Epidemiology: Incidence and Prevalence

Figure 26-1 indicates the most common cancers expected to occur in men and women in 2010.^1,2 Among men, cancers of the prostate, lung and bronchus, and colon and rectum account for more than 56% of all newly diagnosed cancers. In women the most common cancers are breast, lung, colon, and uterine.³

FIGURE 26-1 Ten leading cancer types in estimated new cancer cases and deaths, by gender, United States, 2006. Indicated are the most common cancers that were expected to occur in men and women in 2006. Among men, cancers of the prostate, lung and bronchus, and colon and rectum account for more than 56% of all newly diagnosed cancers. Prostate cancer alone accounts for about 33% (234,460) of incident cases in men. On the basis of cases diagnosed between 1995 and 2001, an estimated 91% of new cases of prostate cancer were expected to be diagnosed at local or regional stages, for which relative 5-year survival approaches 100%.

(From Jamal A, et al: Cancer statistics, 2010, CA Cancer J Clin 60;277-300, 2010.

Etiology and Prevention

Carcinogenesis is a complex multistep process that involves the accumulation of mutations and the loss of regulatory control over cell division, differentiation, apoptosis, and adhesion⁴ (Figure 26-2). The process originates at the level of gene and cell cycle control, either by a hereditary mutation, acquired mutation or inappropriate expression of a transcription factor. Some syndromes which predispose individuals to cancer can be seen in Table 26-2.

FIGURE 26-2 Carcinogenesis: pathologic sequence in gastrointestinal mucosa. Examples in colon and oral mucosa.

(Adapted from Jänne PA, Mayer RJ: Chemoprevention of colorectal cancer, N Engl J Med 342:1960-1968, 2000.)

TABLE 26-2 Syndromes of Inherited Cancer Predisposition in Clinical Oncology Syndrome

Adapted from Garber JE, Offit K: Hereditary cancer predisposition syndromes, J Clin Oncol 23:276-292, 2005.

The aggregation of cancer in a family can be due to genetic or nongenetic causes, the former through mendelian (single-gene mutation) or nonmendelian (polygenic or multifactorial) inheritance of genes that predispose to cancer and the latter related to common exposure to carcinogenic agents or lifestyle, or simple coincidence. The modern understanding of familial aggregation of cancer has required increasingly sophisticated epidemiologic and statistical methods in combination with genetic concepts and technologies.⁴

Although mendelian inheritance accounts for a small minority of all cancers, mutations that predispose to cancer have provided some of the most penetrating insights into the understanding of the genetic basis of normal as well as abnormal development; these mutations manifest the classical recessive or dominant modes of inheritance. Nonmendelian inheritance, which also plays a major role in the overall incidence of cancer, has been more difficult to characterize. In addition, the interaction of mutated genes with the environment adds another level of complexity in deciphering the role of genetics of cancer in individual patients as well as in families.⁴ Some of the genetic associations with cancer are shown in Table 26-2.

At least three to six somatic mutations are needed to transform a normal cell into a malignant cell. Acquired mutations can arise from exposure to hazardous chemicals and pathogens that lead to activation of oncogenes, inactivation of tumor suppressor genes (pRb and TP53), and chromosomal abnormalities (translocations, deletions, insertions). The accumulation of these abnormalities leads to a cell that becomes functionally independent and aggressive. Natural killer cells provide surveillance for cancerous cells. Reduction in numbers or function of natural killer cells, which occurs during immunosuppression, increases the risk for cancer.⁵

National efforts currently focus on the reduction or elimination of factors known to be associated with cancer. Recommendations from the American Cancer Society (ACS) are to minimize exposure to tobacco smoke and to environmental and occupational carcinogens (e.g., asbestos fibers, arsenic compounds, chromium compounds, pesticides); decrease intake of fat and exposure to ultraviolet light; moderate the intake of alcohol; obtain an adequate intake of dietary fiber and antioxidants (vitamins C and E, selenium); and perform moderate levels of physical activity.⁵

Pathophysiology and Complications

The loss of regulatory control in a cell destined to become a cancer cell results in a series of pathologic changes that eventuate in hyperproliferative epithelium, dysplasia, and finally carcinoma. Dysplastic tissue is characterized by atypical cell proliferation, nuclear enlargement, failure of maturation, and differentiation short of malignancy (see Figure 26-2).

