›

Lung Cancer: Diagnosis, Complications, & Staging

Notes

Lung Cancer: Diagnosis, Complications, & Staging

Sections




Lung Cancer: Diagnosis, Complications, & Staging

Overview

Signs and symptoms
Primary lung tumors can cause chest pain, cough, dyspnea, and hemoptysis, particularly in the later stages. Early stages are often asymptomatic, which contributes to the difficulty in early diagnosis.

Complications of lung cancer depend on the location and/or cell type of the tumors.

Diagnosis
– Initial diagnosis is via chest x-ray or CT scans, and is often incidental.
– Sputum collection and biopsies are performed so that histopathology and molecular analyses can tell us the type of lung cancer.
–Unfortunately, many patients are diagnosed in advanced stages, when metastasis has already begun and prognosis is poorer.
–Thus, screening is recommended for high-risk individuals (patients with a history of heavy smoking and who are between 55 and 80 years old).

Treatment
Varies by patient, cancer type, and stage; list the following options, which are often combined for maximal efficacy:

  • Surgical removal of tumor
  • Radiation
  • Chemotherapy
  • Targeted drug therapy
  • Immunotherapy

Targeted therapy is particularly useful in non-small cell lung carcinomas harboring specific genetic mutations – for example, Tyrosine Kinase Inhibitors (such as erlotinib and gefitinib) are effective for patients with EGFR mutations, and ALK inhibitors (such as crizotinib) for ALK mutations.

Targeted therapies are celebrated for their relative safety and tolerability, since they only act against cancer cells; however, be aware that resistance to targeted inhibitors can occur, which is another reason for combination therapy.

Immunotherapy is a form of targeted therapy; immune checkpoint inhibitors (such as nivolumab) amplify the immune response to cancer cells.

Paraneoplastic syndromes and complications

Small-cell lung cancer

  • Ectopic Cushing syndrome; we draw a "moon face" to remind ourselves that Cushing syndrome is caused by over-secretion of ACTH and is associated with fat accumulation in the head, neck, and trunk, which can produce an exaggerated roundness in the face.

Adenocarcinoma

Squamous cell carcinoma

  • Hypercalcemia due to production of parathyroid hormone-related protein; common symptoms of hypercalcemia include weakness, nausea, vomiting, abdominal cramps, and dehydration.

Large cell lung cancer

  • Gynecomastia.

Non-small cell lung cancers, as a group

  • Hypertrophic pulmonary osteoarthropy, (aka, Marie-Bamberger syndrome), which is a rare condition comprising the following triad: periostitis, arthropathy, and digit clubbing.

Small and Non-Small lung cancers

  • Hematological disorders including anemia, disseminated intravascular coagulation, granulocytosis (increased granulocytes), and thrombocytosis (increased platelets).
  • Dermatomyositis
    Dermatomyositis Tutorial

Complications of lung cancer more broadly

  • Superior vena cava syndrome is obstruction of blood flow through the superior vena cava due to direct tumor invasion or external compression of the vessel.
    – Patients present with facial and neck swelling, edema, and jugular venous distention.
    – SVC syndrome is more likely to occur in small-cell lung cancer, but, because non-small cell lung cancer is more common than small-cell, it is a frequent cause of SVC syndrome.
  • Pancoast tumors, aka, superior sulcus tumors, occur when tumors at the lung apex compress nearby structures.
    – We think about Pancoast tumors in brachial plexopathies, which cause shoulder pain and weakness, and also in proximal ulnar neuropathies, which cause weakness and atrophy of the intrinsic hand muscles.

– Pancoast tumors are also responsible for Horner syndrome, which is characterized by ptosis (eyelid drooping), miosis (pupil constriction), and facial anhidrosis (lack of sweating).

  • Lung tumors can cause compression of the recurrent laryngeal nerve (from CN 10)

Staging

Tumor staging determines treatment options and prognosis. Staging can involve imaging studies as well as surgical resections and biopsy.

Non-Small Cell Lung Cancer

  • TNM system asseses Tumor size/invasiveness, lymph Node involvement, and Metastasis to distant sites.

