epidemic. N Eng J Med 2013;368:2352–2353.

50. Tagaito Y, Isono S, Tanaka A, et al. Sitting posture decreases collapsibility of the passive pharynx in

anesthetized paralyzed patients with obstructive sleep apnea. Anesthesiology 2010;113:812–818.

51. Brown KA, Laferriere A, Lakheeram I, et al. Recurrent hypoxemia in children is associated with

increased analgesic sensitivity to opiates. Anesthesiology 2006;105:665–669.

52. Mutter TC, Chateau D, Moffatt M, et al. A matched cohort study of postoperative outcomes in

obstructive sleep apnea: Could preoperative diagnosis and treatment prevent complications?

Anesthesiology 2014;121:707–718.

53. Abdelsattar ZM, Hendren S, Wong SL, et al. The Impact of Untreated Obstructive Sleep Apnea on

Cardiopulmonary Complications in General and Vascular Surgery: A Cohort Study. Sleep

2015;38:1205–1210.

54. Horlocker TT, Wedel DJ, Rowlingson JC, et al. Regional anesthesia in the patient receiving

antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain

Medicine Evidence-Based Guidelines (Third Edition). Reg Anesth Pain Med 2010;35:64–101.

55. Wijeysundera DN, Duncan D, Nkonde-Price C, et al. Perioperative beta blockade in noncardiac

surgery: A systematic review for the 2014 ACC/AHA guideline on perioperative cardiovascular

evaluation and management of patients undergoing noncardiac surgery: A report of the American

College of Cardiology/American Heart Association Task Force on practice guidelines. J Am Coll

Cardiol 2014;64:2406–2425.

56. Roberts DM, Meyer-Witting M. High-dose buprenorphine: Perioperative precautions and

management strategies. Anaesth Intensive Care 2005; 33:17–25.

57. Barker SJ, Badal JJ. The measurement of dyshemoglobins and total hemoglobin by pulse oximetry.

Curr Opin Anaesthesiol 2008;21:805–810.

58. Wahr J, Parks R, Boisvert D. Pulse oximetry. In: Blitt H, ed. Monitoring in Anesthesia and Critical

Care Medicine. 3rd ed. New York, NY: Churchill Livingstone; 1994:385.

59. Coriat P, Vrillon M, Perel A, et al. A comparison of systolic blood pressure variations and

echocardiographic estimates of end-diastolic left ventricular size in patients after aortic surgery.

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60. Minto G, Scott MJ, Miller TE. Monitoring needs and goal-directed fluid therapy within an enhanced

recovery program. Anesthesiol Clin 2015; 33:35–49.

61. Wuethrich PY, Burkhard FC, Thalmann GN, et al. Restrictive deferred hydration combined with

preemptive norepinephrine infusion during radical cystectomy reduces postoperative complications

and hospitalization time: A randomized clinical trial. Anesthesiology 2014;120:365–377.

62. Avidan MS, Zhang L, Burnside BA, et al. Anesthesia awareness and the bispectral index. N Eng J

Med 2008;358:1097–1108.

63. Myles PS, Leslie K, McNeil J, et al. Bispectral index monitoring to prevent awareness during

anaesthesia: The B-Aware randomised controlled trial. Lancet 2004;363:1757–1763.

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for intraoperative awareness and brain function monitoring: A report by the American society of

anesthesiologists task force on intraoperative awareness. Anesthesiology 2006;104:847–864.

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66. Avidan MS, Jacobsohn E, Glick D, et al. Prevention of intraoperative awareness in a high-risk

surgical population. N Eng J Med 2011;365:591–600.

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recall in an unselected surgical population: A randomized comparative effectiveness trial.

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69. Breslow MJ, Miller CF, Parker SD, et al. Changes in T-wave morphology following anesthesia and

surgery: A common recovery-room phenomenon. Anesthesiology 1986;64:398–402.

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postoperative nausea and vomiting. N Eng J Med 2004;350:2441–2451.

71. Charbit B, Funck-Brentano C. Droperidol-induced proarrhythmia: The beginning of an answer?

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Anesthesiology 2007;107:524–526.

72. Nuttall GA, Eckerman KM, Jacob KA, et al. Does low-dose droperidol administration increase the

risk of drug-induced QT prolongation and torsade de pointes in the general surgical population?

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77. Tverskoy M, Cozacov C, Ayache M, et al. Postoperative pain after inguinal herniorrhaphy with

different types of anesthesia. Anesth Analg 1990;70:29–35.

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Chapter 14

Oncology

Adam C. Yopp and John C. Mansour

Key Points

1 Cancer is responsible for nearly 1 in 4 deaths within the United States and is the second leading allage cause of death, regardless of gender.

2 Five percent to 10% of reported cancers are secondary to familial cancer syndromes.

3 Tobacco use and dietary factors are the two most common environmental risk factors associated

with cancer.

4 Population-based screening tests are available for the following cancers: cervical, colon, breast, and

prostate.

The earliest known description of cancer is documented in a series of Egyptian papyri, the Edwin Smith

and George Ebers papyri, written circa 1500 BC. These scrolls detail events approximately 1,000 years

earlier, documenting surgical, pharmacologic, mechanical, and magical treatments of cancer. Although

illustrated in the papyri, the word “cancer” is first attributed to Hippocrates (460 to 370 BC) nearly a

thousand years later. Cancer, the Greek term for crab (“karkinoma”) describes the finger-like spreading

projections of an ulcer-forming tumor. Later the Roman physician, Celsus (28 to 50 BC), translated

karkinoma into the Latin term cancer, the term most commonly used today. The study of cancer or

oncology is attributed to another Greek physician, Galen (130 to 200 AD), who used the Greek word for

swelling, oncos, to describe tumors.

EPIDEMIOLOGY

1 Cancer is responsible for nearly 1 in 4 deaths within the United States and is the second leading allage cause of death, regardless of gender. In 2015, an estimated 1.6 million new cases will be diagnosed

and over a half million patients will die of cancer within the United States. In men, the most common

forms of cancer are from prostate, lung and bronchus, and colorectal origins. In women, the most

common forms are breast, lung and bronchus, and colorectal. Cancers of the lung and bronchus,

prostate, and colorectum in men and cancers of the lung and bronchus, breast, and colorectum in

women are, in order, the most common cause of cancer-related deaths (Table 14-1).1

Although, the overall incidence rate of cancer has been 23% lower among women compared with men

since 1992, the rate in men has also declined by −0.6% over the period from 2006 to 2011, largely due

to decreases in colorectal, prostate, and lung cancers. During the same time period there was no change

in incidence of cancer among women, largely due to the stable rate of breast cancer (Fig. 14-1).1

The decline in incidence for the most common cancer types is secondary to improvements in both

cancer control and prevention. The long-term decline in colorectal cancer incidence rates since 1985 can

be attributed to both changes in associated risk factors and the introduction of effective screening

programs. For example, increased rates of diagnostic and therapeutic polypectomies during screening

colonoscopies have contributed to declining colorectal cancer incidence rates by interrupting the

adenoma to carcinoma sequence.2–4 Similarly, lung cancer incidence rates declined in the mid-1980s in

men and in the late 1990s in women as a direct result of changed smoking habits.1,5,6 In contrast to

stable or declining incidence rates in the leading cancer subtypes, increased incidence rates for skin

melanoma, esophageal adenocarcinoma, thyroid carcinoma, primary liver carcinoma, kidney carcinoma,

pancreas carcinoma, and human papillomavirus (HPV)-related oropharyngeal cancers were observed

over the past two decades. Among both men and women the largest increase in annual incidence rates

over the last decade was in thyroid cancer and primary liver cancer (Fig. 14-2).1,7

Throughout most of the 20th century overall mortality rate associated with cancer rose secondary to

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smoking-related lung cancer deaths, especially in men, peaking at 215.1 deaths per 100,000 persons in

1991.1 However, over the past two decades the mortality rate has steadily declined as a direct result of

advances in prevention, early detection, and treatment.1 The most current, 2010 cancer mortality rate

estimate is 171.8 deaths per 100,000 persons.1 Mortality rates for the most common cancers: breast,

prostate, and colorectal cancers are down from peak rates by 34%, 45%, and 46%, respectively.3,8,9 In

contrast, mortality rates are rising for cancers of the oropharynx, anus, liver, pancreas, skin melanoma,

and soft tissue. Although thyroid cancer is increasing in incidence the observed mortality rate is stable

over time, likely a result of indolent underlying tumor biology and a lead time screening bias (Figs. 14-

