A description of the current epidemiology of lung cancer would not be complete without a discussion of the complicated relationship between the history of tobacco smoking and the epidemiology of the disease. Today, the causative relationship between tobacco smoking and lung cancer is universally accepted. However, a review of history reveals that the relationship between the smoking and lung cancer was not easily established.

Given the magnitude of the health problem that is lung cancer today, it may be surprising to note that as recent as 100 years ago, lung cancer was considered an extremely rare disease that warranted reporting. In the mid-1850s, medical texts [3] considered the lungs “less prone than most other organs to cancerous disease.” A review done at the Institute of Pathology of the University of Dresden in Germany in 1878 [4] showed that cancers of the lung represented only 1% of all cancers seen at autopsy. In 1912, Adler [5] published a book entitled Primary Malignant Growths of the Lungs and Bronchi where he reviewed the reports of major hospitals in the United States and Western Europe and verified only 374 cases of lung cancer, constituting less than 0.5% of autopsied cancer cases.

Cigarette smoking, on the other hand, only became popular at the turn of the twentieth century. At that time, cigarettes were hand rolled and expensive, which limited their popularity. This changed significantly with the introduction of machines to mass produce cigarettes in 1876 [4]. Cigarettes were routinely distributed to soldiers in World War I and were considered part of their essential provisions during the wartime period [6].

The ensuing decades were marked by rapidly increasing incidence rates in lung cancer in men and later women. The increasing incidence of lung malignancies was of concern in the 1930s; however, its connection to cigarette smoking took time to establish. Early studies in 1923 [7] and 1929 [8] had posited the connection between lung cancer and cigarette smoking but failed to garner interest. The 1930 edition of the influential Springer Handbook of Special Pathology noted that lung malignancies had begun to increase in incidence at the turn of the century and accelerated after World War I and were still on the rise. Although a multitude of other putative etiologies were mentioned (air pollution, automobile traffic, the 1918 influenza epidemic, and even exposure to gas in World War I), smoking was only briefly mentioned as a “possibility.” It was pointed out that there were as many investigations that failed to show an association between smoking and lung cancer as there were positive studies [4].

In 1950, landmark studies were published by Wynder and Graham [9] in the Journal of the American Medical Association and by Doll and Hill [10] in the British Medical Journal. Both were case control studies involving more than 600 patients each, revealing that smokers comprised 98.7 and 99.7% of those who developed cancer in their reports, respectively.

Despite this, smoking continued to be popular well into the 1950s and was considered fashionable at that time. In movies of the era, it was common to note that actors smoked and, at medical meetings, most doctors were smoking [5]. Physicians could be seen advocating smoking in tobacco advertisements, and the claims by the tobacco industry went unchallenged [6]. The incidence of tobacco use reached its peak at this time despite the mounting evidence of harm.

It was not until 1964 that a landmark publication by the US Surgeon General categorically stated that smoking was harmful. The public was then encouraged to not take up the habit or to quit [11]. This resulted in a decline in the rate of smoking, with a decrease in lung cancer rates 20 years later [6]. The annual US per capita cigarette consumption among adults 18 years of age or older rose from almost 0 in the early 1900s to more than 4000 in the 1960s, before declining to 1700 in 2006, a level not seen since 1935 [12].

Lung cancer incidence trends follow that of tobacco, except that there is a roughly 20-year lag, so that changes in tobacco use result in changes in lung cancer incidence approximately 20 years later. However, while tobacco use is declining in the developed world, tobacco use is increasing in developing countries.

Because of the high case fatality rate of lung cancer, incidence and mortality rates are nearly equivalent [13]. Due to advocacy for tobacco cessation that started since the US Surgeon General’s report in 1964 [11], the incidence of lung cancer in most countries in the developed world has started to decline in the past decade.

In the United States, lung cancer incidence can be readily obtained from the National Program of Cancer Registries (NPCR) of the US Centers for Disease Control (CDC) and the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program [14]. Data from SEER 9 (1975–2013) show that the age-adjusted incidence rate of lung cancer increased from 52.2/100,000 in 1975 to a peak of 69.8/100,000 in 1991. The latest rate is now 53.2/100,000 in 2013 (Fig. 20.2). After a general trend of increasing 2.5% per year from 1975 to 1991, incidence rates are now decreasing at a rate of 2.4% per year since 2007 (Fig. 20.3). Age-adjusted lung cancer incidence rates in males peaked and started to decline consistently since 1984, but in females, the peak occurred later, plateauing in 1992–2009, and only started to decline at a slower rate starting in 2010 (Fig. 20.4). Tobacco use rates in women peaked at a later time than in men, which is thought to account for the difference in the trends in lung cancer incidence [15].

