Lung Cancer Staging and the Home Insurance Building Constructed in 1884–1885

Abstract

In the massive reconstruction of Chicago after the “Great Fire” of 1871, thousands of buildings were erected in a typical architectural style.1Salig P The sky's the limit. Rizzoli, New York, NY1990Google Scholar They were four to five stories in height, had masonry foundations and supporting walls, and relied on internal staircases. Technological advances, though, would soon change architecture profoundly. Elisha Graves Otis invented the safety brake in 1853, which would distinguish modern elevators from mechanical hoists. In 1857, the first steam-driven elevator had been installed in the Haughwont Building in New York. By the 1870s, electric safety elevators and methods for building fireproof, reinforced iron-and-steel skeletons had been developed, enabling the design of larger, taller, and safer buildings. The new elevators and structural design features were used in 1885 in the construction of the 10-story Home Insurance Building in Chicago, the first “skyscraper.” By the 1890s, there were > 3,000 elevators in Chicago and 10- to 20-story skyscrapers had become the “modern” architectural form for cities. In 1902, the Flatiron Building in New York was completed and, at 23 stories, was considered a marvel. The Empire State Building, completed in 1931 and reaching > 100 stories and 1,250 feet, was the ultimate standard in “high-rise” construction. This dramatic revolution in architectural form, based on technological advances in engineering, has clear parallels to what I expect to occur soon in our approach to staging non-small cell lung cancer (NSCLC).In this issue of CHEST (see page 260), Detterbeck and colleagues2Detterbeck F Tanoue L Boffa D The new lung cancer staging system.Chest. 2009; 136: 260-271Abstract Full Text Full Text PDF PubMed Scopus (779) Google Scholar nicely summarize the development of the most recent iteration of the NSCLC staging approach. The tumor-node-metastases (TNM) method for staging NSCLC has served the lung cancer community well. It provides a framework for understanding the prognosis, treatment options, and value of new interventions. This newest revision of the TNM method, which reflects an enormous effort by a dedicated group of physicians, will allow us to care for the lung cancer patient even more effectively because the refinements in staging classifications better reflect prognosis. However, we should appreciate that there may be more to staging NSCLC than the TNM method. For instance, in 1968 Feinstein3Feinstein A A new staging system for cancer and reappraisal of“early” treatment and “cure” by radical surgery.N Engl J Med. 1968; 279: 747-753Crossref Google Scholar proposed a method of staging lung cancer that included the classification of patient symptoms (local vs systemic) along with conventional anatomic stages. He astutely pointed out that tumors may look the same but act differently, an observation shared by many clinicians since. Hooper and colleagues4Hooper RG Beechler CR Johnson MC Radioisotope scanning in the initial staging of bronchogenic carcinoma.Am Rev Respir Dis. 1978; 118: 279-286PubMed Google Scholar in 1978 suggested using easily obtained and relevant clinical factors as a method for identifying NSCLC patients with metastatic disease. We subsequently found that adrenal metastases seen on a CT scan were found only in NSCLC patients with abnormalities in the clinical factors described by Silvestri et al.5Silvestri GA Lenz JE Harper SN et al.The relationship of clinical findings to CT scan evidence of adrenal gland metastases in the staging of bronchogenic carcinoma.Chest. 1992; 102: 1748-1751Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar Multiple studies6Silvestri GA Littenberg B Colice GL The clinical evaluation for detecting metastatic lung cancer.Am J Respir Crit Care Med. 1995; 152: 225-230Crossref PubMed Scopus (129) Google Scholar have confirmed that an unremarkable clinical evaluation was a useful method for excluding metastatic disease in patients with NSCLC. The American College of Chest Physicians lung cancer guidelines7Silvestri GA Bould MK Margolis ML et al.Noninvasive staging of non-small cell lung cancer.Chest. 