1, 14-2).1

RISK FACTORS

Genetic Risk Factors

In 1971, Alfred Knudson described his “two-hit hypothesis” model for retinoblastoma, a rare form of

childhood retinal cancer affecting 11.8 patients per one million live births in the United States.10,11 In

his hypothesis, Knudson postulated that familial retinoblastoma required a first “hit” in the form of an

inherited germline mutation and a second “hit” through an acquired mutation for development of retinal

tumors.10 This hypothesis was validated more than two decades later following cloning of RB1 as the

tumor suppressor gene implicated in familial retinoblastoma, thereby ushering in a new frontier of

study: cancer susceptibility or familial cancer syndromes.12

Table 14-1 Ten Leading Cancer Types for Men and Women by Incidence and

Mortality, United States, 2015

Familial Cancer Syndromes

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2 The discovery of inherited mutations of genes associated with an increased risk of cancer provides

important opportunities for early detection and prevention of common and rare forms of human

malignancies. Genetically related cancer is a spectrum, ranging from common variants with low

penetrance to rare variants with either moderate or high penetrance (Fig. 14-3). Linkage studies have

successfully identified the majority of familial cancer syndromes through DNA analysis of large families

with affected individuals, linking disease phenotypes or cancer subtypes to regions of the genome, with

candidate genes subsequently sequenced for a causative mutation. These linkage studies have identified

the rare, highly penetrant cancers of hereditary cancer syndromes that account for about 5% to 10% of

reported cancers (Table 14-2).12 The more common, but lower-penetrant variants of genetic-,

nonsyndrome-related cancers are typically found through large, genome-wide analysis of unrelated

persons with common cancers. In genome-wide association studies (GWAS) the entire genome is

sequenced and single alterations, or single-nucleotide polymorphisms (SNPs), are used to delineate

increased risks of cancer related to genetic risks.13

In both high and low penetrant genetically related cancers a high clinical suspicion is necessary for

diagnosis and to formulate appropriate screening and treatment plans. To aid the clinician, tools have

been developed to obtain an accurate family history, thereby assessing the risk of genetically related

cancers (Table 14-3).14 If the clinician has a reasonable suspicion that a patient may be either at risk for

or has a genetically related cancer, further follow-up with a dedicated genetic counselor is

recommend.15 We herein summarize the five most prevalent familial cancer syndromes with regard to

genetic mechanism and diagnosis.

Hereditary Nonpolyposis Colon Cancer

Hereditary nonpolyposis colon cancer (HNPCC), previously known as Lynch syndrome, is the most

prevalent familial cancer syndrome and is responsible for 2% to 5% of all colorectal cancer.16 An

autosomal dominant syndrome, HNPCC is caused by a germline mutation in one of six genes: MLH1,

MSH2, MSH3, MSH6, PMS1, or PMS2.17–21 All six of the genes function in DNA mismatch repair and

between 45% and 70% of HNPCC families have mutations in the most common gene variants: MLH1,

MSH2, or MSH6. Patients with mutations in mismatch repair genes exhibit microsatellite instability,

with errors in replication of highly repetitive sequences unable to be repaired, resulting in alterations of

the length of the total repeat sequence.

Figure 14-1. Trends in age-adjusted cancer incidence and death by gender, United States, 1975 to 2011. (From Siegel RL, Miller

KD, Jemal A. Cancer statistics, 2015. Ca Cancer J Clin 2015;65:5–29.)

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Figure 14-2. Trends in age-adjusted cancer incidence by gender and site, United States, 1975 to 2011. (From Siegel RL, Miller KD,

Jemal A. Cancer statistics, 2015. Ca Cancer J Clin 2015;65:5–29.)

Figure 14-3. Genetic architecture by cancer risk.

