Abstract
Purpose
Histology samples are important for the appropriate administration of tumor type-specific cytotoxic and molecular-targeted therapies for the treatment of non-small cell lung cancer (NSCLC). When biopsy samples lack a definite morphology, a diagnosis can be selected from three subtypes based on immunohistochemistry (IHC) results, as follows: favor adenocarcinoma (ADC), favor squamous cell carcinoma (SQC), or not otherwise specified (NOS)-null. In terms of patient outcome, however, the validity of IHC-based classifications remains unknown.
Methods
A large series of 152 patients with advanced NSCLC whose diagnoses had been made based on morphological findings and who had been homogeneously treated were enrolled. We used IHC staining (TTF-1, SP-A, p40, and CK5/6) to examine tumor samples and refined the diagnoses. We then analyzed the pathological subgroups according to the IHC staining results.
Results
IHC profiling resulted in 50% of the cases being classified as favor ADC, 31% being classified as favor SQC, and 19% being classified as NOS-null groups. Compared with the favor ADC and favor SQC groups, the NOS-null group had a significantly poorer outcome. Pemetrexed-containing platinum regimens produced a response rate similar to that of other platinum doublet regimens in the favor ADC group (44% vs. 46%), whereas it produced a poorer response in the favor SQC group (0% vs. 52%) and the NOS-null group (0% vs. 24%). The favor ADC group tended to have a higher percentage of EGFR positivity and ALK positivity than the favor SQC group (25% vs. 11% and 7% vs. 0%, respectively).
Conclusions
These findings support the use of immunohistological subtyping of NSCLC biopsy specimens to select patient-appropriate treatments.
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Change history
23 July 2021
A Correction to this paper has been published: https://doi.org/10.1007/s00432-021-03737-w
References
Bando H (2017) The current status and problems confronted in delivering precision medicine in Japan and Europe. Curr Probl Cancer 41:166–175. https://doi.org/10.1016/j.currproblcancer.2017.02.003
Barlesi F et al (2014) Maintenance bevacizumab–pemetrexed after first-line cisplatin–pemetrexed–bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial. Ann Oncol 25:1044–1052. https://doi.org/10.1093/annonc/mdu098
Comprehensive genomic characterization of squamous cell lung cancers (2012) Nature 489:519-525 https://doi.org/10.1038/nature11404
Einhorn LH (2008) First-line chemotherapy for non-small-cell lung cancer: is there a superior regimen based on histology? J Clin Oncol 26:3485–3486. https://doi.org/10.1200/jco.2008.17.2056
Facchinetti F, Aldigeri R, Aloe R, Bortesi B, Ardizzoni A, Tiseo M (2015) CEA serum level as early predictive marker of outcome during EGFR-TKI therapy in advanced NSCLC patients. Tumour Biol 36:5943–5951. https://doi.org/10.1007/s13277-015-3269-6
Fishback NF, Travis WD, Moran CA, Guinee DG Jr., McCarthy WF, Koss MN (1994) Pleomorphic (spindle/giant cell) carcinoma of the lung. A clinicopathologic correlation of 78 cases. Cancer 73:2936–2945
Govindan R et al (2017) Phase III trial of ipilimumab combined with paclitaxel and carboplatin in advanced squamous non-small-cell lung cancer. J Clin Oncol 35:3449–3457. https://doi.org/10.1200/jco.2016.71.7629
Hirsch FR, Spreafico A, Novello S, Wood MD, Simms L, Papotti M (2008) The prognostic and predictive role of histology in advanced non-small cell lung cancer: a literature review. J Thorac Oncol 3:1468–1481. https://doi.org/10.1097/JTO.0b013e318189f551
Inamura K et al (2008) EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers. J Thorac Oncol 3:13–17. https://doi.org/10.1097/jto.0b013e31815e8b60
Inamura K et al (2009) EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset. Mod Pathol 22:508–515. https://doi.org/10.1038/modpathol.2009.2
Lin Y et al (2016) Characteristics and prognostic analysis of 69 patients with pulmonary sarcomatoid carcinoma. Am J Clin Oncol 39:215–222. https://doi.org/10.1097/coc.0000000000000101