The stages I-IV progress from cancer in the lungs, then the lymph nodes, then other body sites.
Stage I: tumor is present only in the lungs (no lymph node involvement or metastasis).
Stage II: tumor is present in the lungs and there is nearby lymph node involvement (but no metastasis).
Stage III: tumor in the lungs is accompanied by cancer in the lymph nodes in the middle of the chest (but no metastasis).
–Stage IIIa involves lymph nodes on the same side as the original tumor.
– Stage IIIb involves lymph nodes on the opposite side.
Stage IV tumors are in both lungs, the pleural fluid, and/or has metastasized (most often to the brain, liver, or bones).

Small-cell Lung Cancer

Staging is much simpler.
Limited stage: in which tumors lie within the ipsilateral hemithorax (tumors on one side of the chest only) and can be encompassed within a single radiation port.
Extensive stage: metastatic cancer that involves both sides of the chest or is present in pleural or pericardial effusions.

Clinical Cases

Case 1: Lung Nodule

A 62 year-old woman was admitted through the emergency department yesterday with a diagnosis of lobar pneumonia. A review of her chart indicates appropriate initial therapeutic interventions including oxygen therapy for mild hypoxemia, sputum and blood cultures, and broad-spectrum IV antibiotics. Along with a right lower lobe consolidated pneumonia, a chect CT with and without contrast performed on admission showed a radiodense 1.5 cm single perifissural nodule with lentiform morphology in the left lower lung field. The patient denies any recent weight loss, occupational exposure, or recent travel. She reports a 20-pack year history of smoking.

On physical examination, she is afebrile and in no acute distress. Her heart rate is 65/min, respiratory rate 18/min, and her blood pressure is 130/80 mmHg. She is breathing comfortably on 2L of oxygen via nasal cannula, and her oxygen saturation is 98 percent.

What is a sign of malignancy?

Answer

  • Spiculated rays radiating out from the nodule

Explanation

A solitary pulmonary nodule (SPN) is a single lung nodule measuring less than 3 cm. The majority of these nodules are benign in nature when discovered during routine CT scans of the chest or incidentally detected as in this clinical scenario. Certain characteristics, including smooth, well-defined borders, are more suggestive of a benign lesion versus malignancy. Differentiating the nature of these nodules can be challenging in the absence of biopsy. Adherence to established guidelines, such as those published by the Fleischner Society in 2005 (updated in 2017), will greatly reduce unnecessary imaging and surgical intervention.

The Fleischner Society guidelines are used for clinical decision-making in the management of solitary pulmonary nodules (SPN) detected incidentally on CT examinations. Occurences in patients over 40 years-old, a history of heavy smoking, a prior disgnosis of cancer, size greater than 2 cm, spiculated or ragged edges, and upper lobe location, are all characteristics suggestive of a malignant lesion.

Calcification in a pulmonary nodule suggest a high probability that the lesion is benign. Calcium deposits can form nodules following lung infections, and can also be the result of normal tissue in an abnormal location (hamartoma).

The presence of a nodule (especially a stable one) on a previous radiologic study does not necessarily suggest malignancy. The tumor volume doubling time (VDT) is a key parameter used to distinguish fast-growing tumors from slow-growing tumors. Most studies define pulmonary nodules with a VDT greater than 400 days as slow-growing, and a VDT of less than 400 days as fast-growing.

References

Gould MK, Donington J, Lynch WR, et al. Evaluation of individuals with pulmonary nodules: when is it lung cancer? diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143(5 suppl):e93S–e120S.

McWilliams A, Tammemagi MC, Mayo JR, et al. Probability of cancer in pulmonary nodules detected on first screening CT. N Engl J Med 2013;369(10):910–919.

Tanner NT, Porter A, Gould MK, Li XJ, Vachani A, Silvestri GA. Physician assessment of pretest probability of malignancy and adherence with guidelines for pulmonary nodule evaluation. Chest 2017;152(2):263–270.

