Differential cytological diagnosis of typical and atypical lung carcinoids

Abstract

Background: The potential for diagnosing lung carcinoids using cytological methods has been underexplored, with limited publications available to support evidence-based conclusions.

Aim: This study aims to evaluate the of cytological diagnostic capabilities for differentiating typical and atypical lung carcinoids.

Materials and Methods: The study included cytological examination results from 18 patients diagnosed with carcinoid tumor at the cytological laboratory of the Altai Regional Oncology Dispensary (Barnaul). The cell material of carcinoid tumors was obtained during diagnostic video bronchoscopy and stained using the Pappenheim method. In all observations, the final diagnosis was the result of histological examination of tumors with immunohistochemical reactions. The obtained results were evaluated using Microsoft Office Excel 2010 and Statistica 10.0. Significant cellular signs (using multivariate analysis) were determined which were assessed to solve diagnostic problems when establishing a cytological diagnosis. Differences between carcinoids were assessed using discriminant analysis with Fisher’s F-test.

Results: Carcinoid tumors accounted for 2.72% of the number of neuroendocrine lung neoplasms. Typical carcinoid was diagnosed in 13 patients, atypical carcinoid was observed in 5 cases. The average age at onset of typical carcinoid was 58.46±19.04 years, of atypical carcinoid — 63.2±4.66 years. Cellular features of typical and atypical carcinoids were assessed, which formed the basis for the statistical analysis. To identify the most informative combinations of cellular features, a multivariate analysis was used that determined the main cytological features for carcinoids characterization, using only light microscopy. The values of the first, second, and third factors were determined; the factor value of the cellular feature variants was 96.02% of the sample (variance). In the discriminant analysis, 14 initial tumor cell parameters (discriminant indices) were used to classify patients into one of two groups (typical and atypical carcinoids), on the basis of which the results of the carcinoid study were classified. Step-by-step assessment using Fisher’s F-test revealed differences that amounted to 37.97% only, suggesting that the cellular features are statistically insignificant.

Conclusion: The data obtained demonstrate the possibilities of cytological diagnosis of lung carcinoids using only light microscopy at the first stage of patient examination. Cellular features enable to diagnose the carcinoid tumor with an accuracy of more than 96%. However, it is possible to differentiate between typical and atypical carcinoids in less than 40% of cases due to the large number of similar features.

Keywords

typical carcinoid / atypical carcinoid / cytological diagnosis / light microscopy / multivariate analysis / discriminant analysis

References

[1] WHO Classification of Tumours Editorial Board. WHO Classification of Tumours, 5th Edition, Volume 5. Thoracic tumours. Lyon: International Agency for Research on Cancer; 2021.

[2] WHO Classification of Tumours Editorial Board. WHO Classification of Tumours, 5th Edition, Volume 5. Thoracic tumours. Lyon : International Agency for Research on Cancer, 2021.

[3] Metovic J, Barella M, Bianchi F, et al. Morphologic and molecular classification of lung neuroendocrine neoplasms. Virchows Arch. 2021;478(1):5–19. doi: 10.1007/s00428-020-03015-z

[4] Metovic J., Barella M., Bianchi F., et al. Morphologic and molecular classification of lung neuroendocrine neoplasms // Virchows Arch. 2021. Vol. 478, N 1. P. 5–19. doi: 10.1007/s00428-020-03015-z

[5] Faggiano A, Ferolla P, Grimaldi F, et al. Natural history of gastro-entero-pancreatic and thoracic neuroendocrine tumors. Data from a large prospective and retrospective Italian epidemiological study: the NET management study. J Endocrinol Invest. 2012;35(9):817–823. doi: 10.3275/8102

[6] Faggiano A., Ferolla P., Grimaldi F., et al. Natural history of gastro-entero-pancreatic and thoracic neuroendocrine tumors. Data from a large prospective and retrospective Italian epidemiological study: the NET management study // J Endocrinol Invest. 2012. Vol. 35, N 9. P. 817–823. doi: 10.3275/8102

[7] McCaughan BC, Martini N, Bains MS. Bronchial carcinoids. Review of 124 cases. J Thorac Cardiovasc Surg. 1985;89(1):8–17.

[8] McCaughan B.C., Martini N., Bains M.S. Bronchial carcinoids. Review of 124 cases // J Thorac Cardiovasc Surg. 1985. Vol. 89, N 1. P. 8–17.

[9] Halperin DM, Shen C, Dasari A, et al. Frequency of carcinoid syndrome at neuroendocrine tumour diagnosis: a population-based study. Lancet Oncol. 2017;18(4):525–534. doi: 10.1016/S1470-2045(17)30110-9

[10] Halperin D.M., Shen C., Dasari A., et al. Frequency of carcinoid syndrome at neuroendocrine tumour diagnosis: a population-based study // Lancet Oncol. 2017. Vol. 18, N 4. P. 525–534. doi: 10.1016/S1470-2045(17)30110-9

[11] Trevis WD, Brambilla E, Burke AP, et al. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th ed. Lyon: IARC; 2015.