In Europe, lung cancer incidence rates were estimated using available national rates for 2012 [16]. Available data suggest that the highest rates were seen in Hungary and lowest in Cyprus. In men, the incidence was highest in Central and Eastern European countries (Serbia, Hungary, Macedonia, and Poland) and lowest in Northern European countries (Finland and Sweden). The reverse was seen in women, with higher rates in Northern Europe and lower rates in Eastern Europe. Lung cancer, however, is still the leading cause of cancer death in Europe in 2012 [16]. Incidence and mortality rates in men are decreasing particularly in Northern and Western European countries, while rates in Central and Eastern Europe remain high and are showing signs of stabilization or decline [17]. Rates in women are still largely increasing in Europe [17], but there are signs that this may be stabilizing.

At the start of the lung cancer epidemic, the highest incidence rates were found in Europe and the United States, with the lowest rates found primarily in South America and Asia [6]. However, the epidemic in the developing world is just unfolding, and the geographic pattern is rapidly changing. The figures in developing countries are thought to be underestimated as many go undiagnosed or unreported in areas where healthcare is not available [18, 19]. The International Agency for Research on Cancer (IARC) reports that as of 2012, the estimated age-standardized incidence rate is now high in both Central and Eastern Europe (53.5/100,000) and East Asia (50.4/100,000) [20]. Notably lower incidence rates are seen in Africa (Fig. 20.5).

An important case study of the current epidemiologic trends in lung cancer in the developing world is China. It is estimated that 67% of the male population is smoking in China, which is equivalent to the highest rate ever seen in the United States [19, 21]. It is estimated that one third of the world’s smokers reside in China [21]. In 2000, the age-standardized incidence rate in China was 35.2/100,000. That rate increased to 46/100,000 by 2010 [22]. China contains 19% of the world population, with 36% of all newly diagnosed lung cancer cases and 38% of lung cancer deaths worldwide [20]. There is data to suggest that high lung cancer mortality rates among Chinese women may not be associated with the high prevalence of cigarette smoking. Exposure to other risk factors such as indoor air pollution from cooking fumes is theorized to be a significant contributor [23]. The burden of the tobacco epidemic in China exemplifies the shift in the global burden of lung cancer from high-income Western countries to low- and middle-income countries, particularly in Asia [13]. In 2008, newly diagnosed lung cancers in developing countries (884,5000) exceeded the number in developed countries (724,300) by 22% [23].

The survival rate for lung cancer has improved in the past few decades, albeit slowly. The 5-year survival rate for lung cancer in the United States was 12.3% in 1978 to 1977, which has increased to 17.7% in 2006–2012 [24]. However, this varies widely depending on the stage of diagnosis, from 55.2%, to 28%, to 4.3% for localized, regional, and distant disease, respectively [24]. Based on the SEER 18 data (2006–2012) [24], 57% of patients present with distant/metastatic disease, 22% with regional disease, and 16% with localized disease. Undoubtedly, stage at presentation influences overall mortality significantly. It is uncertain at this time whether the advent of low-dose computed tomographic screening will change these rates [25].

Based on the above data, it is clear that the epidemiologic trends in lung cancer incidence are intimately related to tobacco use rates. Histologic patterns have also changed dramatically during this time as smoking patterns and cigarettes have changed. The next section explores this further.

Four types of lung cancer account for more than 90% of lung cancer cases in the United States: [26] adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and small cell carcinoma. These are traditionally identified by histologic appearance. However, there has been a concerted effort in the scientific community to revise the classification system using molecular markers that may convey clinically meaningful and prognostic information [27, 28]. At this time, however, epidemiologic studies still use histologic classification.

All four histologic subtypes mentioned above are associated with tobacco exposure. However, the relative risk (RR) associated with tobacco exposure may vary significantly depending on the subtype. The relative risk of smoking has been noted to be higher for squamous cell carcinoma (RR 10–50) than for adenocarcinoma (RR 2–15) [29–31]. The decline in risk after smoking cessation has been less consistent for adenocarcinoma [32] than for squamous cell, small cell, or large cell carcinoma, which may have implications for future histologic trends of lung cancer.

In the United States, squamous cell carcinoma was historically the most common type of lung carcinoma in the United States until the 1970s. Since the 1970s, adenocarcinoma has become more common [33]. Adenocarcinomas are now the most common histologic type of lung cancer in both men and women [34]. Age-specific histologic rates by year of birth show strong birth cohort effects. Rates for squamous cell carcinoma were higher among cohorts born earlier (e.g., 1930s), while rates for adenocarcinoma are higher among those born more recently [35].

The changes in histologic trends have been theorized to be largely due to the composition and usage pattern of tobacco products. When cigarettes were first introduced, they were largely unfiltered. The smoke composition discouraged deep inhalation, thereby exposing the trachea and the proximal bronchi to a greater degree, producing more squamous cell carcinomas [12]. Filters were later introduced, enabling smaller particles to be inhaled deeper into the respiratory tract, which may predispose to adenocarcinomas [12]. Changes in the formulation of cigarettes have also resulted in lower amounts of tar being released but a higher concentration of nitrosamines. These compounds have been found to induce lung adenocarcinomas in an animal model [36, 37]. Such changes in the design and formulation of cigarettes over time may in part explain some of the observed variability in histology and location of tumors observed over time in the population.