Cytogenetic studies of various leukemias established four cardinal attributes of genetic change in cancer: (1) Specific or nonrandom chromosomal changes may characterize individual cancer types; (2) tumor genomes are genetically unstable and subject to continuing change, a feature now recognized as genomic instability; (3) all cells in a given tumor trace back to a single progenitor cell and therefore are clonal; and (4) tumor progression often is associated with additional specific or nonrandom chromosomal changes, presumably “selected” from the genomic instability, in subpopulations of tumor cells that lead clonal diversity and evolution. Chromosomal changes are of many types, the most common being gain of an entire chromosome (aneuploidy) or a region of it (duplication), loss of an entire chromosome (monosomy) or a region of it (deletion), translocation or inversion (rearrangement), and amplification (Figure 26-3).

FIGURE 26-3 Common cytogenetic changes in cancer. The chromosome (at metaphase) is traditionally distinguished by its short and long arms separated by a centromere. Stylized bands (dark and light stripes along the length of the chromosome) produced by special treatments are also shown. The abnormality (right) and the corresponding normal image of the chromosome are illustrated in each panel. A, Gain of a chromosome leading to aneuploidy. B, Deletion of a chromosomal segment from one of the two homologues. C, Translocation showing exchange of segments between nonhomologous chromosomes. D, Amplification, with an increase in a region of a chromosome by replicating many times in place.

(From Goldman L, Ausiello D, editors: Cecil textbook of medicine, ed 23, Philadelphia, 2008, Saunders.)

Malignant cells exhibit antigenic, karyotypic, biochemical, and membrane changes that cause loss of contact inhibition, changes in chromosomal morphology, and increased permeability. Malignant tumors lack cell cycle control and replicate rapidly, becoming clinically detectable after about 30 cell doublings, when the mass contains about 10⁹ cells (1 g). A three-log increase to 10¹² cells produces a tumor that weighs 1 kg and often is lethal. After reaching clinically detectable size, tumors slow in growth as they reach anatomic boundaries and begin to outgrow their blood supply. Malignant tumors overcome the limitation of anatomic boundaries by losing cell adherence and by metastasizing. Metastasis is a distinct form of cancerous spread that occurs when malignant cells enter blood or lymphatic vessels and travel to distant sites. Metastasis is related to factors produced by tumors cells that allow individual cells to invade tissues and endothelium. It often results in end-organ failure and death.⁵

Screening

Each year the ACS publishes a summary of its recommendations for early cancer detection. Obviously, the earlier any form of cancer is diagnosed, the more expeditiously and effectively it can be treated in order to minimize adverse outcomes: morbidity and mortality.

Table 26-3 outlines the most recent ACS recommendations for early cancer detection for several cancers. Further information can be found at http://cacancerjournal.org.

Signs and Symptoms

Cancers often manifest as a palpable mass that increase in size over time. Preceding the development of the tumor are subtle changes that are dependent on the anatomic site involved and the cell type of origin. Initial features can include a change in surface color, a lump, enlarged lymph node, or altered organ function. Symptoms include pain and paresthesia. Tumors permitted to increase in size often result in a reddened epithelial surface (due to increased blood vessels) that ulcerates.⁶

Staging

Most cancers are assigned a stage (I, II, III, or IV) by the medical team on the basis of the size of the tumor and how far it has spread (Box 26-1). Generically speaking, stage I disease is localized and confined to the organ of origin. Stage II disease is regional, affecting nearby structures. Regional head and neck lymph node anatomy can be seen in Figure 26-4. Stage III disease extends beyond the regional site, crossing several tissue planes, and stage IV disease is widely disseminated. This system often is supplemented by detailed and specific staging systems developed for particular cancers and generally does not apply to leukemia (because leukemia is a disease of the blood cells that does not usually form a solid mass or tumor). The tumor-node-metastasis (TNM) system frequently is used for this purpose (see Box 26-1). The patient’s prognosis depends in large part on the stage of disease at the time of diagnosis.⁶

FIGURE 26-4 Regional lymph node anatomy.