References

  • ":Lung Cancer Immunotherapy | Immune Checkpoint Inhibitors." Accessed January 22, 2020. https://www.cancer.org/cancer/lung-cancer/treating-non-small-cell/immunotherapy.html.
  • Anwar, Asad, Firas Jafri, Sara Ashraf, Mohammad Ali S. Jafri, and Michael Fanucchi. "Paraneoplastic Syndromes in Lung Cancer and Their Management." Annals of Translational Medicine 7, no. 15 (August 2019). https://doi.org/10.21037/atm.2019.04.86.
  • Bech, Anneke, Koen Smolders, Darryl Telting, and Hans de Boer. "Cinacalcet for Hypercalcemia Caused by Pulmonary Squamous Cell Carcinoma Producing Parathyroid Hormone-Related Peptide." Case Reports in Oncology 5, no. 1 (January 7, 2012): 1–8. https://doi.org/10.1159/000335676.
  • Brägelmann, Johannes, Stefanie Böhm, Matthew R. Guthrie, Gurkan Mollaoglu, Trudy G. Oliver, and Martin L. Sos. "Family Matters: How MYC Family Oncogenes Impact Small Cell Lung Cancer." Cell Cycle 16, no. 16 (July 24, 2017): 1489–98. https://doi.org/10.1080/15384101.2017.1339849.
  • Bubendorf, Lukas, Sylvie Lantuejoul, Adrianus J. de Langen, and Erik Thunnissen. "Nonsmall Cell Lung Carcinoma: Diagnostic Difficulties in Small Biopsies and Cytological Specimens: Number 2 in the Series 'Pathology for the Clinician' Edited by Peter Dorfmüller and Alberto Cavazza." European Respiratory Review 26, no. 144 (June 30, 2017). https://doi.org/10.1183/16000617.0007-2017.
  • "Cancer." Accessed December 17, 2019. https://www.who.int/news-room/fact-sheets/detail/cancer.
  • Castellanos, Emily H., and Leora Horn. "Immunotherapy in Lung Cancer." Cancer Treatment and Research 170 (2016): 203–23. https://doi.org/10.1007/978-3-319-40389-2_10.
  • "Cavities in the Lung in Oncology Patients: Imaging Overview and Differential Diagnoses." Accessed December 20, 2019. https://appliedradiology.com/articles/cavities-in-the-lung-in-oncology-patients-imaging-overview-and-differential-diagnoses.
  • Cesar A. Moran, M. D. "Slide Show: Non–Small-Cell Lung Cancer Pathology." Cancer Network. Accessed January 21, 2020. https://www.cancernetwork.com/slideshows/slide-show-non-small-cell-lung-cancer-pathology.
  • Chen, Huanhuan Joyce, Asaf Poran, Arun M. Unni, Sarah Xuelian Huang, Olivier Elemento, Hans-Willem Snoeck, and Harold Varmus. "Generation of Pulmonary Neuroendocrine Cells and SCLC-like Tumors from Human Embryonic Stem * * CellshESC-Derived Pulmonary Neuroendocrine Cells and Tumors." The Journal of Experimental Medicine 216, no. 3 (March 4, 2019): 674–87. https://doi.org/10.1084/jem.20181155.
  • Collisson, Eric A., Joshua D. Campbell, Angela N. Brooks, Alice H. Berger, William Lee, Juliann Chmielecki, David G. Beer, et al. "Comprehensive Molecular Profiling of Lung Adenocarcinoma." Nature 511, no. 7511 (July 2014): 543–50. https://doi.org/10.1038/nature13385.
  • Derman, Benjamin A., Kathryn F. Mileham, Philip D. Bonomi, Marta Batus, and Mary J. Fidler. "Treatment of Advanced Squamous Cell Carcinoma of the Lung: A Review." Translational Lung Cancer Research 4, no. 5 (October 2015): 524–32. https://doi.org/10.3978/j.issn.2218-6751.2015.06.07.
