the right hepatic vein drainage area. We planned complete resection of metastases in a two-stage hepatectomy. The first stage comprised concomitant left lateral segmentectomy, partial hepatectomy of segment 5/8 and portal vein embolization of the posterior segmental branches. The second stage comprised resection of the right hepatic vein drainage area, performed 21 days after the first surgery. Histopathological diagnosis was liver metastases of atypical pulmonary carcinoid. Postoperative bile leak developed, which was treated with endoscopic retrograde biliary drainage and percutaneous bile leak drainage. He has been followed for 24 months postoperatively without tumor recurrence. Two-stage hepatectomy may represent an option for bilobar multiple liver metastases from atypical pulmonary carcinoid. We successfully treated a patient with multiple liver metastases of atypical pulmonary carcinoid using a two-stage hepatectomy combined with portal vein embolization of the posterior segmental branches. [ABSTRACT FROM AUTHOR]

Pulmonary neuroendocrine tumors represent a spectrum of disease ranging from typical carcinoid tumors to small cell lung cancers. The incidence of low-grade pulmonary NETs has been increasing, leading to improved awareness and the need for more treatment options for this rare cancer. Somatostatin analogs continue to be the backbone of therapy and may be followed or accompanied by targeted therapy, chemotherapy, and immune therapy. The recent addition of peptide receptor radionuclide therapy (PRRT) to the treatment armamentarium of NETs has led to the development of targeted alpha therapy to overcome PRRT resistance and minimize off-target adverse effects. Herein, we aim to highlight current treatment options for patients with advanced low grade pulmonary NETs along with emerging therapies, sequencing of therapies, upcoming clinical trials, and the importance of a multidisciplinary team to improve patient outcomes. [ABSTRACT FROM AUTHOR]

Finnish hospital-integrated biobanks administer millions of formalin-fixed paraffin-embedded tissue samples collected within the clinical diagnostics. According to the Finnish Biobank Act, these samples can be coupled with patients' clinical follow-up data and the data retrieved from national health registries. We collected a nationwide pulmonary carcinoid tumour series from Finnish biobanks to study prognostic factors as well as to explore how the number of tumours found in the Finnish biobanks corresponds to the number of tumours registered by the Finnish Cancer Registry (FCR). Finnish biobanks identified 88% of the tumours registered by the FCR and were able to deliver 63%. The main reasons for lacking samples were paucity of resected primary tumour tissue, incompatible primary diagnosis, and the absence of tissue blocks in the archives. The main bottleneck in the sample application process was retrieving patient data. Altogether, we received 224 tumour samples with appropriate patient data and identified six prognostic factors for shorter disease-specific survival: age over 56 years at the time of diagnosis, tumour size over 2.5 cm, atypical histology, Ki-67 proliferation index higher than 2.5%, hilar/mediastinal lymph node involvement at the time of diagnosis, and the presence of metastatic disease. In conclusion, the Finnish biobank infrastructure offers excellent opportunities for tissue-based research. However, to be able to develop the biobank operations further, involving more medical knowledge in the sample and data acquisition process is a necessity. Also, when working with tissue samples collected over decades, histological expertise is essential for re-evaluation and re-classification of the samples. [ABSTRACT FROM AUTHOR]

Background and objective The incidence of pulmonary carcinoid (PC) is very rare in primary lung malignant tumors, and the prognosis of this disease is closely associated with its pathological features. In this study, the expressions of programmed death 1 (PD-1) and programmed death ligand-1 (PD-L1) in lung carcinoid cells were detected, and the correlation between the expression and corresponding clinical physiological and pathologic features was further analyzed. Methods The expressions of PD-1 and PD-L1 in 20 cases of PC paraffin-embedded tissue specimens were detected through immunohistochemistry. The H-score of immunohistochemical staining (range, 0-300) was employed to evaluate the expression of PD-1 and PD-L1 in the tumor tissues. Results In the 20 cases of patients with PC, 40% (8/20) showed positive expressions of PD-1, and 45% (9/20) showed positive expressions of PD-L1. Significantly higher expressions of PD-1 were observed in the smoking patients than in the nonsmoking patients (63.64% vs 11.11%, P0.05). Conclusion Approximately 40% of PC patients had positive expressions of PD-1or PD-L1. The positive expression rate of PD-1 in the smoking patients was significantly higher than that in the nonsmoking patients. These results suggest that the expressions of PD-1 and PD-L1 may be associated with the occurrence and development of PC.

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Objective Neuroendocrine tumors of the lung are currently staged with the 7th edition TNM non–small cell lung cancer staging system. This decision, based on data analysis without data on histology or disease-specific survival, makes its applicability limited. This study proposes a specific staging system for these tumors. Methods We retrospectively analyzed 510 consecutive patients (female/male, 313/197; median age, 61 years; interquartile range, 51-70) undergoing lung resection for a primary neuroendocrine tumor between 2000 and 2015 in 8 centers. Multivariable analysis was performed using a Cox proportional hazard model to identify factors associated with disease-specific survival. A new staging system was proposed on the basis of the results of this analysis. Kaplan–Meier disease-specific survival was analyzed by stage using the proposed and the 7th TNM staging system. Results Follow-up was completed in 490 of 510 patients at a median of 51 months (interquartile range, 18-99). Histology (G1-typical carcinoid vs G2-atypical carcinoid vs G3-large-cell neuroendocrine carcinoma) and pT were independently associated with survival, but pN was not. After regrouping histology and pT, we proposed the following staging system: IA (pT1-2G1), IB (pT3G1, pT1G2), IIA (pT4G1, pT2-3G2, pT1G3), IIB (pT4G2, pT2-3G3), and III (pT4G3). The 5-year survivals were 97.9%, 81.0%, 69.1%, 51.8%, and 0%, respectively. By using the 7th TNM, 5-year survivals were 95.0%, 92.3%, 67.7%, 70.9%, and 65.1% for stage IA, IB, IIA, IIB, and III, respectively. Conclusions Incorporating histology and regrouping tumor stage create a unique neuroendocrine tumor staging system that seems to predict survival better than the 7th TNM classification. [ABSTRACT FROM AUTHOR]