Capabilities of immunohistochemistry in the diagnostics of malignant solitary pulmonary nodules in practice

Authors

Keywords:

solitary malignant pulmonary nodule, diagnostics, immunohistochemistry

Abstract

Background. At present morphological diagnostics with immunohistochemistry (IHC) examination offers to objectively establish the histological type of malignant solitary pulmonary nodules (SPN). The aim is to present our own experience and evaluate the possibilities of immunohistochemisty in diagnostics of solitary malignant focal lung lesions in clinical practice. Methods. A retrospective cohort study was conducted, which included 56 cases of primary malignant SPNs that were surgically removed. Conventional histological examination was performed in all cases followed by IHC study according to a standard protocol. The antigen reaction was assessed as diffuse (≥ 60 % of stained tumors cells), focal (10–59 % of stained tumors cells) and negative (less than 10 % of stained tumors cells). Results. Lung adenocarcinomas of various histological subtypes were diagnosed by conventional morphological examination in 34 (60,7 %) cases. Squamous cell carcinoma, large cell carcinoma and neuroendocrine tumour were diagnosed (6 cases, 10,7 %, respectively) less frequently. In 3 (5,4 %) cases salivary gland-type lung tumors were diagnosed, and in 1 (1,8 %) case, the need for differential diagnosis of a precancerous process and a true tumor arose. The IHC study made it possible to identify lung adenocarcinomas of various histological structure in 36 cases. A positive reaction with TTF-1, Napsin A and CK7 was detected in all cases of their use. In 2 cases mucinous adenocarcinoma (positive reaction with CK20) and in 2 cases fetal adenocarcinoma (positive reaction with Synaptophysin and/or Chromogranin A) were confirmed. In the case of squamous cell lung carcinoma, diffuse expression of p40 and/or p63 was observed, with diffuse and focal expression of CK5/6 in all cases of their use. In adenosquamous carcinoma, diffuse and focal positive reaction with CK7, TTF-1, Napsin A, p63 and CK5/6 was detected. In the case of large cell carcinoma, a diffuse positive reaction with CK7, CK8 and TTF-1 was observed, with a negative reaction with Napsin A, CK5/6, p40, p63, Synaptophysin and CD56. In cases of previously diagnosed lung carcinoids, staining with Synaptophysin and CD56 showed a diffuse positive reaction, with a focal reaction with Chromogranin A, TTF-1, CK7, CK8 and CK18 in all cases of their use. The proliferation index (Ki-67) was in the range of 5–20 %. In the case of large cell neuroendocrine carcinoma, a diffuse positive reaction was observed with Synaptophysin, TTF-1 and CD56 when use, and in one case with Chromogranin A and CK7. The proliferation index (Ki-67) was 40–80 %. In cases of salivary gland-type lung tumors, the panel of IHC markers was selected individually, and included a relatively large number of antibodies. Comparison of conventional histological examination and the results of the IHC study confirmed the previously determined histological type/subtype of lung tumor in 47 (83,9 %) cases. In 9 (16,1 %) cases, the determined immunoprofile led to a change in the histological type of lung tumor, which is crucial important for the further medical management of such patients. Conclusion. Today morphological diagnostics using immunohistochemistry has leading value for the most accurate determination of the histological type and clarification of malignancy degree of malignant solitary pulmonary nodules. The marker panels that are appropriate for use in IHC study in cases of the most common primary lung tumors have been proposed.

