Atypical Carcinoid Research Articles

Abstract 5034: Targeting CXCR4 and thioredoxin reductase in high grade neuroendocrine tumors and neuroendocrine carcinomas

Abstract Introduction/Background: Atypical lung carcinoids and lung neuroendocrine carcinomas (NECs) are currently incurable. Most of these cancers express the C-X-C chemokine receptor 4 (CXCR4), making CXCR4 an attractive target for cancer diagnosis and treatment using radioligand therapy (RLT) with nuclides such as alpha emitter Pb212 conjugated to Pentixather (Pent). Alpha particles produce dense ionization tracks and damage cytosolic structures such as mitochondria, leading to the generation of reactive oxygen species such as superoxide (O2 ●−) and hydroperoxides (H2O2 and ROOH) in targeted cancer cells. The FDA approved thioredoxin reductase inhibitor, auranofin (Aur), inhibits peroxiredoxin-mediated hydroperoxide metabolism increasing cell killing in targeted cancer cells. Hypothesis: Inhibition of hydroperoxide metabolism using Aur can enhance therapeutic efficacy of alpha particle emitting 212Pb-Pent in preclinical models of lung carcinoids and NECs. Results: Clinically, IHC revealed greater than 75% of atypical carcinoids and NECs tested had moderate to high CXCR4. qRT-PCR, flow cytometry and immunohistochemistry performed on different lung carcinoid and NEC lung cell lines, determined that the majority moderately or highly express CXCR4. The minimal non-toxic dose of Aur that inhibits 50-70% of thioredoxin reductase activity was 4 mg/kg (intraperitoneal once a day) in DMS273 (small cell lung cancer) xenografts 212Pb-Pent given IV (1 and 3 µCu/g) was effective at increasing the survival of mice with DMS273 xenografts. Mice were then treated with 1.5, 3 or 6 µCu/g 212Pb-Pent w/wo Aur 4 mg/kg/day. A trend test showed that both increasing dose of 212Pb-Pent and the addition of Aur, caused a significant (p<0.01) delay in tumor growth. There were no significant changes in body weights, complete blood counts, and serum alanine aminotransferase indicating the combination treatments were well tolerated. Radiation dosimetry estimates using quantitative SPECT/CT imaging with Pb203-Pent demonstrated average absorbed doses of 0.133 Gy/µCi (liver), 0.098 Gy/µCi (kidneys), 0.013 Gy/µCi (H292 xenografts), 0.028 Gy/µCi (DMS53 xenografts), 0.057 Gy/µCi (DMS273 xenografts), and 0.096 Gy/µCi (H69AR xenografts). Xenograft absorbed dose levels were positively correlated with CXCR4 expression. Conclusion: The use of 212Pb-Pent therapy to target CXCR4 on NECs showed pre-clinical efficacy in a dose dependent manner that was enhanced by Aur without significant normal tissue toxicity supporting the hypothesis that CXCR4 can be successfully targeted with the radionuclide theragnostic pair, Pb212/Pb203-pentixather. Citation Format: Melissa A. Fath, Dijie Liu, Claudia Robles-Planells, Jordan T. Ewald, Keegan A. Christensen, Spenser S. Johnson, Stephen A. Graves, Douglas R. Spitz, Yusuf Menda, M. Sue O’Dorisio. Targeting CXCR4 and thioredoxin reductase in high grade neuroendocrine tumors and neuroendocrine carcinomas. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5034.

Incidence and prognostic nomogram for resected non-small cell neuroendocrine tumor: A population-based respective study in China and the SEER database

