Lung neuroendocrine neoplasms: recent progress and persistent challenges
Natasha Rekhtman, Natasha Rekhtman
Abstract
This review summarizes key recent developments relevant to the pathologic diagnosis of lung neuroendocrine neoplasms, including carcinoids, small cell lung carcinoma (SCLC), and large cell neuroendocrine carcinoma (LCNEC). Covered are recent insights into the biological subtypes within each main tumor type, progress in pathological diagnosis and immunohistochemical markers, and persistent challenging areas. Highlighted topics include highly proliferative carcinoids and their distinction from small cell and large cell neuroendocrine carcinomas (NECs), the evolving role of Ki67, the update on the differential diagnosis of NEC to include thoracic SMARCA4-deficient undifferentiated tumors, the recent data on SCLC transcriptional subtypes with the emergence of POU2F3 as a novel marker for the diagnosis of SCLC with low/negative expression of standard neuroendocrine markers, and the update on the diagnosis of LCNEC, particularly in biopsies. There has been remarkable recent progress in the understanding of the genetic and expression-based profiles within each type of lung neuroendocrine neoplasm, and it is hoped that these insights will enable the development of novel diagnostic, prognostic, and predictive biomarkers to aid in the pathologic assessment of these tumors in the future.
Conflict of interest statement
The author declares no competing interests.
© 2021. The Author(s).
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References
- WHO Classification of Tumours Editorial Board. Thoracic Tumours. 5th ed. Lyon (France): International Agency for Research on Cancer. (2021).
- Rekhtman N. Neuroendocrine tumors of the lung: an update. Arch. Pathol. Lab. Med. 2010;134:1628–1638.
- Seidel D, et al. A genomics-based classification of human lung tumors. Sci. Transl. Med. 2013;5:1–15.
- Cree, I. A. et al. Counting mitoses: SI(ze) matters! Modern Pathol.10.1038/s41379-021-00825-7 (2021).
- WHO Classification of Tumours Editorial Board. Digestive System Tumours. 5th ed. Lyon (France): International Agency for Research on Cancer. (2019).
- Riihimäki M, Hemminki A, Sundquist K, Sundquist J, Hemminki K. The epidemiology of metastases in neuroendocrine tumors. Int. J. Cancer. 2016;139:2679–2686.
- Rekhtman N, et al. Stage IV lung carcinoids: spectrum and evolution of proliferation rate, focusing on variants with elevated proliferation indices. Mod. Pathol. 2019;32:1106–1122.
- Hermans B. C. M. et al. Unique metastatic patterns in neuroendocrine neoplasms of different primary origin. Neuroendocrinology10.1159/000513249 (2020).
- Walenkamp AME, Sonke GS, Sleijfer DT. Clinical and therapeutic aspects of extrapulmonary small cell carcinoma. Cancer Treat. Rev. 2009;35:228–236.
- Shia J, et al. Is nonsmall cell type high-grade neuroendocrine carcinoma of the tubular gastrointestinal tract a distinct disease entity? Am. J. Surg. Pathol. 2008;32:719–731.
- Basturk O, et al. Poorly differentiated neuroendocrine carcinomas of the pancreas. Am. J. Surg. Pathol. 2014;38:437–447.
- Yatabe Y, et al. Best practices recommendations for diagnostic immunohistochemistry in lung cancer. J. Thorac. Oncol. 2019;14:377–407.
- 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;41:1561–1569.
- 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;32:100–109.
- Sakakibara 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;44:757–764.
- Yoshida A, Makise N, Wakai S, Kawai A, Hiraoka N. INSM1 expression and its diagnostic significance in extraskeletal myxoid chondrosarcoma. Mod. Pathol. 2018;31:744–752.
- 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;33:1571–1580.
- Warmke LM, et al. INSM1 expression in angiosarcoma: a potential diagnostic pitfall. Am. J. Clin. Pathol. 2020;155:575–580.
- Ye B, et al. hASH1 is a specific immunohistochemical marker for lung neuroendocrine tumors. Hum. Pathol. 2016;48:142–147.
