Cancer Epidemiology: Incidence and Etiology of Human Neoplasms

Coleman, William B.; Tsongalis, Gregory J.

doi:10.1007/978-1-59745-458-2_1

William B. Coleman Ph.D.³ &
Gregory J. Tsongalis^4,5

3335 Accesses

Abstract

Cancer is a myriad collection of diseases with as many different manifestations as there are tissues and cell types in the human body, involving innumerable endogenous or exogenous carcinogenic agents, and various etiological mechanisms. It is now recognized that cancer, in its simplest form, is a genetic disease, or more precisely, a disease of abnormal gene expression. Recent research efforts have revealed that different forms of cancer share common molecular mechanisms governing uncontrolled cellular proliferation, involving loss, mutation, or dysregulation of genes that positively and negatively regulate cell proliferation, migration, and differentiation (generally classified as proto-oncogenes and tumor suppressor genes). This introduction describes cancer incidence and mortality for the major forms of human cancer, and briefly reviews some of the known risk factors and/or causes of these cancers for specific at-risk populations.

Access provided by CONRICYT-eBooks. Download chapter PDF

Cancer Epidemiology

Basis of Carcinogenesis

Epidemiology of Cancer

Keywords

1.1 Introduction

Cancer does not represent a single disease. Rather, cancer is a myriad collection of diseases with as many different manifestations as there are tissues and cell types in the human body, involving innumerable endogenous or exogenous carcinogenic agents, and various etiological mechanisms. What all of these disease states share in common are certain biological properties of the cells that compose the cancer, including unregulated (clonal) cellular growth, impaired cellular differentiation, invasiveness, and metastatic potential. It is now recognized that cancer, in its simplest form, is a genetic disease, or more precisely, a disease of abnormal gene expression. Recent research efforts have revealed that different forms of cancer share common molecular mechanisms governing uncontrolled cellular proliferation, involving loss, mutation, or dysregulation of genes that positively and negatively regulate cell proliferation , migration, and differentiation (generally classified as proto-oncogenes and tumor suppressor genes). Essential to any discussion of the molecular mechanisms that govern disease pathogenesis for specific cancers is an appreciation for the distribution of these diseases among world populations, with consideration of specific risk factors and etiologic agents involved in disease causation. This introduction will describe cancer incidence and mortality for the major forms of human cancer, and will briefly review some of the known risk factors and/or causes of these cancers for specific at-risk populations.

1.2 Cancer Incidence and Mortality

Cancer is an important public health concern in the USA and worldwide. Due to the lack of nationwide cancer registries for all countries, the exact numbers of the various forms of cancer occurring in the world populations are unknown. Nevertheless, estimations of cancer incidence and mortality are generated on an annual basis by several domestic and world organizations. Estimations of cancer incidence and mortality for the USA are provided annually by the American Cancer Society (ACS —www.cancer.org) and the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program (http://seer.cancer.gov/data/). Global cancer statistics are provided by the International Agency for Research on Cancer (IARC —http://globocan.iarc.fr/), the World Health Organization (WHO—http://www.who.int/en/), and Cancer Research UK (http://info.cancerresearchuk.org/cancerstats/world/). Monitoring of long-range trends in cancer incidence and mortality among different populations is important for investigations of cancer etiology. Given the long latency for formation of a clinically detectable neoplasm (up to 20–30 years) following initiation of the carcinogenic process (exposure to carcinogenic agent), current trends in cancer incidence probably reflect exposures that occurred many years (and possibly decades) before. Thus, correlative analysis of current trends in cancer incidence with recent trends in occupational, habitual, and environmental exposures to known or suspect carcinogens can provide clues to cancer etiology. Other factors that influence cancer incidence include the size and average age of the affected population. The average age at the time of cancer diagnosis for all tumor sites is approximately 65 years [1, 2]. As a higher percentage of the population reaches age 60, the general incidence of cancer will increase proportionally. Thus, as the life expectancy of the human population increases due to reductions in other causes of premature death (due to infectious and cardiovascular diseases), the average risk of developing cancer will increase.

1.3 Cancer Incidence and Mortality in the USA

1.3.1 General Trends in Cancer Incidence

The American Cancer Society estimates that 1,658,370 new cases of invasive cancer were diagnosed in the USA in 2015 [3]. This number of new cancer cases reflects 848,200 male cancer cases (51 %) and 810,170 female cancer cases (49 %). The estimate of total new cases of invasive cancer does not include carcinoma in situ occurring at any site other than in the urinary bladder, and does not include basal and squamous cell carcinomas of the skin. In fact, basal and squamous cell carcinomas of the skin represent the most frequently occurring neoplasms in the USA, with an estimated occurrence of >1 million total cases in 2015 [3]. Likewise, carcinoma in situ represents a significant number of new cancer cases in 2015 with 60,290 newly diagnosed breast carcinomas in situ and 63,440 new cases of melanoma carcinoma in situ [3].

Estimated site-specific cancer incidence for both sexes combined is shown in Fig. 1.1. Cancers of the reproductive organs represent the largest group of newly diagnosed cancers in 2015 with 329,330 new cases [3]. This group of cancers includes prostate (220,800 new cases), uterine corpus (54,870 new cases), ovary (21,290 new cases), and uterine cervix (12,900 new cases), in addition to other organs of the genital system (vulva, vagina, and other female genital organs; testis, penis, and other male genital organs). The next most frequently occurring cancers originated in the digestive tract (291,150 new cases), respiratory system (240,390 new cases), and breast (234,190 new cases). The majority of digestive system cancers involved colon (93,090 new cases), rectum (39,610 new cases), pancreas (48,960 new cases), stomach (24,590 new cases), liver and intrahepatic bile duct (35,660 new cases), and esophagus (16,980 new cases), in addition to the other digestive system organs (small intestine, gallbladder, and others). Most new cases of cancer involving the respiratory system affected the lung and bronchus (221,200 new cases), with the remaining cases affecting the larynx or other components of the respiratory system. Other sites with significant cancer burden include the urinary system (138,710 new cases), lymphomas (80,900 new cases), melanoma of the skin (80,100 new cases), leukemias (54,270 new cases), and the oral cavity and pharynx (45,780 new cases).

Estimated cancer incidence by cancer site for males and females are shown in Fig. 1.2. Among men, cancers of the prostate, respiratory system (lung and bronchus), and digestive system (colon and rectum) occur most frequently. Together, these cancers account for 61 % of all cancers diagnosed in men. Prostate is the leading site, accounting for 220,800 new cases and 26 % of cancers diagnosed in men (Fig. 1.3). Among women, cancers of the breast, respiratory system (lung and bronchus), and digestive system (colon and rectum) occur most frequently. Cancers at these sites combine to account for 58 % of all cancers diagnosed in women. Breast is the leading site for cancers affecting women, accounting for 231,840 new cases and 29 % of all cancers diagnosed in women (Fig. 1.3).

1.3.2 General Trends in Cancer Mortality in the USA

Mortality attributable to invasive cancers produced 589,430 cancer deaths in 2015. This reflects 312,150 male cancer deaths (53 % of total) and 277,280 female cancer deaths (47 % of total). Estimated numbers of cancer deaths by site for both sexes are shown in Fig. 1.1. The leading cause of cancer death involves tumors of the respiratory system (162,460 deaths), the majority of which are neoplasms of the lung and bronchus (158,040 deaths). The second leading cause of cancer deaths involve tumors of the digestive system (149,300 deaths), most of which are tumors of the colorectum (49,700 deaths), pancreas (40,560 deaths), stomach (10,720 deaths), liver and intrahepatic bile duct (24,550 deaths), and esophagus (15,590 deaths). Together, cancers of the respiratory and digestive systems account for 53 % of cancer-associated death.

Trends in cancer mortality among men and women mirror in large part cancer incidence (Fig. 1.2). Cancers of the prostate, lung and bronchus, and colorectum represent the three leading sites for cancer incidence and cancer mortality among men (Fig. 1.3). In a similar fashion, cancers of the breast, lung and bronchus, and colorectum represent the leading sites for cancer incidence and mortality among women (Fig. 1.3). While cancers of the prostate and breast represent the leading sites for new cancer diagnoses among men and women (respectively), the majority of cancer deaths in both sexes are related to cancers of the lung and bronchus (Fig. 1.3). Cancers of the lung and bronchus are responsible for 28 % of all cancer deaths among men and 26 % of all cancer deaths among women (Fig. 1.3). The age-adjusted death rate for lung cancer among men increased dramatically during the six decades between 1930 and 1990, while the death rates for other cancers (like prostate and colorectal) remained relatively stable (Fig. 1.4). However, since 1990, the age-adjusted death rate for lung cancer among men has decreased, although it remains very high compared to all other cancers. The lung cancer death rate for women increased in an equally dramatic fashion since about 1960, becoming the leading cause of female cancer death in the mid-1980s after surpassing the death rate for breast cancer (Fig. 1.4).

1.4 Global Cancer Incidence and Mortality

1.4.1 Current Trends in Cancer Incidence and Mortality Worldwide

The IARC estimates that 12,667,500 new cancer cases were diagnosed worldwide in 2008 [4]. This number of new cases represents 6,629,100 male cancer cases (52 %) and 6,038,400 female cancer cases (48 %). Mortality attributed to cancer for the same year produced 7,571,500 deaths worldwide [4]. This reflects 4,225,700 male cancer deaths (56 %) and 3,345,800 female cancer deaths (44 %). The leading sites for cancer incidence worldwide in 2008 included cancers of the lung (1,609,000 new cases), breast (1,383,500 new cases), colorectum (1,233,700 new cases), stomach (989,600 new cases), and prostate (903,500 new cases; Fig. 1.5). The leading sites for cancer mortality worldwide in 2008 included cancers of the lung (1,378,400 deaths), stomach (738,000 deaths), liver (695,900 deaths), colorectum (608,700 deaths), and breast (458,400 deaths; Fig. 1.5). As can be seen, lung cancer accounted for the most new cancer cases and the most cancer deaths among men and women combined during this period of time (Fig. 1.5). The leading sites for cancer incidence among males worldwide included cancers of the lung (1,095,200 new cases), prostate (903,500 new cases), colorectum (663,600 new cases), stomach (640,600 new cases), and liver (522,400 new cases). Combined, cancers at these five sites account for nearly 48 % of all cancer cases among men [4]. The leading causes of cancer death among men included tumors of the lung (951,000 deaths), liver (478,300 deaths), stomach (464,400 deaths), colorectum (320,600 deaths), and esophagus (276,100 deaths). Deaths from these cancers account for 59 % of all male cancer deaths [4]. The leading sites for cancer incidence among females included breast (1,383,500 new cases), colorectum (570,100 new cases), cervix uteri (529,800 new cases), lung (513,600 new cases), and stomach (349,000 new cases). The leading causes of cancer death among females directly mirrors the leading causes of cancer incidence: breast (458,400 deaths), lung (427,400 deaths), colorectum (288,100 deaths), cervix uteri (275,100 deaths), and stomach (230,000 deaths). Combined, these five cancer sites accounted for approximately 55 % of all female cancer cases and 51 % of female cancer deaths [4].