(From Fehrenbach MJ, Herring SW: Illustrated anatomy of the head and neck, ed 4, St. Louis, 2012, Saunders.)

Laboratory Findings

The diagnosis of cancer is dependent on microscopic examination of an adequate sample of tissue taken from the lesion (Box 26-2). Tissue can be obtained by cytologic smears, needle biopsy, or incisional or excisional biopsy. Cells also can be subjected to flow cytometry, chromosomal analyses, in situ hybridization, or other molecular procedures to identify specific cancer markers, ploidy, and DNA analysis. Serum tumor markers such as carcinoembryonic antigen (CEA) for colorectal carcinoma (CA 15-3 or CEA in breast cancer and CA 125 for ovarian cancer) have low sensitivity for the detection of early-stage cancers but are useful in monitoring disease progression and response to therapy.

Breast Cancer

Breast cancer is the most common type of cancer in the United States, with 98% of cases occurring in women. In 2010, approximately 207,000 cases of breast cancer were reported in the United States, with about 40,000 persons dying of the disease in that year.² The incidence increases with age. Risk factors include early menarche, late menopause, and nulliparity (women who do not bear children). All breast cancers are the result of somatic genetic abnormalities. The most important risk factor of breast cancer is family history of the disease with 5% to 10% of cases arising in high-risk families. The most common mutations identified in breast cancer cells are in the BRCA1 and BRCA2 genes. These mutations confer a 50% to 85% lifetime risk of breast cancer. Abnormalities also have been identified in genes (bcl-2, c-myc, c-myb and TP53) and gene products (Her2/neu and cyclin D1) that regulate the cell cycle and DNA replication. Gonadal steroid hormones, growth factors, and various chemokines (such as IL-6) influence the behavior and dissemination of the disease. Cancer in one breast increases the risk for cancer development in the other.^7,9,10

Breast cancer often is detected as a lump in the breast with or without nipple discharge, breast skin changes and breast pain. Mammography detects the mass in only 75% to 85% of patients (Figure 26-5). Although mammography recently has been controversial, it is still a valuable screening technique as considered by the ACS.¹¹ In a small percentage of patients, the first sign is an axillary mass. Diagnosis is made from a tissue core biopsy of breast tissue. Most breast cancers are infiltrating ductal carcinomas, whereas a smaller percentage of tumors are infiltrating lobular carcinomas, medullary carcinomas, mucinous carcinoma, or tubular carcinoma. Metastasis occurs after the cancer becomes clinically detectable and is primarily to regional lymph nodes and within the chest wall, bone, lung, and liver.¹²

FIGURE 26-5 Mammogram showing a radiodense area in the breast suggestive of a malignancy that should be recommended for biopsy.

(Courtesy A.R. Moore, Lexington, Kentucky.)

Treatment of breast cancer depends on the histologic type of cancer and stage. Cellular markers such as the Her2/neu molecule (target of drug herceptin) and the sodium-iodide symporter (NIS) aid in the diagnosis and treatment planning. Lumpectomy (when the tumor is less than 5 cm) or lumpectomy plus radiotherapy is preferred over radical mastectomy. Axillary node dissection is performed if the regional sentinel node is positive for malignancy. Hormone therapy (tamoxifen) and chemotherapy combined with local therapy is recommended when invasive carcinoma exceeding 1 cm in diameter or axillary lymph nodes are positive. The combination of fluorouracil, doxorubicin, and cyclophophamide usually is administered for 4 to 6 months, given at 3- to 4-week intervals. At present, metastatic breast cancer is incurable. Accordingly, the ACS recommends a mammogram and professional clinical examination every year for women 40 years of age and older (Box 26-3; see also Table 26-3). Women 20 to 39 years of age should have a professional breast examination at least every 3 years. Breast self-examination is an option for women starting in their 20s. The American Geriatrics Society recommends mammography every 2 or 3 years for healthy women between the ages of 65 and 85.¹²

