Thoracic Pathology: 100 Years of Progress

By Sanjay Mukhopadhyay - November 02, 2022

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This article compares the practice of thoracic pathology in 1922 and today (2022), briefly touching on the most important discoveries/advancements in technology and practice in this field over the last 100 years. 

In 1922, immunohistochemistry as we know it did not exist. Beginning with Dr. Albert H. Coons’ seminal publication in 1942,1 several key technical advances allowed the gradual introduction of immunohistochemistry into diagnostic pathology. In the 1980s, several investigators began reporting of the use of immunohistochemical markers in routine surgical pathology.2,3 It is during this time that the antibody CAM5.2, named after Dr. Carol A. Makin, was introduced in 1984;2 this antibody is commonly used by pathologists to this day. Thyroid transcription factor 1 (TTF-1) was introduced after a monoclonal antibody to this antigen was described in 1996,4 and became one of the most widely used markers in thoracic pathology. Today, immunohistochemistry is an indispensable part of the diagnostic armamentarium of pathologists, especially for the diagnosis and subtyping of lung cancer.5-8   

Smoking and lung disease  
In the 1920s, surgeons encountering cases of lung cancer were puzzled by its cause.9 One of the first studies linking smoking and lung cancer was by Franz Hermann Müller in 1939, followed by several confirmatory studies in the 1940s and 1950s. Since then, several ground-breaking studies have demonstrated that smoking causes a host of other lung diseases including eosinophilic granuloma (now known as pulmonary Langerhans cell histiocytosis), emphysema,10 and interstitial lung disease.11,12 Despite years of denial and propaganda by tobacco companies, public health measures to combat smoking resulted in a decrease in cigarette smoking in the United States, followed by a decrease in deaths from lung cancer.  

Lung transplantation 
The first human lung transplant was performed in 1963, and the first successful lung transplant was performed in 1971.13 Survival was poor in the initial cases, but advances in surgical techniques gradually improved the prognosis. In 2017, the median survival after lung transplantation was six years. Today, lung transplantation is offered at several specialized centers, and offers hope of a few more years of life to patients with severe emphysema, idiopathic pulmonary fibrosis, cystic fibrosis, and a wide range of other end-stage lung diseases. Lung pathologists routinely assist in the diagnosis of rejection, infection, and malignancy in lung transplant recipients. 

Computed tomography (CT) 
Dr. Godfrey Hounsfield invented the first CT scanner in 1967, and this technique began to be used in the 1970s, with the first CT scans in the United States installed in 1973. Prior to this, thoracic radiology consisted of chest radiographs (chest x-rays). CT scans greatly enhanced the resolution of imaging and enabled improved detection and characterization of a wide range of lung diseases. CT scans also enabled the performance of CT-guided core needle biopsies, which are commonly used to diagnose lung nodules to this day. For his invention of CT scanning, Dr. Hounsfield was awarded the Nobel Prize in 1979. 

Bronchoscopy and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA)  
The only tool available in 1922 for evaluation of the airways was the rigid bronchoscope. In the 1960s, Dr. Shigeto Ikeda developed the first fiberoptic bronchoscope, which began to be used in the 1970s.14 The 1970s also saw the introduction of transbronchial lung biopsies, which continue to be a cornerstone of lung pathology in 2022. Following the introduction of radial probe ultrasound in 1992 and the publication of Dr. Kazuhiro Yasufuku’s seminal work on ultrasound-guided transbronchial needle aspiration (TBNA) in 2003,15 endobronchial ultrasound (EBUS) began to be used for TBNA of a wide variety of mediastinal lesions. Over the next two decades, this technique led to a true paradigm shift in lung cancer staging, as interventional pulmonologists began to stage the mediastinum instead of thoracic surgeons. Pathologists saw the impact of this shift as EBUS-TBNA exploded in volume and mediastinoscopic lymph node biopsies plummeted. Correspondingly, the evaluation of this anatomic compartment shifted from surgical pathology to cytopathology. 

Molecular testing and targeted therapies for lung cancer  
In 1922, our understanding of lung cancer was in its infancy. Until the end of the 20th century, metastatic non-small cell cancer was treated with chemotherapy, which traditionally included a platinum doublet. Efficacy was poor and the rate of adverse events was high. This landscape changed in the 21st century with the discovery of molecular driver mutations for lung cancer and the success of several clinical trials of targeted therapies such as EGFR and ALK inhibitors.16,17 These discoveries increased the importance of the identification of lung adenocarcinoma and put a spotlight on the importance of accurate histologic subtyping of non-small cell lung carcinomas. Advanced stage lung adenocarcinomas are now routinely tested by pathologists for molecular alterations such as EGFR, ALK, ROS1, RET, MET, Her2 and BRAF, and patients with a “druggable” target are treated with newer agents that have been shown to have higher efficacy and less toxicity than traditional chemotherapy.   