BackgroundPulmonary neuroendocrine tumors, including small cell lung cancer (SCLC) and non-small cell neuroendocrine tumor (NSCLC-NET), have obvious heterogeneity. The comparison between SCLC and NSCLC-NET, and prognostic nomogram of resected NSCLC-NET have not been performed. MethodsWe retrieved data from SEER database. The incidence and prognostic factors were compared between SCLC and NSCLC-NET. By Cox regression, we constructed prognostic nomogram of resected NSCLC-NET. The nomogram was evaluated by ROC, calibration plot and decision curve analysis (DCA) and compared with 8th TNM staging system. A Chinese cohort was used for external validation. ResultsThe age-adjusted incidence of SCLC declined after 1991 but the incidence of NSCLC-NET continuously rose. Patients with typical carcinoid had the best prognosis in both overall survival and lung cancer specific survival, followed by atypical carcinoid, large cell neuroendocrine tumor and SCLC after operation. Patients receiving sleeve resection in NSCLC-NET had longer survival but segmental resection was more recommended in SCLC. High-smoking index was associated with worse overall survival in both SCLC and NSCLC-NET. Histological subtype, age, surgery type, N, M stage and chemotherapy were independent prognostic factors and used to construct prognostic nomogram of resected NSCLC-NET. The nomogram performed well with good discrimination, calibration and clinical usefulness, which was validated by a Chinese cohort (1, 3, 5-year AUC: SEER cohort 0.873, 0.901, 0.875; Chinese cohort 0.867, 0.892, 0.874). Compared to the 8th staging system, the nomogram had higher C-index (0.87 vs 0.728, P < 0.001), clinical usefulness, increasing AUC value over time and improved 68%. ConclusionThe prognostic nomogram of resected NSCLC-NET performed better than the 8th TNM staging system. It may have certain value in risk stratification and survival prediction of patients with resected NSCLC-NET and help clinicians to take measures for high-risk patients in advance.

Clinical profile, surgical management and outcome of bronchial carcinoids - a single centre experience

Background and objectives: Bronchial carcinoid tumors are neuroendocrine neoplasms that range from low-grade typical carcinoids to more aggressive atypical carcinoids and, therefore demonstrate a wide spectrum of clinical behaviors, histologic features and outcome. The aim of the present study was to investigate the clinical profile, surgical management and outcome of bronchial carcinoids at a single centre over two years period. Materials and methods: Patients with a final histologic diagnosis of bronchial carcinoid tumor were included in the study. Evaluation comprised of clinical history and physical examination, postero-anterior and lateral chest radiographs, and computed tomographic (CT) scans of the chest and upper abdomen (including liver and adrenal glands). Performance status was assessed by the Karnofsky scale. Pulmonary function tests were performed routinely. Results: A total of 18 patients were included in the study. Out of 18 cases, 10 (55.6%) were female and 8 (44.4%) were males. Sixteen (88.9%) patients had typical carcinoid tumor and 2 (11.1%) had atypical carcinoid tumor. The tumor was located in the right lung in 11 (61.1%) and in the left lung in 7 patients (38.9%). Surgeries included 15 standard lobectomies and 3 bronchial sleeve resection. At one month post surgery, there was 13-22% increase in post operative FEV1 in patients who underwent bronchial sleeve resection while in patients who underwent lobectomy, the post operative FEV1 was 84% of pre-operative FEV1. Post surgery, all patients were in group A as per Karnofsky performance status. Conclusion: Standard care of bronchial carcinoid tumors is surgical resection, and the surgical approach should depend on tumor’s size, location and histology. IMC J Med Sci. 2023; 17(2):003. DOI: https://doi.org/10.55010/imcjms.17.013 *Correspondence: Farooq Ahmad Ganie, Department of Cardiovascular and Thoracic Surgery, SKIMS, Soura, Srinagar, Kashmir, India. Email: farooq.ganie@ymail.com

A case of atypical carcinoid of the lung with abnormal elevation of plasma progastrin-releasing peptide (ProGRP)

症例は87歳女性．健診の胸部X線写真で緩徐な増大傾向を示す肺腫瘤影を主訴に当院を受診．胸部CTにて右肺S7に40 mm大の腫瘤影を認めた．腫瘍マーカーでは，ProGRPが3650 pg/mLと異常高値を示した．気管支鏡下生検で肺カルチノイドと診断した．高齢であることから消極的縮小手術として胸腔鏡下右肺S7区域切除を施行した．摘出標本の病理検査で最終的に異型カルチノイドと診断した．ProGRPは術後基準値範囲内まで低下を認め，術後18ヵ月経過して無再発生存中である．肺カルチノイドでProGRP高値症例は報告されているが，検索した限りでは自験例は報告例のうち最も高値であった．さらに肺カルチノイドにおいてProGRPが治療効果判定に有用である可能性が示唆された．

A Competing Risk Model Nomogram to Predict the Long-Term Prognosis of Lung Carcinoid.