  • Dorantes-Heredia, Rita, José Manuel Ruiz-Morales, and Fernando Cano-García. "Histopathological Transformation to Small-Cell Lung Carcinoma in Non-Small Cell Lung Carcinoma Tumors." Translational Lung Cancer Research 5, no. 4 (August 2016): 401–12. https://doi.org/10.21037/tlcr.2016.07.10.
  • Fisseler-Eckhoff, Annette, and Melanie Demes. "Neuroendocrine Tumors of the Lung." Cancers 4, no. 3 (July 31, 2012): 777–98. https://doi.org/10.3390/cancers4030777.
  • Furrukh, Muhammad. "Tobacco Smoking and Lung Cancer." Sultan Qaboos University Medical Journal 13, no. 3 (August 2013): 345–58.
  • Gardiner, Natasha, Sanjay Jogai, and Adam Wallis. "The Revised Lung Adenocarcinoma Classification—an Imaging Guide." Journal of Thoracic Disease 6, no. Suppl 5 (October 2014): S537–46. https://doi.org/10.3978/j.issn.2072-1439.2014.04.05.
  • Ghorbani, Hosein, Mohsen Vakili Sadeghi, Tahereh Hejazian, and Majid Sharbatdaran. "Superior Vena Cava Syndrome as a Paraneoplastic Manifestation of Soft Tissue Sarcoma." Hematology, Transfusion and Cell Therapy 40, no. 1 (2018): 75–78. https://doi.org/10.1016/j.htct.2017.09.001.
  • Goldner, Whitney. "Cancer-Related Hypercalcemia." Journal of Oncology Practice 12, no. 5 (May 1, 2016): 426–32. https://doi.org/10.1200/JOP.2016.011155.
  • Großerueschkamp, Frederik, Angela Kallenbach-Thieltges, Thomas Behrens, Thomas Brüning, Matthias Altmayer, Georgios Stamatis, Dirk Theegarten, and Klaus Gerwert. "Marker-Free Automated Histopathological Annotation of Lung Tumour Subtypes by FTIR Imaging." Analyst 140, no. 7 (2015): 2114–20. https://doi.org/10.1039/C4AN01978D.
  • Hecht, Stephen S. "Lung Carcinogenesis by Tobacco Smoke." International Journal of Cancer. Journal International Du Cancer 131, no. 12 (December 15, 2012): 2724–32. https://doi.org/10.1002/ijc.27816.
  • Herbst, Roy S., Daniel Morgensztern, and Chris Boshoff. "The Biology and Management of Non-Small Cell Lung Cancer." Nature 553, no. 7689 (January 2018): 446–54. https://doi.org/10.1038/nature25183.
  • Hirsch, Fred R, Giorgio V Scagliotti, James L Mulshine, Regina Kwon, Walter J Curran, Yi-Long Wu, and Luis Paz-Ares. "Lung Cancer: Current Therapies and New Targeted Treatments." The Lancet 389, no. 10066 (January 2017): 299–311. https://doi.org/10.1016/S0140-6736(16)30958-8.
  • "Histology of Lung Cancer." Accessed December 17, 2019. http://oncolex.org/Lung-cancer/Background/Histology.
    Inamura, Kentaro. "Lung Cancer: Understanding Its Molecular Pathology and the 2015 WHO Classification." Frontiers in Oncology 7 (August 28, 2017). https://doi.org/10.3389/fonc.2017.00193.
  • Iwata, Hisashi. "Adenocarcinoma Containing Lepidic Growth." Journal of Thoracic Disease 8, no. 9 (September 2016): E1050–52. https://doi.org/10.21037/jtd.2016.08.78.
  • Jeong, Chaiho, Jinhee Lee, Seongyul Ryu, Hwa Young Lee, Ah Young Shin, Ju Sang Kim, Joong Hyun Ahn, and Hye Seon Kang. "A Case of Ectopic Adrenocorticotropic Hormone Syndrome in Small Cell Lung Cancer." Tuberculosis and Respiratory Diseases 78, no. 4 (October 2015): 436–39. https://doi.org/10.4046/trd.2015.78.4.436.