Marchetti A et al (2005) EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J CLin Oncol 23:857–865. https://doi.org/10.1200/jco.2005.08.043
Midha A, Dearden S, McCormack R (2015) EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res 5:2892–2911
Miyamae Y et al (2011) Significance of epidermal growth factor receptor gene mutations in squamous cell lung carcinoma. Oncol Rep 25:921–928. https://doi.org/10.3892/or.2011.1182
Paez JG et al (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science (New York, NY) 304:1497–1500. https://doi.org/10.1126/science.1099314
Pao W et al (2004) EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 101:13306–13311. https://doi.org/10.1073/pnas.0405220101
Patel JD et al (2013) PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol 31:4349–4357. https://doi.org/10.1200/jco.2012.47.9626
Paz-Ares LG et al (2013) PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol 31:2895–2902. https://doi.org/10.1200/jco.2012.47.1102
Pelosi G et al (2014) Does immunohistochemistry affect response to therapy and survival of inoperable non-small cell lung carcinoma patients? A survey of 145 stage III-IV consecutive cases. Int J Surg Pathol 22:136–148. https://doi.org/10.1177/1066896913511527
Rekhtman N, Ang DC, Sima CS, Travis WD, Moreira AL (2011) 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 24:1348–1359. https://doi.org/10.1038/modpathol.2011.92
Rekhtman N et al (2013) Distinct profile of driver mutations and clinical features in immunomarker-defined subsets of pulmonary large-cell carcinoma. Mod Pathol 26:511–522. https://doi.org/10.1038/modpathol.2012.195
Righi L et al (2014) Impact of non-small-cell lung cancer-not otherwise specified immunophenotyping on treatment outcome. J Thorac Oncol 9:1540–1546. https://doi.org/10.1097/jto.0000000000000271
Salido M et al (2011) Increased ALK gene copy number and amplification are frequent in non-small cell lung cancer. J Thorac Oncol 6:21–27. https://doi.org/10.1097/JTO.0b013e3181fb7cd6
Scagliotti GV et al (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26:3543–3551. https://doi.org/10.1200/jco.2007.15.0375
Shoji F et al (2007) Serum carcinoembryonic antigen level is associated with epidermal growth factor receptor mutations in recurrent lung adenocarcinomas. Cancer 110:2793–2798. https://doi.org/10.1002/cncr.23101
Shukuya T et al (2015) Nedaplatin plus docetaxel versus cisplatin plus docetaxel for advanced or relapsed squamous cell carcinoma of the lung (WJOG5208L): a randomised, open-label, phase 3 trial. Lancet Oncol 16:1630–1638. https://doi.org/10.1016/s1470-2045(15)00305-8
Soda M et al (2007) Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561–566. https://doi.org/10.1038/nature05945
Stinchcombe TE, Grilley-Olson JE, Socinski MA (2010) If histology matters. J Clin Oncol 28:1810–1812. https://doi.org/10.1200/jco.2009.27.1247
Sugio K et al (2006) Mutations within the tyrosine kinase domain of EGFR gene specifically occur in lung adenocarcinoma patients with a low exposure of tobacco smoking. Br J Cancer 94:896–903. https://doi.org/10.1038/sj.bjc.6603040
Takeuchi K et al (2008) Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts. Clin Cancer Res 14:6618–6624. https://doi.org/10.1158/1078-0432.ccr-08-1018
Travis WD et al (2013) Diagnosis of lung cancer in small biopsies and cytology: implications of the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. Arch Pathol Lab Med 137:668–684. https://doi.org/10.5858/arpa.2012-0263-RA
Travis WD et al (2015) The 2015 World Health Organization Classification of Lung Tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol 10:1243–1260. https://doi.org/10.1097/jto.0000000000000630
Tsao MS et al (2011) Prognostic and predictive value of epidermal growth factor receptor tyrosine kinase domain mutation status and gene copy number for adjuvant chemotherapy in non-small cell lung cancer. J Thorac Oncol 6:139–147. https://doi.org/10.1097/JTO.0b013e3181fd83a4
Venissac N, Pop D, Lassalle S, Berthier F, Hofman P, Mouroux J (2007) Sarcomatoid lung cancer (spindle/giant cells): an aggressive disease? J Thorac Cardiovasc Surg 134:619–623. https://doi.org/10.1016/j.jtcvs.2007.05.031
Whithaus K, Fukuoka J, Prihoda TJ, Jagirdar J (2012) 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 136:155–162. https://doi.org/10.5858/arpa.2011-0232-oa
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Dr. Kirita reports personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Chugai Pharmaceutical, personal fees from MSD, personal fees from Novartis Pharma, personal fees from Pfizer, personal fees from Roche, and personal fees from Boston, outside the submitted work. Dr. Udagawa reports personal fees from AstraZeneca, grants and personal fees from MSD, personal fees from Taiho, personal fees from Amco, grants and personal fees from AbbVie, personal fees from Chugai Pharmaceutical, personal fees from Bristol-Myers Squibb, personal fees from Ono Pharmaceutical, grants from Daiichi Sankyo, and grants from AMGEN, outside the submitted work. Dr. Matsumoto reports grants from Chugai Pharmaceutical Co., Ltd., grants from Novartis Pharma K.K., and grants from Merck Serono Co., Ltd., outside the submitted work. Dr. Yoh reports grants and personal fees from Ono Pharmaceutical, grants and personal fees from Taiho Pharmaceutical, grants and personal fees from Chugai Pharma, grants and personal fees from AstraZeneca, grants and personal fees from Lilly Japan, personal fees from Boehringer Ingelheim, grants and personal fees from Novartis, grants from Pfizer, grants and personal fees from MSD, grants from Bristol-Myers Squibb, and grants from Bayer, outside the submitted work. Dr. Niho reports personal fees from Bristol-Myers Squibb, personal fees from MSD, personal fees from Chugai, grants and personal fees from AstraZeneca, grants from Merck Serono, and grants and personal fees from Pfizer, outside the submitted work. Dr. Goto reports grants and personal fees from Eli Lilly, during the conduct of the study; grants and personal fees from AbbVie Stemcentrx, grants from Ignyta, personal fees from F. Hoffmann-La Roche, grants and personal fees from Life Technologies Japan, grants from Oxonc, personal fees from Otsuka Pharmaceutical, grants and personal fees from RIKEN GENESIS, personal fees from SRL, grants and personal fees from Sumitomo Dainippon Pharma, grants and personal fees from AstraZeneca, grants from Astellas Pharma, grants from Amgen Astellas BioPharma, grants and personal fees from Boehringer Ingelheim, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Chugai Pharmaceutical, grants and personal fees from Daiichi Sankyo, grants from Eisai, grants and personal fees from Kyowa Hakko Kirin, grants and personal fees from MSD, grants and personal fees from Merck Serono, grants and personal fees from Novartis Pharma, grants and personal fees from ONO Pharmaceutical, grants and personal fees from Pfizer, grants and personal fees from Taiho, grants and personal fees from Takeda Pharmaceutical, and grants from Janssen Pharmaceutical, outside the submitted work. None of the other authors has any conflict of interest to declare.
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The study was conducted with the approval of the Institutional Review Boards of the National Cancer Center. The IRB approval number for this study was 2016-125. All the methods were performed in accordance with the approved guidelines.
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All the specimens were collected after obtaining written comprehensive informed consent from the patients.
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Ota, T., Kirita, K., Matsuzawa, R. et al. Validity of using immunohistochemistry to predict treatment outcome in patients with non-small cell lung cancer not otherwise specified. J Cancer Res Clin Oncol 145, 2495–2506 (2019). https://doi.org/10.1007/s00432-019-03012-z
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DOI: https://doi.org/10.1007/s00432-019-03012-z