1.4.2 Geographic Differences in Cancer Incidence and Mortality

Cancer incidence and mortality differs between developed and developing countries [4]. In 2008, developed countries accounted for 43.9 % of new cancers (5,560,000 cases) and 36.3 % of cancer deaths (2,751,400 deaths), whereas developing countries accounted for 56.1 % of new cancers (7,107,600 cases) and 63.7 % of cancer deaths (4,820,100 deaths). The leading sites for cancer occurrence among men from developed countries include prostate (648,400 new cases), lung (482,600 new cases), and colorectum (389,700 new cases). In contrast, the leading sites for cancer occurrence among men from developing countries include lung (612,500 new cases), stomach (466,900 new cases), and liver (440,700 new cases). The incidence of prostate cancer and liver cancer provide excellent examples of differences in incidence between men from developed and developing countries. In 2008, prostate cancer affected 648,400 men in developed countries (ranked first for cancer incidence in this cohort) compared to 255,000 men in developing countries (ranked sixth for cancer incidence in this cohort). Likewise, in 2008, liver cancer affected 440,700 men in developing countries (ranked third for cancer incidence in this cohort) compared to 81,700 men in developed countries (ranked tenth for cancer incidence in this cohort). While incidence rates vary, lung cancer represents the most frequent cause of cancer death among men from both developed and developing countries. Among women, breast cancer is the most frequent site of cancer in both developed (692,200 new cases) and developing countries (691,300 new cases) in 2008. Likewise, lung cancer occurs frequently in both groups—241,700 new cases in developed countries (ranked third for cancer incidence) and 272,000 new cases in developing countries (ranked third for cancer incidence). However, significant differences in cancer incidence among women from developed and developing countries can be seen for cancer of the cervix. Women from developing countries develop cervical cancer frequently (453,300 new cases, ranked second for cancer incidence), while women in developed countries develop cervical cancer less often (76,500 new cases, ranked tenth for cancer incidence).

New cancer incidence and cancer-related mortality can differ tremendously from world area to world area, country to country, and even from region to region within a single country. The leading world areas for new cancer cases includes Eastern Asia/China (17.3 % of new cases), North America (14.9 % of new cases), South Central Asia (11.6 % of new cases), Eastern Europe (10.4 % of new cases), and Western Europe (8.3 % of new cases). Collectively, Asia accounted for approximately 40 % of all new cancer cases worldwide in 1990 [5]. Recognizing the significant contribution of the population density of China and other regions of Asia to these numbers of cancers, it is appropriate to consider the cancer burden of these countries after correction for population. The numbers of cases/deaths and the incidence/mortality rates for these world regions in 1999 are given in Fig. 1.6. It is evident from the data contained in Fig. 1.6 that there is a marked disparity between total numbers of cancer cases/deaths and the incidence/mortality rate for specific world regions [5]. In 2012, men from Australia/New Zealand exhibit the highest cancer incidence rate worldwide (365 cases per 100,000 population), followed closely by men from North America (344 cases per 100,000 population) and Western Europe (344 cases per 100,000 population), while the lowest cancer incidence rate is found among men from Western Africa (79 cases per 100,000 population) [6]. While demonstrating the highest cancer incidence rate worldwide, the male populations of Australia/New Zealand, North America, and Western Europe rank 13th, 9th, and 5th (respectively) for cancer mortality rate, possibly reflecting the relative quality and availability of healthcare and treatment options among the various world regions [6]. The highest cancer mortality rate for men is found in Central/Eastern Europe (173 deaths per 100,000 population), followed by Eastern Asia (159 deaths per 100,000 population), Southern Europe (138 deaths per 100,000 population), Southern Africa (137 deaths per 100,000 population), and Western Europe (131 deaths per 100,000 population), while the lowest mortality rate is found among men from West Africa (69 deaths per 100,000 population) [6]. The North American female population shows the highest cancer incidence rate worldwide (295 cases per 100,000 population), followed by Australia/New Zealand (278 cases per 100,000 population), Northern Europe (264 cases per 100,000 population), and Western Europe (264 cases per 100,000 population), while the lowest incidence rate is found among women from South/Central Asia (103 cases per 100,000 population) [6]. The highest mortality rate for females worldwide is found in Melanesia (119 deaths per 100,000 population), followed by Eastern Africa (111 deaths per 100,000 population), Southern Africa (99 deaths per 100,000 population), Northern Europe (94 deaths per 100,000 population), and Polynesia (93 deaths per 100,000 population), while the lowest mortality rate is found among women from Micronesia (56 deaths per 100,000 population) [6].

1.5 Population Factors Contributing to Cancer Incidence and Mortality

1.5.1 Age-Dependence of Cancer Incidence and Mortality

Cancer is predominantly a disease of old age. Most malignant neoplasms are diagnosed in patients over the age of 65, making age the most important risk factor for development of many types of cancer [7, 8]. The age-specific incidence and death rates for cancers of the prostate, breast (female), lung (both sexes combined), and colorectum (both sexes combined) for the period of 1992–2012 [2] are shown in Fig. 1.7. The trends depicted in this figure clearly show that the majority of each of these cancer types occur in individuals of advanced age. In the case of prostate cancer, 86 % of all cases occur in men over the age of 65, and 99.5 % occur in men over the age of 50. Likewise, 97 % of prostate cancer deaths occur in men over the age of 65 (Fig. 1.7). In contrast, female breast cancer occurs much more frequently in younger individuals. Nonetheless, 63 % of cases occur in women over the age of 65, and 88 % of cases occur in women over the age of 50 (Fig. 1.7). A notable exception to this relationship between advanced age and cancer incidence involves some forms of leukemia and other cancers of childhood. Acute lymphocytic leukemia (ALL) occurs with a bimodal distribution, with highest incidence among individuals less than 20 years of age, and a second peak of increased incidence among individuals of advanced age (Fig. 1.8). The majority of ALL cases are diagnosed in children, with 40 % of cases diagnosed in children under the age of 15, and 45 % of cases occurring in individuals under the age of 20. Despite the prevalence of this disease in childhood, a significant number of adults are affected. In fact, 32 % of ALL cases are diagnosed in individuals over the age of 65 years of age. In contrast to ALL, the other major forms of leukemia demonstrate the usual pattern of age-dependence observed with solid tumors, with large numbers of cases in older segments of the population (Fig. 1.8). Among 54,270 new cases of leukemia in 2015, 88 % (48,020 new cases) represent forms of leukemia that primarily affect older individuals (acute myeloid leukemia, chronic myeloid leukemia, or chronic lymphocytic leukemia), with the remainder (6250 new cases) reflecting childhood ALL.

1.5.2 Cancer Incidence and Mortality by Race and Ethnicity

Cancer incidence and mortality can vary tremendously with race and ethnicity [9]. In the USA, African Americans and Caucasians are more likely to develop cancer than individuals of other races or ethnicities (Fig. 1.9). African Americans demonstrated a cancer incidence for all sites combined of approximately 443 cases per 100,000 population, and Caucasians exhibited a cancer incidence rate of 403 cases per 100,000 population. In contrast, American Indians showed the lowest cancer incidence among populations of the USA with 153 cases per 100,000 population for all sites combined. Mortality due to cancer also differs among patients depending upon their race or ethnicity. Similar to the cancer incidence rates, mortality due to cancer is higher among African Americans (223 per 100,000 population) and Caucasians (167 deaths per 100,000 population) than other populations, including Asian/Pacific Islanders, American Indians, and Hispanics (Fig. 1.9). For both cancer incidence and mortality, racial and ethnic variations for all sites combined differ from those for individual cancer sites. African Americans and Caucasians demonstrate an excess of cancer incidence compared to the general population for a number of primary sites. African Americans exhibit high incidence rates for cancers of the prostate (223 cases per 100,000 population), lung (74 cases per 100,000 population for both sexes combined), colorectum (50 cases per 100,000 population), pancreas (13 cases per 100,000 population), oral cavity and pharynx (13 cases per 100,000), stomach (12 cases per 100,000 population), cervix uteri (12 cases per 100,000 population), and esophagus (8 cases per 100,000 population). The cancer incidence rates for lung, prostate, pancreas, and esophagus among African Americans are 33 %, 47 %, 50 %, and 115 % (respectively) higher than those rates for the general population. Caucasians exhibit high incidence rates for cancers of the breast (113 cases per 100,000 population), uterine corpus (23 cases per 100,000 population), urinary bladder (18 cases per 100,000), ovary (16 per 100,000 population), and melanoma (14 cases per 100,000 population). The excess of melanoma in the Caucasian population compared with populations possessing darker skin pigmentation is clearly shown in Fig. 1.10. The Asian/Pacific Islander population exhibit high rates of liver cancer (11 cases per 100,000 population) and stomach cancer (15 cases per 100,000 population), which are 173 % and 97 % (respectively) higher than the rates for the general population (Fig. 1.10). The Hispanic population demonstrates high rates of incidence for cancers of the cervix uteri (16 cases per 100,000 population) and stomach (11 cases per 100,000 population). These rates are 78 % and 36 % (respectively) higher than rates for these cancers in the general population (Fig. 1.10).

1.6 Trends in Cancer Incidence and Mortality for Specific Sites

1.6.1 Lung Cancer

A pproximately 221,200 new cases of lung cancer were diagnosed in the USA in 2015, with 115,610 new cases among men and 105,590 new cases among women, and 13 % of all invasive cancer diagnoses [3]. The relative lung cancer incidence for all races and genders was estimated to be 56 cancers per 100,000 population in 2012 [2]. The relative lung cancer incidence for men (all races) was estimated to be 65 cancers per 100,000 population in 2012, down from the all-time high of 102 cases per 100,000 population in 1984 [2]. African-American men exhibit a higher incidence of lung cancer (90 cancers per 100,000 population in 2012) compared to Caucasian-American men (64 cancers per 100,000 population in 2012). However, lung cancer incidence has declined among both groups from their all-time highs (159 cancers per 100,000 population for African-American men in 1984, and 101 cancers per 100,000 population for Caucasian-American men in 1987). The relative lung cancer incidence rate among women increased to 54 cancers per 100,000 population in 2007, but has been declining since that time, reaching approximately 50 cases per 100,000 population in 2012 [2]. Cancer of the lung and bronchus accounted for an estimated 158,040 deaths in 2015, which represents 27 % of all cancer deaths [3]. Furthermore, lung cancer is the leading cause of cancer deaths among men (86,380 deaths, 28 % of cancer deaths) and women (71,660 deaths, 26 % of cancer deaths) (Fig. 1.3).

Cancers of the lung and bronchus represent 92 % of all respiratory system cancers [3]. The remainder of respiratory system cancers include tumors of the larnyx and nasal cavities. The majority of lung cancers are histologically classified as either small cell lung carcinoma (SCLC, 13 % of all lung cancers) or non-small-cell lung carcinoma (NSCLC, 83 % of all lung cancers). The NSCLC class includes the morphologic subtypes of squamous cell carcinoma (SCC), adenocarcinoma, and large cell undifferentiated carcinoma. Squamous cell carcinomas (SCC) account for approximately 35 % of lung cancers [10]. This histologic subtype of lung cancer is closely correlated with cigarette smoking and represents the most common type of lung cancer among men. SCCs display varying levels of differentiation, from tumors consisting of well-differentiated keratinized squamous epithelium to tumors consisting of undifferentiated anaplastic cells. Adenocarcinomas have increased in frequency in recent years and now account for nearly 35 % of lung cancers [10]. These tumors grow faster than SCCs and frequently metastasize to the brain. Lung adenocarcinomas can present as well-differentiated tumors consisting of well-differentiated glandular epithelium, or as undifferentiated tumors composed of highly mitotic anaplastic cells. Large cell undifferentiated carcinomas account for approximately 15 % of all lung cancers [10]. These tumors lack squamous or glandular cell characteristics and are typically composed of large anaplastic cells with frequent mitotic figures. Clinically, these tumors metastasize early and have a poor prognosis. Small cell lung carcinomas (SCLC) make up the majority of the remaining cancers (13 %) [3, 10]. These cancers are also associated with smoking history. SCLCs tend to produce a variety of neuroendocrine substances that can cause symptoms related to the biological activity of the hormonal substance. About 10 % of SCLCs display a paraneoplastic phenotype related to production of these neuroendocrine effectors [11]. These cancers grow rapidly, metastasize early, and have a very poor prognosis.