  • Kadota, Kyuichi, Jun-ichi Nitadori, Kaitlin M. Woo, Camelia S. Sima, David J. Finley, Valerie W. Rusch, Prasad S. Adusumilli, and William D. Travis. "Comprehensive Pathological Analyses in Lung Squamous Cell Carcinoma: Single Cell Invasion, Nuclear Diameter, and Tumor Budding Are Independent Prognostic Factors for Worse Outcomes." Journal of Thoracic Oncology 9, no. 8 (August 1, 2014): 1126–39. https://doi.org/10.1097/JTO.0000000000000253.
  • Kanaji, Nobuhiro, Naoki Watanabe, Nobuyuki Kita, Shuji Bandoh, Akira Tadokoro, Tomoya Ishii, Hiroaki Dobashi, and Takuya Matsunaga. "Paraneoplastic Syndromes Associated with Lung Cancer." World Journal of Clinical Oncology 5, no. 3 (August 10, 2014): 197–223. https://doi.org/10.5306/wjco.v5.i3.197.
  • Kay, Fernando U, Asha Kandathil, Kiran Batra, Sachin S Saboo, Suhny Abbara, and Prabhakar Rajiah. "Revisions to the Tumor, Node, Metastasis Staging of Lung Cancer (8th Edition): Rationale, Radiologic Findings and Clinical Implications." World Journal of Radiology 9, no. 6 (June 28, 2017): 269–79. https://doi.org/10.4329/wjr.v9.i6.269.
  • Lázaro, Sara, Miriam Pérez-Crespo, Corina Lorz, Alejandra Bernardini, Marta Oteo, Ana Belén Enguita, Eduardo Romero, et al. "Differential Development of Large-Cell Neuroendocrine or Small-Cell Lung Carcinoma upon Inactivation of 4 Tumor Suppressor Genes." Proceedings of the National Academy of Sciences 116, no. 44 (October 29, 2019): 22300–306. https://doi.org/10.1073/pnas.1821745116.
  • Li, Shuyu D., Meng Ma, Hui Li, Aneta Waluszko, Tatyana Sidorenko, Eric E. Schadt, David Y. Zhang, Rong Chen, and Fei Ye. "Cancer Gene Profiling in Non-Small Cell Lung Cancers Reveals Activating Mutations in JAK2 and JAK3 with Therapeutic Implications." Genome Medicine 9, no. 1 (October 30, 2017): 89. https://doi.org/10.1186/s13073-017-0478-1.
  • Lim, Wanyin, Carole A. Ridge, Andrew G. Nicholson, and Saeed Mirsadraee. "The 8th Lung Cancer TNM Classification and Clinical Staging System: Review of the Changes and Clinical Implications." Quantitative Imaging in Medicine and Surgery 8, no. 7 (August 2018): 709–18. https://doi.org/10.21037/qims.2018.08.02.
  • "Lung Cancer 101 | Lungcancer.Org." Accessed January 21, 2020. https://www.lungcancer.org/find_information/publications/163-lung_cancer_101/269-non_small_cell_lung_cancer_treatment.
  • Merck Manuals Professional Edition. "Lung Carcinoma - Pulmonary Disorders." Accessed December 17, 2019. https://www.merckmanuals.com/professional/pulmonary-disorders/tumors-of-the-lungs/lung-carcinoma.
  • Moon, Youngkyu, Kyo Young Lee, Sook Whan Sung, and Jae Kil Park. "Differing Histopathology and Prognosis in Pulmonary Adenocarcinoma at Central and Peripheral Locations." Journal of Thoracic Disease 8, no. 1 (January 2016): 169–77. https://doi.org/10.3978/j.issn.2072-1439.2016.01.15.
  • DoveMed. "Non-Keratinizing Squamous Cell Carcinoma of Lung." Accessed January 20, 2020. http://www.dovemed.com/diseases-conditions/non-keratinizing-squamous-cell-carcinoma-lung/.
  • National Cancer Institute. "Non-Small Cell Lung Cancer Treatment (PDQ®)–Patient Version." PdqCancerInfoSummary, October 18, 2019. https://www.cancer.gov/types/lung/patient/non-small-cell-lung-treatment-pdq.
  • Novello, S., F. Barlesi, R. Califano, T. Cufer, S. Ekman, M. Giaj Levra, K. Kerr, et al. "Metastatic Non-Small-Cell Lung Cancer: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up." Annals of Oncology 27, no. suppl_5 (September 1, 2016): v1–27. https://doi.org/10.1093/annonc/mdw326.
  • Ouadah, Youcef, Enrique R. Rojas, Daniel P. Riordan, Sarah Capostagno, Christin S. Kuo, and Mark A. Krasnow. "Rare Pulmonary Neuroendocrine Cells Are Stem Cells Regulated by Rb, P53, and Notch." Cell 179, no. 2 (October 3, 2019): 403-416.e23. https://doi.org/10.1016/j.cell.2019.09.010.
  • Pelosi, Giuseppe, Angelica Sonzogni, Sergio Harari, Adriana Albini, Enrica Bresaola, Caterina Marchiò, Federica Massa, et al. "Classification of Pulmonary Neuroendocrine Tumors: New Insights." Translational Lung Cancer Research 6, no. 5 (October 2017): 513–29. https://doi.org/10.21037/tlcr.2017.09.04.
  • Popper, Helmut H. "Cons: The Confusing Mucinous Adenocarcinoma Classification." Translational Lung Cancer Research 6, no. 2 (April 2017): 234–40. https://doi.org/10.21037/tlcr.2017.04.09.
  • "Pulmonary Pathology for Medical Education - WebPath." Accessed January 20, 2020. https://webpath.med.utah.edu/LUNGHTML/LUNGIDX.html#8.
  • QIAN, XINYU, and JING QIN. "Hypertrophic Pulmonary Osteoarthropathy with Primary Lung Cancer." Oncology Letters 7, no. 6 (June 2014): 2079–82. https://doi.org/10.3892/ol.2014.2022.
    Reference, Genetics Home. "Lung Cancer." Genetics Home Reference. Accessed December 17, 2019. https://ghr.nlm.nih.gov/condition/lung-cancer.
  • Rekhtman, Natasha. "Neuroendocrine Tumors of the Lung: An Update." Arch Pathol Lab Med 134 (2010): 11.
    Rohr, A. von, T. Cerny, R. A. Joss, and K. W. Brunner. "[Syndrome of inappropriate ADH secretion (SIADH) in small-cell bronchus carcinoma]." Schweizerische Medizinische Wochenschrift 121, no. 36 (September 7, 1991): 1271–82.
  • Rolfo, Christian, Francesco Passiglia, Marcin Ostrowski, Lúcia Farracho, Tereza Ondøichová, Ana Dolcan, Marta Castiglia, Roy Remmen, Konstantinos Papadimitriou, and Patrick Pauwels. "Improvement in Lung Cancer Outcomes With Targeted Therapies: An Update for Family Physicians." The Journal of the American Board of Family Medicine 28, no. 1 (January 1, 2015): 124–33. https://doi.org/10.3122/jabfm.2015.01.140072.
  • Solis, Luisa M., Carmen Behrens, M. Gabriela Raso, Heather Y. Lin, Humam Kadara, Ping Yuan, Hector Galindo, et al. "Histologic Patterns and Molecular Characteristics of Lung Adenocarcinoma Associated With Clinical Outcome." Cancer 118, no. 11 (June 1, 2012): 2889–99. https://doi.org/10.1002/cncr.26584.
  • Suarez, Eric, and Barbara E. C. Knollmann-Ritschel. "Squamous Cell Carcinoma of the Lung." Academic Pathology 4 (July 24, 2017). https://doi.org/10.1177/2374289517705950.
  • Swanton, Charles, and Ramaswamy Govindan. "Clinical Implications of Genomic Discoveries in Lung Cancer." New England Journal of Medicine 374, no. 19 (May 12, 2016): 1864–73. https://doi.org/10.1056/NEJMra1504688.
  • TANE, SHINYA, WATARU NISHIO, HIROYUKI OGAWA, DAISUKE HOKKA, KENTA TANE, YUGO TANAKA, SHUNSUKE TAUCHI, et al. "Clinical Significance of the 'Not Otherwise Specified' Subtype in Candidates for Resectable Non-Small Cell Lung Cancer." Oncology Letters 8, no. 3 (September 2014): 1017–24. https://doi.org/10.3892/ol.2014.2302.
