TUMORS, MALIGNANT. Overview. Abstract. Introduction

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1 320 TUMORS, MALIGNANT / Overview Dail DH and Hammar SP (eds.) (1994) Pulmonary Pathology, 2nd edn. New York: Springer. Leslie KO and Wick MR (2005) Practical Pulmonary Pathology: A Diagnostic Approach. Philadelphia: Churchill Livingstone. Travis WD, Brambilla E, Müller-Hermelink HK, and Harris CC (eds.) (2004) Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: International Agency for Research on Cancer. Travis WD, Colby TV, and Corrin B (1999). Histological Typing of Lung and Pleural Tumours, 3rd edn., World Health Organization International Histological Classification of Tumours. Berlin: Springer. TUMORS, MALIGNANT Contents Overview Bronchogenic Carcinoma Chemotherapeutic Agents Hematological Malignancies Lymphoma Metastases from Lung Cancer Bronchial Gland and Carcinoid Tumor Rare Tumors Carcinoma, Lymph Node Involvement Overview K M Fong, P V Zimmerman, and R V Bowman, Prince Charles Hospital, The University of Queensland, Brisbane, QLD, Australia & 2006 Elsevier Ltd. All rights reserved. Abstract Although the most common malignancies of the lung are primary bronchogenic carcinomas and metastatic tumors, a wide range of rarer tumor types can occur in humans. Newer techniques to establish histological confirmation of malignancy include the use of ultrasound and fluorescence to enhance the precision of bronchoscopic biopsy. Needle aspiration of lung lesions can also be of high diagnostic yield. Certain tumor types can now be differentiated using new immunohistochemical markers, although tumor heterogeneity and sampling issues can occasionally influence the accuracy of the final diagnosis. The varying susceptibilities of cigarette smokers to developing bronchogenic carcinoma appear increasingly likely to be related to mutations at multiple genetic loci and their interactions. Recent advances in imaging techniques such as positron emission tomography, computed tomography densitometry, perfusion CT algorithms, and magnetic resonance imaging are increasing the accuracy of pretreatment staging and also improving the overall functional assessment of patients. Introduction There are a large number of malignant tumors that affect the lungs, ranging from metastatic malignancies to the most common type, bronchogenic carcinoma (see Tumors, Malignant: Bronchogenic Carcinoma). Bronchogenic cancers can also metastasize to the lungs, as well as other sites; this subject is covered elsewhere in this encyclopedia (see Tumors, Malignant: Metastases from Lung Cancer). Other primary cancers arising within the chest include tumors of lymphoid origin (see Tumors, Malignant: Lymphoma), vascular/blood origin (see Tumors, Malignant: Hematological Malignancies), and rare tumors (see Tumors, Malignant: Rare Tumors). Metastatic cancers can involve the lung parenchyma, the lymph nodes (see Tumors, Malignant: Carcinoma, Lymph Node Involvement), or other thoracic structures. Thus, the usual clinical challenge when faced with the possibility of cancer in the lung is to ascertain firstly the presence of malignancy, secondly the origin of the cancer, and finally the extent or stage of cancer so that therapy may be appropriately individualized. In future, this challenge may be magnified if low-dose helical computed tomography (CT) scanning is shown from randomized trial data to be effective in reducing lung cancer mortality. This technique has already been shown to be severalfold more sensitive than conventional chest radiography for detecting pulmonary nodules. Indeed, studies to date show that low-dose CT scanning can potentially detect a large number of pulmonary nodules in at-risk populations. Most of these pulmonary nodules turn out not to be malignant but require further evaluation using a variety of follow-up algorithms or invasive investigations.

2 TUMORS, MALIGNANT / Overview 321 Etiology Bronchogenic carcinomas are estimated to be due to smoking in 85 90% of cases. Prior to the nineteenth century when smoking was less common and mostly in the form of cigars smoked by men, lung cancer was rare. An often-quoted anecdote is that in 1919, a medical student called Alton Oschner was invited to observe lung cancer surgery, it being a rare procedure. Indeed, another notable anecdote is the report of the first successful pneumonectomy being performed by Dr E A Graham of St Louis whose patient eventually outlived his surgeon, who himself succumbed to the disease. In the early twentieth century, smoking became more prevalent, particularly after World War I when cigarettes were widely available. As there is a time lag of about 20 years or more before the development of invasive lung cancer, it is not surprising that by the 1970s, lung cancer became the commonest cause of cancer deaths in males in some Western countries. Recently, lung cancer has become the commonest cause of cancer deaths in females. The lag between the sexes is explained by the temporal differences in smoking habits between men and women. Currently it is young females who represent an ongoing target population for tobacco control strategies as they continue to have relatively high rates of smoking. The epidemiology of lung cancer is further discussed elsewhere in this encyclopedia, including the role and interactions of asbestos and other lung carcinogens in nontobacco smoke-related lung cancer (see Tumors, Malignant: Bronchogenic Carcinoma). Although the risk of malignancy long after curative radiotherapy delivery has long been known, there is recent concern regarding the increasing use of medical radiation, particularly for diagnostic purposes, for example, CT scans. The issue of a genetic basis for lung cancer risk has long been debated since only a minority of smokers develop lung cancer and familial aggregation of lung cancer has been reported since the 1950s. Segregation analysis models range from Mendelian inheritance (codominant) to pure environmental models, although recent work provides evidence that multiple genetic factors, possibly multiple genetic loci and interactions, contribute to susceptibility and age-ofonset of primary lung cancer. Furthermore, a major susceptibility locus on 6q23-25 has been recently mapped through genome-wide linkage analysis. The lung is also a common destination for the metastatic spread of human malignancies. Pulmonary metastases may occur in 30 40% of cancer patients, although clearly the prevalence of metastases is a function of the natural history of the cancer, and the point in the clinical course at which investigation for pulmonary involvement is undertaken. Even though pulmonary metastases are relatively common, they may not be clinically significant during life, and many are discovered only at postmortem. Pathology and Pathogenesis The common classification of bronchogenic cancers into the small cell lung cancer (SCLC; previously also called oat-cell) and non-sclc (NSCLC) subtypes has useful clinical implications for the diagnosis and treatment due to their differing characteristics (Table 1). Whilst the natural history of preinvasive squamous carcinomas has been relatively well studied due to their often proximal airway location and the ability to sample sequentially bronchial epithelium at bronchoscopy, much less is known about precursor lesions for the other subtypes. For squamous carcinogenesis, the multistep process affecting the bronchial epithelium includes basal cell hyperplasia, squamous metaplasia, dysplasia, and finally carcinoma-in-situ (CIS). Nonetheless, foci of atypical adenomatous hyperplasia, a bronchioloalveolar proliferation, are regarded as a precursor for peripheral adenocarcinoma and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, a rare condition in which the peripheral airways are involved diffusely by neuroendocrine cell hyperplasia and tumorlets, for peripheral typical carcinoids. Metastatic lung malignancies may arise from primaries within or external to the thoracic cavity. The process of lung metastases is complex and not fully understood, but includes tumor and host factors that modify the ability for micrometastases to adhere, invade, grow, cause angiogenesis, and avoid immune surveillance. Metastases may seed the lungs by several routes: hematogenous spread, lymphatic invasion, direct invasion, and possibly endobronchial dissemination. Certain tumors such as sarcomas and carcinomas of kidney, thyroid, breast, and lung appear particularly prone to disseminate to the lung by blood-borne spread. Lymphatic invasion by distant tumors reaching the large lymphatic channels, then the thoracic duct and pulmonary vasculature appears to explain the propensity for testicular tumors to spread to the lungs. Alternatively, local thoracic lymphadenopathic involvement (see Tumors, Malignant: Carcinoma, Lymph Node Involvement) may result in retrograde spread into pulmonary lymphatics, sometimes producing the clinical and radiological picture of lymphangitis carcinomatosis. Direct invasion of the lungs can occur from tumors arising in the mediastinum such as esophageal cancers, thymoma, lymphoma, or germ cell tumors; those arising

3 Table 1 The 1999 World Health Organization/International Association for the Study of Lung Cancer Histological Classification of Lung and Pleural Tumors 1 Epithelial tumors 1.1. Benign Papillomas Squamous cell papilloma Exophytic Inverted Glandular papilloma Mixed squamous cell and glandular papilloma Adenomas Alveolar adenoma Papillary adenoma Adenomas of salivary gland type Mucous gland adenoma Pleomorphic adenoma Others Mucinous cystadenoma Others 1.2. Preinvasive lesions Squamous dysplasia/carcinoma in situ Atypical adenomatous hyperplasia (AAH) Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) 1.3. Malignant Squamous cell carcinoma (SCC) Variants Papillary Clear cell Small cell Basaloid Small cell carcinoma (SCLC) Variant Combined small cell carcinoma Adenocarcinoma Acinar Papillary Broncholoalveolar carcinoma Nonmucinous (Clara/pneumocyte type II) Mucinous Mixed mucinous and nonmucinous or intermediate cell type Solid adenocarcinoma with mucin Adenocarcinoma with mixed subtypes Variants Well-differentiated fetal adenocarcinoma Mucinous ( colloid ) adenocarcinoma Mucinous cystadenocarcinoma Signet-ring adenocarcinoma Clear cell adenocarcinoma Large cell carcinoma Variants Large cell neuroendocrine carcinoma Combined large cell neuroendocrine carcinoma Basaloid carcinoma Lymphoepithelioma-like carcinoma Clear cell carcinoma Large cell carcinoma with rhabdoid phenotype Adenosquamous carcinoma Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements Carcinomas with spindle and/or giant cells Pleomorphic carcinoma Spindle cell carcinoma Giant cell carcinoma Carcinosarcoma Pulmonary blastoma Others Carcinoid tumor Typical carcinoid Atypical carcinoid Carcinomas of salivary gland type Mucoepidermoid carcinoma Adenoid cystic carcinoma Others Unclassified carcinoma 2 Soft tissue tumors 2.1. Localized fibrous tumor 2.2. Epithelioid hemangioendothelioma 2.3. Pleuropulmonary blastoma 2.4. Chondroma 2.5. Calcifying fibrous pseudotumor of the pleura 2.6. Congenital peribronchial myofibroblastic tumor 2.7. Diffuse pulmonary lymphangiomatosis 2.8. Desmoplastic small round cell tumor 2.9. Other 3 Mesothelial tumors 3.1. Benign Adenomatoid tumor 3.2. Malignant Epithelioid mesothelioma Sarcomatoid mesothelioma Desmoplastic mesothelioma Biphasic mesothelioma Other 4 Miscellaneous tumors 4.1. Hamartoma 4.2. Sclerosing hemangioma 4.3. Clear cell tumor 4.4. Germ cell neoplasms Teratoma, mature or immature Malignant germ cell tumor 4.5. Thymona 4.6. Melanoma 4.7. Others 5 Lymphoproliferative disease 5.1. Lymphoid interstitial pneumonia 5.2. Nodular lymphoid hyperplasia 5.3. Low-grade marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue 5.4. Lymphomatoid granulomatosis 6 Secondary tumors 7 Unclassified tumors 8 Tumor-like lesions 8.1. Tumorlet 8.2. Multiple meningothelioid nodules 8.3. Langerhans cell histiocytosis 8.4. Inflammatory pseudotumor (inflammatory myofibroblastic tumor) 8.5. Organizing pneumonia 8.6. Amyloid tumor 8.7. Hyalinizing granuloma 8.8. Lymphangioleiomyomatosis 8.9. Multifocal micronodular pneumocyte hyperplasia Endometriosis Reproduced from Brambilla E, Travis WD, Colby TV, Corrin B, and Shimosato Y (2001) The New World Health Organization classification of lung tumors. European Respiratory Journal 18(6): , with permission from European Respiratory Society Journals Limited.

4 TUMORS, MALIGNANT / Overview 323 in the chest wall such as sarcomas; and those arising in the abdominal cavity such as liver or gastric tumors. Animal Models Humans appear to be one of the few species susceptible to developing spontaneous lung cancer. The initial histologic description 100 years ago of a papillary tumor in a mouse led to the idea of using animals as experimental tools for learning about lung cancer. Several types of animal models are used for experimental lung cancer research, including chemically induced lung tumors, transgenic mouse models, and human tumor xenografts. Chemical or carcinogen-induced lung tumors have been described in a variety of species, including dogs, cats, hamsters, mice, and ferrets. Transgenic mouse technology has proved useful in creating models of lung tumor development, for example, lung adenocarcinoma with mutant Kras transgene, as well as for testing experimental therapeutic approaches. In orthotopic models, human tumors are implanted into the appropriate organ of the animal, and have been described using endobronchial, intrathoracic, or intravenous injection of tumor cell suspensions and by surgical implantation of fresh tumor tissue. Thus, several lung cancer models are serving to increase our knowledge of lung cancer biology. Each has advantages and disadvantages and no single model is informative on the complexity of all aspects of lung cancer from carcinogenesis, proliferation, invasion, angiogenesis, and metastasis, to chemoprevention and therapeutic development. Clinical Features The clinical features may be the same regardless of whether the lung cancer is a primary or secondary cancer. Symptoms clearly depend upon the local structures involved; patients commonly present with cough, hemoptysis, wheeze, obstructive infection or atelectasis, chest pain, and dyspnea. Particular symptoms such as stridor, dysphagia, facial edema from superior vena cava obstruction, or hoarseness due to recurrent laryngeal nerve involvement are a result of local damage to vital structures. Systemic symptoms such as anorexia or weight loss may also be present, and often indicate the presence of disseminated disease. Paraneoplastic syndromes occur in approximately 10% of patients with bronchogenic carcinoma and are not due to direct physical effects of the cancer, the best known perhaps being finger-clubbing and hypertrophic pulmonary osteoarthropathy. Unlike bronchogenic cancers, which are frequently symptomatic, the majority of lung metastases are asymptomatic at the time of clinical detection. The clinical importance of lung metastases is highly dependent on the natural history of the originating cancer. When more than one site of cancer in the lung is evident, it may be difficult to decide whether the situation is one of satellite nodules, multiple primary lung cancers, or blood-borne metastases. Various models have been developed to guide clinical management in these circumstances. Clearly, when there is known cancer elsewhere, the probability of lung metastases is correspondingly higher although other conditions should always be considered in the differential diagnosis. Radiographic imaging may show a variety of abnormalities ranging from solitary pulmonary nodules (SPNs), multiple nodules, masses, pleural effusions, collapse/atelectasis, lymphadenopathy, or lymphangitis. Recent advances in nuclear medicine have led to the increasing use of metabolic imaging with positron emission tomography (PET) using 18Ffluoro-2-deoxy-glucose (FDG) where the glucose analog is highly taken up by certain malignancies including lung cancer. Despite high overall sensitivity and specificity of PET scans for lung cancer, imaging can usually only provide a guide to the likelihood of cancer, being neither diagnostic, nor able to determine the type of cancer. Consequently, the main diagnostic strategy is to obtain histological or cytological confirmation where possible. However, as lung cancer patients are often relatively older and have been smokers, there may be significant comorbidities precluding the use of invasive investigations. The common diagnostic tools include white light bronchoscopy, fine needle aspiration biopsy, mediastinoscopy, and rarely thoracotomy (open or videoassisted) or other biopsies. Modern techniques such as endobronchial ultrasound fluorescent bronchoscopy are likely to improve diagnostic capabilities. The safest technique likely to produce a histological diagnosis should be chosen, with consideration given to tumor factors (location, size, number, accessibility) and patient factors (fitness, comorbidities, age, concomitant lung and heart disease), as well as local expertise. Histology should be classified according to the World Health Organization/International Association for the Study of Lung Cancer, 1999 classification (Table 1). There are occasions, however, when accurate classification of morphology using the standard WHO classification may be difficult, even with the use of immunohistochemistry. Cytokeratin (CK) 7 and 20 are commonly used to help distinguish

5 324 TUMORS, MALIGNANT / Overview adenocarcinomas from various organs, and thyroid transcription factor 1 (TTF-1), a 38 kda protein located primarily in type II pneumocytes and Clara cells, is present in a variety of lung tumors as well as thyroid carcinomas. Although pathological diagnosis can be complex due to intratumoral heterogeneity, mixed tumors, and sampling issues, classification of a particular tumor into one of the major subtypes is usually possible from small biopsies. In the future, it is likely that tumor classification by genetic and/or genomic approaches such as mutation analyses and microarray technology will be translated from the research to the clinical arena. The tumor molecular profile may also have implications for therapy (e.g., mutations predicting sensitivity to targeted therapies such as tyrosine kinase inhibitors) and prognosis (e.g., predictive gene panels). Once a diagnosis of bronchogenic cancer is made, the next management step is staging the extent of disease. In NSCLC, staging is carried out according to the current tumor node metastasis (TNM) schema (see Tumors, Malignant: Bronchogenic Carcinoma) with the aim of identifying patients who will benefit from surgery, radiation, chemotherapy, or multimodality treatment. In contrast, a simpler staging system (limited and extensive) is used for SCLC, which is essentially demarcated as to whether disease is confined to a single hemithorax. The usefulness of staging procedures depends on test characteristics, that is, sensitivity and specificity, and also on the potential of a staging test result to alter management. Tests that are useful for staging lung cancer include computed axial tomography (CAT) scans, PET scans, magnetic resonance imaging (MRI) scans, nuclear medicine bone scans, and even surgical biopsies. Participation of the radiologist and nuclear medicine physician in the multidisciplinary lung cancer team allows the greatest advantage to be taken of advanced imaging techniques such as PET, fusion CT PET, CT densitometry, and perfusion CT in patient care. In management planning, physiological and functional assessment for performance status, lung function, and exercise capacity is essential to determine fitness for specific therapies. As chronic obstructive pulmonary disease (COPD) is frequent in smokers, diminished lung function is an important consideration, particularly in evaluation for treatments such as surgery and radiotherapy, which will further impair lung function. Advances in operative technique and perioperative care have reduced surgical morbidity and mortality considerably after pulmonary resection. In the past, only patients with normal or slightly impaired pulmonary function (forced expiratory volume in 1 s (FEV 1 ) and diffusing capacity of the lung for carbon monoxide (DLCO) X80% predicted) and no cardiovascular risk factors were considered suitable for a pneumonectomy. Now it is possible to predict postsurgical functional outcomes reasonably accurately in patients with abnormal lung function and other comorbidities using cardiopulmonary exercise testing and differential ventilation or perfusion lung scans. Lessons learned from tumor resection in the course of lung volume reduction, and evolving techniques including limited resection and minimally invasive surgery will challenge traditional concepts of surgical criteria further. Management and Current Therapy The treatment of pulmonary malignancy hinges on the natural history and outcome from the primary tumor. The underlying principles include establishing a histological diagnosis where possible, followed by staging the extent of disease, and treatment planning with curative or palliative endpoints as appropriate to stage. Supportive and symptomatic therapy (potentially including radiotherapy and chemotherapy) are indicated where the disease is predicted to be incurable. In certain cases, where the primary tumor is controlled and with no other evidence of extrapulmonary disease, resection of a solitary metastasis may be considered in a suitably fit patient. The details of treatment for bronchogenic cancer are described elsewhere in this encyclopedia (see Tumors, Malignant: Bronchogenic Carcinoma). Briefly, for NSCLC, optimal treatment is surgery where appropriate, that is in those cases where the tumor is at an early stage and the patient is fit for resection. When disease is more advanced, technically unresectable, the patient is unfit, or the patient declines surgery, other modalities of treatment including radiotherapy, chemotherapy, supportive care, or a combination thereof are indicated. In comparison, SCLC, as a systemic disease, has the best outcome with systemic therapy (chemotherapy), which is combined with thoracic radiation therapy for limited stage disease, and with prophylactic cranial irradiation offered to those with complete responses. Provision of information, involvement of the patient and their carers, and consideration of patient preferences represent important aspects of both curative and palliative management of lung cancers. Summary The most effective management for lung cancer is its prevention by tobacco control, which would ultimately reduce the worldwide impact of this and other smoking-related diseases. In the meantime, clinicians continue to strive to optimize conventional