The majority of lung cancers are attributable to exposure to known carcinogenic agents, particularly cigarette smoke. Several lines of evidence strongly link cigarette smoking to lung cancer. Smokers have a significantly increased risk (11- to 22-fold) for development of lung cancer compared to nonsmokers [12], and cessation of smoking decreases the risk for lung cancer compared to continued smoking [12, 13]. Furthermore, heavy smokers exhibit a greater risk than light smokers, suggesting a dose-response relationship between cigarette consumption and lung cancer risk [12, 13]. Numerous mutagenic and carcinogenic substances have been identified as constituents of the particulate and vapor phases of cigarette smoke, including benzo[a]pyrene, dibenza[a]anthracene, nickel, cadmium, polonium, urethane, formaldehyde, nitrogen oxides, and nitrosodiethylamine [14]. There is also evidence that smoking combined with certain environmental (or occupational) exposures results in potentiation of lung cancer risk. Urban smokers exhibit a significantly higher incidence of lung cancer than smokers from rural areas, suggesting a possible role for air pollution in development of lung cancer [15]. Occupational exposure to asbestos, bis(chloromethyl) ether, chromium has been associated with increased risk for development of lung cancer [16, 17]. Exposure to the radioactive gas radon has been suggested to increase the risk of lung cancer development. This gas is ubiquitous in the earth’s atmosphere, creating the opportunity for exposure of vast numbers of people. However, passive exposure to the background levels of radon found in domestic dwellings and other enclosures are not sufficiently high to increase lung cancer risk appreciably [18, 19]. High level radon exposure has been documented among miners working in uranium, iron, zinc, tin, and fluorspar mines [20, 21]. These workers show an excess of lung cancer (compared to non-miners) that varies depending upon the radon concentration encountered in the ambient air of the specific mine [20, 21].

Therapy for lung cancer varies depending upon the tumor type and other clinical variables (tumor stage, grade, location, and size). Surgery is the preferred treatment choice for SCC and adenocarcinoma, whereas SCLC is generally treated with chemotherapy. In some cases special treatment modalities are employed, such as chemotherapy followed by surgery or surgery followed by radiation treatment. Despite the variety of treatment modalities that can be applied to lung cancer management, the overall survival rates for affected individuals are not good (Fig. 1.11). The average 5-year survival rate for all patients and all stages of disease is only 17 % [3, 9, 22]. The survival rate increases to 54 % if the disease is detected early (localized), but few lung cancers (15 %) are discovered this early (Fig. 1.12). The majority of lung cancer cases are not detected until after the development of regional spread (27 %) or distant metastases (58 %). The 5-year survival rate for patients with regional disease is 27 %, and this drops to 4 % in patients with distant metastasis (Fig. 1.12). The overall poor probability of surviving lung cancer probably reflects the difficulty with early detection of this tumor (or the failure to detect tumors while localized) and the ineffectiveness of traditional therapies (radiation and chemotherapy). However, over the last decade or so, a variety of targeted drugs have received market approval for treating NSCLC [23]. These new drug modalities for early stage or advanced NSCLC include inhibitors of the epidermal growth factor receptor (gefitinib, erlotinib, and afatinib), the anaplastic lymphoma kinase inhibitor crizotinib, and the antivascular endothelial growth factor receptor monoclonal antibody, bevacizumab [23]. In parallel, molecular alterations of the epidermal growth factor receptor (EGFR) and the anaplastic lymphoma kinase (ALK) have been characterized, enabling the development of molecular diagnostics of discrimination of lung cancer patients that are more likely to benefit from specific targeted therapies versus those patients that will not respond to a specific drug [23].

1.6.2 Colorectal Cancer

Approximately 132,700 new cases of colorectal cancer were diagnosed in the USA in 2015 (approximately 8 % of all cancers), with 69,090 new cases among men and 63,610 new cases among women [3]. Colorectal cancer represent 46 % of all digestive system tumors, and is the third leading site for cancer diagnosis among men (8 % of new cases among men) and women (8 % of new cases among women). In 2012, the relative incidence rate for colorectal cancer was 45 cancers per 100,000 population for men (all races) and 35 cancers per 100,000 for women (all races) [2]. However, colorectal cancer incidence rates vary by race (as well as gender). The overall incidence rates for colorectal cancer among Caucasians in 2012 was 39 cancers per 100,000 population compared to 48 cancers per 100,000 population among African-Americans. African-American men exhibit the highest incidence rate for colorectal cancer at 57 cancers per 100,000 population (versus 43 cancers per 100,000 population for Caucasian men), and colorectal cancer incidence rates for African-American women (41 cases per 100,000 population in 2012) exceed that for Caucasian women (34 cases per 100,000 population in 2012) [2]. Colorectal cancer accounted for an estimated 49,700 deaths in 2015, which represents 8 % of all cancer deaths [3]. Colorectal cancer is the third leading cause of death among men and women, accounting for 8 % and 9 % of all cancer deaths, respectively (Fig. 1.3).

Colorectal tumors are often first recognized as a polyp protruding from the wall of the bowel, which may be either hyperplastic (non-dysplastic) or dysplastic (adenomatous). Hyperplastic polyps consist of large numbers of cells with normal morphology that do not have a tendency to become malignant [24]. Adenomatous polyps contain dysplastic cells that fail to show normal intracellular and intercellular organization. Expanding adenomas become progressively more dysplastic and likely to become malignant. The majority of malignant neoplasms of the colon are thought to be derived from benign polyps. The malignant nature of colorectal tumors are defined by their invasiveness. The major histologic type of colorectal cancer is adenocarcinoma, which account for 90–95 % of all colorectal cancers [25, 26], although other rare epithelial tumor types do occur, including squamous cell carcinomas, adenosquamous carcinomas, and undifferentiated carcinomas which contain no glandular structures or features such as mucinous secretions [25, 27].

There are several recognized risk factors for development of colorectal cancer, some of which are genetic or related to benign pathological lesions of the colorectum, and others that are related to lifestyle or environment. Approximately 5–10 % of colorectal cancers are thought to be related to an inherited predisposition. Familial colorectal cancer can arise in presence or absence of polyposis, which is characterized by the occurrence of multiple benign polyps lining the walls of the colon. Several polyposis syndromes have been described, the major form of which is familial adenomatous polyposis (FAP) [28]. The hereditary nonpolyposis colorectal cancer (HNPCC) syndrome predisposes affected individuals to the development of colorectal cancer, as well as tumors at other tissue sites [29, 30]. These two hereditary syndromes account for a large percentage of familial colorectal cancers. Individuals affected by these syndromes carry mutations in one or more genes that function as tumor suppressor genes or that encode critical components of the DNA repair mechanisms that protect the genome from mutation [28]. Patients with inflammatory bowel disease (ulcerative colitis) or Crohn’s disease (granulomatous colitis) exhibit an increased risk for development of colorectal cancer [28, 31]. Epidemiologic studies indicate that individuals consuming diets that are high in animal fat and red meat [32–34], or low in fiber [35, 36] are associated with increased risk for development of colorectal cancer. In addition, there is some evidence that alcohol intake and cigarette smoking can increase the risk for colorectal cancer [37, 38].

Treatment for colorectal cancer may include surgery, radiation therapy, chemotherapy, or a combination of these treatment modalities. Chemotherapy alone is not very effective, but some drug combinations that are now employed show promise. In general, survival of colorectal cancer is closely correlated with early detection of localized disease, and the mortality due to this disease has been declining in recent years [3, 39]. The average 5-year relative survival rate for colorectal cancer is 65 % (Fig. 1.11). The relative survival rate increases to 90 % if the cancer is detected early (localized), and remains relatively high (71 % survival) when detected with regional metastasis (Fig. 1.12). In contrast, the 5-year survival is only 13 % when the cancer is detected after development of distant metastases [3, 9]. Most colorectal cancers are now detected while localized (40 % of tumors) or with limited regional spread (37 % of tumors), which contributes to the generally favorable probability of survival for this form of cancer. Several screening methods are available for surveillance of patients that are at high risk for development of colorectal cancer, and some screening strategies are now routinely applied to the general population. These screening methods include digital rectal examination, fecal occult blood testing, and various forms of colonoscopy [40].

1.6.3 Liver Cancer

Hepatocellular carcinoma (HCC) is a relatively rare neoplasm in the USA, with 35,660 new cases diagnosed in 2015 [3]. However, liver cancer occurs at high incidence when the world population is considered. In 2008, there were 748,300 new cases of liver cancer worldwide [3], which represents 5.9 % of all cancers and the fifth leading site for cancer incidence (Fig. 1.5). Deaths attributed to liver cancer for the same year totaled 695,900, which represents 9.2 % of all cancer deaths and the third leading site for cancer mortality (Fig. 1.5). The prevalence of primary liver cancer varies greatly from world region to world region (Fig. 1.13). Approximately 85 % of all liver cancers worldwide occur in regions of Asia and Africa [41, 42]. The highest incidence of liver cancer worldwide is found in China [41, 42], where men exhibit an incidence rate of approximately 36 cases per 100,000 population (Fig. 1.13). In fact, >50 % of liver cancers worldwide occur in China [41, 42]. High rates of liver cancer incidence are found throughout large portions of Asia and Africa, with much lower incidence rates for this cancer found in Europe and the Americas (Fig. 1.13). Early studies called attention to the extremely high incidence of hepatocellular carcinoma among black males in Mozambique [43, 44], which demonstrate the highest incidence worldwide at 113 cases per 100,000 population [45]. In fact, the incidence of this tumor among black Mozambican males aged 25–34 years is over 500-fold higher than the incidence for comparably aged while males in the USA and UK [44, 46]. These statistics strongly suggest that factors related to genetic background and/or environmental exposure contribute significantly to the incidence of this tumor among world populations. Whereas the incidence rate for primary HCC in the USA has remained fairly low compared to other world regions, the occurrence of this neoplasm has been increasing dramatically over the last two decades (Fig. 1.14). As shown in Fig. 1.14, the incidence of primary liver cancer in the USA has increased from approximately 15,000 new cases in 2000 to >35,000 new cases in 2015 (233 % increase in 15 years). Likewise, deaths associated with liver cancer have increased from approximately 15,000 in 2005 to nearly 25,000 in 2015 (159 % increase in 10 years). The likely cause of this dramatic increase in liver cancer incidence in the USA is the increase in HCV infection prevalence. Increased incidence of liver cancer has been observed in a number of developed countries during the last decade [41, 42]. There has also been a dramatic rise in HCC incidence among Japanese men during the last 30 years [47], possibly reflecting some significant change in risk factors or environmental exposures.

Liver cancer affects men more often than women. The ratio of male to female incidence in the USA is approximately 2:1 [2], and worldwide is approximately 2.6:1 [4]. However, in high incidence countries or world regions, the male to female incidence ration can be as high as 8:1 [48, 49]. This consistent observation suggests that sex hormones and/or their receptors may play a significant role in the development of primary liver tumors. Some investigators have suggested that hepatocellular carcinomas overexpress androgen receptors [50], and that androgens are important in the promotion of abnormal liver cell proliferation [51, 52]. Others have suggested that the male predominance of liver cancer is related to the tendency for men to drink and smoke more heavily than women, and are more likely to develop cirrhosis [53].