[12] Trevis W.D., Brambilla E., Burke A.P., et al. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heard. 4th ed. Lyon : IARC, 2015.

[13] Melosky B. Low Grade Neuroendocrine Tumors of the Lung. Front Oncol. 2017;7:119. doi: 10.3389/fonc.2017.00119

[14] Melosky B. Low Grade Neuroendocrine Tumors of the Lung // Front Oncol. 2017. Vol. 7. P. 119. doi: 10.3389/fonc.2017.00119

[15] Riihimaki M, Hemminki A, Sundquist K, et al. The epidemiology of metastases in neuroendocrine tumors. Int J. Cancer. 2016;139:2679–2686. doi: 10.1002/ijc.30400

[16] Riihimaki M., Hemminki A., Sundquist K., et al. The epidemiology of metastases in neuroendocrine tumors // Int J. Cancer. 2016. Vol. 139. P. 2679–2686. doi: 10.1002/ijc.30400

[17] Travis WD. Pathology and diagnosis of neuroendocrine tumors: lung neuroendocrine. Thorac Surg Clin. 2014;24(3):257–266. doi: 10.1016/j.thorsurg.2014.04.001

[18] Travis W.D. Pathology and diagnosis of neuroendocrine tumors: lung neuroendocrine // Thorac Surg Clin. 2014. Vol. 24, N 3. P. 257–266. doi: 10.1016/j.thorsurg.2014.04.001

[19] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7–30. doi: 10.3322/caac.21590

[20] Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2020 // CA Cancer J Clin. 2020. Vol. 70, N 1. P. 7–30. doi: 10.3322/caac.21590

[21] Rindi G, Klimstra DS, Abedi-Ardekani B, 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. doi: 10.1038/s41379-018-0110-y

[22] Rindi G., Klimstra D.S., Abedi-Ardekani B., 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. Vol. 31, N 12. P. 1770–1786. doi: 10.1038/s41379-018-0110-y

[23] Caplin ME, Baudin E, Ferolla P, 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. doi: 10.1093/annonc/mdv041

[24] Caplin M.E., Baudin E., Ferolla P., et al. Pulmonary neuroendocrine, N carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids // Ann Oncol. 2015. Vol. 26, N 8. P. 1604–1620. doi: 10.1093/annonc/mdv041

[25] 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. doi: 10.1097/PAS.0000000000000916

[26] Rooper L.M., Sharma R., Li Q.K., Illei P.B., Westra W.H. 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. Vol. 41, N 11. P. 1561–1569. doi: 10.1097/PAS.0000000000000916

[27] Fujino K, Motooka Y, Hassan WA, et al. Insulinoma-Associated Protein 1 Is a Crucial Regulator of Neuroendocrine Differentiation in Lung Cancer. Am J Pathol. 2015;185(12):3164–3177. doi: 10.1016/j.ajpath.2015.08.018

[28] Fujino K., Motooka Y., Hassan W.A., et al. Insulinoma-Associated Protein 1 Is a Crucial Regulator of Neuroendocrine Differentiation in Lung Cancer // Am J Pathol. 2015. Vol. 185, N 12. P. 3164–3177. doi: 10.1016/j.ajpath.2015.08.018

[29] Walts AE, Ines D, Marchevsky AM. Limited role of Ki-67 proliferative index in predicting overall short-term survival in patients with typical and atypical pulmonary carcinoid tumors. Mod Pathol. 2012;25(9):1258–1264. doi: 10.1038/modpathol.2012.81

[30] Walts A.E., Ines D., Marchevsky A.M. Limited role of Ki-67 proliferative index in predicting overall short-term survival in patients with typical and atypical pulmonary carcinoid tumors // Mod Pathol. 2012. Vol. 25, N 9. P. 1258–1264. doi: 10.1038/modpathol.2012.81

[31] Swarts DR, Rudelius M, Claessen SM, et al. Limited additive value of the Ki-67 proliferative index on patient survival in World Health Organization-classified pulmonary carcinoids. Histopathology. 2017;70(3):412–422. doi: 10.1111/his.13096

[32] Swarts D.R., Rudelius M., Claessen S.M., et al. Limited additive value of the Ki-67 proliferative index on patient survival in World Health Organization-classified pulmonary carcinoids // Histopathology. 2017. Vol. 70, N 3. P. 412–422. doi: 10.1111/his.13096

[33] Marchiò C, Gatti G, Massa F, et al. Distinctive pathological and clinical features of lung carcinoids with high proliferation index. Virchows Arch. 2017;471(6):713–720. doi: 10.1007/s00428-017-2177-0

[34] Marchiò C., Gatti G., Massa F., et al. Distinctive pathological and clinical features of lung carcinoids with high proliferation index // Virchows Arch. 2017. Vol. 471, N 6. P. 713–720. doi: 10.1007/s00428-017-2177-0

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