The prediction of long-term, cancer-specific survival of lung carcinoid remains controversial. We aimed to build a prognostic model by using competing-risk analysis to predict the long-term, cancer-specific survival of lung carcinoid patients. Patients were retrospectively enrolled from the SEER database, and clinicopathological data were collected. Univariable and multivariable competing-risk analyses were conducted to identify prognostic factors. A competing-risk model and a nomogram were developed by using independent prognostic factors. The model was assessed by using concordance index and calibration curves. A total of 2496 patients were enrolled, of which 267 (10.7%) died of diagnosed carcinoma; 316 (12.7%) died because of other reasons. The 5-year, 10-year, and 15-year cancer-specific survival of carcinoid patients were 91.35%, 86.60%, and 84.39%, respectively. Multivariable analysis demonstrated that increasing age, male, larger tumor size, higher N stage, M1, atypical carcinoid, and undergoing no surgery were independent risk factors. A competing-risk model based on the risk factors and a corresponding nomogram were developed. Concordance index of the developed model for 5-year, 10-year, and 15-year were 0.891, 0.856, 0.836 respectively in the training cohort and 0.876, 0.841, 0.819 respectively in the validation cohort after bootstrap adjustment. The calibration curves of 5-year, 10-year, and 15-year showed good agreement. Increasing age, male, larger tumor size, higher N stage, M1, atypical carcinoid, and undergoing no surgery were independent risk factors. A competing risk model of excellent performance in predicting long-term survival was developed, and a nomogram was established.

The Surgical Management of Lung Neuroendocrine Neoplasms.

This review summarizes key recent developments relevant to the surgical management of lung neuroendocrine neoplasms (L-NENs), including typical and atypical carcinoids, large cell neuroendocrine carcinoma, and small cell lung carcinoma. This review includes recent insights into the classification, clinical presentation, diagnostic workup, treatment options, and follow-up. Highlighted topics include general principles of surgery in localized or locally advanced or metastatic L-NENs, lung-sparing surgery for small, peripheral typical carcinoids, adjuvant and systemic therapies for typical and atypical carcinoids, and surgery and adjuvant therapies for large cell neuroendocrine carcinoma and small cell lung carcinoma.

Cushing's syndrome due to atypical carcinoid of the mediastinum

Ectopic Cushing's syndrome, caused by a neuroendocrine tumor (NET), is a rare finding. NETs of the mediastinum are extremely rare. NETs arising from the anterior mediastinum are generally aggressive. They are widely characterized at clinical presentations, and may be asymptomatic or present with atypical symptoms. Prognosis is often poor due to their local recurrence and distant metastasis despite a multimodal approach. A 33-year-old male patient was admitted to our department with a femoral soft tissue abscess, diabetes, and hypokalemia. He had no typical features of Cushing's syndrome. However, with a few simple tests, that is, a basal hormone profile, and low-dose and high-dose dexamethasone suppression tests, we diagnosed this complicated condition of ectopic adrenocorticotrophic hormone (ACTH) secretion. Thoracic computed tomography revealed an anterior mediastinal mass of 35×22 mm. A surgical excision of the tumor was proposed, and intra-operative pathology consultation returned positive for the suspected NET. Immunohistochemically, the tumor cells were positive for CK, CD56, Chromogranin, Synaptophysin, S100, and CD117. No thymic tissue was found. The Ki-67 was 4%. A diagnosis of primary NETs of the mediastinum, intermediate grade (G2), of atypical carcinoids according to WHO 2015 was established. This patient survived with no sequelae, no distant metastasis, no recurrence, and without adjuvant radiotherapy or chemotherapy 2 years after surgery thanks to earlier diagnosis and prompt surgical intervention. Mediastinum ectopic ACTH-secreting tumors are a rare type of cancer. According to recent research, these tumors frequently display more aggressive behavior and are linked to endocrinopathies. It is noted that patient might have a better outcome and a longer survival time due to earlier detection and complete resection of malignancies.

Ascl1 and OTP tumour expressions are associated with disease-free survival in lung atypical carcinoids.