The etiology of HCC is clearly multifactorial [54]. HCC is usually associated with chronic hepatitis [55–58], and 60–80 % of HCC occurring worldwide develop in cirrhotic livers [55, 58–61], most commonly nonalcoholic post-hepatitic cirrhosis [62]. Numerous causative factors have been identified that are suggested to contribute to the development of HCC in humans, including exposure to naturally occurring carcinogens, industrial chemicals, pharmacologic agents, and various pollutants [63, 64]. In addition, viral infection, genetic disease, and life-style factors (like alcohol consumption) contribute to the risk for development of HCC [41, 63, 64]. The most well studied hepatocarcinogen is a natural chemical carcinogen known as aflatoxin B₁ that is produced by the Aspergillus flavus mold [41, 65, 66]. This mold grows on rice or other grains (including corn) that are stored without refrigeration in hot and humid parts of the world. Ingestion of food that is contaminated with Aspergillus flavus mold results in exposure to potentially high levels of aflatoxin B₁ [67]. Aflatoxin B₁ is a potent, direct-acting liver carcinogen in humans, and chronic exposure leads inevitably to development of HCC [66]. Numerous studies have shown a strong correlation between hepatitis B virus (HBV) infection and increased incidence of HCC [45, 68–70]. More recently, an association between chronic HCV infection and HCC has been recognized [70–73]. In certain geographic areas (such as China), large portions of the population are concurrently exposed to aflatoxin B₁ and HBV, which increases their relative risk for development of liver cancer [68]. Pharmacologic exposure to anabolic steroids and estrogens can lead to development of liver cancer [74]. Several genetic diseases that result in liver pathology can increase the risk of development of a liver cancer, including hemochromatosis, hereditary tyrosinemia, glycogen storage disease types 1 and 3, galactosemia, Wilson’s disease, and others [75]. Chronic alcohol consumption is associated with an elevated risk for HCC [76–79]. Alcohol is not directly carcinogenic to the liver, rather it is thought that the chronic liver damage produced by sustained alcohol consumption (hepatitis and cirrhosis) may contribute secondarily to liver tumor formation [80]. Other lifestyle factors may also contribute to risk for development of HCC, including tobacco smoking [81, 82]. Several chemicals, complex chemical mixtures, industrial processes, and/or therapeutic agents have been associated with development of HCC in exposed human populations [64]. These include therapeutic exposure to the radioactive compound thorium dioxide (Thoratrast) for the radiological imaging of blood vessels [83, 84], and exposures to certain industrial chemicals, such as vinyl chloride monomer [85].

Treatment of hepatocellular carcinoma may include surgery, chemotherapy, radiotherapy, or some combination of these treatments. The overall 5-year survival rate for HCC is only 5 % (Fig. 1.11). The poor survival rate for HCC primarily reflects both the lack of effective treatment options and the advanced stage of disease at diagnosis. HCC is diagnosed as localized disease in approximately 21 % of cases, with region spread in 23 % of cases, and with distant metastases in 22 % of cases [9]. The 5-year survival for patients diagnosed with distant metastases is only 1.2 %, and survival improves to only 14.7 % when the patient presents with localized disease [9]. Most patients with HCC also have underlying cirrhosis which makes surgical resection of the tumor very difficult. Furthermore, cirrhosis itself is a preneoplastic condition, which opens the possibility for development of additional secondary neoplasms in the unresected tissue after surgery. In fact, the recurrence rate after surgery for HCC was found to be 74 % within 5 years [86]. However, orthotopic liver transplantation can afford a complete cure for HCC if surgery is carried out prior to tumor spread from the liver [87]. While the application of liver transplant in the treatment of HCC is not favored by transplant surgeons, the results emerging from such treatment are very encouraging in some cases. In one study of 17 patients [88], liver transplant was performed to correct metabolic disorders of the liver (such as tyrosinemia) and small HCCs (without invasion or local spread) were incidentally discovered in the resected specimens. Of these patients, 90 % survived >5 years without recurrence of the HCC [88]. Other studies have not produced such favorable results [89], but it appears that certain types of HCC (such as fibrolamellar carcinoma) do very well after transplant, with >50 % survival 5 years after transplant [90]. A number of chemotherapeutic agents and combinations of these agents have been used to treat HCC. However, chemotherapy for HCC is generally not very effective and the response rates are very low, particularly when a single agent is used [91]. Nonetheless, there are occasional reports of dramatic responses using systemic chemotherapy, and some reports of complete remission [92], suggesting that responsiveness of HCC to chemotherapy is totally unpredictable [62]. Radiation therapy for HCC can be effective at reduction of tumor size, but produces a number of serious side effects, including progressive atrophy of the liver parenchyma which leads to fulminant liver failure in some patients [62]. More recent developments in radiation therapy have resulted in treatment modalities that limit collateral damage to the liver and surrounding tissues but are effective at reducing tumor burden [93].

1.6.4 Skin Cancer

There are several major forms of skin cancer , including basal cell carcinoma, squamous cell carcinoma, and malignant melanoma [94]. Non-melanoma skin cancer represents the most frequently occurring tumor-type in the USA, with several million total cases in 2015 [3]. These types of skin cancer tend to be slow growing, minimally invasive, not readily metastatic, and usually curable (given appropriate treatment). Thus, these forms of skin cancer are not typically included in cancer statistics for incidence, mortality, and survival rates (and these cancers are not reported to cancer registries making it difficult to quantify the magnitude of the disease). Nonetheless, the common occurrence of these tumors among the human population suggests that it is an important group of diseases to consider. Basal cell carcinoma accounts for most cases of non-melanoma skin cancer and is the most frequently occurring form of skin cancer. Squamous cell carcinoma is the second-most common form of skin cancer. Basal cell carcinoma accounts for at least 75 % of non-melanoma skin cancers diagnosed each year in the USA, while squamous cell carcinomas account for approximately 20 % [95]. In contrast to the other forms of skin cancer, malignant melanoma of the skin is an aggressive and invasive cancer that can metastasize to many tissue locations. The incidence of melanoma has been rising about 4 % per year in the USA. In 2015, there were 73,870 new cases of malignant melanoma, representing 5 % of all male cancers (42,670 new cases) and 4 % of all female cancers (31,200 new cases) (Fig. 1.3). Mortality due to malignant melanoma accounted for 9940 deaths in 2015 [2].

Basal cell carcinoma is a malignant neoplasm of the basal cells of the epidermis and this tumor occurs predominately on sun-damaged skin. The carcinogenic agent that accounts for the neoplastic transformation of the basal cells is ultraviolet (UV) radiation. Thus, sun bathing and sun tanning using artificial UV light sources represent significant lifestyle risk factors for development of these tumors. Basal cell carcinoma is now diagnosed in some people at very young ages (second or third decade of life) reflecting increased exposures to UV irradiation early in life. The incidence of this tumor increases with increasing age and increasing exposure to sunlight. Some researchers have suggested that the increasing frequencies of skin cancer can be partially attributed to depletion of the ozone layer of the earth’s atmosphere [96], which filters out (thereby reducing) some of the UV light produced by the sun. Squamous cell carcinoma is a malignant neoplasm of the keratinizing cells of the epidermis. It tends to occur later in life and is diagnosed more frequently in men than in women. Like basal cell carcinoma, extensive exposure to UV irradiation is the most important risk factor for development of this neoplasm. When left untreated, squamous cell carcinoma can metastasize to regional lymph nodes and/or distant sites. Development of malignant melanoma occurs most frequently in fair-skinned individuals and is associated to some extent with exposure to UV irradiation. This accounts for the observation that Caucasians develop malignant melanoma at a much higher rate than individuals of other races and ethnicity’s (Fig. 1.10).

The preferred treatment of skin cancer is surgery. In fact, many, if not most, cases of basal cell carcinoma and squamous cell carcinoma are treated with minor surgery in the setting of the physician’s office. In the case of malignant melanoma, surgery is employed for localized disease, with radiotherapy used in the palliative treatment of metastasis to the central nervous system and bone. Chemotherapy is employed for metastatic disease, but clinical responsiveness is limited to 15–20 % of patients [97]. More recently, targeted therapies and immunotherapy has been employed to treat advanced melanoma. The 5-year survival rate for malignant melanoma is 91 % (Fig. 1.11), reflecting the high rate of diagnosis (82 %) of localized disease where survival is high (98 %) [3, 9]. The 5-year survival of this disease drops precipitously with increasing spread of the cancer. Patients diagnosed with region disease exhibit a 5-year survival of 63 % and this drops to 16 % with distant metastasis [3, 9].

1.6.5 Prostate Cancer

An estimated 220,800 new cases of prostate cancer were diagnosed in the USA in 2015 [3], representing approximately 150 cases per 100,000 population (Fig. 1.9), and 26 % of all cancers in men (Fig. 1.3). The incidence rate for prostate cancer has been increasing in the last several decades at a rate of approximately 4 % per year, and this increase is paralleled by an increase in the mortality rate (Fig. 1.4). These increases are probably related to the increasing average age of the male population, increased reporting, and increased screening of older men [98]. Detection of prostate cancer can be achieved through the application of the digital rectal examination, screening based upon detection of the prostate specific antigen (PSA) in serum, and using ultrasonography. Elevations of PSA can be detected in both benign prostatic hypertrophy and in prostate cancer, but levels of this protein in the serum are markedly elevated in cancer. While the serum PSA assay is extremely sensitive, it lacks specificity which limits its usefulness as a definitive diagnostic for prostate cancer. However, when used in combination with the digital rectal exam and ultrasonography, PSA increases the ability to detect occult prostate cancer [99].

Cancer of the prostate provides a dramatic example of the age-dependent cancer development (Fig. 1.7). Cancers at this site occur with negligible frequency in men that are less than 55 years of age, and the vast majority of cases (56 %) occur in men over the age of 65 (Fig. 1.7). Almost all prostate cancer cases (97 %) occur in men older than age 50 [3]. In addition, prostate cancer occurs with greatly varied frequency among men of different races and ethnicity (Fig. 1.9). In the USA, African-American men exhibit a significantly higher incidence of this cancer than Caucasian men, whereas American Indians demonstrate the lowest incidence of all groups (Fig. 1.9). The reason for these dramatic differences in prostate cancer incidence are not readily apparent. However, differences in the levels of circulating testosterone among men from these different groups has been suggested as one factor contributing to the observed variations in prostate cancer occurrence. The incidence of prostate cancer also varies widely from world region to world region, with the highest incidence among men living in North America (Fig. 1.15). It is notable that the incidence of prostate cancer among men from the various regions of Africa are significantly lower than the rates for African-American men living in the USA.

Treatment for prostate cancer includes surgical removal of the prostate, radiation therapy for locally invasive tumors, and hormone therapy. Strategies for hormone therapy in the treatment of prostate cancer include both administration of estrogenic hormones (such as diethylstilbesterol) or ablation of androgenic hormones through surgical or chemical castration methods. The 5-year survival rate for prostate cancer has increased from 50 % in the years 1963–1965 to 93 % in the years 1989–1995 to 99 % in the years 2004–2010 [3, 9]. This dramatic improvement in survival can be attributed to advances in early detection of this cancer. Currently, approximately 79 % of prostate cancers are detected while they are still localized with minimal regional spread, and the 5-year survival among this group >99 % [9]. While the overall survival of prostate cancer is excellent (Fig. 1.11), early diagnosis and treatment are essential. This point is highlighted by the observation that the 5-year survival among prostate cancer patients that have distant metastasis at the time of diagnosis drops to 9 % [9].

1.6.6 Breast Cancer

An estimated 231,840 new cases of breast cancer among women were diagnosed in the USA in 2015 [3], accounting for 29 % of all female cancers diagnosed (Fig. 1.3). Breast cancer occurs more frequently among women in North America than among women from other parts of the world, while women in Asia have the lowest occurrence of breast cancer worldwide (Fig. 1.16). During the 1980s the number of new cases of breast cancer among women each year rose at a rate of about 4 % per year [9]. The incidence of breast cancer among women (all races) in the USA in the mid-1970s was approximately 100 cancers per 100,000 population, and rose to 142 cancers per 100,000 population by 1999 [2]. In 1999, the incidence rate for breast cancer among Caucasian women peaked at 147 cases per 100,000 population and has since declined [2]. In contrast, the incidence rate for breast cancer among African-American women has increased steadily since 1976 when it was 86 cases per 100,000 population [2]. Since 1999, the incidence rate for breast cancer among women (all races) has declined somewhat and is now apparently stabilized at approximately 130 cases per 100,000 women [2]. The relative incidence of breast cancer is similar between Caucasian women (132 cases per 100,000 population in 2012) and African-American women (132 cases per 100,000 population in 2012) [2]. The increases in breast cancer incidence that were observed in the 1980s and 1990s have been suggested to reflect increased early diagnosis as mammography screening became an established standard for surveillance of the general female population. Evidence supporting this suggestion includes the fact that the average primary breast tumor at diagnosis is of smaller size and earlier stage than those diagnosed more than a decade ago. The 5-year survival for breast cancer patients diagnosed in the 1975 was approximately 75 %, compared to approximately 85 % for patients diagnosed in 1990 [9], and 89 % for patients diagnosed from 2004–2010 [3]. Nonetheless, the overall mortality rate for breast cancer has not changed substantially during this same period (Fig. 1.4), suggesting that earlier diagnosis has not significantly impacted patient outcome for this cancer. These observations suggest that the earlier diagnosis of smaller (and lower stage) cancers has impacted on the 5-year survival, without affecting the overall survival for breast cancer patients. In fact, it has been documented that breast cancer can recur after long periods of time, well after 5-years from the initial diagnosis. There are also differences in mortality rates associated with breast cancer depending upon the race of the patient. In 2012, the breast cancer-associated death rate for all women (all races) was 21 deaths per 100,000 population, which is closely mirrored by the breast cancer-associated death rate for Caucasian women (21 deaths per 100,000 population in 2012, down from the high of 33 deaths per 100,000 population in 1977). In contrast, African-American women exhibit higher death rates from breast cancer—29 deaths per 100,000 population in 2012 (down from 38 deaths per 100,000 population in 1995). An estimated 40,290 women died as a result of breast cancer during 2015 [2], making breast cancer the second leading cause of cancer death among women, accounting for 15 % of all cancer deaths (Fig. 1.3).