Cervical Cancer

Cancer of the uterine cervix occurred in nearly 12,000 women in the United States in 2010, and more than 4000 women died of the disease.⁸ Cervical cancer is relatively uncommon in developed countries because of the intensive screening programs in place. Since the widespread use of screening Papanicolaou (Pap) smears, which detect asymptomatic cancerous precursor lesions at early stages, the incidence of cervical cancer has decreased dramatically, from 32 cases per 100,000 women in the 1940s to 8.3 cases per 100,000 women at present. However, approximately 30% of these patients die of the disease within 5 years, and the death rate for African Americans is more than twice the national average.¹³

Human papillomaviruses (HPVs), which are epitheliotropic sexually transmitted DNA viruses, are the major etiologic agent of cervical carcinogenesis. These viruses dysregulate the cell cycle and tumor suppressor genes (TP53 and pRb) through overexpression of viral early genes E6 and E7. Certain HPV strains (HPV serotypes 16, 18, 45, and 56) are classified as high-risk types, because they are associated with a majority of cases. HPV types 30, 31, 33, 35, 39, 51, 52, 58, and 66 are classified as intermediate oncogenic risk. In addition to viral infection, chronic cigarette smoking, multiple sexual partners, and immunosuppression increase the risk of cervical cancer^14,15 (see Figure 26-6).

FIGURE 26-6 A, Biopsy specimen revealing cancerous epithelium of the uterine cervix (hematoxylin and eosin stain). B, Human papillomavirus DNA detected in cervical epithelium by in situ hybridization.

(Courtesy Dr. Michael Cibull, Lexington, Kentucky.)

Cervical cancer typically has a long asymptomatic period before the disease becomes clinically evident. The cancer classically manifests in women who are between 40 and 60 years of age. The earliest preinvasive changes are diagnosed by Pap smear. Further evaluation is made by colposcopy and colposcopy-directed biopsy. If neoplastic cells penetrate the underlying basement membrane of the uterine cervix, widespread dissemination can occur. Metastases often affect renal tissues, resulting in ureteral obstruction and azotemia. Treatment is based on the stage of the disease and involves hysterectomy in the early stages and radiation therapy for disease that extends to or invades local organs. The 5-year survival rate is relatively high (see Table 26-1) but drops below 50% when the cancer extends to and beyond the pelvic wall.¹⁵

The ACS recommends that a Pap smear and professional pelvic examination be performed in women at the onset of sexually activity or at 18 years of age. Because cervical cancer is associated with immunosuppression, the Centers for Disease Control and Prevention (CDC) advises all women who are seropositive for human immunodeficiency virus (HIV) to receive semiannual screening beginning the first year after diagnosis. Health care providers may elect to screen less often when three annual examinations in a row are negative.¹⁶

Colorectal Cancer

Cancer of the large bowel (colon and rectum) is the most common malignancy of the gastrointestinal tract and overall the fourth most common cancer of persons living in the United States. This cancer was diagnosed in approximately 160,000 persons in the United States in 2010, and nearly 60,000 people died of the disease in that year.⁸ Colorectal cancer accounts for about 10% of all cancers in the United States and carries a 5-year survival rate of 61%. Over the past 2 decades, mortality has decreased for white women and men but increased in African American men and women.^8,17

The vast majority of colorectal cancers are adenocarcinomas (Figure 26-7). Inherited predisposition and environmental factors contribute to their development. Genetic abnormalities in chromosome 5 (in familial adenomatous polyposis), chromosome 17 (TP53 gene), and chromosome 18 (DCC gene) are contributory. An initiating and probably obligatory event is the oncogenic activation of the adhesion protein, beta-catenin, resulting from its overexpression, or loss of its negative regulator, the adenomatous polyposis cancer protein (APC). These abnormalities result in an upregulation in cell cycle signaling. Patients with chronic inflammation (ulcerative colitis) have approximately 10 to 20 times the risk of colorectal cancer as in the general population. The risk also increases with high-fat diet (40% of total calories), low dietary fiber intake, and smoking cigarettes for 20 years or more. By contrast, use of nonsteroidal antiinflammatory drugs (NSAIDs) and folate supplementation reduces the risk for colorectal cancer. Colonic adenomas (polyps) have malignant potential; however, less than 5% develop into carcinomas. The exception to this rule is in Gardner’s syndrome, in which virtually all affected patients develop malignant polyposis by age 40 unless treated.^18–20

FIGURE 26-7 Destructive effects of colon cancer.