Immunotherapy for lung cancer 
The discovery of the programmed cell death 1 (PD-1) and programmed cell death 1 ligand (PD-L1) axis and the efficacy of immunotherapy in cancer has been one of the most exciting success stories in medicine. For their work in this area, the 2018 Nobel Prize for Physiology or Medicine was awarded jointly to immunotherapy researchers Dr. James P. Allison and Dr. Tasuku Honjo. Noting that tumors are very poor at initiating effective immune responses, Dr. Allison’s group showed that blockade of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) enhanced antitumor immunity.18 Dr. Honjo's group focused on the PD-1 immune inhibitory receptor and showed that inhibition of this receptor resulted in negative regulation of lymphocyte activation.19 

The role of immunotherapy in cancer was brought to the forefront by a landmark clinical trial in 2012,20 followed by other seminal trials in subsequent years.21 It is now widely recognized that PD-L1 expression in solid tumors is a predictive biomarker of benefit from PD-1/PD-L1 axis inhibitors.22 Immunotherapy has become an option for first-line treatment of metastatic lung non-small cell lung cancer since 2016. Today, the choice of immune checkpoint inhibitors is often guided by the interpretation of PD-L1 immunohistochemistry by pathologists.  



  1. Coons AH, Creech HJ, Jones RN, Berliner E. The demonstration of pneumococcal antigen in tissues by the use of fluorescent antibody. J Immunol 1942;45:159-70.

  2. Makin CA, Bobrow LG, Bodmer WF, et al. Monoclonal antibody to cytokeratin for use and routine histopathology.  J Clin Pathol 1984;37:975-83.

  3. Schwab U, Stein H Gerdes J, et al. Production of a mouse monoclonal antibody specific for Hodgkin and Sternberg-Reed cells of Hodgkin’s disease and a subset of normal lymphoid cells. Nature 1982;299:65-7. 

  4. Holzinger A, Dingle S, Bejarano PA, et al. Monoclonal antibody to thyroid transcription factor-1: production, characterization, and usefulness in tumor diagnosis. Hybridoma 1996;15:49-53.

  5. Yatabe Y, Dacic S, Borczuk A, et al. Best practices recommendations for diagnostic immunohistochemistry and lung cancer.  J Thorac Oncol 2019;14:377-407.

  6. Mukhopadhyay S, Katzenstein A-L A. Subclassification of non-small cell lung carcinomas lacking morphologic differentiation on biopsy specimens: utility of an immunohistochemical panel containing TTF-1, napsin A, p63 and CK5/6. Am J Surg Pathol 2011;35:15-25.   

  7. Mukhopadhyay S. Utility of small biopsies for diagnosis of lung nodules: doing more with less. Mod Pathol 2012;25(S1):S43-S57.

  8. Mukhopadhyay S, Dermawan JK, Lanigan CP, et al. 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;32:100-9.

  9. Proctor RN. The history of the discovery of the cigarette-lung cancer link: evidentiary traditions, corporate denial, global toll. Tob Control 2012;21:87-91.

  10. Fletcher C, Peto R, Tinker C, Speizer F. The natural history of chronic bronchitis and emphysema. Oxford University Press: New York; 1976. 

  11. Myers JL, Veal CF, Shin MS, Katzenstein AL. Respiratory bronchiolitis causing interstitial lung disease: a clinicopathologic study of six cases. Am Rev Respir Dis 1987;135:880-4.

  12. Katzenstein AL, Mukhopadhyay S, Zanardi C, Dexter E. Clinically occult interstitial fibrosis in smokers: classification and significance of a surprisingly common finding in lobectomy specimens. Hum Pathol 2010;41:316-25.

  13. Panchabhai TS, Chaddha U, McCurry KR, et al. Historical perspectives of lung transplantation: connecting the dots. J Thorac Dis 2018;10:4516-31.

  14. Panchabhai TS, Mehta AC. Historical perspectives of bronchoscopy: connecting the dots. Ann Am Thorac Soc 2015;12:631-41.

  15. Yasufuku K, Sekine Y, Chhajed PN, et al. Direct endobronchial ultrasound-guided transbronchial needle aspiration of mediastinal lymph nodes using a new convex probe bronchoscope: A novel approach [abstract]. Am J Respir Crit Care Med 2003;167:A577.

  16. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380-8.

  17. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013:368;25:2385-94.

  18. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996; 271:1734-6.

  19. Freeman GJ, Long AJ, Yoshiko I, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000; 192:1027-34.

  20. Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. New Engl J Med 2012;36:2455-65.

  21. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1 positive non-small cell lung cancer. N Engl J Med 2016;375:1823-33.

  22. Khunger M, Hernandez AV, Pasupuleti V, et al. Programmed cell death 1 (PD-1) ligand (PD-L1) expression in solid tumors as a predictive biomarker of benefit from PD-1/PD-L1 axis inhibitors: systematic review and meta-analysis. JCO Precision Oncology 2017; DOI:10.1200/PO.16.00030 JCO Precision Oncology - published online May 18, 2017 

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