Risk factors for development of breast cancer include, advancing age (over 50 years of age), early age at menarche, late age at menopause, first childbirth after age of 35, nulliparity, family history of breast cancer, obesity, dietary factors (such as high-fat diet), and exposure to high dose radiation to the chest before age 35 [100–104]. In addition, fibrocystic breast disease is recognized as an established risk factor for breast cancer, especially when accompanied by cellular proliferation and atypia [105]. Epidemiologic evidence has consistently pointed to family history as a strong and independent predictor of breast cancer risk. A substantial amount of research has led to the discovery of several breast cancer susceptibility genes, including BRCA1, BRCA2, and p53 [106], which may account for the majority of inherited breast cancers. It has been estimated that 5–10 % of breast cancers occurring in the USA each year are related to genetic predisposition [107]. Despite the recognition of multiple genetic and environmental risk factors for development of breast cancer, approximately 50 % of affected women have no identifiable risk factors other than being female and aging [108].

Treatment of breast cancer includes surgery, radiation therapy, chemotherapy, and hormone-modification therapy. Overall 5-year survival rates for breast cancer are very good—89 % irrespective of stage at diagnosis (Fig. 1.11). Localized disease can very often be cured by partial mastectomy (lumpectomy) alone or in combination with localized radiation treatment. Hence, survival of early stage (localized) breast cancer is 99 % (Fig. 1.12). Total mastectomy remains a treatment of choice for more extensive localized disease, but breast-conserving surgery has been used with increasing frequency in recent years [109]. Outcome data indicate that patients that undergo more conservative surgery with radiation therapy demonstrate survival rates that are similar to patients that are treated with total mastectomy for localized disease [110]. Five year survival rates for breast cancer patients with regional disease is 85 % (Fig. 1.12). Patients presenting with metastatic spread to regional lymph nodes are typically treated with chemotherapy, and the 5-year survival rate drops to 25 % (Fig. 1.12). The antiestrogenic drug tamoxifen is effective when used as a single agent or when used in combination with other chemotherapeutic agents in patients that are postmenopausal, have positive regional lymph node involvement, and whose tumors express estrogen or progesterone receptors [111]. Patients that receive adjuvant chemotherapy respond better to regimes that employ multiple drugs in combination. Commonly employed combinations include cyclophosphomide, methotrexate, and 5-fluorouracil (CMF), adriamycin plus cyclophosphomide, adriamycin followed by CMF, or one of these combinations with the addition of tamoxifen [109]. The decision to use adjuvant chemotherapy depends upon several variables (patient’s age and general health), including the patient’s estimated risk for recurrence. Typically, patients with a risk for recurrence of less than 10–15 % are spared adjuvant chemotherapy, while all others are expected to benefit from the adjuvant treatment [109].

1.6.7 Ovarian Cancer

An estimated 21,290 new cases of ovarian carcinoma were diagnosed in the USA in 2015 [3], accounting for 3 % of all female cancers (Fig. 1.3). The majority of these cancers are diagnosed in postmenopausal women. Recognized risk factors for development of ovarian cancer include advancing age (>60 years-old), infertility, use of fertility drugs (such as clomiphene), history of breast cancer and other genetic predispositions, as well as some lifestyle and dietary factors [112–119]. Pregnancy decreases the risk for ovarian cancer and multiple pregnancies increase the protective effect [120]. In addition, the use of oral contraceptives in nulliparous women reduces the risk for ovarian cancer to that for parous women [121].

Treatment for ovarian cancer typically involves surgical removal of the ovaries, the uterus, and fallopian tubes. This is usually accomplished as part of a comprehensive staging laparotomy, after which the clinical findings and histologic evaluation of the tumor are used to select appropriate postoperative therapy. A subset of patients (stage IA or IB, with well-differentiated or moderately well-differentiated tumors) exhibit excellent long-term disease-free survival in the absence of adjuvant therapy [122]. Several options exist for treatment of early-stage ovarian cancer with unfavorable prognosis, including radiation (external beam radiotherapy or intraperitoneal radioisotope) and chemotherapy. However, it is a matter of controversy whether treatment should be immediate or delayed until the disease begins to progress. The generally accepted therapy for advanced ovarian cancer is surgery followed by chemotherapy. The standard chemotherapy combination consist of paclitaxel and one of several platinum compounds (such as cisplatin or carboplatin).

Ovarian cancer accounted for 14,180 deaths in 2015 [3], making this the leading cause of death among the cancers of the female reproductive tract (Fig. 1.3). Contributing to the significant mortality associated with this cancer is the fact that there are no obvious symptoms in affected patients until late in the disease. This is reflected in the poor 5-year survival rate among patients with distant metastases at the time of diagnosis (27 %) (Fig. 1.12). In contrast, the 5-year survival rates for patients diagnosed with localized disease or regional disease are 92 % and 72 %, respectively (Fig. 1.12). However, most patients are diagnosed after development of distant metastases; 34 % of cases are diagnosed as localized/regional disease, while 60 % of cases present with distant metastases [9]. The overall 5-year survival rate for ovarian cancer is 45 % (Fig. 1.11). Successful screening for ovarian cancer would be expected to decrease mortality by increasing the percentage of affected individuals that are diagnosed early in the progression of the disease. However, the currently available screening techniques (ovarian palpation, transvaginal ultrasonography, and serum CA125 measurements) lack sufficient s pecificity and sensitivity to allow for routine screening [123].

1.6.8 Leukemia

Approximately 54,270 new cases of leukemia were diagnosed in the USA in 2015 [2]. These new cases were divided between myeloid (51 %) and lymphocytic (38 %) forms of the disease, with chronic forms of the disease representing 39 % of all leukemias versus acute disease representing 50 % of all leukemias [3]. The major types of leukemia include acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). AML represents the most common form of leukemia (20,830 new cases), followed by CLL (14,620 new cases), CML (6660 new cases), and ALL (6250 new cases). Rarer forms of leukemia include monocytic, basophilic, eosinophilic, and erythroid leukemia (combining for approximately 11 % of all leukemias). Although it is commonly regarded as a childhood cancer, leukemia affects more adults than children on an annual basis [3, 9]. Development of leukemia has been linked to certain environmental and genetic risk factors, including exposure to radiation (such as atomic bomb radiation), toxic chemicals (such as benzene), previous exposures to chemotherapeutic agents (mutagenic drugs), Down’s syndrome, genetic disorders associated with chromosomal instability (Fanconi’s anemia, Bloom syndrome, ataxia telangiectasia), and some viral infections [124–129]. Cigarette smoking has also been linked causally to development of leukemia, particularly in patients of advancing age [130, 131]. Exposure to electromagnetic radiation or fields has been suggested as a risk factor for development of leukemia [132], but a causal relationship has not been firmly established [129].

Acute leukemia is relatively rare, representing approximately 1.6 % of all cancers [3]. However, the acute leukemias are the leading cause of cancer-related mortality in the USA for persons less than 35 years of age [133, 134]. In 1993, leukemias accounted for 3.9 % of total cancer-related deaths among men in the USA [135]. However, leukemias were responsible for approximately 37 % of cancer-related deaths among men less than 15 years of age, and approximately 22 % of cancer-related deaths among men less than 35 years of age [135]. Likewise, in 1997, leukemia was responsible for approximately 33 % of all cancer-related deaths (both sexes combined) among individuals <20 years of age [136]. Figure 1.8 shows the age-specific incidence rates for the major forms of leukemia. ALL occurs with an incidence of >5 cases per 100,000 population for children that are less than 4 years-old, declining with increasing age to approximately one case per 100,000 population in individuals over 15 years of age [9]. In fact, ALL accounts for the majority (approximately 76 %) of childhood leukemias (individuals <20 years-old). In contrast, AML is rare in individuals less than 40 years of age, but increases with advancing age from approximately 1.6 cases per 100,000 population at age 40 to >13 cases per 100,000 at age 70 [9]. Likewise, CML occurs very rarely in individuals less than 40 (≤1 case per 100,000 population), but increase to >6 cases per 100,000 population in individuals over age 70 [9]. The incidence of CLL is strictly age-dependent, occurring only rarely in individuals less than 45 years of age, increasing with advancing age to six cases per 100,000 population by age 65 years, and to >31 cases per 100,000 population in individuals over 85 years [6]. As can be seen in Fig. 1.8, >90 % of all leukemias occur in individuals >20 years of age [3].

Conventional treatment of leukemia involves aggressive chemotherapy. Post-remission therapy can involve bone marrow ablation (through high dose chemotherapy or whole body radiation) with allogeneic bone marrow transplant. A variety of drugs and drug combinations have been evaluated for treatment efficacy in various forms of leukemia [137, 138]. Appropriate drug regimens are chosen based upon various diagnostic and prognostic factors, including the nature of chromosomal rearrangements in the leukemic clone [139]. Improvements in chemotherapeutic drugs and drug regimens for leukemia have dramatically improved treatment success rates for several forms of leukemia. Whereas childhood ALL was nearly uniformly fatal in the 1950s, today the majority (90–95 %) of affected children achieve complete remission, and long-term survival (5-year survival) for patients diagnosed at <45 years of age is approximately 69 % [9]. The overall 5-year survival rate for patients with CLL is approximately 71 %, but is somewhat lower (58 %) among older patients (diagnosed at ≥75 years of age). In contrast, the overall 5-year survival rates for AML (approximately 15 %) and CML (approximately 32 %) remain dismally low despite improvements in treatments during the last 25 years [9]. With the exception of CLL, the long-term survival of older leukemia patients is dramatically lower than that of younger patients. In fact, most adult patients with acute leukemia ultimately succumb to their disease [140]. The 5-year survival of patients older than 65 years of age is approximately 6 % for ALL, compared to 63 % for patients younger than 65 years of age [9]. Likewise, the 5-year survival of patients older than 65 years of age is approximately 3 % for AML, compared to 25 % for patients younger than 65 years of age, and 35 % for patients younger than 45 years of age [9].