2007; 132: 178S-201SAbstract Full Text Full Text PDF PubMed Scopus (558) Google Scholar recommend using clinical factors as a useful guide to the presence of metastatic disease. Systemic complaints, not currently included in the TNM approach to staging NSCLC, may provide important clues to disease extent.Wallace and colleagues8Wallace MB Block M Hoffman BJ et al.Detection of telomerase expression in mediastinal lymph nodes of patients with lung cancer.Am J Respir Crit Care Med. 2003; 167: 1670-1675Crossref PubMed Scopus (60) Google Scholar used histologic specimens from mediastinal nodes obtained by endoscopic ultrasound-guided fine-needle aspiration to detect the expression of human telomerase reverse transcriptase using the reverse transcription-polymerase chain reaction method. The human telomerase reverse transcriptase encodes a protein that seems to develop early in the course of tumorigenesis and is expressed in all histologic types of lung cancer. Wallace and colleagues8Wallace MB Block M Hoffman BJ et al.Detection of telomerase expression in mediastinal lymph nodes of patients with lung cancer.Am J Respir Crit Care Med. 2003; 167: 1670-1675Crossref PubMed Scopus (60) Google Scholar found this protein in the mediastinal lymph nodes of patients with NSCLC who were not found to have mediastinal involvement by standard histocytologic techniques. Because the reverse transcription-polymerase chain reaction method requires only small numbers of cells, it can detect “micrometastases” (ie, metastases not detectable with standard histocytologic methods). In a recent study,9Mohamed S Yasufuku K Nakajima T et al.Analysis of cell cycle-related proteins in mediastinal lymph nodes of patients with N2-NSCLC obtained by EBUS-TBNA: relevance to chemotherapy response.Thorax. 2008; 63: 642-647Crossref PubMed Scopus (56) Google Scholar histologic specimens from mediastinal lymph nodes were obtained by endobronchial ultrasound-guided transbronchial needle aspiration. Metastatic lung cancer was found in these nodes by standard light microscopy; the expression of six cell cycle-related proteins in the nodes was also studied. Increased levels of p53 in these nodes, detected by immunostaining, significantly related to the clinical response to chemotherapy. This is a biologically relevant finding because p53 is involved in cellular DNA repair systems. Mutant p53 proteins have an extended half-life and accumulate in cancer cells. Standard histocytologic methods, the foundation for determining extent of disease in the TNM system, may not truly reflect either the extent of NSCLC or its behavior in response to therapy.There have been important advances in our understanding of the molecular origin and biology of squamous-cell carcinoma and adenocarcinoma.10Herbst RS Heymach JV Lippman SM Lung cancer.N Engl J Med. 2008; 359: 1367-1380Crossref PubMed Scopus (2045) Google Scholar One study11Chen HY Yu SL Chen CH et al.A five-gene signature and clinical outcome in non-small-cell lung cancer.N Engl J Med. 2007; 356: 11-20Crossref PubMed Scopus (766) Google Scholar found that the levels of expression of 16 genes in NSCLC patients were significantly correlated with survival, associated with either a reduced or an increased risk of death. Patients with a high-risk five-gene signature were found to have shorter overall median survival times than those with a low-risk gene signature. Molecular targeted research has resulted in the approval of drugs for treating NSCLC that act by inhibiting either the epidermal growth factor receptor (EGFR) or vascular endothelial growth factor. Our level of sophistication with the use of EGFR inhibitors is increasing rapidly. Circulating lung cancer cells can be identified, purified, and used to test for mutations in EGFRs as the basis for monitoring response to therapy.12Maheswaran S Sequist LV Nagrath S et al.Detection of mutations in EGFR in circulating lung-cancer cells.N Engl J Med. 2008; 359: 366-377Crossref PubMed Scopus (1463) Google Scholar Insights into the biology of NSCLC offer the promise of more effectively staging the disease and also individually tailoring therapy.The TNM NSCLC staging classification has served the medical community well since the seminal work by Dr. Mountain.13Mountain CF A new international staging system for lung cancer.Chest. 1986; 89: 225S-233SAbstract Full Text Full Text PDF PubMed Google Scholar It is a useful common denominator for generally predicting outcomes and comparing treatment effects. Detterbeck and colleagues2Detterbeck F Tanoue L Boffa D The new lung cancer staging system.Chest. 2009; 136: 260-271Abstract Full Text Full Text PDF PubMed Scopus (779) Google Scholar have performed an enormously useful service for the lung cancer community by describing the most recent revisions to this NSCLC staging classification approved by the American Joint Committee on Cancer in 2008. This revised approach should be accepted as the standard for clinicians managing NSCLC. However, we should begin to consider how to advance beyond the TNM method, which is based on anatomic features and empiric observations of survival, and to evaluate how insights into the biology of lung cancer will provide us new ways of understanding prognosis and treatment response. When I visit New York, I relish the isolated areas of remaining “brownstones” as remnants of historical interest, but appreciate that the growth of the modern city has been based on the skyscraper. In the future, we might consider the TNM method for NSCLC staging to be similar to brownstones and accept biological markers of disease extent and