(From Klatt ED: Robbins and Cotran atlas of pathology, ed 2, Philadelphia, 2010, Saunders.)

Colorectal cancer often is not diagnosed until age 40 and increases in incidence after age 50. Risk rises sharply by age 60 and doubles every decade until it peaks at age 75 years. Spread is by direct extension through the bowel wall and invasion of adjacent organs by lymphatics and the portal vein to the liver. The major signs and symptoms of colorectal cancer are rectal bleeding, abdominal pain, and change in bowel habits (constipation). Presenting symptoms may include those referable to invasion of adjacent organs (kidney, liver, vagina).^18–20 Screening for colorectal cancer as recommended by the ACS is summarized in Box 26-4 and also Table 26-3.

Colonoscopy is the preferred approach for evaluating a patient for colorectal cancer. This approach permits tissue and brush biopsy to be performed. Staging of the patient is aided by endoscopic ultrasonography and computed tomography (CT) scanning. Surgical excision is the treatment of choice with lesions encroaching the distal 5 cm of the colon, resulting in colostomy. Radiation therapy is used for treatment of rectal and anal cancer. Chemotherapy (fluorouracil and leucovorin for up to 6 months or, more recently, topoisomerase I inhibitors [camptothecins] and oxaliplatin) are used when metastatic spread occurs. Liver metastases have been treated with hepatic arterial therapy using implantable pumps and injection ports to deliver chemotherapeutic agents.^18–20

The poor prognosis with advanced colorectal cancer (stage III or IV) emphasizes the need for annual screening of at-risk adults. Digital rectal examination, fecal occult blood test, stool DNA testing, sigmoidoscopy, colonoscopy, and barium enema with air contrast are the screening procedures for colorectal cancer. The ACS recommends that screening start at age 50 for both men and women and even earlier if a family history exists, especially among first-degree relatives of colorectal cancer, preexisting inflammatory bowel disease, a personal history of colorectal cancer or adenomatous polyp, or a family history of hereditary colorectal cancer syndromes (e.g., familial adenomatous polyposis, Peutz-Jeghers syndrome, Gardner’s syndrome). Digital rectal examination and a test for occult blood should be performed once a year. Sigmoidoscopy is recommended every 5 years and colonoscopy every 10 years. A barium enema can be performed in place of the sigmoidoscopy and colonoscopy.²¹

Lung Cancer

Lung cancer is the cause of 14% of cancer cases and is the leading cause of cancer deaths (almost 157,000 deaths annually) in the United States (see Table 26-1).⁸ Although it maintains a similar incidence with breast and prostate cancer, the number of deaths caused by lung cancer exceeds the two combined. The number of new cases has been declining in men since 1984; by contrast, the incidence in women increased in the 1980s and 1990s and only recently declined. Lung cancer is more prevalent in industrialized countries, but increased incidence in nonindustrialized countries has resulted from the introduction of cigarettes into these regions. Overall, more than 85% of cases are related to smoking tobacco with a dose-dependent effect. In 60% of human lung cancers, the p53 tumor suppressor gene is mutated. Current evidence suggests that polycyclic aromatic hydrocarbons (e.g., benzopyrene metabolite) of tobacco smoke form adducts within the TP53 gene that contribute to an abnormally functioning p53. Deletions in chromosomal 3p and 9p and overexpression of the ras and myc oncogenes and growth factor receptor c-erbB-2 appear to be important steps in malignant transformation. Risk of lung cancer increases in persons who are exposed to certain inorganic minerals (asbestos and crystalline silica), metals (arsenic, chromium, and nickel), and ionizing radiation (e.g., radon).⁷

Histologically, lung cancers are divided into two groups. About 80% are non–small cell lung cancers (large cell undifferentiated 10%; squamous cell carcinoma [SCC] 30%; and adenocarcinoma 40%) (Figure 26-8), and 20% are small cell lung cancers (i.e., oat cell carcinoma). Small cell cancers have a rapid growth rate and metastasize early.²²

FIGURE 26-8 Large cell undifferentiated carcinoma infiltrating the entire lung shown in cross section.