1.6.9 Lymphoma

Approximately 80,900 new cases of lymphoma were diagnosed in the USA in 2015 [3]. The majority of lymphomas are classified as non-Hodgkin lymphoma (71,850 new cases), representing 89 % of all lymphomas diagnosed [3], and the remaining cases are classified as Hodgkin lymphoma. Non-Hodgkin lymphoma is a broad category consisting of several distinct lymphoid neoplasms [141], 85 % of which are B-cell lymphomas (including follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, and several others), and 15 % of which are T-cell lymphomas (including peripheral T-cell lymphoma, anaplastic large-cell lymphoma, and several others). Risk factors associated with non-Hodgkin lymphoma include immunodeficiency associated with congenital diseases (such as ataxia telangiectasia, severe combined immunodeficiency, and X-linked lymphoproliferative disorder), acquired immunodeficiency (related to HIV infection, bone marrow transplant, or organ transplant with iatrogenic immunosuppression), various autoimmune disorders, infectious agents (Epstein-Barr virus, HTLV-1, and others), and chemical and physical agents (diphenylhydantoin, certain herbicides, radiation) [141]. Hodgkin lymphoma is a unique form of neoplasm consisting of small numbers of putative neoplastic cells (known as Reed-Sternberg cells) in an inflammatory background [142]. Most immunophenotypic and genetic data suggest that Reed-Sternberg cells represent some form of altered B-cell [142], while other evidence supports the suggestion that these cells represent a novel lymphoid cell type [143]. Risk factors for development of Hodgkin lymphoma have not been definitively characterized. However, increased incidence of this disease is associated with HIV infection, other immunodeficiency syndromes (such as ataxia telangiectasia), autoimmune disorders (such as rheumatoid arthritis), certain genetic factors, and viral infections (such as Epstein Barr virus) [144–147].

Therapeutic approaches for the treatment of non-Hodgkin lymphoma are based upon a number of factors, including the specific lymphoid neoplasm, cancer stage, prognostic factors, and the physiologic status of the patient. Treatment options include radiotherapy alone, single-agent chemotherapy, or combination chemotherapy (mild or aggressive). The majority of patients with aggressive forms of non-Hodgkin lymphoma require aggressive combination chemotherapy, often with additional radiotherapy. Treatment of Hodgkin lymphoma involves radiation therapy, radiation and chemotherapy, or chemotherapy alone. The results from a large number of randomized trials suggest some advantages of combine modality radiation/chemotherapy in the treatment of Hodgkin lymphoma over radiation alone [148]. However, there was no significant difference in the overall survival of patients between these approaches to treatment [148, 149]. Chemotherapy is effective against Hodgkin lymphoma. However, the use of drugs in combination is essential to effect complete and lasting remission of the disease [150–152].

Approximately 20,940 deaths were attributed to lymphoma in 2015, including 1150 deaths related to Hodgkin lymphoma and 19,790 deaths related to non-Hodgkin lymphoma [3]. Lymphoma affects more men than women on an annual basis, and non-Hodgkin lymphoma represents a leading site for cancer-related mortality among men. Non-Hodgkin lymphoma is the leading site for cancer-related mortality among men 20–39 years of age, accounting for 13 % of cancer deaths [136]. Furthermore, non-Hodgkin lymphoma accounts for significant numbers of cancer-related deaths among men <20 years-old (7 % of cancer deaths), and 40–79 years-old (5 % of cancer deaths). The overall 5-year survival rate for non-Hodgkin lymphoma is 72 % [2]. In general terms, long-term survival among non-Hodgkin’s lymphoma patients does not differ with age. Despite an overall 5-year survival of 88 % (all races/genders) [2], there is a clear age-related difference in long-term survival among patients with Hodgkin lymphoma. Hodgkin lymphoma patients under the age of 65 display a 5-year survival rate of nearly 87 %, whereas patients older than 65 have a 5-year survival rate of only 45 %, and patients older than 75 exhibit a 5-year survival of only 31 % [9].