According to World Health Organization guidelines, atypical carcinoids (ACs) are well-differentiated lung neuroendocrine tumours with 2-10 mitoses/2 mm2 and/or foci of necrosis (usually punctate). Besides morphological criteria, no further tools in predicting AC clinical outcomes are proposed. The aim of this work was to identify novel factors able to predict AC disease aggressiveness and progression. METHODS AND RESULTS: Three hundred-seventy lung carcinoids were collected and centrally reviewed by two expert pathologists. Morphology and immunohistochemical markers (Ki-67, TTF-1, CD44, OTP, SSTR2A, Ascl1, p53, and Rb1) were studied and correlated with disease-free survival (DFS) and overall survival (OS). Fifty-eight of 370 tumours were defined as AC. Survival analysis showed that patients with Ascl1 + ACs and those with OTP-ACs had a significantly worse DFS than patients with Ascl1-ACs and OTP + ACs, respectively. Combining Ascl1 and OTP expressions, groups were formed reflecting the aggressiveness of disease (P=0.0005). Ki-67 ≥10% patients had a significantly worse DFS than patients with Ki-67 <10%. At multivariable analysis, Ascl1 (present versus absent, hazard ratio [HR]=3.42, 95% confidence interval [CI] 1.35-8.65, P=0.009) and OTP (present versus absent, HR=0.26, 95% CI 0.10-0.68, P=0.006) were independently associated with DFS. The prognosis of patients with Ki-67 ≥10% tended to be worse compared to that with Ki-67 <10%. On the contrary, OTP (present versus absent, HR=0.28, 95% CI 0.09-0.89, P=0.03), tumour stage (III-IV versus I-II, HR=4.25, 95% CI 1.42-12.73, P=0.01) and increasing age (10-year increase, HR=1.67, 95% CI 1.04-2.68, P=0.03) were independently associated with OS. CONCLUSION: This retrospective analysis of lung ACs showed that Ascl1 and OTP could be the main prognostic drivers of postoperative recurrence.

Surgical cytoreduction and hyperthermic intrathoracic chemotherapy for thymic tumours with pleural spread is effective on survival: results from the multicentre German hyperthermic intrathoracic chemotherapy study.

Cytoreductive surgery and hyperthermic intrathoracic chemotherapy (HITOC) is effective on survival for patients with pleural metastatic thymic tumours. Multicentre, retrospective analysis of patients with stage IVa thymic tumours treated with surgical resection and HITOC. Primary end point was overall survival, secondary end points were recurrence-/progression-free survival and morbidity/mortality. A total of n = 58 patients (thymoma, n = 42; thymic carcinoma, n = 15; atypical carcinoid of the thymus, n = 1) were included, who had primary pleural metastases (n = 50; 86%) or pleural recurrence (n = 8; 14%). Lung-preserving resection (n = 56; 97%) was the preferred approach. Macroscopically complete tumour resection was achieved in n = 49 patients (85%). HITOC was performed with cisplatin alone (n = 38; 66%) or in combination with doxorubicin (n = 20; 34%). Almost half of the patients (n = 28; 48%) received high-dose cisplatin > 125 mg/m2 body surface area. Surgical revision was required in 8 (14%) patients. In-hospital mortality rate was 2%. During follow-up, tumour recurrence/progression was evident in n = 31 (53%) patients. Median follow-up time was 59 months. The 1-, 3- and 5-year survival rates were 95%, 83% and 77%, respectively. Recurrence/progression-free survival rates were 89%, 54% and 44%, respectively. Patients with thymoma had significantly better survival compared to patients with thymic carcinoma (P-value ≤0.001). Promising survival rates in patients with pleural metastatic stage IVa in thymoma (94%) and even in thymic carcinoma (41%) were achieved. Surgical resection and HITOC is safe and effective for treatment of patients with pleural metastatic thymic tumours stage IVa.

Prognostic factors for pulmonary carcinoid with positive lymph node after surgical resection: a SEER database study.

Prognostic factors and role with chemotherapy (CT) and radiotherapy (RT) remain unclear for patients of pulmonary carcinoid (PC) with positive lymph node after surgery. 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). 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. 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.

Gene fusions are frequent in ACTH-secreting neuroendocrine neoplasms of the pancreas, but not in their non-pancreatic counterparts

