Prognostic Factors in Pulmonary Neuroendocrine Tumors’ Treatment: A Single-center Experience
Article Sidebar
Main Article Content
Abstract
Introduction: Lung neuroendocrine tumors (NETs) are rare lung cancers classified by differentiation into well-differentiated (typical and atypical carcinoids) and poorly-differentiated forms (large cell neuroendocrine carcinomas [LCNEC] and small cell carcinomas). Carcinoid tumor management requires a multidisciplinary approach, with surgery as the main treatment.
Objectives: To identify prognostic factors and evaluate survival outcomes following surgical treatment of NETs in our institution.
Methods: We reviewed surgical outcomes for NETs treated in our Department between January 2016 and January 2021. Survival analysis included 80 patients: 28 with typical carcinoids (TC), 21 with atypical carcinoids (AC), and 31 with LCNEC, all undergoing lobectomy, segmentectomy, pneumonectomy, or wedge resection. Variables assessed included demographics, tumor size, histology, Ki-67 index, nodal upstaging, and survival. We also compared survival by surgical type (segmentectomy vs. lobectomy) and surgical margin status. Poorly differentiated small cell carcinomas were excluded.
Results: Histological type and Ki-67 index significantly correlated with survival (p < 0.05). Tumor size and lymph node metastasis also influenced prognosis (p < 0.02). Lymph node metastases were more frequent in AC and LCNEC cases. By the last follow-up, mortality was 41.25%.
Conclusion: Surgery remains the primary treatment for TCs and ACs with localized disease, including cases with thoracic lymph node metastases. Prognosis is affected by factors such as gender, tumor subtype, cellular markers, size, and lymph node involvement.
Article Details
Copyright (c) 2025 Glykeria C
This work is licensed under a Creative Commons Attribution 4.0 International License.
Modlin IM, Kidd M, Filosso PL, Roffinella M, Lewczuk A, Cwikla J, et al. Molecular strategies in the management of bronchopulmonary and thymic neuroendocrine neoplasms. J Thorac Dis. 2017;9(Suppl 15):S1458-S1473. Available from: https://doi.org/10.21037/jtd.2017.03.82
Rekhtman N. Lung neuroendocrine neoplasms: recent progress and persistent challenges. Mod Pathol. 2022;35(Suppl 1):36-50. Available from: https://doi.org/10.1038/s41379-021-00943-2
Zhang S, Chen J, Zhang R, Xu L, Wang Y, Yuan Z, et al. Pulmonary neuroendocrine tumors: study of 266 cases focusing on clinicopathological characteristics, immunophenotype, and prognosis. J Cancer Res Clin Oncol. 2023;149(3):1063-1077. Available from: https://doi.org/10.1007/s00432-022-03970-x
Yang H, Liu T, Li M, Fang Z, Luo L. Does examined lymph node count influence survival in surgically resected early-stage pulmonary typical carcinoid tumors? Am J Clin Oncol. 2022;45(12):506-513. Available from: https://doi.org/10.1097/coc.0000000000000958
Feola T, Centello R, Sesti F, Puliani G, Verrico M, Di Vito V, et al. Neuroendocrine carcinomas with atypical proliferation index and clinical behavior: a systematic review. Cancers (Basel). 2021;13(6):1247. Available from: https://doi.org/10.3390/cancers13061247
Rosai J, Higa E. Mediastinal endocrine neoplasm, of probable thymic origin, related to carcinoid tumor. Clinicopathologic study of 8 cases. Cancer. 1972;29:1061-1074. Available from: https://doi.org/10.1002/1097-0142(197204)29:4%3C1061::aid-cncr2820290456%3E3.0.co;2-3
Goldman A, Conner CL. Benign tumors of the lungs with special reference to adenomatous bronchial tumors. Dis Chest. 1950;17(6):644-680. Available from: https://doi.org/10.1378/chest.17.6.644
Bensch KG, Corrin B, Pariente R, Spencer H. Oat-cell carcinoma of the lung: its origin and relationship to bronchial carcinoid. Cancer. 1968;22(6):1163-1172. Available from: https://doi.org/10.1002/1097-0142(196811)22:6%3C1163::aid-cncr2820220612%3E3.0.co;2-l