- Singhi AD, Klimstra DS. Well‐differentiated pancreatic neuroendocrine tumours (PanNETs) and poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs): concepts, issues and a practical diagnostic approach to high‐grade (G3) cases. Histopathology. 2018;72:168–177.
- Hermans BCM, 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.
- Rekhtman N, 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;22:3618–3629.
- Quinn AM, Chaturvedi A, Nonaka D. High-grade neuroendocrine carcinoma of the lung with carcinoid morphology. Am. J. Surg. Pathol. 2017;41:263–270.
- Pelosi G, et al. Ki-67 evaluation for clinical decision in metastatic lung carcinoids: a proof of concept. Clin. Pathol. 2019;12:1–6.
- Shi C, et al. Liver metastases of small intestine neuroendocrine tumors: Ki-67 heterogeneity and World Health Organization grade discordance with primary tumors. Am. J. Clin. Pathol. 2015;143:398–404.
- Uccella S, Rosa SL, Volante M, Papotti M. Immunohistochemical biomarkers of gastrointestinal, pancreatic, pulmonary, and thymic neuroendocrine neoplasms. Endocr. Pathol. 2018;29:150–168.
- Alcala N, et al. Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids. Nat. Commun. 2019;10:1–21.
- Rindi G, 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;31:1770–1786.
- Singh S, et al. CommNETs/NANETS guidelines for the diagnosis and management of patients with lung neuroendocrine tumors: an international collaborative endorsement and update of the 2015 ENETS expert consensus guidelines. J. Thorac. Oncol. 2020;15:1577–1598.
- Caplin ME, 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;26:1604–1620.
- Marchiò C, et al. Distinctive pathological and clinical features of lung carcinoids with high proliferation index. Virchows Arch. 2017;471:713–720.
- Zahel T, et al. Phenotyping of pulmonary carcinoids and a Ki-67-based grading approach. Virchows Arch. 2012;460:299–308.
- 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;44:224–231.
- 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;9:273–284.
- Clay V, et al. Evaluation of diagnostic and prognostic significance of Ki-67 index in pulmonary carcinoid tumours. Clin. Transl. Oncol. 2017;19:579–586.
- 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;31:1523–1531.
- Vilhena AF, 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.
- Swarts DRA, et al. Interobserver variability for the WHO classification of pulmonary carcinoids. Am. J. Surg. Pathol. 2014;38:1429–1436.
- Warth A, et al. Interobserver agreement of proliferation index (Ki-67) outperforms mitotic count in pulmonary carcinoids. Virchows Arch. 2013;462:507–513.
- Derks, J. L. et al. Clinical-pathological challenges in the classification of pulmonary neuroendocrine neoplasms and targets on the horizon for future clinical practice. J. Thorac. Oncol.10.1016/j.jtho.2021.05.020 (2021).
- Moonen L, et al. Preoperative biopsy diagnosis in pulmonary carcinoids, a shot in the dark. J. Thorac. Oncol. 2021;16:610–618.
- Fabbri A, et al. Ki-67 labeling index of neuroendocrine tumors of the lung has a high level of correspondence between biopsy samples and surgical specimens when strict counting guidelines are applied. Virchows Arch. 2017;470:153–164.
- NCCN Clinical Practice Guidelines in Oncology. Neuroendocrine and Adrenal Tumors. Version 2.2021 Available at . (2021).
- Baudin E, et al. Lung and thymic carcinoids: ESMO clinical practice guidelines for diagnosis, treatment and follow-up †. Ann. Oncol. 2021;32:439–451.
- Pelosi G, Rodriguez J, Viale G, Rosai J. Typical and atypical pulmonary carcinoid tumor overdiagnosed as small-cell carcinoma on biopsy specimens. Am. J. Surg. Pathol. 2005;29:179–187.
- Aslan DL, Gulbahce HE, Pambuccian SE, Manivel JC, Jessurun J. Ki-67 immunoreactivity in the differential diagnosis of pulmonary neuroendocrine neoplasms in specimens with extensive crush artifact. Am. J. Clin. Pathol. 2005;123:874–878.
- Buonocore DJ, et al. CytoLyt fixation significantly inhibits MIB1 immunoreactivity whereas alternative Ki‐67 clone 30‐9 is not susceptible to the inhibition: critical diagnostic implications. Cancer Cytopathol. 2019;127:643–649.
- Swarts DRA, et al. CD44 and OTP are strong prognostic markers for pulmonary carcinoids. Clin. Cancer Res. 2013;19:2197–2207.
- Papaxoinis G, et al. Prognostic significance of CD44 and Orthopedia Homeobox Protein (OTP) expression in pulmonary carcinoid tumours. Endocr. Pathol. 2017;28:60–70.
- Moonen L, Derks J, Dingemans A-M, Speel E-J. Orthopedia Homeobox (OTP) in pulmonary neuroendocrine tumors: the diagnostic value and possible molecular interactions. Cancers. 2019;11:1–13.
- Bellizzi AM. Immunohistochemistry in the diagnosis and classification of neuroendocrine neoplasms: what can Brown do for you? Hum. Pathol. 2019;96:8–33.
- Laddha SV, et al. Integrative genomic characterization identifies molecular subtypes of lung carcinoids. Cancer Res. 2019;79:4339–4347.
- Min K-W. Two different types of carcinoid tumors of the lung: immunohistochemical and ultrastructural investigation and their histogenetic consideration. Ultrastruct. Pathol. 2013;37:23–35.
- Papaxoinis G, Lamarca A, Quinn AM, Mansoor W, Nonaka D. Clinical and pathologic characteristics of pulmonary carcinoid tumors in central and peripheral locations. Endocr. Pathol. 2018;29:259–268.
- Little BP, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: imaging and clinical features of a frequently delayed diagnosis. Am. J. Roentgenol. 2020;215:1312–1320.
- Foran PJ, Hayes SA, Blair DJ, Zakowski MF, Ginsberg MS. Imaging appearances of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Clin. Imag. 2015;39:243–246.
- Rossi G, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia syndrome. Eur. Respir. J. 2016;47:1829–1841.
- Aguayo SM, et al. Idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease. N. Engl. J. Med. 1992;327:1285–1288.
- Marchevsky AM, Walts AE. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) Semin. Diagn. Pathol. 2015;32:438–444.
- Travis WD. Update on small cell carcinoma and its differentiation from squamous cell carcinoma and other non-small cell carcinomas. Mod. Pathol. 2012;25:S18–S30.
- Nicholson SA, et al. Small Cell Lung Carcinoma (SCLC) Am. J. Surg. Pathol. 2002;26:1184–1197.
- Charles MR, Elisabeth B, Corinne F-F, Julien S. Small-cell lung cancer. Nat. Rev. Dis. Prim. 2021;7:3.
- Rudin CM, et al. Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. Nat. Rev. Cancer. 2019;19:289–297.
- Baine MK, et al. SCLC subtypes defined by ASCL1, NEUROD1, POU2F3, and YAP1: a comprehensive immunohistochemical and histopathologic characterization. J. Thorac. Oncol. 2020;15:1823–1835.
- Poirier JT, et al. Selective tropism of Seneca valley virus for variant subtype small cell lung cancer. Jnci J. Natl Cancer Inst. 2013;105:1059–1065.
- Huang Y-H, et al. POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer. Gene Dev. 2018;32:915–928.
- Gay CM, et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell. 2021;39:346–360.
- Thunnissen E, et al. The use of immunohistochemistry improves the diagnosis of small cell lung cancer and its differential diagnosis. an international reproducibility study in a demanding set of cases. J. Thorac. Oncol. 2017;12:334–346.
- Baine MK, et al. Tuft cell master regulator POU2F3 is a novel helpful diagnostic immunohistochemical marker in neuroendocrine-low small cell lung carcinomas. Mod. Pathol. 2021;34:1090.
- Nevo S, Kadouri N, Abramson J. Tuft cells: from the mucosa to the thymus. Immunol. Lett. 2019;210:1–9.
- O'Leary ClaireE, Schneider Christoph, Locksley. RichardM. Tuft cells—systemically dispersed sensory epithelia integrating immune and neural circuitry. Annu. Rev. Immunol. 2019;37:47–74.