  • Tang, Moon-shong, Xue-Ru Wu, Hyun-Wook Lee, Yong Xia, Fang-Ming Deng, Andre L. Moreira, Lung-Chi Chen, William C. Huang, and Herbert Lepor. "Electronic-Cigarette Smoke Induces Lung Adenocarcinoma and Bladder Urothelial Hyperplasia in Mice." Proceedings of the National Academy of Sciences 116, no. 43 (October 22, 2019): 21727–31. https://doi.org/10.1073/pnas.1911321116.
  • Travis, William D., Elisabeth Brambilla, Allen P. Burke, Alexander Marx, and Andrew G. Nicholson. "Introduction to The 2015 World Health Organization Classification of Tumors of the Lung, Pleura, Thymus, and Heart." Journal of Thoracic Oncology 10, no. 9 (September 1, 2015): 1240–42. https://doi.org/10.1097/JTO.0000000000000663.
  • Travis, William D., Elisabeth Brambilla, Andrew G. Nicholson, Yasushi Yatabe, John H.M. Austin, Mary Beth Beasley, Lucian. R. Chirieac, et al. "The 2015 World Health Organization Classification of Lung Tumors." Journal of Thoracic Oncology 10, no. 9 (September 2015): 1243–60. https://doi.org/10.1097/JTO.0000000000000630.
  • "Treatment of Mesothelioma Based on the Extent of the Cancer." Accessed January 21, 2020. https://www.cancer.org/cancer/malignant-mesothelioma/treating/by-extent.html.
    Uruga, Hironori, Takeshi Fujii, and Kazuma Kishi. "What Is Spread through Air Space?" Journal of Thoracic Disease 9, no. 10 (October 2017): E943–44. https://doi.org/10.21037/jtd.2017.08.159.
  • Villalobos, Pamela, and Ignacio I. Wistuba. "Lung Cancer Biomarkers." Hematology/Oncology Clinics of North America 31, no. 1 (February 2017): 13–29. https://doi.org/10.1016/j.hoc.2016.08.006.
  • Warth, Arne. "Spread through Air Spaces (STAS): A Comprehensive Update." Translational Lung Cancer Research 6, no. 5 (October 2017): 501–7. https://doi.org/10.21037/tlcr.2017.06.08.
  • "What Are Lung Carcinoid Tumors?" Accessed December 17, 2019. https://www.cancer.org/cancer/lung-carcinoid-tumor/about/what-is-lung-carcinoid-tumor.html.
  • "What Is Lung Cancer? | Types of Lung Cancer." Accessed December 17, 2019. https://www.cancer.org/cancer/lung-cancer/about/what-is.html.
  • "Who Should Be Screened for Lung Cancer? | CDC," November 18, 2019. https://www.cdc.gov/cancer/lung/basic_info/screening.htm.
  • Zamay, Tatiana N., Galina S. Zamay, Olga S. Kolovskaya, Ruslan A. Zukov, Marina M. Petrova, Ana Gargaun, Maxim V. Berezovski, and Anna S. Kichkailo. "Current and Prospective Protein Biomarkers of Lung Cancer." Cancers 9, no. 11 (November 13, 2017). https://doi.org/10.3390/cancers9110155.
  • Zappa, Cecilia, and Shaker A. Mousa. "Non-Small Cell Lung Cancer: Current Treatment and Future Advances." Translational Lung Cancer Research 5, no. 3 (June 2016): 288–300. https://doi.org/10.21037/tlcr.2016.06.07.
  • Zhang, Bin, Yueying Zhang, and Dongmei Yu. "Lung Cancer Gene Therapy: Transferrin and Hyaluronic Acid Dual Ligand-Decorated Novel Lipid Carriers for Targeted Gene Delivery." Oncology Reports 37, no. 2 (February 1, 2017): 937–44. https://doi.org/10.3892/or.2016.5298.