6 TUMORS, MALIGNANT / Bronchogenic Carcinoma 325 therapies and outcomes for patients. Future challenges for lung cancer clinicians include optimizing strategies for clinical deployment of the new generation of technologies including early detection by helical low-dose CT scanning, functional imaging, and targeted biological therapies. For healthcare providers, the emerging challenge is how best to balance the costs and benefits of these differing technological developments. For scientists, it will be harnessing the clinical potential in the vast amount of biologic knowledge emerging from genomics and proteomics. See also: Tumors, Malignant: Bronchogenic Carcinoma; Chemotherapeutic Agents; Hematological Malignancies; Lymphoma; Metastases from Lung Cancer; Rare Tumors; Carcinoma, Lymph Node Involvement. Further Reading Anonymous (2003) Diagnosis and management of lung cancer: ACCP Evidence-Based Guidelines. Chest 123 (1 supplement). Beasley MB, Brambilla E, and Travis WD (2005) The 2004 World Health Organization classification of lung tumors. Seminars in Roentgenology 40(2): Brambilla E, Travis WD, Colby TV, Corrin B, and Shimosato Y (2001) The New World Health Organization Classification of Lung Tumors. European Respiratory Journal 18(6): Fong KM, Sekido Y, Gazdar AF, and Minna JD (2003) Lung cancer 9: molecular biology of lung cancer: clinical implications. Thorax 58(10): Leslie WT and Bonomi PD (2004) Novel treatments in non-small cell lung cancer. Hematology/Oncology Clinics of North America 18(1): Liu J and Johnston MR (2002) Animal models for studying lung cancer and evaluation of novel intervention strategies. Surgical Oncology 11: Matthay RA (ed.) (2002) Lung cancer. In: Clincs in Chest Medicine, vol. 23(1), pp Philadelphia, PA: Saunders. Elsevier Inc. Murray N, Salgia R, and Fossella FV (2004) Targeted molecules in small cell lung cancer. Seminars in Oncology 31(supplement 1): Roth JA and Grammer SF (2004) Gene replacement therapy for non-small cell lung cancer: a review. Hematology/Oncology Clinics of North America 18(1): Xu H, Spitz MR, Amos CI, and Shete S (2005) Complex segregation analysis reveals a multigene model for lung cancer. Human Genetics 116(1 2): Bronchogenic Carcinoma K M Fong, R V Bowman, and P V Zimmerman, Prince Charles Hospital, The University of Queensland, Brisbane, QLD, Australia & 2006 Elsevier Ltd. All rights reserved. Abstract Lung cancer is the most devastating, yet preventable, cause of premature cancer mortality and morbidity in the Western world. While death rates for all other major cancers have been stable or declining, the age-adjusted death rate due to lung cancer steadily increased in both men and women during the second half of the twentieth century. Public education and measures to control tobacco smoking have resulted in a steady decline in lung cancer deaths in men, and a stable rate in women in some Western countries during the past decade. The ultimate key to controlling the current prevalence and mortality of lung cancer lies in a global solution to tobacco smoking. Meanwhile, the impact of low dose CT screening in high-risk populations on lung cancer mortality is currently under evaluation. Secondary prevention strategies trialled during the latter part of last century did not reduce the incidence of lung cancer, and discovery of effective new agents for secondary prevention is a priority. Strategies to identify and treat very early disease such as carcinoma in situ and atypical adenomatous hyperplasia need to be more practical. Meanwhile refined clinical staging, reduced surgical morbidity and mortality, strategic application of chemotherapy, and definition of optimal combined modality therapy have contributed to improvements in clinical management and outcomes for individual patients. The outstanding issue in clinical lung cancer management remains the limited effectiveness of current agents and treatment modalities. Despite the development of new treatments targeting specific molecular vulnerabilities, a far more comprehensive understanding of the cell and molecular biology of lung cancer is still required before translational therapies can reach their full potential to make an impact on survival. Introduction Bronchogenic carcinoma (lung cancer) is the highest ranking cause of cancer associated mortality in the world. Historically more prevalent in men, bronchogenic carcinoma is currently causing higher mortality among women living in several Western countries than breast or any other cancer. At present, it also has highest incidence among the major cancers affecting women in several Western countries. Non-small cell lung cancer accounts for approximately 80 85% of primary lung cancer and small cell cancer accounts for most of the remainder. The two types differ in both biological characteristics and clinical behavior. The International Agency for Research on Cancer (IARC) designates lung cancer as causally related to tobacco based upon the consistency, strength, temporal relationship, coherence, and specificity of the epidemiologic relationship between tobacco smoking and lung cancer. Compared with a twofold increased risk of breast cancer conferred by having an affected first degree relative, the relative risk of lung cancer in smokers is 20-fold the risk in nonsmokers one of the highest associations between any agent and cancer. Epidemiology of Tobacco Use and Lung Cancer Seminal health reports by Wynder and Graham (USA) and Doll and Hill (UK) in 1950 linked smoking with lung cancer and in the early 1960s