behavior as the skyscrapers of our future. In the massive reconstruction of Chicago after the “Great Fire” of 1871, thousands of buildings were erected in a typical architectural style.1Salig P The sky's the limit. Rizzoli, New York, NY1990Google Scholar They were four to five stories in height, had masonry foundations and supporting walls, and relied on internal staircases. Technological advances, though, would soon change architecture profoundly. Elisha Graves Otis invented the safety brake in 1853, which would distinguish modern elevators from mechanical hoists. In 1857, the first steam-driven elevator had been installed in the Haughwont Building in New York. By the 1870s, electric safety elevators and methods for building fireproof, reinforced iron-and-steel skeletons had been developed, enabling the design of larger, taller, and safer buildings. The new elevators and structural design features were used in 1885 in the construction of the 10-story Home Insurance Building in Chicago, the first “skyscraper.” By the 1890s, there were > 3,000 elevators in Chicago and 10- to 20-story skyscrapers had become the “modern” architectural form for cities. In 1902, the Flatiron Building in New York was completed and, at 23 stories, was considered a marvel. The Empire State Building, completed in 1931 and reaching > 100 stories and 1,250 feet, was the ultimate standard in “high-rise” construction. This dramatic revolution in architectural form, based on technological advances in engineering, has clear parallels to what I expect to occur soon in our approach to staging non-small cell lung cancer (NSCLC). In this issue of CHEST (see page 260), Detterbeck and colleagues2Detterbeck F Tanoue L Boffa D The new lung cancer staging system.Chest. 2009; 136: 260-271Abstract Full Text Full Text PDF PubMed Scopus (779) Google Scholar nicely summarize the development of the most recent iteration of the NSCLC staging approach. The tumor-node-metastases (TNM) method for staging NSCLC has served the lung cancer community well. It provides a framework for understanding the prognosis, treatment options, and value of new interventions. This newest revision of the TNM method, which reflects an enormous effort by a dedicated group of physicians, will allow us to care for the lung cancer patient even more effectively because the refinements in staging classifications better reflect prognosis. However, we should appreciate that there may be more to staging NSCLC than the TNM method. For instance, in 1968 Feinstein3Feinstein A A new staging system for cancer and reappraisal of“early” treatment and “cure” by radical surgery.N Engl J Med. 1968; 279: 747-753Crossref Google Scholar proposed a method of staging lung cancer that included the classification of patient symptoms (local vs systemic) along with conventional anatomic stages. He astutely pointed out that tumors may look the same but act differently, an observation shared by many clinicians since. Hooper and colleagues4Hooper RG Beechler CR Johnson MC Radioisotope scanning in the initial staging of bronchogenic carcinoma.Am Rev Respir Dis. 1978; 118: 279-286PubMed Google Scholar in 1978 suggested using easily obtained and relevant clinical factors as a method for identifying NSCLC patients with metastatic disease. We subsequently found that adrenal metastases seen on a CT scan were found only in NSCLC patients with abnormalities in the clinical factors described by Silvestri et al.5Silvestri GA Lenz JE Harper SN et al.The relationship of clinical findings to CT scan evidence of adrenal gland metastases in the staging of bronchogenic carcinoma.Chest. 1992; 102: 1748-1751Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar Multiple studies6Silvestri GA Littenberg B Colice GL The clinical evaluation for detecting metastatic lung cancer.Am J Respir Crit Care Med. 1995; 152: 225-230Crossref PubMed Scopus (129) Google Scholar have confirmed that an unremarkable clinical evaluation was a useful method for excluding metastatic disease in patients with NSCLC. The American College of Chest Physicians lung cancer guidelines7Silvestri GA Bould MK Margolis ML et al.Noninvasive staging of non-small cell lung cancer.Chest. 