References

Hankey BF, Gloeckler-Ries LA, Miller BA, Kosary CL. Overview. In: Cancer statistics review 1973–1989. NIH Publication No. 92-2789, I.1–17.
Google Scholar
Howlander N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA, editors. SEER cancer statistics review, 1975–2012. Bethesda, MD: National Cancer Institute; 2015. http://seer.cancer.gov/csr/1975_2012/.
Google Scholar
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.
Article PubMed Google Scholar
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.
Article PubMed Google Scholar
Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA Cancer J Clin. 1999;49:33–64.
Article CAS PubMed Google Scholar
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.
Article PubMed Google Scholar
Newell GR, Spitz MR, Sider JG. Cancer and age. Semin Oncol. 1989;16:3–9.
CAS PubMed Google Scholar
Miller RA. Gerontology as oncology. Research on aging as the key to the understanding of cancer. Cancer. 1991;68:2496–501.
Article CAS PubMed Google Scholar
Reis LAG, Kosary CL, Hankey BF, Miller BA, Clegg L, Edwards BK, editors. SEER cancer statistics review, 1973–1996. Bethesda, MD: National Cancer Institute; 1999.
Google Scholar
Faber LP. Lung cancer. In: Holleb AI, Fink DJ, Murphy GP, editors. Clinical oncology. Atlanta: American Cancer Society Inc.; 1991. p. 194–212.
Google Scholar
Bunn Jr PA, Minna JD. Paraneoplastic syndromes. In: DeVita VT, Hellman S, Rosenberg SA, editors. Principles and practice of oncology. Philadelphia: J.B. Lippincott; 1985. p. 1797–842.
Google Scholar
Shopland DR, Eyre HJ, Pechacek TF. Smoking-attributable cancer mortality in 1991: is lung cancer now the leading cause of death among smokers in the United States? J Natl Cancer Inst. 1991;83:1142–8.
Article CAS PubMed Google Scholar
Garfinkel L, Silverberg E. Lung cancer and smoking trends in the United States over the past 25 years. CA Cancer J Clin. 1991;41:137–45.
Article CAS PubMed Google Scholar
U.S. Public Health Service. The health consequences of smoking-cancer: a report of the surgeon general. Rockville, MD: U.S. Department of Health and Human Services, Office on Smoking and Health; 1982.
Google Scholar
Haenszel W, Loveland DB, Sirken MG. Lung cancer mortality as related to residence and smoking histories: I. White males. J Natl Cancer Inst. 1962;28:947–1001.
CAS PubMed Google Scholar
Hammond EC, Selikoff IJ, Seidman H. Asbestos exposure, cigarette smoking, and death rates. Ann N Y Acad Sci. 1979;330:473–90.
Article CAS PubMed Google Scholar
International Agency for Research on Cancer. Report of an IARC working group: an evaluation of chemicals and industrial processes associated with cancer in humans based on human and animal data: IARC monographs, vol 1–20. Cancer Res. 1980;40:1–12.
Google Scholar
Schoenberg J, Klotz J. A case-control study of radon and lung cancer among New Jersey women. New Jersey State Department of Health Technical Report, Phase I, Trenton, NJ, 1989.
Google Scholar
Blot WJ, Xu Z-Y, Boice Jr JD, Zhao D-Z, Stone BJ, Sun J, Jing L-B, Fraumeni Jr JF. Indoor radon and lung cancer in China. J Natl Cancer Inst. 1990;82:1025–30.
Article CAS PubMed Google Scholar
Archer VE, Gillam JD, Wagoner JK. Respiratory disease mortality among uranium workers. Ann N Y Acad Sci. 1976;271:280–93.
Article CAS PubMed Google Scholar
Harley NH, Harley JH. Potential lung cancer risk from indoor radon exposure. CA Cancer J Clin. 1990;40:265–75.
Article CAS PubMed Google Scholar
Kessler LA. Lung and bronchus. In: Cancer statistics review 1973–1989. NIH Publication No. 92-2789, 1992, p. XV.1–13.
Google Scholar
Minquet J, Smith KH, Bramlage P. Targeted therapies for treatment of non-small cell lung cancer—recent advances and future perspectives. Int J Cancer. 2015;138:2549–61.
Article CAS Google Scholar
Kent TH, Mitros FA. Polyps of the colon and small bowel, polyp syndromes, and the polyp-carcinoma sequence. In: Norris HT, editor. Pathology of the colon, small intestine, and anus. 2nd ed. New York: Churchill Livingstone; 1991. p. 189–224.
Google Scholar
Cooper HS. Carcinoma of the colon and rectum. In: Norris HT, editor. Pathology of the colon, small intestine, and anus. 2nd ed. New York: Churchill Livingstone; 1983. p. 225–62.
Google Scholar
Spjut HJ. Pathology of neoplasms. In: Spratt JS, editor. Neoplasms of the colon, rectum, and anus: mucosal and epithelial. Philadelphia: W.B. Saunders; 1984. p. 159–204.
Google Scholar
DiSario JA, Burt R, Kendrick ML, McWhorter WP. Colorectal cancers of rare histologic types compared with adenocarcinoma. Dis Colon Rectum. 1994;37:1277–80.
Article CAS PubMed Google Scholar
Kinzler KW, Vogelstein B. Colorectal tumors. In: Vogelstein B, Kinzler KW, editors. The genetic basis of human cancer. New York: McGraw-Hill; 1998. p. 565–87.
Google Scholar
Lynch HT, Smyrk T, Jass JR. Hereditary nonpolyposis colorectal cancer and colonic adenomas: aggressive adenomas? Semin Surg Oncol. 1995;11:406–10.
Article CAS PubMed Google Scholar
Lynch HT, Smyrk T, Lynch JF. Overview of natural history, pathology, molecular genetics and management of HNPCC (Lynch Syndrome). Int J Cancer. 1996;69:38–43.
Article CAS PubMed Google Scholar
Hamilton SR. Colorectal carcinoma in patients with Crohn’s disease. Gastroenterology. 1985;89:398–407.
Article CAS PubMed Google Scholar
Armstrong B, Doll R. Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices. Int J Cancer. 1975;15:617–31.
Article CAS PubMed Google Scholar
Pickle LW, Greene MH, Zeigler RG, Toledo A, Hoover R, Lynch HT, et al. Colorectal cancer in rural Nebraska. Cancer Res. 1984;44:363–9.
CAS PubMed Google Scholar
Willett WC, Stampfer MJ, Colditz GA, Rosner BA, Speizer FE. Relation of meat, fat, and fiber intake to the risk of colon cancer in a prospective study among women. N Engl J Med. 1990;323:1664–72.
Article CAS PubMed Google Scholar
Burkitt DP. Epidemiology of cancer of the colon and rectum. Cancer. 1971;28:3–13.
Article CAS PubMed Google Scholar
Bingham S, Williams DR, Cole TJ, James WP. Dietary fibre and regional large-bowel cancer mortality in Britain. Br J Cancer. 1979;40:456–63.
Article CAS PubMed PubMed Central Google Scholar
Martinez ME, McPherson RS, Annegers JF, Levin B. Cigarette smoking and alcohol consumption as risk factors for colorectal adenomatous polyps. J Natl Cancer Inst. 1995;87:274–9.
Article CAS PubMed Google Scholar
Giovannucci E, Rimm EB, Ascherio A, Stampfer MJ, Colditz GA, Willett WC. Alcohol, low methionine low folate diets, and the risk of colon cancer in men. J Natl Cancer Inst. 1995;87:265–73.
Article CAS PubMed Google Scholar
Gloeckler Ries LA. Colon and rectum. In: Cancer statistics review 1973–1989. NIH Publication No. 92-2789, 1992, p. VI.1–2.
Google Scholar
Cohen AM, Minsky BD, Schilsky RL. Cancer of the colon. In: DeVita Jr VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven; 1997. p. 1144–97.
Google Scholar
McGlynn KA, London WT. The global epidemiology of hepatocellular carcinoma: present and future. Clin Liver Dis. 2011;15:223–43.
Article PubMed PubMed Central Google Scholar
McGlynn KA, Petrick JL, London WT. Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis. 2015;19:223–38.
Article PubMed PubMed Central Google Scholar
Berman C. Primary carcinoma of the liver. London: Lewis; 1951.
Google Scholar
Higginson J. The geographical pathology of primary liver cancer. Cancer Res. 1963;23:1624–33.
CAS PubMed Google Scholar
Munoz N, Bosch X. Epidemiology of hepatocellular carcinoma. In: Okuda K, Ishak KG, editors. Neoplasms of the Liver. Tokyo: Springer; 1987. p. 3–19.
Chapter Google Scholar
Munoz N, Linsell A. Epidemiology of primary liver cancer. In: Correa P, Haenszel W, editors. Epidemiology of cancer of the digestive tract. The Hague: Martinus Nijhoff; 1982. p. 161–95.
Chapter Google Scholar
Okuda K, Fujimoto I, Hanai A, Urano Y. Changing incidence of hepatocellular carcinoma in Japan. Cancer Res. 1987;47:4967–72.
CAS PubMed Google Scholar
Stevens RG, Merkle EJ, Lustbader ED. Age and cohort effects in primary liver cancer. Int J Cancer. 1984;33:453–8.
Article CAS PubMed Google Scholar
Simonetti RG, Camma C, Fiorello F, Politi F, d’Amico G, Pagliari L. Hepatocellular carcinoma: a worldwide problem and major risk factors. Dig Dis Sci. 1991;36:962–72.
Article CAS PubMed Google Scholar
Eagon PK, Francavilla A, Di Leo A, Elm MS, Gennari L, Mazzaferro V, et al. Quantitation of estrogen and androgen receptors in hepatocellular carcinoma and adjacent normal human liver. Dig Dis Sci. 1991;36:1303–8.
Article CAS PubMed Google Scholar
Ohnishi S, Murakami T, Moriyama T, Mitamura K, Imawari M. Androgen and estrogen receptors in hepatocellular carcinoma and in surrounding non-cancerous liver tissue. Hepatology. 1986;3:440–3.
Article Google Scholar
Carr BI, Van Theil DH. Hormonal manipulation of human hepatocellular carcinoma. J Hepatol. 1990;11:287–9.
Article CAS PubMed Google Scholar
Lai C-L, Gregory PB, Wu P-C, Lok ASF, Wong K-P, Ng MMT. Hepatocellular carcinoma in Chinese males and females: possible causes of the male predominance. Cancer. 1987;60:1107–10.
Article CAS PubMed Google Scholar
Harris CC, Sun T-T. Multifactorial etiology of human liver cancer. Carcinogenesis. 1984;5:697–701.
Article CAS PubMed Google Scholar
Edmondson HA, Steiner PE. Primary carcinoma of the liver. A study of 100 cases among 48,900 necropsies. Cancer. 1954;7:462–503.
Article CAS PubMed Google Scholar
Popper H, Thug SN, McMahon BJ, Lanier AP, Hawkins I, Alberts SB. Evolution of hepatocellular carcinoma associated with chronic hepatitis B virus infection in Alaskan Eskimos. Arch Pathol Lab Med. 1988;112:498–504.
CAS PubMed Google Scholar
Unoura M, Kaneko S, Matsushita E, Shimoda A, Takeuchi M, Adachi H, et al. High-risk groups and screening strategies for early detection of hepatocellular carcinoma in patients with chronic liver disease. Hepato-Gastroenterology. 1993;40:305–10.
CAS PubMed Google Scholar
Altmann HW. Hepatic neoformations. Pathol Res Pract. 1994;190:513–77.
Article CAS PubMed Google Scholar
Johnson PJ, Williams R. Cirrhosis and the etiology of hepatocellular carcinoma. J Hepatol. 1987;4:140–7.
Article CAS PubMed Google Scholar
Craig JR, Peters RL, Edmondson HA. Tumors of the liver and intrahepatic bile ducts. Washington, DC: Armed Forces Institute of Pathology; 1988.
Google Scholar
Tiribelli C, Melato M, Croce LS, Giarelli L, Okuda K, Ohnishi K. Prevalence of hepatocellular carcinoma and relation to cirrhosis: comparison of two different cities in the world: Trieste, Italy and Chiba, Japan. Hepatology. 1989;10:998–1002.
Article CAS PubMed Google Scholar
Okuda K, Okuda H. Primary liver cell carcinoma. In: Bircher J, Benhamou JP, McIntyre N, Rizzetto M, Rodes J, editors. Oxford textbook of clinical hepatology. 2nd ed. New York: Oxford University Press; 1999. p. 1491–530.
Google Scholar
Grisham JW. Liver. In: Craighead JE, editor. Pathology of environmental and occupational disease. St. Louis: Mosby; 1995. p. 491–509.
Google Scholar
Grisham JW. Interspecies comparison of liver carcinogenesis: implications for cancer risk assessment. Carcinogenesis. 1997;18:59–81.
Article CAS PubMed Google Scholar
International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks to humans, vol 56. Some naturally occurring substances: food items and constituents, heterocylic aromatic amines and mycotoxins. Lyon, France: IARC Scientific Publications; 1994.
Google Scholar
International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks to humans, vol 58. Aflatoxins. Lyon, France: IARC Scientific Publications; 1994.
Google Scholar
Linsell CA. Environmental and chemical carcinogens and liver cancer. In: Lapis K, Johannessen JV, editors. Liver carcinogenesis. Washington, DC: Hemisphere Publishing Co.; 1979.
Google Scholar
Lutwick LI. Relation between aflatoxins and hepatitis B virus and hepatocellular carcinoma. Lancet. 1979;1:755–7.
Article CAS PubMed Google Scholar
Beasley RP, Hwang L-Y, Lin CC, Chien C-S. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22707 men in Taiwan. Lancet. 1981;2:1129–33.
Article CAS PubMed Google Scholar
International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks to humans, vol 59. Hepatitis viruses. Lyon, France: IARC Scientific Publications; 1994.
Google Scholar
Stroffolini T, Chiaramonte M, Tiribelli C, Villa E, Simonetti RG, Rapicetta M, et al. Hepatitis C virus infection, HbsAg carrier state and hepatocellular carcinoma, relative risk and population attributable risk from a case-control study in Italy. J Hepatol. 1992;16:360–3.
Article CAS PubMed Google Scholar
Benvegnu L, Fattivich G, Noventa F, Tremolada F, Chemello L, Cecchetto A, et al. Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma in cirrhosis. Cancer. 1994;74:2442–8.
Article CAS PubMed Google Scholar
Okuda K. Hepatocellular carcinomas associated with hepatitis B and C virus infections: are they different? Hepatology. 1995;22:1883–5.
Article CAS PubMed Google Scholar
Henderson BE, Preston-Martin S, Edmondson HA, Peters RL, Pike MC. Hepatocellular carcinoma and oral contraceptives. Br J Cancer. 1983;48:437–40.
Article CAS PubMed PubMed Central Google Scholar
Cox DW. α₁-Antitrypsin deficiency. In: Scriver CR, Beaudet al, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. 7th ed. New York: McGraw-Hill Inc.; 1995. p. 4125–58.
Google Scholar
International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks to humans, vol 44. Alcohol drinking. Lyon, France: IARC Scientific Publications; 1988.
Google Scholar
Ikeda K, Saitoh S, Koida I, Arase Y, Tsubota A, Chayaman K, et al. A multivariant analysis of risk factors for hepatocellular carcinogenesis, a prospective observation of 795 patients with viral and alcoholic cirrhosis. Hepatology. 1993;18:47–53.
Article CAS PubMed Google Scholar
Nalpas B, Feitelson M, Brechot C, Rubin E. Alcohol, hepatotropic viruses and hepatocellular carcinoma. Alcohol Clin Exp Res. 1995;19:1089–95.
Article CAS PubMed Google Scholar
Noda K, Yoshihara H, Suzuki K, Yamada Y, Kasahara A, Haynashi N, et al. Progression of type C chronic hepatitis to liver cirrhosis and hepatocellular carcinoma—its relationship to alcohol drinking and age of transfusion. Alcohol Clin Exp Res. 1996;20:95A–100.
Article CAS PubMed Google Scholar
Lieber CS. Interactions of alcohol and other drugs and nutrients: implication for the therapy of alcoholic liver disease. Drugs. 1990;40:23–44.
Article CAS PubMed Google Scholar
Trichopoulos D, MacMahon B, Sparros L, Merikas G. Smoking and hepatitis B-negative hepatocellular carcinoma. J Natl Cancer Inst. 1980;65:111–4.
CAS PubMed Google Scholar
Chen C-J, Liang K-Y, Chang A-S, Chang Y-C, Lu S-N, Liaw Y-F, et al. Effects of hepatitis B virus, alcohol drinking, cigarette smoking, and familial tendency on hepatocellular carcinoma. Hepatology. 1991;13:398–406.
Article CAS PubMed Google Scholar
Andersson M, Storm HH. Cancer incidence among Danish Thoratrast-exposed patients. J Natl Cancer Inst. 1992;84:1318–25.
Article CAS PubMed Google Scholar
Andersson M, Vyberg M, Visfeldt J, Carstensen B, Storm HH. Primary liver tumors among Danish patients exposed to Thoratrast. Radiat Res. 1994;137:262–73.
Article CAS PubMed Google Scholar
Vainio H, Wilbourn J. Cancer etiology: agents associated with human cancer. Pharmacol Toxicol. 1993;72:S4–11.
Article CAS Google Scholar
Takayasu K, Wakao F, Moriyama N, Muramatsu Y, Yamazaki S, Kosuge T, et al. Postresection recurrence of hepatocellular carcinoma treated by arterial embolization: analysis of prognostic factors. Hepatology. 1992;16:906–11.
Article CAS PubMed Google Scholar
Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334:693–9.
Article CAS PubMed Google Scholar
Iwatsuki S, Starzl TE, Gordon RD, Esquivel CO, Tzakis AG, Makowka TL, et al. Experience in 1,000 liver transplants under cyclosporine-steroid therapy: a survival report. Transplant Proc. 1988;20 Suppl 1:498–504.
CAS PubMed PubMed Central Google Scholar
Scharschmidt BF. Human liver transplantation: analysis of data on 540 patients from four centers. Hepatology. 1984;4:95S–106.
Article CAS PubMed Google Scholar
O’Grady JG, Polson RJ, Rolles K, Calne RY, Williams R. Liver transplantation for malignant disease: results from 93 consecutive patients. Ann Surg. 1988;207:373–9.
Article PubMed PubMed Central Google Scholar
Simonetti RG, Liberati A, Angiolini C, Pagliaro L. Treatment of hepatocellular carcinoma: a systemic review of randomized controlled trials. Ann Oncol. 1997;8:117–1136.
Article CAS PubMed Google Scholar
Harada T, Makisaka Y, Nishimura H, Okuda K. Complete necrotization of hepatocellular carcinoma by chemotherapy and subsequent intravascular coagulation. Cancer. 1978;42:67–73.
Article CAS PubMed Google Scholar
Matsuzaki Y, Osuga T, Saito Y, Chuganii Y, Tanaka N, Shoda J, et al. A new, effective, and safe therapeutic option using proton irradiation for hepatocellular carcinoma. Gastroenterology. 1994;106:1032–41.
Article CAS PubMed Google Scholar
Marks R. An overview of skin cancers: incidence and causation. Cancer. 1995;75:607–12.
Article CAS PubMed Google Scholar
Boring CC, Squires TS, Tong T. Cancer statistics 1992. CA Cancer J Clin. 1992;42:19–38.
Article CAS PubMed Google Scholar
Friedman RJ, Rigel DS, Berson DS, Rivers J. Skin cancer: basal cell and squamous cell carcinoma. In: Holleb AI, Fink DJ, Murphy GP, editors. Clinical oncology. Atlanta: American Cancer Society, Inc.; 1991. p. 290–305.
Google Scholar
Singletary SE, Balch CM. Malignant melanoma. In: Holleb AI, Fink DJ, Murphy GP, editors. Clinical oncology. Atlanta: American Cancer Society, Inc.; 1991. p. 263–70.
Google Scholar
Miller BA, Potosky AL. Prostate. In Cancer statistic review, 1973–1989. NIH Publication Number 92-2789, 1992, XXII.1–8.
Google Scholar
Littrup PJ, Lee F, Mettlin C. Prostate cancer screening: current trends and future implications. CA Cancer J Clin. 1992;42:198–211.
Article CAS PubMed Google Scholar
Kelsey JL, Berkowitz GS. Breast cancer epidemiology. Cancer Res. 1988;48:5617–23.
Google Scholar
Hsieh C-C, Trichopoulos D, Katsouyanni K, Yuasa S. Age at menarche, age at menopause, height and obesity as risk factors for breast cancer: associations and interactions in an international case-control study. Int J Cancer. 1990;46:796–800.
Article CAS PubMed Google Scholar
Scanlon EF. Breast cancer. In: Holleb AI, Fink DJ, Murphy GP, editors. Clinical oncology. Atlanta: American Cancer Society, Inc.; 1991. p. 177–93.
Google Scholar
Kelsey JL, Gammon MD, John EM. Reproductive factors and breast cancer. Epidemiol Rev. 1993;15:36–47.
CAS PubMed Google Scholar
Lipworth L. Epidemiology of breast cancer. Eur J Cancer Prev. 1995;4:7–30.
Article CAS PubMed Google Scholar
Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med. 1985;312:146–51.
Article CAS PubMed Google Scholar
Gayther SA, Pharoah PD, Ponder BA. The genetics of inherited breast cancer. J Mammary Gland Biol Neoplasia. 1998;3:365–76.
Article CAS PubMed Google Scholar
Sutcliffe S, Pharoah PD, Easton DF, Ponder BA. Ovarian and breast cancer risks to women in families with two or more cases of ovarian cancer. Int J Cancer. 2000;87:110–7.
Article CAS PubMed Google Scholar
Madigan MP, Zeigler RG, Benichou J, Byrne C, Hoover RN. Proportion of breast cancers cases in the United States explained by well established risk factors. J Natl Cancer Inst. 1995;87:1681–5.
Article CAS PubMed Google Scholar
Morris J, Morrow M, Norton L. Malignant tumors of the breast. In: DeVita Jr VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven; 1997. p. 1557–616.
Google Scholar
Pierce SM, Harris JR. The role of radiation therapy in the management of primary breast cancer. CA Cancer J Clin. 1991;41:85–91.
Article CAS PubMed Google Scholar
National Cancer Institute Clinical Announcement. Adjuvant therapy of breast cancer—tamoxifen update. U.S. Department of Health Human Services. Washington, DC; National Institutes of Health: 1995.
Google Scholar
Lynch HT, Bewtra C, Lynch JF. Familial ovarian cancer. Clinical nuances. Am J Med. 1986;81:1073–6.
Article CAS PubMed Google Scholar
Schildkraut JM, Thompson WD. Familial ovarian cancer: a population-based case-control study. Am J Epidemiol. 1988;128:456–66.
CAS PubMed Google Scholar
Whittemore AS, Wu ML, Paffenbarger RS, Sarles DL, Kampert JB, Grosser S, et al. Epithelial ovarian cancer and the ability to conceive. Cancer Res. 1989;49:4047–52.
CAS PubMed Google Scholar
Piver MS, Baker TR, Piedmonte M, Sandecki AM. Epidemiology and etiology of ovarian cancer. Semin Oncol. 1991;18:177–85.
CAS PubMed Google Scholar
Gusberg SB, Runowicz CD. Gynecologic cancer. In: Holleb AI, Fink DJ, Murphey GP, editors. Clinical oncology. Atlanta: American Cancer Society Inc.; 1991. p. 481–97.
Google Scholar
Yancik R. Ovarian cancer: age contrasts in incidence, histology, disease stage at diagnosis, and mortality. Cancer. 1993;71:517–23.
Article CAS PubMed Google Scholar
Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG. Ovarian tumors in a cohort of infertile women. N Engl J Med. 1994;331:771–6.
Article CAS PubMed Google Scholar
Whittemore AS. The risk of ovarian cancer after treatment for infertility. N Engl J Med. 1994;331:805–6.
Article CAS PubMed Google Scholar
Greene MH, Clark JW, Blayney DW. The epidemiology of ovarian cancer. Semin Oncol. 1984;11:209–26.
CAS PubMed Google Scholar
Gross TP, Schlesselman JJ. The estimated effect of oral contraceptive use on the cumulative risk of epithelial ovarian cancer. Obstet Gynecol. 1994;83:419–24.
CAS PubMed Google Scholar
Young RC, Walton LA, Ellenberg SS, Homesley HD, Wilbanks GD, Decker DG, et al. Adjuvant chemotherapy in stage I and stage II epithelial ovarian cancer: results from two prospective randomized trials. N Engl J Med. 1990;322:1021–7.
Article CAS PubMed Google Scholar
Ozols RF, Schwartz PE, Eifel PJ. Ovarian cancer, fallopian tube carcinoma, and peritoneal carcinoma. In: DeVita Jr VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven; 1997. p. 1502–39.
Google Scholar
Austin A, Delzell E, Cole P. Benzene and leukemia: a review of the literature and risk assessment. Am J Epidemiol. 1988;127:419–39.
CAS PubMed Google Scholar
Kojima S, Matsuyama T, Sato T, Horibe K, Konishi S, Tsuchida M, et al. Down’s syndrome and acute leukemia in children: an analysis of phenotype by use of monoclonal antibodies and electron microscopic platelet peroxidase reaction. Blood. 1990;76:2348–53.
CAS PubMed Google Scholar
Feuer G, Chen ISY. Mechanisms of human T-cell leukemia virus-induced leukemogenesis. Biochim Biophys Acta. 1992;1114:223–33.
CAS PubMed Google Scholar
Pui C-H, Raimondi SC, Borowitz MJ, Land VJ, Behm FG, Pullen DJ, et al. Immunophenotypes and karyotypes of leukemic cells in children with Down syndrome and acute lymphoblastic leukemia. J Clin Oncol. 1993;11:1361–2.
CAS PubMed Google Scholar
Preston DL, Kusumi S, Tomonaga M, Izumi S, Ron E, Kuramoto A, et al. Cancer incidence in atomic bomb survivors: III. Leukemia, lymphoma and multiple myeloma. Radiat Res. 1994;137:S68–97.
Article CAS PubMed Google Scholar
Sandler DP. Recent studies in leukemia epidemiology. Curr Opin Oncol. 1995;7:12–8.
Article CAS PubMed Google Scholar
Kabat GC, Augustine A, Herbert JR. Smoking and adult leukemia: a case-control study. J Clin Epidemiol. 1988;41:907–14.
Article CAS PubMed Google Scholar
Siegel M. Smoking and leukemia: evaluation of a causal hypothesis. Am J Epidemiol. 1993;138:1–9.
CAS PubMed Google Scholar
Feychting M, Ahlbom A. Magnetic fields and cancer in children residing near Swedish high-voltage power lines. Am J Epidemiol. 1993;138:467–81.
CAS PubMed Google Scholar
Hernandez JA, Land KJ, McKenna RW. Leukemias, myeloma, and other lymphoreticular neoplasms. Cancer. 1995;75:381–94.
Article CAS PubMed Google Scholar
Wingo PA, Tong T, Bolden S. Cancer statistics, 1995. CA Cancer J Clin. 1995;45:8–30.
Article CAS PubMed Google Scholar
Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics, 1997. CA Cancer J Clin. 1997;47:5–27.
Article CAS PubMed Google Scholar
Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. CA Cancer J Clin. 2000;50:7–33.
Article CAS PubMed Google Scholar
Scheinberg DA, Maslak P, Weiss M. Acute leukemias. In: DeVita Jr VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven; 1997. p. 2293–321.
Google Scholar
Deisseroth AB, Kantarjian H, Andreeff M, Talpaz M, Keating MJ, Khouri I, et al. Chronic leukemias. In: DeVita Jr VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven; 1997. p. 2321–43.
Google Scholar
Khouri I, Sanchez FG, Deisseroth A. Molecular biology of the leukemias. In: DeVita Jr VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven; 1997. p. 2285–93.
Google Scholar
Brincker H. Estimates of overall treatment results in acute non-lymphocytic leukemia based on age-specific rates of incidence and of complete remission. Cancer Treat Rep. 1985;69:5–11.
CAS PubMed Google Scholar
Shipp MA, Mauch PM, Harris NL. Non-Hodgkin’s lymphomas. In: DeVita Jr VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven; 1997. p. 2165–220.
Google Scholar
DeVita VT, Mauch PM, Harris NL. Hodgkin’s disease. In: DeVita Jr VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven; 1997. p. 2242–83.
Google Scholar
Delsol G, Meggetto F, Brousett P, Cohen-Knafo E, al Saati T, Rochaix P, et al. Relation of follicular dendritic reticular cells to Reed-Sternberg cells of Hodgkin’s disease with emphasis on the expression of CD21q antigen. Am J Pathol. 1993;142:1729–38.
CAS PubMed PubMed Central Google Scholar
Connelly RR, Chistene BW. A cohort study of cancer following infectious mononucleosis. Cancer Res. 1974;34:1172–8.
CAS PubMed Google Scholar
Graff KS, Simon RM, Yankee RA, DeVita VT, Rogentine GN. HL-A antigens in Hodgkin’s disease: histopathologic and clinical correlations. J Natl Cancer Inst. 1974;52:1087–90.
CAS PubMed Google Scholar
Biggar RJ, Horm J, Goedert JJ, Melbye M. Cancer in a group at risk of acquired immunodeficiency syndrome (AIDS) through 1984. Am J Epidemiol. 1987;126:578–86.
CAS PubMed Google Scholar
Robertson SJ, Lowman JT, Grufferman S, Kostyu D, van der Horst CM, Matthews TJ, et al. Familial Hodgkin’s disease: a clinical and laboratory investigation. Cancer. 1987;59:1314–9.
Article CAS PubMed Google Scholar
Specht L, Carde P, Mauch P, Magrini SM, Santarelli MT. Radiotherapy versus combined modality in early stages. Ann Oncol. 1992;3:77–81.
Article PubMed Google Scholar
Nissen NI, Nordentoft AM. Radiotherapy versus combined modality treatment of stage I and II Hodgkin’s disease. Cancer Treat Rep. 1982;66:799–803.
CAS PubMed Google Scholar
DeVita VT, Serpick AA, Carbone PP. Combination chemotherapy in the treatment of advanced Hodgkin’s disease. Ann Intern Med. 1970;73:881–95.
Article PubMed Google Scholar
Klimo P, Conners JM. MOPP/ABV hybrid program: combination chemotherapy based on early introduction of seven effective drugs for advanced Hodgkin’s disease. J Clin Oncol. 1985;3:1174–82.
CAS PubMed Google Scholar
Prosnitz LR, Farber LR, Scott J, Bertino JR, Fischer JJ, Cadman EC. Combine modality therapy for advanced Hodgkin’s disease: a 15-year follow-up data. J Clin Oncol. 1988;6:603–12.
CAS PubMed Google Scholar