Ectopic Cushing syndrome is a rare clinical disorder resulting from excessive adrenocorticotrophic hormone (ACTH) produced by non-pituitary neoplasms, mainly neuroendocrine neoplasms (NENs) of the lung, pancreas, and gastrointestinal tract, and other less common sites. The genetic background of ACTH-producing NENs has not been well studied. Inspired by an index case of ACTH-producing pancreatic NEN carrying a gene fusion, we postulated that ACTH-producing NENs might be enriched for gene fusions. We herein examined 21 ACTH-secreting NENs of the pancreas (10), lung (9), thymus (1), and kidney (1) using targeted RNA sequencing. The tumors were classified according to the most recent WHO classification as NET-G1/typical carcinoid (n = 4), NETG-2/atypical carcinoid (n = 14), and NET-G3 (n = 3). Overall, targeted RNA sequencing was successful in 11 cases (4 of 10 pancreatic tumors, 5 of 9 pulmonary tumors, and in the one renal and one thymic tumor). All four successfully tested pancreatic tumors revealed a gene fusion: two had a EWSR1::BEND2 and one case each had a KMT2A::BCOR and a TFG::ADGRG7 fusion, respectively. EWSR1 rearrangements were confirmed in both tumors with a EWSR1::BEND2 by FISH. Gene fusions were mutually exclusive with ATRX, DAXX, and MEN1 mutations (the most frequently mutated genes in NETs) in all four cases. Using RNA-based variant assessment (n = 16) or via the TSO500 panel (n = 5), no pathogenic BCOR mutations were detected in any of the cases. Taken together, gene fusions were detected in 4/4 (100%) pancreatic versus 0/7 (0%) non-pancreatic tumors, respectively. These results suggest a potential role for gene fusions in triggering the ACTH production in pancreatic NENs presenting with ectopic Cushing syndrome. While the exact mechanisms responsible for the ectopic ACTH secretion are beyond the scope of this study, overexpressed fusion proteins might be involved in promoter-mediated overexpression of pre-ACTH precursors in analogy to the mechanisms postulated for EWSR1::CREB1-mediated paraneoplastic phenomena in certain mesenchymal neoplasms. The genetic background of the ACTH-producing non-pancreatic NENs remains to be further studied.

GLI1 Immunohistochemistry Distinguishes Mesenchymal Neoplasms With GLI1 Alterations From Morphologic Mimics.

Glioma-associated oncogene 1 ( GLI1 ) alterations have been described in pericytoma with t(7;12), gastroblastoma, plexiform fibromyxoma, and an emerging class of GLI1 -rearranged or amplified mesenchymal neoplasms including "nested glomoid neoplasm". The immunophenotype of these tumor types is nonspecific, making some cases difficult to diagnose without sequencing. The utility of GLI1 immunohistochemistry (IHC) in distinguishing nested glomoid neoplasms and pericytomas with t(7;12) from morphologic mimics is unknown. To investigate the diagnostic value of GLI1 IHC, we determined its sensitivity and specificity in a "test cohort" of 23 mesenchymal neoplasms characterized by GLI1 alterations, including 12 nested glomoid neoplasms (7 GLI1 -rearranged, 4 GLI1 amplified, and 1 unknown GLI1 status), 9 pericytomas with t(7;12), 1 gastroblastoma, and 1 malignant epithelioid neoplasm with PTCH1 :: GLI1 fusion. GLI1 IHC was 91.3% sensitive in this cohort; all tumors except 2 pericytomas with t(7;12) expressed GLI1. GLI1 was also expressed in 1 of 8 (12%) plexiform fibromyxomas. Nineteen of 22 GLI1-positive tumors showed nuclear and cytoplasmic staining, while 3 showed nuclear staining only. GLI1 IHC was 98.0% specific; among morphologic mimics [40 well-differentiated neuroendocrine tumors, 10 atypical lung carcinoids, 20 paragangliomas, 20 glomus tumors, 20 solitary fibrous tumors, 10 Ewing sarcomas, 10 alveolar rhabdomyosarcomas (ARMS), 10 BCOR -altered sarcomas, 10 myoepitheliomas, 9 myopericytomas, 9 epithelioid schwannomas, 9 ossifying fibromyxoid tumors, 10 biphasic synovial sarcomas, 10 PEComas, 31 gastrointestinal stromal tumors, 10 inflammatory fibroid polyps, 11 pseudoendocrine sarcomas], 5 of 249 tumors expressed GLI1 (2 well-differentiated neuroendocrine tumors, 1 ARMS, 1 Ewing sarcoma, 1 BCOR -altered sarcoma). GLI1 IHC was also performed on a separate cohort of 13 molecularly characterized mesenchymal neoplasms in which GLI1 copy number gain was identified as a putatively secondary event by DNA sequencing (5 dedifferentiated liposarcoma [DDLPS], 2 adenosarcomas, 2 unclassified uterine sarcomas, 1 leiomyosarcoma, 1 ARMS, 1 intimal sarcoma, 1 osteosarcoma); 2 DDLPS, 1 ARMS, and 1 unclassified uterine sarcoma expressed GLI1. Lastly, because pleomorphic sarcomas sometimes show GLI1 amplification or copy number gain, GLI1 IHC was performed on a separate "pleomorphic sarcoma" cohort: GLI1 was expressed in 1 of 27 DDLPS, 1 of 9 leiomyosarcomas, and 2 of 10 pleomorphic liposarcomas, and it was negative in 23 well-differentiated liposarcomas and 9 unclassified pleomorphic sarcomas. Overall, GLI1 IHC was 91.3% sensitive and 98.0% specific for mesenchymal tumor types with driver GLI1 alterations among morphologic mimics. GLI1 expression was less frequent in other tumor types with GLI1 copy number gain. Given its specificity, in the appropriate morphologic context, GLI1 IHC may be a useful diagnostic adjunct for mesenchymal neoplasms with GLI1 alterations.