- Rekhtman N, et al. SMARCA4-deficient thoracic sarcomatoid tumors represent primarily smoking-related undifferentiated carcinomas rather than primary thoracic sarcomas. J. Thorac. Oncol. 2020;15:231–247.
- Loarer FL, et al. SMARCA4 inactivation defines a group of undifferentiated thoracic malignancies transcriptionally related to BAF-deficient sarcomas. Nat. Genet. 2015;47:1200–1205.
- Yoshida A, et al. Clinicopathological and molecular characterization of SMARCA4-deficient thoracic sarcomas with comparison to potentially related entities. Mod. Pathol. 2017;30:797–809.
- Madahian S, et al. CD56 expression in basaloid anal squamous cell carcinoma–—a potential diagnostic pitfall. Ann. Diagn. Pathol. 2021;53:1–4.
- Hung Y. P. et al. Thoracic NUT carcinoma: expanded pathologic spectrum with expression of TTF‐1 and neuroendocrine markers. Histopathology10.1111/his.14306 (2020).
- Pezzuto F, et al. Immunohistochemical neuroendocrine marker expression in primary pulmonary NUT carcinoma: a diagnostic pitfall. Histopathology. 2020;77:508–510.
- Coit DG. Merkel cell carcinoma. Ann. Surg. Oncol. 2001;8:99S–102S.
- Tatematsu A, et al. Epidermal growth factor receptor mutations in small cell lung cancer. Clin. Cancer Res. 2008;14:6092–6096.
- Yu HA, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin. Cancer Res. 2013;19:2240–2247.
- Offin M, et al. Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes. J. Thorac. Oncol. 2019;14:1784–1793.
- Quintanal-Villalonga Á, et al. Lineage plasticity in cancer: a shared pathway of therapeutic resistance. Nat. Rev. Clin. Oncol. 2020;17:360–371.
- Levacq D, D’Haene N, Wind R, de, Remmelink M, Berghmans T. Histological transformation of ALK rearranged adenocarcinoma into small cell lung cancer: a new mechanism of resistance to ALK inhibitors. Lung Cancer. 2016;102:38–41.
- Rubin MA, Bristow RG, Thienger PD, Dive C, Imielinski M. Impact of lineage plasticity to and from a neuroendocrine phenotype on progression and response in prostate and lung cancers. Mol Cell. 2020;80:562–577.
- Schultheis AM, et al. PD-L1 expression in small cell neuroendocrine carcinomas. Eur. J. Cancer. 2015;51:421–426.
- Matsuo K. et al. Delta‐like canonical Notch ligand 3 as a potential therapeutic target in malignancies: a brief overview. Cancer Sci.10.1111/cas.15017 (2021).
- Lantuejoul S, Fernandez-Cuesta L, Damiola F, Girard N, McLeer A. New molecular classification of large cell neuroendocrine carcinoma and small cell lung carcinoma with potential therapeutic impacts. Transl. Lung Cancer Res. 2020;9:2233–2244.
- Xie H, et al. Expression of delta-like protein 3 is reproducibly present in a subset of small cell lung carcinomas and pulmonary carcinoid tumors. Lung Cancer. 2019;135:73–79.
- Hermans BCM, et al. DLL3 expression in large cell neuroendocrine carcinoma (LCNEC) and association with molecular subtypes and neuroendocrine profile. Lung Cancer. 2019;138:102–108.
- Milione M, et al. Ki-67 index of 55% distinguishes two groups of bronchopulmonary pure and composite large cell neuroendocrine carcinomas with distinct prognosis. Neuroendocrinology. 2020;111:475–489.
- Baine MK, Rekhtman N. Multiple faces of pulmonary large cell neuroendocrine carcinoma: update with a focus on practical approach to diagnosis. Transl. Lung Cancer Res. 2020;9:860–878.
- Travis WD, et al. Reproducibility of neuroendocrine lung tumor classification. Hum. Pathol. 1998;29:272–279.
- Bakker MAD, et al. Small cell carcinoma of the lung and large cell neuroendocrine carcinoma interobserver variability. Histopathology. 2010;56:356–363.
- George J, et al. Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. Nat. Commun. 2018;9:1–13.
- Derks JL, et al. New insights into the molecular characteristics of pulmonary carcinoids and large-cell neuroendocrine carcinomas, and the impact on their clinical management. J. Thorac. Oncol. 2018;13:752–766.
- Gazdar AF, Carney DN, Nau MM, Minna JD. Characterization of variant subclasses of cell lines derived from small cell lung cancer having distinctive biochemical, morphological, and growth properties. Cancer Res. 1985;45:2924–2930.
- Gazdar AF, et al. The comparative pathology of genetically engineered mouse models for neuroendocrine carcinomas of the lung. J Thorac. Oncol. 2015;10:553–564.
- Shen R, et al. Harnessing clinical sequencing data for survival stratification of patients with metastatic lung adenocarcinomas. JCO Precis. Oncol. 2019;3:1–9.
- Derks JL, et al. Chemotherapy for pulmonary large cell neuroendocrine carcinomas: does the regimen matter? Eur. Respir. J. 2017;49:1–9.
- Naidoo J, et al. Large cell neuroendocrine carcinoma of the lung: clinico-pathologic features, treatment, and outcomes. Clin. Lung Cancer. 2016;17:e121–e129.
- Derks J, et al. Molecular subtypes of pulmonary large cell neuroendocrine carcinoma predict chemotherapy treatment outcome. Clin. Cancer Res. 2017;24:33–42.
- Zhuo M, et al. The prognostic and therapeutic role of genomic subtyping by sequencing tumor or cell-free DNA in pulmonary large-cell neuroendocrine carcinoma. Clin. Cancer Res. 2020;26:892–901.
- Feola T, et al. Neuroendocrine carcinomas with atypical proliferation index and clinical behavior: a systematic review. Cancers. 2021;13:1–11.
- Esfahani HS, Vela CM, Chauhan A. Prevalence of TP-53/Rb-1 co-mutation in large cell neuroendocrine carcinoma. Front. Oncol. 2021;11:1–5.
- Hong DS, et al. KRASG12C inhibition with sotorasib in advanced solid tumors. N. Engl. J. Med. 2020;383:1207–1217.
- Kriegsmann K, et al. Role of synaptophysin, chromogranin and CD56 in adenocarcinoma and squamous cell carcinoma of the lung lacking morphological features of neuroendocrine differentiation: a retrospective large-scale study on 1170 tissue samples. BMC Cancer. 2021;21:1–9.
- Rekhtman N, et al. Pulmonary large cell neuroendocrine carcinoma with adenocarcinoma-like features: napsin A expression and genomic alterations. Mod. Pathol. 2018;31:111–121.
- Baine MK, Sinard JH, Cai G, Homer RJ. A semiquantitative scoring system may allow biopsy diagnosis of pulmonary large cell neuroendocrine carcinoma. Am. J. Clin. Pathol. 2019;153:165–174.
- Dowlati A, et al. Clinical correlation of extensive-stage small-cell lung cancer genomics. Ann. Oncol. 2016;27:642–647.
- Travis WD, et al. International association for the study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011;6:244–285.
- Derks JL, et al. Is the sum of positive neuroendocrine immunohistochemical stains useful for diagnosis of large cell neuroendocrine carcinoma (LCNEC) on biopsy specimens? Histopathology. 2019;74:555–566.
- Weissferdt A. Pulmonary carcinomas with mucinous and neuroendocrine differentiation. Am. J. Surg. Pathol. 2018;42:1246–1252.
- Rosa SL, Sessa F, Uccella S. Mixed Neuroendocrine-Nonneuroendocrine Neoplasms (MiNENs): unifying the concept of a heterogeneous group of neoplasms. Endocr. Pathol. 2016;27:284–311.
- Quintanal-Villalonga A. et al. Multi-omic analysis of lung tumors defines pathways activated in neuroendocrine transformation. Cancer Discov. 10.1158/-20-1863 (2021).
- Sen F, Borczuk AC. Combined carcinoid tumor of the lung: a combination of carcinoid and adenocarcinoma. Lung Cancer. 1998;21:53–58.
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