(From Klatt ED: Robbins and Cotran atlas of pathology, ed 2, Philadelphia, 2010, Saunders.)

Lung cancer is a clinically silent disease until late in its course. Tumors that grow locally can produce a cough or change the nature of a chronic cough or manifest as dyspnea on exertion. Cancers that invade adjacent structures can produce chest pain and dyspnea, hemoptysis or produce syndromes (e.g., Horner’s syndrome) from disruption of nerves in the chest and neck or endocrine, cutaneous, or neurologic manifestations. Metastases to the brain, bone, adrenal gland, and liver produce features associated with malfunction of these organs and lymphadenopathy. With advanced disease, patients present with anorexia, weight loss, weakness, and profound fatigue.²²

Unfortunately, so far there is not any lung cancer screening test that has been shown to prevent people from dying of this disease. The use of chest x-ray imaging and sputum cytology (evaluating phlegm microscopically for abnormal cells) has been studied for several years. The recently updated studies have not yet yielded any value in screening programs for the early detection of lung cancer. Lung cancer screening is not recommended even for persons at high risk such as smokers.

The diagnosis of lung cancer is made by imaging studies, bronchoscopy, bronchial washings, brush and tissue biopsies, and histologic examination of the cells and tissue. Stage I and stage II non–small cell lung cancers are treated by surgical resection. Radiotherapy is used for more advanced non–small cell lung cancers and when patients with stage I or II disease refuse or are medically unfit for surgery. Chemotherapy using two or three agents (e.g., cisplatin, carboplatin, etoposide, vinblastine, vindesine) is employed in combination with radiotherapy for stage III and stage IV non–small cell lung cancers. Chemotherapy is the mainstay of treatment for small cell lung cancer. Adjuvant radiotherapy is used in patients with limited disease. Stage I lung cancer and stage II squamous cell lung cancers are associated with 5-year survival rates of more than 50%. The current 5-year survival rate for all stages of lung cancer is just 15.8%.²³ Despite the poor prognosis, national recommendations have not been made in the United States to deploy diagnostic image screening for the detection of lung cancer even in high-risk persons.²²

Prostate Cancer

Prostate cancer is the second most common cancer (approximately 234,000 cases per year) and the most common cancer of men in the United States (see Table 26-1). It is the second leading cause of cancer deaths among men (nearly 28,000 per year).⁸ Prostate cancer develops in approximately 9% of white men and in 11% of African American men. Family history and race (African American) are definitive risk factors for the development of this disease.²⁴

At present, the etiologic factors for prostate cancer remain unknown. High dietary fat intake and mutations in chromosome 1 (1q24-25) and X (Xq27-28) appear to increase the risk for prostate cancer. Overexpression of the c-myc oncogene also is commonly detected in solid tumors such as prostate cancer.²⁴

More than 90% of all prostate carcinomas are adenocarcinomas. They typically arise at multiple locations within the gland. Cancer of the prostate produces few signs and symptoms other than problems in urination (hesitancy, decreased force of urination) that, if present, occur late in the course of the disease. Thus screening procedures are paramount to the successful management of this disease. Methods used to screen for prostate cancer include the digital rectal examination (DRE) in combination with blood tests for prostate-specific antigen (PSA), and endorectal ultrasound imaging (Box 26-5; see also Table 26-3). The PSA velocity (change in the PSA level over time) aid in the diagnosis. The upper normal level for the PSA is 4 ng/mL. Transrectal ultrasound–guided needle biopsy is recommended for patients with the following findings²⁴:

Radionuclide scanning or pelvic magnetic resonance imaging (MRI) is recommended for men diagnosed with prostate cancer with a PSA greater than 10 ng/mL to determine the extent of the disease. Metastasis occurs by lymphatic or hematogenous d/>