References

  1. Ost DE, Gould MK. Decision making in patients with pulmonary nodules. Am J Respir Crit Care Med. 2012;185(4):363–72. doi: 10.1164/rccm.201104-0679CI.
  2. Khan T, Usman Y, Abdo T, Chaudry F, Keddissi JI, Youness HA. Diagnosis and manage-ment of peripheral lung nodule. Ann Transl Med. 2019 Aug;7(15):348. doi: 10.21037/atm.2019.03.59.
  3. Bororov LV, Semivolos AV, Kobzev OI, Sovenko VM, Borisyuk BO, Shevchenko AI, Klapchuk OG. [Treatment of patients with malignancies of various localizations spread into the lungs]. Oncology. 2009;11:286–287. http://dspace.nbuv.gov.ua/handle/123456789/19707. Ukrainian.
  4. Raad RA, Suh J, Harari S, Naidich DP, Shiau M, Ko JP. Nodule characterization: subsolid nodules. Radiol Clin North Am. 2014 Jan;52(1):47-67. doi: 10.1016/j.rcl.2013.08.011.
  5. Bertolaccini L, Batirel H, Brunelli A, Gonzalez-Rivas D, Ismail M, Ucar AM, Ng CSH, Scarci M, Sihoe ADL, Ugalde PA, Akar FA, Bedetti B, Nadal SB, Brandolini J, Crucitti P, Enyedi A, Fernando HC, Furak J, Gallego-Poveda J, Galvez-Munos C, Hanke I, Hernandez-Arenas LA, Janik M, Juhos P, Libretti L, Lucciarini P, Macrì P, Margaritora S, Mahoozi HR, Nachira D, Pardolesi A, Pischik V, Sagan D, Schreurs H, Sekhniaidze D, Socci L, Tosi D, Turna A, Vannucci F, Zielinski M, Rocco G. Corrigendum to 'Uniportal video-assisted thoracic surgery lobectomy: a consensus report from the Uniportal VATS Interest Group (UVIG) of the European Society of Thoracic Surgeons (ESTS). Eur J Cardiothorac Surg. 2019;56(3): 628-629. doi: 10.1093/ejcts/ezz229.
  6. Zappa C, Mousa SA. Non-small cell lung cancer: current treatment and future advances. Transl Lung Cancer Res. 2016;5(3):288-300. doi:10.21037/tlcr.2016.06.07.
  7. Zhu F, Liu Z, Hou Y, He D, Ge X, Bai C, Jiang L, Li S. Primary salivary gland-type lung cancer: clinicopathological analysis of 88 cases from China. J Thorac Oncol. 2013 Dec;8(12):1578-84. doi: 10.1097/JTO.0b013e3182a7d272.
  8. Petrov SV, Raikhlin NT. [Manual on immunohistochemical diagnostics of human tu-mors]. 4th, revised and extended edition. Kazan, 2012, 623 p. Russian.
  9. Gurda GT, Zhang L, Wang Y, Chen L, Geddes S, Cho WC, Askin F, Gabrielson E, Li QK. Utility of five commonly used immunohistochemical markers TTF-1, Napsin A, CK7, CK5/6 and P63 in primary and metastatic adenocarcinoma and squamous cell carcinoma of the lung: a retrospective study of 246 fine needle aspiration cases. Clin Transl Med. 2015 Apr 21;4:16. doi: 10.1186/s40169-015-0057-2.
  10. Umakanthan S, Chalapathi Rao AV, Mo-hammed W. Role of immunohistochemistry markers in neoplastic lung lesions. J Cancer Res Ther. 2021 Oct-Dec;17(6):1382-1388. doi: 10.4103/jcrt.JCRT_187_19.
  11. Argon A, Nart D, Veral A. The Value of Cytokeratin 5/6, p63 and Thyroid Transcription Factor-1 in adenocarcinoma, squamous cell carcinoma and non-small-cell lung cancer of the lung. Turk Patoloji Derg. 2015;31(2):81-8. doi: 10.5146/tjpath.2015.01302.
  12. Rekhtman N, Ang DC, Sima CS, Travis WD, Moreira AL. Immunohistochemical algorithm for differentiation of lung adenocarcinoma and squamous cell carcinoma based on large series of whole-tissue sections with validation in small specimens. Mod Pathol. 2011 Oct;24(10):1348-59. doi: 10.1038/modpathol.2011.92.
  13. Walia R, Jain D, Madan K, Sharma MC, Mathur SR, Mohan A, Iyer VK, Kumar L. p40 & thyroid transcription factor-1 immunohistochemi-stry: a useful panel to characterize non-small cell lung carcinoma-not otherwise specified (NSCLC-NOS) category. Indian J Med Res. 2017 Jul;146(1):42-48. doi: 10.4103/ijmr.IJMR_1221_15.
  14. Carney JM, Kraynie AM, Roggli VL. Im-munostaining in lung cancer for the clinician. Commonly used markers for differentiating primary and metastatic pulmonary tumors. Ann Am Thorac Soc. 2015 Mar;12(3):429-35. doi: 10.1513/AnnalsATS.201501-004FR.
  15. Hofman P. ALK in non-small cell lung cancer (NSCLC) pathobiology, epidemiology, detection from tumor tissue and algorithm diagnosis in a daily practice. Cancers (Basel). 2017 Aug 12;9(8):107. doi: 10.3390/cancers9080107.
  16. Nicholson AG, Tsao MS, Beasley MB, Borczuk AC, Brambilla E, Cooper WA, Dacic S, Jain D, Kerr KM, Lantuejoul S, Noguchi M, Papotti M, Rekhtman N, Scagliotti G, van Schil P, Sholl L, Yatabe Y, Yoshida A, Travis WD. The 2021 WHO classification of lung tumors: impact of advances since 2015. J Thorac Oncol. 2022 Mar;17(3):362-387. doi: 10.1016/j.jtho.2021.11.003.
  17. Duma N, Santana-Davila R, Molina JR. Non-small cell lung cancer: epidemiology, screening, diagnosis, and treatment. Mayo Clin Proc. 2019 Aug;94(8):1623-1640. doi: 10.1016/j.mayocp.2019.01.013.
  18. Yang L, Zhang Q, Bai L, Li TY, He C, Ma QL, Li LS, Huang XQ, Qian GS. Assessment of the cancer risk factors of solitary pulmonary nodules. Oncotarget. 2017 Apr 25;8(17):29318-29327. doi: 10.18632/oncotarget.16426.
  19. Korzhevskiy DE, Gilyarov AV. [Basics of histological technique]. SPb(Rus): SpetsLit, 2010. 63-64 p. Russian.
  20. Fedchenko N, Reifenrath J. Different ap-proaches for interpretation and reporting of immunohistochemistry analysis results in the bone tissue – a review. Diagn Pathol. 2014 Nov 29;9:221. doi: 10.1186/s13000-014-0221-9.
  21. Fletcher CDM. Diagnostic histopathology of tumors. 4th ed. PA: Elsevier; 2013. 1148 p.
  22. Brunnström H, Johansson L, Jirström K, Jönsson M, Jönsson P, Planck M. Immunohistochemistry in the differential diagnostics of primary lung cancer: an investigation within the Southern Swedish Lung Cancer Study. Am J Clin Pathol. 2013 Jul;140(1):37-46. doi: 10.1309/AJCP50RDXSCSBTBO.
  23. Neumann JM, Freitag H, Hartmann JS, Niehaus K, Galanis M, Griesshammer M, Kellner U, Bednarz H. Subtyping non-small cell lung cancer by histology-guided spatial metabolomics. J Cancer Res Clin Oncol. 2022 Feb;148(2):351-360. doi: 10.1007/s00432-021-03834-w.
  24. Tuffaha SAM, Gichka S, Guski H, Christiansen G. [Immunohistochemistry in the diagnosis of tumors]. 2018. 316 р. Russian.
  25. Rekhtman N, Braine MK, Bishop JA. [Quick reference handbook for surgical patholo-gists]; per. from english. Ed. Krivolapova YuA. 2021. 300 p. Russian.
  26. Yatabe Y, Dacic S, Borczuk AC, Warth A, Russell PA, Lantuejoul S, Beasley MB, Thunnissen E, Pelosi G, Rekhtman N, Bubendorf L, Mino-Kenudson M, Yoshida A, Geisinger KR, Noguchi M, Chirieac LR, Bolting J, Chung JH, Chou TY, Chen G, Poleri C, Lopez-Rios F, Papotti M, Sholl LM, Roden AC, Travis WD, Hirsch FR, Kerr KM, Tsao MS, Nicholson AG, Wistuba I, Moreira AL. Best practices recommendations for diagnostic immunohistochemistry in lung cancer. J Thorac Oncol. 2019 Mar;14(3):377-407. doi: 10.1016/j.jtho.2018.12.005.
  27. Völkel C, De Wispelaere N, Weidemann S, Gorbokon N, Lennartz M, Luebke AM, Hube-Magg C, Kluth M, Fraune C, Möller K, Bernreuther C, Lebok P, Clauditz TS, Jacobsen F, Sauter G, Uhlig R, Wilczak W, Steurer S, Minner S, Krech RH, Dum D, Krech T, Marx AH, Simon R, Burandt E, Menz A. Cytokeratin 5 and cytokeratin 6 expressions are unconnected in normal and cancerous tissues and have separate diagnostic implications. Virchows Arch. 2022 Feb;480(2):433-447. doi: 10.1007/s00428-021-03204-4.
  28. Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, Chirieac LR, Dacic S, Duhig E, Flieder DB, Geisinger K, Hirsch FR, Ishikawa Y, Kerr KM, Noguchi M, Pelosi G, Powell CA, Tsao MS, Wistuba I., WHO Panel. The 2015 World Health Organization classification of lung tumors: impact of genetic, clinical and radi-ologic advances since the 2004 classification. J Thorac Oncol. 2015 Sep;10(9):1243-1260.
  29. Masuda D, Masuda R, Matsuzaki T, Im-amura N, Aruga N, Tanaka M, Inokuchi S, Kijima H, Iwazaki M. Ki-67 labeling index affects tumor infiltration patterns of lung squamous cell carcinoma. Mol Med Rep. 2015 Nov;12(5):7303-9. doi: 10.3892/mmr.2015.4354.
  30. Li C, Lu H. Adenosquamous carcinoma of the lung. Onco Targets Ther. 2018 Aug 14;11:4829-4835. doi: 10.2147/OTT.S164574.
  31. Li C, Zheng X, Li P, Wang H, Hu J, Wu L, Wang Z, Guo H, Wu F, Zhong W, Zhou C, Chu Q, Zhao J, Zheng X, Xiao W, Zhu W, Zhang L, Li Q, Jiang K, Miao Q, Wu B, Xu Y, Wu S, Wang H, Yang S, Li Y, Xia X, Yi X, Huang C, Zhu B, Lin G. Heterogeneity of tumor immune microenvironment and real-world analysis of immunotherapy efficacy in lung adenosquamous carcinoma. Front Immunol. 2022 Aug 12;13:944812. doi: 10.3389/fimmu.2022.944812.
  32. Rao N. Adenosquamous carcinoma. Semin Diagn Pathol. 2014 Jul;31(4):271-7. doi: 10.1053/j.semdp.2014.06.004.
  33. Borczuk AC. Uncommon types of lung carcinoma with mixed histology: sarcomatoid carcinoma, adenosquamous carcinoma, and mucoepidermoid carcinoma. Arch Pathol Lab Med. 2018 Aug;142(8):914-921. doi: 10.5858/arpa.2017-0584-RA. PMID: 30040455.
  34. Metovic J, Barella M, Bianchi F, Hofman P, Hofman V, Remmelink M, Kern I, Carvalho L, Pattini L, Sonzogni A, Veronesi G, Harari S, Forest F, Papotti M, Pelosi G. Morphologic and molecular classification of lung neuroendocrine neoplasms. Virchows Arch. 2021 Jan;478(1):5-19. doi: 10.1007/s00428-020-03015-z.
  35. Andrini E, Marchese PV, De Biase D, Mosconi C, Siepe G, Panzuto F, Ardizzoni A, Campana D, Lamberti G. Large cell neuroendocrine carcinoma of the lung: current understanding and challenges. J Clin Med. 2022 Mar 7;11(5):1461. doi: 10.3390/jcm11051461.
  36. Modlin I. M., Gustafsson B. I., Moss S. F. et al. Chromogranin A – biological function and clinical utility in neuroendocrine tumor disease. Ann Surg Oncol 2010;17 (9):2427–43. doi: 10.1245/s10434-010-1006-3.
  37. Hayoune A, Mahfoud I, Thouil A, Kouismi H. Large cell neuroendocrine carcinoma of the lung: a case series of 14 cases. Cureus. 2022 Aug 1;14(8):e27559. doi: 10.7759/cureus.27559.
  38. Lindsay CR, Shaw EC, Moore DA, Rassl D, Jamal-Hanjani M, Steele N, Naheed S, Dick C, Taylor F, Adderley H, Black F, Summers Y, Evans M, Rice A, Fabre A, Wallace WA, Nicholson S, Haragan A, Taniere P, Nicholson AG, Laing G, Cave J, Forster MD, Blackhall F, Gosney J, Popat S, Kerr KM. Large cell neuroendocrine lung carcinoma: consensus statement from The British Thoracic Oncology Group and the Association of Pulmonary Pathologists. Br J Cancer. 2021 Oct;125(9):1210-1216. doi: 10.1038/s41416-021-01407-9.
  39. Finkova EP. [The results of immunohisto-chemical study of signaling pathways’ markers of proliferation in uterine leiomyoma in women using hormonal contraception]. Morphologia. 2021;15(1):67-72. doi: https://doi.org/10.26641/1997-9665.2021.1.67-72. Ukrainian.
  40. Ramirez RA, Beyer DT, Diebold AE, Vo-ros BA, Chester MM, Wang YZ, Boudreaux JP, Woltering EA, Uhlhorn AP, Ryan P, Campeau RJ, Anthony LB. Prognostic factors in typical and atypical pulmonary carcinoids. Ochsner J. 2017 Winter;17(4):335-340.
  41. Falk N, Weissferdt A, Kalhor N, Moran CA. Primary pulmonary salivary gland-type tumors: A Review and Update. Adv Anat Pathol. 2016 Jan;23(1):13-23. doi: 10.1097/PAP.0000000000000099.
  42. Wang M, Gilani S, Xu H, Cai G. Salivary gland-type tumors of the lung. Arch Pathol Lab Med. 2021 Nov 1;145(11):1379-1386. doi: 10.5858/arpa.2021-0093-RA.
  43. Weissferdt A., Kalhor N., Moran C. A. Primary pulmonary salivary gland-type tumors: a review and update. Adv Anat Pathol 2016;23:13–23.
  44. Limaiem F, Lekkala MR, Sharma S. Mu-coepidermoid lung tumor. 2023 Jan 1. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. PMID: 30725962. https://www.ncbi.nlm.nih.gov/books/NBK537277/.

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2025-04-18

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Liskina , I., & Zagaba , L. (2025). Capabilities of immunohistochemistry in the diagnostics of malignant solitary pulmonary nodules in practice. Морфологія / Morphologia / Morfologìâ, 17(1), 29–41. Retrieved from https://morphology.dma.edu.ua/article/view/278697

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Vol. 17 No. 1 (2023)

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