Arrigoni MG, Woolner LB, Bernatz PE. Atypical carcinoid tumors of the lung. J Thorac Cardiovasc Surg. 1972;64(3):413-421. PMID: 5054879. Available from: https://pubmed.ncbi.nlm.nih.gov/5054879/
Mills SE, Cooper PH, Walker AN, Kron IL. Atypical carcinoid tumor of the lung: a clinicopathologic study of 17 cases. Am J Surg Pathol. 1982;6(7):643-654. Available from: https://doi.org/10.1097/00000478-198210000-00006
DeLellis RA, Dayal Y, Wolfe HJ. Carcinoid tumors. Changing concepts and new perspectives. Am J Surg Pathol. 1984;8(4):295-300. Available from: https://pubmed.ncbi.nlm.nih.gov/6369998/
Klöppel G. Oberndorfer and his successors: from carcinoid to neuroendocrine carcinoma. Endocr Pathol. 2007;18(3):141-144. Available from: https://doi.org/10.1007/s12022-007-0021-9
Bernatz PE, Harrison EG, Clagett OT. Thymoma: a clinicopathologic study. J Thorac Cardiovasc Surg. 1961;42:424-444. Available from: https://pubmed.ncbi.nlm.nih.gov/13868094/
Lausi PO, Refai M, Filosso PL, Ruffini E, Oliaro A, Guerrera F, Brunelli A. Thymic neuroendocrine tumors. Thorac Surg Clin. 2014;24(3):327-332. Available from: https://doi.org/10.1016/j.thorsurg.2014.05.007
Rosai J, Higa E, Davie J. Mediastinal endocrine neoplasm in patients with multiple endocrine adenomatosis. A previously unrecognized association. Cancer. 1972;29(4):1075-1083. Available from: https://doi.org/10.1002/1097-0142(197204)29:4%3C1075::aid-cncr2820290457%3E3.0.co;2-o
Filosso PL, Yao X, Ahmad U, Zhan Y, Huang J, Ruffini E, et al. Outcome of primary neuroendocrine tumors of the thymus: a joint analysis of the International Thymic Malignancy Interest Group and the European Society of Thoracic Surgeons databases. J Thorac Cardiovasc Surg. 2015;149(1):103-109.e2. Available from: https://doi.org/10.1016/j.jtcvs.2014.08.061
Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26(18):3063-3072. Available from: https://doi.org/10.1200/jco.2007.15.4377
Gustafsson BI, Kidd M, Chan A, Malfertheiner MV, Modlin IM. Bronchopulmonary neuroendocrine tumors. Cancer. 2008;113(1):5-21. Available from: https://doi.org/10.1002/cncr.23542
de Laat JM, Pieterman CR, van den Broek MF, Twisk JW, Hermus AR, Dekkers OM, et al. Natural course and survival of neuroendocrine tumors of the thymus and lung in MEN1 patients. J Clin Endocrinol Metab. 2014;99(9):3325-3333. Available from: https://doi.org/10.1210/jc.2014-1560
Caplin ME, Baudin E, Ferolla P, Filosso P, Garcia-Yuste M, Lim E, et al. Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol. 2015;26(8):1604-1620. Available from: https://doi.org/10.1093/annonc/mdv041
Jeung MY, Gasser B, Gangi A, Charneau D, Ducroq X, Kessler R, et al. Bronchial carcinoid tumors of the thorax: spectrum of radiologic findings. Radiographics. 2002;22(2):351-365. Available from: https://doi.org/10.1148/radiographics.22.2.g02mr01351
Oberg K, Hellman P, Kwekkeboom D, Jelic S; ESMO Guidelines Working Group. Neuroendocrine bronchial and thymic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21 Suppl 5:v220-222. Erratum in: Ann Oncol. 2011;22(1):242-243. Available from: https://doi.org/10.1093/annonc/mdq191
Phan AT, Oberg K, Choi J, Harrison LH Jr, Hassan MM, Strosberg JR, et al. NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the thorax (includes lung and thymus). Pancreas. 2010;39(6):784-798. Available from: https://doi.org/10.1097/mpa.0b013e3181eb7451
Rosado de Christenson ML, Abbott GF, Kirejczyk WM, Galvin JR, Travis WD. Thoracic carcinoids: radiologic-pathologic correlation. Radiographics. 1999;19(3):707-736. Available from: https://doi.org/10.1148/radiographics.19.3.g99ma11707
WHO Classification of Tumors Editorial Board. Thoracic Tumors. 5th ed. Lyon (France): International Agency for Research on Cancer; 2021. Available from: https://publications.iarc.who.int/Book-And-Report-Series/Who-Classification-Of-Tumours/Thoracic-Tumours-2021