Prognostic factors in resected pulmonary carcinoid tumors: A retrospective study with 10 years of follow‑up.

The objective of the present study was to characterize the difference in 10-year carcinoid-specific survival (CSS) and disease-free survival (DFS) among patients with resected pulmonary typical carcinoid (TC) and atypical carcinoid (AC). Patients diagnosed with pulmonary carcinoid tumors (PCT) between January 1, 1997, and December 31, 2016, were identified. All patients underwent video-assisted thoracoscopic surgery or thoracotomy with thoracic lymphadenectomy. Cumulative CSS was estimated using the Kaplan-Meier model. The analysis of hazard ratios (HRs) and 95% confidence intervals (CIs) was performed using univariate and multivariate Cox proportional hazards models. A total of 404 patients with PCT were included in the present study. The 10-year CSS and DFS rates of patients with AC were significantly worse than those of patients with TC (49.1 vs. 86.8% and 52.2 vs. 92.6%, respectively; P<0.001). In the CSS multivariate analysis, older age and lymph node involvement (HR, 2.45; P=0.022) were associated with worse survival in AC, while age, male sex, M1 stage, cigarette smoking and inadequate N2 lymphadenectomy were associate with worse survival in TC. In the recurrence multivariate analysis, N1-3 stage (HR, 2.62; 95% CI, 1.16-5.95; P=0.018) and inadequate N2 lymphadenectomy (HR, 2.13; 95% CI, 1.04-4.39; P=0.041) were associated with an increase in recurrence in AC, while male sex (HR, 3.72; 95% CI, 1.33-10.42; P=0.010) and M1 stage (HR, 14.93; 95% CI, 4.77-46.77; P<0.001) were associated with an increase in recurrence in TC. In conclusion, patients with AC tumors had significantly worse CSS and DFS rates compared with patients with TC. The degree of nodal involvement in AC was a prognostic marker, in contrast to that in TC. Inadequate lymphadenectomy increased the risk of recurrence in AC and mortality in TC, although surgical approaches did not have a significant impact. The present study therefore emphasizes the importance of mediastinal nodal dissection in patients with PCTs.

Complex Patterns of Genomic Heterogeneity Identified in 42 Tumor Samples and ctDNA of a Pulmonary Atypical Carcinoid Patient.

DNA sequencing data from tumor samples and blood plasma from a single patient highlighted the critical early role of chromosomal alterations in atypical carcinoid tumor development. Common tumor variants were readily detected in the blood plasma, unlike emerging tumor variants, which has implications for using ctDNA to capture cancer evolution.

Isolated bronchoplastic procedure for typical carcinoid of the left lung

Lung carcinoids (LC) comprise neuroendocrine lung tumors of low (typical carcinoid) and intermediate (atypical carcinoid) grade of malignancy accounting for less than 2% of all lung neoplasms. In Europe, annual incidence of LC varies from 0.2 to 2 per 100 000. This value increased dramatically over the past 30 years. One of the causes is improvement of diagnostic methods. Compared to aggressive high-grade neuroendocrine lung cancer, natural course of early-stage LC is usually indolent. Therefore, surgery with preservation of as much normal lung tissue as possible is preferable for resectable tumors. Nevertheless, the number of isolated bronchial resections with preservation of the entire lung tissue is relatively small, and these procedures remain technically complex interventions. We present isolated resection of interlobular spur, lower medial wall of distal part of the left main bronchus and proximal part of the lower lobular bronchus for typical carcinoid with monobronchial anastomosis and preservation of the entire lung parenchyma.