2007; 132: 178S-201SAbstract Full Text Full Text PDF PubMed Scopus (558) Google Scholar recommend using clinical factors as a useful guide to the presence of metastatic disease. Systemic complaints, not currently included in the TNM approach to staging NSCLC, may provide important clues to disease extent. Wallace and colleagues8Wallace MB Block M Hoffman BJ et al.Detection of telomerase expression in mediastinal lymph nodes of patients with lung cancer.Am J Respir Crit Care Med. 2003; 167: 1670-1675Crossref PubMed Scopus (60) Google Scholar used histologic specimens from mediastinal nodes obtained by endoscopic ultrasound-guided fine-needle aspiration to detect the expression of human telomerase reverse transcriptase using the reverse transcription-polymerase chain reaction method. The human telomerase reverse transcriptase encodes a protein that seems to develop early in the course of tumorigenesis and is expressed in all histologic types of lung cancer. Wallace and colleagues8Wallace MB Block M Hoffman BJ et al.Detection of telomerase expression in mediastinal lymph nodes of patients with lung cancer.Am J Respir Crit Care Med. 2003; 167: 1670-1675Crossref PubMed Scopus (60) Google Scholar found this protein in the mediastinal lymph nodes of patients with NSCLC who were not found to have mediastinal involvement by standard histocytologic techniques. Because the reverse transcription-polymerase chain reaction method requires only small numbers of cells, it can detect “micrometastases” (ie, metastases not detectable with standard histocytologic methods). In a recent study,9Mohamed S Yasufuku K Nakajima T et al.Analysis of cell cycle-related proteins in mediastinal lymph nodes of patients with N2-NSCLC obtained by EBUS-TBNA: relevance to chemotherapy response.Thorax. 2008; 63: 642-647Crossref PubMed Scopus (56) Google Scholar histologic specimens from mediastinal lymph nodes were obtained by endobronchial ultrasound-guided transbronchial needle aspiration. Metastatic lung cancer was found in these nodes by standard light microscopy; the expression of six cell cycle-related proteins in the nodes was also studied. Increased levels of p53 in these nodes, detected by immunostaining, significantly related to the clinical response to chemotherapy. This is a biologically relevant finding because p53 is involved in cellular DNA repair systems. Mutant p53 proteins have an extended half-life and accumulate in cancer cells. Standard histocytologic methods, the foundation for determining extent of disease in the TNM system, may not truly reflect either the extent of NSCLC or its behavior in response to therapy. There have been important advances in our understanding of the molecular origin and biology of squamous-cell carcinoma and adenocarcinoma.10Herbst RS Heymach JV Lippman SM Lung cancer.N Engl J Med. 2008; 359: 1367-1380Crossref PubMed Scopus (2045) Google Scholar One study11Chen HY Yu SL Chen CH et al.A five-gene signature and clinical outcome in non-small-cell lung cancer.N Engl J Med. 2007; 356: 11-20Crossref PubMed Scopus (766) Google Scholar found that the levels of expression of 16 genes in NSCLC patients were significantly correlated with survival, associated with either a reduced or an increased risk of death. Patients with a high-risk five-gene signature were found to have shorter overall median survival times than those with a low-risk gene signature. Molecular targeted research has resulted in the approval of drugs for treating NSCLC that act by inhibiting either the epidermal growth factor receptor (EGFR) or vascular endothelial growth factor. Our level of sophistication with the use of EGFR inhibitors is increasing rapidly. Circulating lung cancer cells can be identified, purified, and used to test for mutations in EGFRs as the basis for monitoring response to therapy.12Maheswaran S Sequist LV Nagrath S et al.Detection of mutations in EGFR in circulating lung-cancer cells.N Engl J Med. 2008; 359: 366-377Crossref PubMed Scopus (1463) Google Scholar Insights into the biology of NSCLC offer the promise of more effectively staging the disease and also individually tailoring therapy. The TNM NSCLC staging classification has served the medical community well since the seminal work by Dr. Mountain.13Mountain CF A new international staging system for lung cancer.Chest. 1986; 89: 225S-233SAbstract Full Text Full Text PDF PubMed Google Scholar It is a useful common denominator for generally predicting outcomes and comparing treatment effects. Detterbeck and colleagues2Detterbeck F Tanoue L Boffa D The new lung cancer staging system.Chest. 2009; 136: 260-271Abstract Full Text Full Text PDF PubMed Scopus (779) Google Scholar have performed an enormously useful service for the lung cancer community by describing the most recent revisions to this NSCLC staging classification approved by the American Joint Committee on Cancer in 2008. This revised approach should be accepted as the standard for clinicians managing NSCLC. However, we should begin to consider how to advance beyond the TNM method, which is based on anatomic features and empiric observations of survival, and to evaluate how insights into the biology of lung cancer will provide us new ways of understanding prognosis and treatment response. When I visit New York, I relish the isolated areas of remaining “brownstones” as remnants of historical interest, but appreciate that the growth of the modern city has been based on the skyscraper. In the future, we might consider the TNM method for NSCLC staging to be similar to brownstones and accept biological markers of disease extent and behavior as the skyscrapers of our future.