Rekhtman N. Neuroendocrine tumors of the lung: an update. Arch Pathol Lab Med. 2010;134(11):1628-1638. Available from: https://doi.org/10.5858/2009-0583-rar.1
Clinical Lung Cancer Genome Project (CLCGP); Network Genomic Medicine (NGM). A genomics-based classification of human lung tumors. Sci Transl Med. 2013;5(209):209ra153. Available from: https://doi.org/10.1126/scitranslmed.3006802
Cree IA, Tan PH, Travis WD, et al. Counting mitoses: SI(ze) matters. Mod Pathol. 2021;34:1651-1657. Available from: https://doi.org/10.1038/s41379-021-00825-7
Riihimäki M, Hemminki A, Sundquist K, Sundquist J, Hemminki K. The epidemiology of metastases in neuroendocrine tumors. Int J Cancer. 2016;139(12):2679-2686. Available from: https://doi.org/10.1002/ijc.30400
Rekhtman N, Desmeules P, Litvak AM, Pietanza MC, Santos-Zabala ML, Ni A, et al. Stage IV lung carcinoids: spectrum and evolution of proliferation rate, focusing on variants with elevated proliferation indices. Mod Pathol. 2019;32(8):1106-1122. Available from: https://doi.org/10.1038/s41379-019-0248-2
Hermans BCM, de Vos-Geelen J, Derks JL, Latten L, Liem IH, van der Zwan JM, et al. Unique metastatic patterns in neuroendocrine neoplasms of different primary origin. Neuroendocrinology. 2021;111(11):1111-1120. Available from: https://doi.org/10.1159/000513249
Yatabe Y, Dacic S, Borczuk AC, Warth A, Russell PA, Lantuejoul S, et al. Best practices recommendations for diagnostic immunohistochemistry in lung cancer. J Thorac Oncol. 2019;14(3):377-407. Available from: https://doi.org/10.1016/j.jtho.2018.12.005
Rooper LM, Sharma R, Li QK, Illei PB, Westra WH. INSM1 demonstrates superior performance to the individual and combined use of synaptophysin, chromogranin, and CD56 for diagnosing neuroendocrine tumors of the thoracic cavity. Am J Surg Pathol. 2017;41(11):1561-1569. Available from: https://doi.org/10.1097/pas.0000000000000916
Mukhopadhyay S, Dermawan JK, Lanigan CP, Farver CF. Insulinoma-associated protein 1 (INSM1) is a sensitive and highly specific marker of neuroendocrine differentiation in primary lung neoplasms: an immunohistochemical study of 345 cases, including 292 whole-tissue sections. Mod Pathol. 2019;32(1):100-109. Available from: https://doi.org/10.1038/s41379-018-0122-7
Sakakibara R, Kobayashi M, Takahashi N, Inamura K, Ninomiya H, Wakejima R, et al. Insulinoma-associated protein 1 (INSM1) is a better marker for the diagnosis and prognosis estimation of small cell lung carcinoma than neuroendocrine phenotype markers such as chromogranin A, synaptophysin, and CD56. Am J Surg Pathol. 2020;44(6):757-764. Available from: https://doi.org/10.1038/s41379-018-0122-7
Yoshida A, Makise N, Wakai S, Kawai A, Hiraoka N. INSM1 expression and its diagnostic significance in extraskeletal myxoid chondrosarcoma. Mod Pathol. 2018;31(5):744-752. Available from: https://doi.org/10.1038/modpathol.2017.189
Rindi G, Klimstra DS, Abedi-Ardekani B, Asa SL, Bosman FT, Brambilla E, et al. A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol. 2018;31(12):1770-1786. Available from: https://doi.org/10.1038/s41379-018-0110-y
Rekhtman N, Pietanza MC, Hellmann MD, Naidoo J, Arora A, Won H, et al. Next-generation sequencing of pulmonary large cell neuroendocrine carcinoma reveals small cell carcinoma-like and non-small cell carcinoma-like subsets. Clin Cancer Res. 2016;22(14):3618-3629. Available from: https://doi.org/10.1158/1078-0432.ccr-15-2946
Quinn AM, Chaturvedi A, Nonaka D. High-grade neuroendocrine carcinoma of the lung with carcinoid morphology: a study of 12 cases. Am J Surg Pathol. 2017;41(2):263-270. Available from: https://doi.org/10.1097/pas.0000000000000767
Tsai HK, Hornick JL, Vivero M. INSM1 expression in a subset of thoracic malignancies and small round cell tumors: rare potential pitfalls for small cell carcinoma. Mod Pathol. 2020;33(8):1571-1580. Available from: https://doi.org/10.1038/s41379-020-0517-0
Warmke LM, Tinkham EG, Ingram DR, Lazar AJ, Panse G, Wang WL. INSM1 expression in angiosarcoma. Am J Clin Pathol. 2021;155(4):575-580. Available from: https://doi.org/10.1093/ajcp/aqaa168
Pelosi G, Massa F, Gatti G, Righi L, Volante M, Birocco N, et al. Ki-67 evaluation for clinical decision in metastatic lung carcinoids: a proof of concept. Clin Pathol. 2019;12:2632010X19829259. Available from: https://doi.org/10.1177/2632010x19829259
Marchiò C, Gatti G, Massa F, Bertero L, Filosso P, Pelosi G, et al. Distinctive pathological and clinical features of lung carcinoids with high proliferation index. Virchows Arch. 2017;471(6):713-720. Available from: https://doi.org/10.1007/s00428-017-2177-0
Zahel T, Krysa S, Herpel E, Stenzinger A, Goeppert B, Schirmacher P, et al. Phenotyping of pulmonary carcinoids and a Ki-67-based grading approach. Virchows Arch. 2012;460(3):299-308. Available from: https://doi.org/10.1007/s00428-012-1194-2
Pelosi G, Rindi G, Travis WD, Papotti M. Ki-67 antigen in lung neuroendocrine tumors: unraveling a role in clinical practice. J Thorac Oncol. 2014;9(3):273-284. Available from: https://doi.org/10.1097/jto.0000000000000092
Marchevsky AM, Hendifar A, Walts AE. The use of Ki-67 labeling index to grade pulmonary well-differentiated neuroendocrine neoplasms: current best evidence. Mod Pathol. 2018;31(10):1523-1531. Available from: https://doi.org/10.1038/s41379-018-0076-9
de Vilhena AF, das Neves Pereira JC, Parra ER, Balancin ML, Ab Saber A, Martins V, et al. Histomorphometric evaluation of the Ki-67 proliferation rate and CD34 microvascular and D2-40 lymphovascular densities drives the pulmonary typical carcinoid outcome. Hum Pathol. 2018;81:201-210. Available from: https://doi.org/10.1016/j.humpath.2018.07.007
Dermawan JKT, Farver CF. The role of histologic grading and Ki-67 index in predicting outcomes in pulmonary carcinoid tumors. Am J Surg Pathol. 2020;44(2):224-231. Available from: https://doi.org/10.1097/pas.0000000000001358
Clay V, Papaxoinis G, Sanderson B, Valle JW, Howell M, Lamarca A, et al. Evaluation of diagnostic and prognostic significance of Ki-67 index in pulmonary carcinoid tumors. Clin Transl Oncol. 2017;19(5):579-586. Epub 2016 Nov 15. Available from: https://doi.org/10.1007/s12094-016-1568-z
Hermans BCM, Derks JL, Moonen L, Habraken CHJ, der Thüsen JV, Hillen LM, et al. Pulmonary neuroendocrine neoplasms with well-differentiated morphology and high proliferative activity: illustrated by a case series and review of the literature. Lung Cancer. 2020;150:152-158. Available from: https://doi.org/10.1016/j.lungcan.2020.10.015
Singh S, Bergsland EK, Card CM, Hope TA, Kunz PL, Laidley DT, et al. Commonwealth Neuroendocrine Tumour Research Collaboration and the North American Neuroendocrine Tumor Society guidelines for the diagnosis and management of patients with lung neuroendocrine tumors: an international collaborative endorsement and update of the 2015 European Neuroendocrine Tumor Society expert consensus guidelines. J Thorac Oncol. 2020;15(10):1577-1598. Available from: https://doi.org/10.1016/j.jtho.2020.06.021
Uccella S, La Rosa S, Volante M, Papotti M. Immunohistochemical biomarkers of gastrointestinal, pancreatic, pulmonary, and thymic neuroendocrine neoplasms. Endocr Pathol. 2018;29(2):150-168. Available from: https://doi.org/10.1007/s12022-018-9522-y
Caplin ME, Baudin E, Ferolla P, Filosso P, Garcia-Yuste M, Lim E, et al. Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol. 2015;26(8):1604-1620. Available from: https://doi.org/10.1093/annonc/mdv041
Alcala N, Leblay N, Gabriel AAG, Mangiante L, Hervas D, Giffon T, et al. Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids. Nat Commun. 2019;10(1):3407. Available from: https://doi.org/10.1038/s41467-019-11276-9