Lobar versus sublobar resection for atypical lung carcinoid: An analysis from the National Cancer Database.

There is a knowledge gap regarding lobar versus sublobar resection for atypical carcinoid (AC) of the lung. As such, the authors sought to understand and analyze the outcomes of sublobar resection versus lobectomy in this patient population. A retrospective analysis using the National Cancer Database was performed to compare overall survival (OS) between patients treated with lobectomy and patients treated with sublobar resection for AC of the lung between the years 2004 and 2016. Patient characteristics were compared with χ2 tests. The Kaplan-Meier method was used to estimate OS distributions, and the log-rank test was used to compare distributions by treatment strategy. A multivariable Cox regression model was used to assess associations between the treatment strategy and OS. A propensity score matching method was also implemented to further eliminate treatment selection bias in the study sample. The database identified 669 patients with T1-T4 and N0-N3 lung ACs that were surgically resected. Unadjusted Kaplan-Meier survival curves did not demonstrate an OS difference between lobectomy and sublobar resection (p=.094). After propensity score matching, curves demonstrated a numerical improvement in OS with lobectomy; however, it was not statistically significant (p=.5). In a subgroup analysis, lobectomy and node-negative disease were associated with the best OS, whereas sublobar resection and node-positive disease were associated with the worst OS (p<.0001). Nodal involvement was associated with worse survival, regardless of surgical treatment (p<.0001). In patients with T1-T4 and N0-N3 ACs of the lung, lobectomy was not associated with an improvement in OS in comparison with sublobar resection.

The diagnostic and prognostic role of combined [18F]FDG and [68Ga]-DOTA-peptides PET/CT in primary pulmonary carcinoids: a multicentric experience.

In the present retrospective multicentric study, we combined [68Ga]-DOTA-peptides and [18F]FDG-PET/CT findings aiming to investigate their capability to differentiate typical (TC) and atypical pulmonary carcinoids (AC) and their prognostic role. From three centers, 61 patients were retrospectively included. Based on a dual tracer combination we classified PET scans as score 1, [18F]FDG- and [68Ga]-DOTA-peptides negative; score 2, [68Ga]-DOTA-peptides positive and [18F]FDG-negative; score 3, [68Ga]-DOTA-peptides negative and [18F]FDG-positive; score 4, both tracers positive. Moreover, for each patient, the ratios of SUVmax on [68Ga]-DOTA-PET to that on [18F]FDG-PET were calculated (SUVr). Thirty-five patients had a final diagnosis of TC. Twenty-two TC (57%) had positive [68Ga]-DOTA-peptides PET; instead, 21/26 (81%) AC had positive [18F]FDG-PET/CT. On dual-tracer analysis, scores 1, 2, 3 and 4 were 13%, 20%, 43% and 24% for all populations; 17%, 26%, 20% and 37% for TC; 8%, 11%, 73% and 8% for AC. Median SUVr was significantly higher in TC than AC (6.4 vs. 0.4, p = 0.011). The best value of SUVr to predict the final diagnosis was 1.05 (AUC 0.889). Relapse or progression of disease happened in 17 patients (11 affected by AC) and death in 10 cases (7 AC). AC diagnosis, positive [18F]FDG-PET, negative DOTA-PET and dual tracer score were significantly correlated with PFS (p = 0.013, p = 0.033, p = 0.029 and p = 0.019), while only AC diagnosis with OS (p = 0.022). PET/CT findings had also a prognostic role in predicting PFS. Dual-tracer PET behavior may be used to predict the nature of pulmonary carcinoids and select the most appropriate management. • Combination of [18F]FDG and [68Ga]-DOTA-peptides PET/CT results may help to differentiate between atypical and typical lung carcinoids. • The SUVmax ratio between [18F]FDG and [68Ga]-DOTA-peptides PET may help to differentiate between atypical and typical lung carcinoids. • Histotype and PET/CT features have a prognostic impact on PFS.