Download references

Author information

Authors and Affiliations

Department of Pathology and Laboratory Medicine, Curriculum in Toxicology, UNC Program in Translational Medicine, UNC Lineberger Comprehensive Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA
William B. Coleman Ph.D.
Laboratory for Clinical Genomics and Advanced Technology (CGAT), Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Norris Cotton Cancer Center, Lebanon, NH, USA
Gregory J. Tsongalis
Geisel School of Medicine at Dartmouth, Hanover, NH, USA
Gregory J. Tsongalis

Authors

William B. Coleman Ph.D.
View author publications
You can also search for this author in PubMed Google Scholar
Gregory J. Tsongalis
View author publications
You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to William B. Coleman Ph.D. .

Editor information

Editors and Affiliations

Department of Pathology and Laboratory Medicine, Curriculum in Toxicology, UNC Program in Translational Medicine, UNC Lineberger Comprehensive Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
William B. Coleman
Laboratory for Clinical Genomics and Advanced Technology (CGAT), Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, Hanover, New Hampshire, USA
Gregory J. Tsongalis

Rights and permissions

Reprints and permissions

Copyright information

About this chapter

Cite this chapter

Coleman, W.B., Tsongalis, G.J. (2017). Cancer Epidemiology: Incidence and Etiology of Human Neoplasms. In: Coleman, W., Tsongalis, G. (eds) The Molecular Basis of Human Cancer. Humana Press, New York, NY. https://doi.org/10.1007/978-1-59745-458-2_1

Download citation

DOI: https://doi.org/10.1007/978-1-59745-458-2_1
Published: 13 November 2016
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-934115-18-3
Online ISBN: 978-1-59745-458-2
eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics