The Role of p40, p63, MAdL and TTF-1 in Differential Diagnosis of Primary Lung Adenocarcinoma, Squamous Cell Carcinoma and Metastatic Adenocarcinomas of The Lung

NAİLE KÖKBUDAK , GÜLŞAH ŞAFAK ÖRKAN, LEMA TAVLI

  • NAİLE KÖKBUDAK: NECMETTİN ERBAKAN ÜNİVERSİTESİ TIP FAKÜLTESİ
  • GÜLŞAH ŞAFAK ÖRKAN: ANKARA SANATORYUM EĞİTİM VE ARAŞTIRMA HASTANESİ
  • LEMA TAVLI: Lefke Avrupa Üniversitesi
  • Year : 2026
  • Vol : 42
  • Issue : 2
  •  Page : 119-126
Objective: Lung cancer is the most common and fatal type of cancer in both women and men. Due to differences in treatment, it is important to accurately distinguish
between lung cancer subtypes. Algorithms recommend using maximum of two markers (ie, a single adenocarcinoma marker and a single squamous marker) in each
case to preserve tissue for molecular studies. This study aimed to determine the optimal combination of these markers.
Materials and Methods: This retrospective study included 62 cases diagnosed between 2010 and 2015, consisting of 29 primary lung adenocarcinoma (ADC), 19
squamous cell carcinoma (SCC), and 14 metastatic ADC to the lung. Immunohistochemical analyses for TTF-1, p40, p63, and MAdL were performed. Staining intensity
and the percentage of positive tumor cells were recorded with sensitivity and specificity values also calculated.
Results: TTF-1 showed high intensity and positivity in 79.31% of primary lung ADCs, with a sensitivity of 96.55% and specificity of 100%. p40 showed high intensity
staining in 84.21% of SCCs, with a sensitivity of 89.47% and specificity of 100%. p63 exhibited 100% sensitivity for SCC but low specificity (44.82%) due to focal
positivity in ADCs. MAdL had 82.75% sensitivity and 100% specificity for ADC. No marker positively stained metastatic ADCs.
Conclusion: Of the tested markers, TTF-1 showed the highest diagnostic accuracy for ADC and p40 for SCC. MAdL could serve as a supportive marker in ADC. p63
should considered with caution due to its low specificity. Particularly in small biopsy samples, to preserve tissue for molecular studies, a limited panel combining p40
and TTF-1 immunohistochemical markers is recommended for routine diagnostic use.
Cite this Article As : Kokbudak N, Orkan SG, Tavli L. The Role of p40, p63, MAdL and TTF-1 in Differential Diagnosis of Primary Lung Adenocarcinoma, Squamous Cell Carcinoma and Metastatic Adenocarcinomas of The Lung. Selcuk Med J 2026;42(2): 119-126

Download Citation: Endnote/Zotero/Mendeley (RIS) RIS File

Download Citation: BibTeX BibTeX File

Conflict of interest : The authors declare that they have no conflict of interest.
This article is published under the CC BY-NC 4.0 license.
Selcuk Medical Journal
2026, Vol. 42 (2)
ISSN: 1017-6616
E-ISSN: 2149-8059
Received : , Accepted : , Published Online :

References

  1. 1- Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-263. doi:10.3322/caac.21834
  2. 2- Kuzey GM, Özdamar ŞO, Zergeroğlu S. Temel Patoloji. Güneş Kitabevi, 2007; 381-390.
  3. 3- Travis WD, Brambilla E, Burke AP,et al. World Health Organisation. International Agency for Research on Cancer. International Academy of Pathology International Association for the Study of Lung Cancer. Pathology and genetics of tumors of lung, pleura, thymus and heart. 4th edition. Lyon, IARC press, 2014:9-151.
  4. 4- Schallenberg S, Dernbach G, Dragomir MP, et al. TTF-1 status in early-stage lung adenocarcinoma is an independent predictor of relapse and survival superior to tumor grading. Eur J Cancer. 2024;197:113474. doi:10.1016/j.ejca.2023.113474
  5. 5- Travis WD, Brambilla E, Nicholson AG, et al. The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol. 2015;10(9):1243-1260. doi:10.1097/JTO.0000000000000630
  6. 6- Yatabe Y, Dacic S, Borczuk AC, et al. Best Practices Recommendations for Diagnostic Immunohistochemistry in Lung Cancer. J Thorac Oncol. 2019;14(3):377-407. doi:10.1016/j.jtho.2018.12.005
  7. 7- Jain D, Satapathy S, Bubendorf L. Diagnostic and Predictive Immunocytochemistry in Lung Cancer. Acta Cytol. Published online September 19, 2024. doi:10.1159/000541478
  8. 8- Affandi KA, Tizen NMS, Mustangin M, et al. p40 Immunohistochemistry is an Excellent Marker in Primary Lung Squamous Cell Carcinoma. J Pathol Transl Med. 2018;52(5):283-289. doi:10.4132/jptm.2018.08.14
  9. 9- Tan D, Li Q, Deeb G, et al. Thyroid transcription factor-1 expression prevalence and its clinical implications in non-small cell lung cancer: a high-throughput tissue microarray and immunohistochemistry study. Hum Pathol. 2003;34(6):597-604. doi:10.1016/s0046-8177(03)00180-1
  10. 10- Kalhor N, Zander DS, Liu J. TTF-1 and p63 for distinguishing pulmonary small-cell carcinoma from poorly differentiated squamous cell carcinoma in previously pap-stained cytologic material. Mod Pathol. 2006;19(8):1117-1123. doi:10.1038/modpathol.3800629
  11. 11- Afify AM, al-Khafaji BM. Diagnostic utility of thyroid transcription factor-1 expression in adenocarcinomas presenting in serous fluids. Acta Cytol. 2002;46(4):675-678. doi:10.1159/000326974
  12. 12- Ikeda K, Clark JC, Shaw-White JR, et al. Gene structure and expression of human thyroid transcription factor-1 in respiratory epithelial cells. J Biol Chem. 1995;270(14):8108-8114. doi:10.1074/jbc.270.14.8108
  13. 13- Reynolds PR, Mucenski ML, Whitsett JA. Thyroid transcription factor (TTF) -1 regulates the expression of midkine (MK) during lung morphogenesis. Dev Dyn. 2003;227(2):227-237. doi:10.1002/dvdy.10304
  14. 14- Moldvay J, Jackel M, Bogos K, et al. The role of TTF-1 in differentiating primary and metastatic lung adenocarcinomas. Pathol Oncol Res. 2004;10(2):85-88. doi:10.1007/BF02893461
  15. 15- Little NA, Jochemsen AG. p63. Int J Biochem Cell Biol. 2002;34(1):6-9. doi:10.1016/s1357-2725(01)00086-3
  16. 16- Pelosi G, Pasini F, Olsen Stenholm C, et al. p63 immunoreactivity in lung cancer: yet another player in the development of squamous cell carcinomas?. J Pathol. 2002;198(1):100-109. doi:10.1002/path.1166
  17. 17- Wang BY, Gil J, Kaufman D, et al. P63 in pulmonary epithelium, pulmonary squamous neoplasms, and other pulmonary tumors. Hum Pathol. 2002;33(9):921-926. doi:10.1053/hupa.2002.126878
  18. 18- Camilo R, Capelozzi VL, Siqueira SA, et al. Expression of p63, keratin 5/6, keratin 7, and surfactant-A in non-small cell lung carcinomas. Hum Pathol. 2006;37(5):542-546. doi:10.1016/j.humpath.2005.12.019
  19. 19- Nobre AR, Albergaria A, Schmitt F. p40: a p63 isoform useful for lung cancer diagnosis - a review of the physiological and pathological role of p63. Acta Cytol. 2013;57(1):1-8. doi:10.1159/000345245
  20. 20- Bishop JA, Teruya-Feldstein J, Westra WH, et al. p40 (ΔNp63) is superior to p63 for the diagnosis of pulmonary squamous cell carcinoma. Mod Pathol. 2012;25(3):405-415. doi:10.1038/modpathol.2011.173
  21. 21- Nonaka D. A study of ΔNp63 expression in lung non-small cell carcinomas. Am J Surg Pathol. 2012;36(6):895-899. doi:10.1097/PAS.0b013e3182498f2b
  22. 22- Tacha D, Bremer R, Haas T, et al. An immunohistochemical analysis of a newly developed, mouse monoclonal p40 (BC28) antibody in lung, bladder, skin, breast, prostate, and head and neck cancers. Arch Pathol Lab Med. 2014;138(10):1358-1364. doi:10.5858/arpa.2013-0342-OA
  23. 23- Schultz H, Marwitz S, Baron-Lühr B, et al. Generation and evaluation of a monoclonal antibody, designated MAdL, as a new specific marker for adenocarcinomas of the lung. Br J Cancer. 2011;105(5):673-681. doi:10.1038/bjc.2011.281
  24. 24- Uramoto H, Yamada S, Hanagiri T. Immunohistochemical staining with deltaNp63 is useful for distinguishing the squamous cell component of adenosquamous cell carcinoma of the lung. Anticancer Res. 2010;30(11):4717-4720
  25. 25- Butnor KJ, Burchette JL. p40 (ΔNp63) and keratin 34βE12 provide greater diagnostic accuracy than p63 in the evaluation of small cell lung carcinoma in small biopsy samples. Hum Pathol. 2013;44(8):1479-1486. doi:10.1016/j.humpath.2013.01.011
  26. 26- Tatsumori T, Tsuta K, Masai K, et al. p40 is the best marker for diagnosing pulmonary squamous cell carcinoma: comparison with p63, cytokeratin 5/6, desmocollin-3, and sox2. Appl Immunohistochem Mol Morphol. 2014;22(5):377-382. doi:10.1097/PAI.0b013e3182980544
  27. 27- Collins BT, Wang JF, Bernadt CT. Utilization of p40 (ΔNp63) with p63 and cytokeratin 5/6 immunohistochemistry in non-small cell lung carcinoma fine-needle aspiration biopsy. Acta Cytol. 2013;57(6):619-624. doi:10.1159/000354213
  28. 28- Montezuma D, Azevedo R, Lopes P, et al. A panel of four immunohistochemical markers (CK7, CK20, TTF-1, and p63) allows accurate diagnosis of primary and metastatic lung carcinoma on biopsy specimens. Virchows Arch. 2013;463(6):749-754. doi:10.1007/s00428-013-1488-z
  29. 29- Pelosi G, Fabbri A, Bianchi F, et al. ΔNp63 (p40) and thyroid transcription factor-1 immunoreactivity on small biopsies or cellblocks for typing non-small cell lung cancer: a novel two-hit, sparing-material approach. J Thorac Oncol. 2012;7(2):281-290. doi:10.1097/JTO.0b013e31823815d3
  30. 30- Whithaus K, Fukuoka J, Prihoda TJ, Jagirdar J. Evaluation of napsin A, cytokeratin 5/6, p63, and thyroid transcription factor 1 in adenocarcinoma versus squamous cell carcinoma of the lung. Arch Pathol Lab Med. 2012;136(2):155-162. doi:10.5858/arpa.2011-0232-OA