Proposing Specific Neuronal Epithelial-to-Mesenchymal Transition Genes as an Ancillary Tool for Differential Diagnosis among Pulmonary Neuroendocrine Neoplasms

Pulmonary neuroendocrine neoplasms (PNENs) are currently classified into four major histotypes, including typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung carcinoma (SCLC). This classification was designed to be applied to surgical specimens mostly anchored in morphological parameters, resulting in considerable overlapping among PNENs, which may result in important challenges for clinicians' decisions in the case of small biopsies. Since PNENs originate from the neuroectodermic cells, epithelial-to-mesenchymal transition (EMT) gene expression shows promise as biomarkers involved in the genotypic transformation of neuroectodermic cells, including mutation burden with the involvement of chromatin remodeling genes, apoptosis, and mitosis rate, leading to modification in final cellular phenotype. In this situation, additional markers also applicable to biopsy specimens, which correlate PNENs subtypes with systemic treatment response, are much needed, and current potential candidates are neurogenic EMT genes. This study investigated EMT genes expression and its association with PNENs histotypes in tumor tissues from 24 patients with PNENs. PCR Array System for 84 EMT-related genes selected 15 differentially expressed genes among the PNENs, allowing to discriminate TC from AC, LCNEC from AC, and SCLC from AC. Functional enrichment analysis of the EMT genes differentially expressed among PNENs subtypes showed that they are involved in cellular proliferation, extracellular matrix degradation, regulation of cell apoptosis, oncogenesis, and tumor cell invasion. Interestingly, four EMT genes (MAP1B, SNAI2, MMP2, WNT5A) are also involved in neurological diseases, in brain metastasis, and interact with platinum-based chemotherapy and tyrosine-kinase inhibitors. Collectively, these findings emerge as an important ancillary tool to improve the strategies of histologic diagnosis in PNENs and unveil the four EMT genes that can play an important role in driving chemical response in PNENs.

A multidisciplinary approach to the work up and management of pulmonary carcinoid tumors and DIPNECH: a narrative review.

Low and intermediate grade neuroendocrine tumors of the lung are uncommon malignancies representing 2% of all lung cancers. These are termed typical and atypical pulmonary carcinoid tumors. These can arise in the setting of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). The presentation, workup, management and outcomes of patients with these tumors can overlap with more common lung cancers but differ in that many of these patients have a prolonged clinical course. The objective of this narrative review is to summarize the literature and provide evidence and expert-based algorithms for work up and treatment of pulmonary carcinoids and DIPNECH. A search of PubMed and Web of Science databases ending April 15, 2022, with the following keywords "lung carcinoid", "DIPNECH", "lung neuroendocrine," and "bronchopulmonary carcinoid". Pulmonary carcinoid tumors benefit from a multidisciplinary approach. Pre-treatment imaging with contrast-enhanced computed tomography, and DOTATATE positron emission tomography is required. Surgical resection is the gold standard for curative intent, and possibly including sublobar resections. Patients can recur or develop new primaries thus emphasizing the importance of surveillance; national guidelines recommend at least a 10-year follow up. A growing body of literature support the use of endobronchial therapy, with long responses documented. Systemic therapy consists of everolimus, somatostatin analogs, peptide receptor radionuclide therapy, and chemotherapy. Diffuse idiopathic pulmonary neuroendocrine tumor cell hyperplasia is rare, but series suggest somatostatin analogs may confer clinical benefit. Pulmonary carcinoid tumors and DIPNECH are rare. Despite lack of regulatory approvals for advanced disease, multiple options are available but should be sequenced according to the clinical status and disease biology. Each patient should be discussed in a multidisciplinary setting and clinical trials should be considered if available.

Atypical thymic carcinoid associated with rapidly progressive symptoms of Cushing's syndrome in a child

Atypical thymic carcinoid in children is rare and its prognosis principally depends on the completeness of the surgical resection. We report a case of atypical thymic carcinoid with lymph node metastasis that had not been identified prior to surgery. An 8-year-old boy was referred because of Cushing's syndrome and a worsening of his symptom, which included facial edema, fatigue, and headache, over 3 weeks. Blood testing revealed high plasma cortisol and adrenocorticotropic hormone (ACTH), and chest computed tomography demonstrated two tumors in his anterior mediastinum, but no findings suggestive of lymph node metastasis. We suspected the presence of an ACTH-producing thymic carcinoid tumor; therefore, the patient underwent total thymectomy and dissection of his anterior mediastinal and bilateral deep cervical lymph nodes. Histopathological examination revealed an atypical carcinoid tumor and left cervical lymph node metastasis. The patients' plasma cortisol and ACTH concentrations decreased after surgery, and he was further treated with radiotherapy and combination chemotherapy. Thus, it is possible that the development of symptoms may indicate more rapid progression of atypical thymic carcinoid, and deep cervical lymphadenectomy is necessary for its complete resection.