Clinically, HNPCC is associated with right-sided colonic tumors with histopathology demonstrating

poorly differentiated adenocarcinoma and signet ring features. Patients with HNPCC have a 50% to 80%

lifetime risk of colorectal cancer, with a median age of diagnosis in the mid-40s. An increased risk of

endometrial cancer, ovarian cancer, stomach cancer, small intestine cancer, ureteral cancer, and kidney

cancer is also seen in HNPCC kindreds.22–24

Currently, testing for HNPCC is recommended for all newly diagnosed cases of colorectal cancer that

fulfill the revised Bethesda guidelines, in families that meet the Amsterdam II criteria, in patients with

endometrial cancer diagnosed before age 50, or in families with known HNPCC (Table 14-4).25,26

Table 14-2 Familial Cancer Syndromes

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Table 14-3 Clinical Aid Suggesting the Presence of a Hereditary Cancer

Disposition

Table 14-4 Amsterdam II and Revised Bethesda Guidelines for the Testing of

Hereditary Nonpolyposis Colorectal Cancer

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Familial Adenomatous Polyposis

Familial adenomatous polyposis (FAP) is a highly penetrant, autosomal dominant syndrome with an

incidence between 1 in 5,000 and 1 in 10,000 and is responsible for approximately 1% of all colon

cancer cases.27 Arising from a mutation in the antigen-presenting cell (APC) gene on chromosome 5q,

nearly 75% of cases are due to familial germline mutations with the remainder secondary to firstgeneration de novo mutations.28

Clinically, FAP manifests with hundreds to thousands of adenomatous polyps at a young age with a

resultant risk of colon cancer of 90% by age 45.29 In addition to colonic manifestations, duodenal and

gastric polyps are also prevalent with a lifetime risk of duodenal cancer ranging from 5% to 12%,

typically periampullary in location. Benign, extraintestinal manifestation of FAP includes desmoid

tumors, mesenteric fibrosis, epidermoid cysts, osteomas, congenital retinal pigment epithelium, and

dental anomalies and typically accompanying adenomatous polyp formation.29

Hereditary Breast and Ovarian Syndrome

Hereditary breast and ovarian syndrome (HBOC) occurs at an incidence rate of 1 in 500 or 1,000 and is

inherited in an autosomal dominant fashion with a penetrance of nearly 85%.30,31 Germline mutations in

BRCA1 (chromosome 17q) or BRCA2 (chromosome 13q) are responsible for approximately 60% of

HBOC, with mutations in ATM, NBM, BRIP1, CHEK2, TP53, PTEN, and RAD51C responsible for the

remaining cases.32,33 BRCA1 and BRCA2 are DNA damage repair genes and more than 1,000 variants

have been identified with founder BRCA mutations documented in genetically isolated populations.34 In

the United States, the most common founder mutations occur in Ashkenazi Jewish lineage with nearly 1

in 40 carrying the common BRCA1 or BRCA2 mutations.34 Genetic linkage studies of families with

HBOC syndrome demonstrate that the lifetime risk of developing breast and ovarian cancers by age 70

is 56% and 17%, respectively.30,32

Familial Gastric Cancer

Hereditary diffuse gastric cancer (HDGC) is autosomal dominant in nature and is characterized by

diffuse gastric cancer and lobular breast cancer with a nearly uniform penetrance and an 80% lifetime

risk of gastric cancer.35 The average age of developing hereditary gastric cancer is 38 years. Thirty to

40% of families with HDGC have germline mutations in CDH1 at chromosome 16q, a gene producing

the E-cadherin protein necessary for cell proliferation and adhesion within the stomach mucosa.36

Currently, the diagnosis of HDGC is suspected if a person or family meets any of the below criteria37:

At least two cases of stomach cancer in a family, with at least one being diffuse gastric cancer

diagnosed before age 50

At least three cases of stomach cancer at any age

Diagnosis of diffuse gastric cancer before the age of 45

Diagnosis with both diffuse gastric cancer and lobular breast cancer

von Hippel–Lindau Disease

von Hippel–Lindau Disease (VHL) is an autosomal dominant syndrome characterized by the formation

of hemangioblastomas of the brain, spinal cord, and retina.38 In addition, individuals with VHL disease

may develop renal or pancreatic cysts and are at an increased risk for clear cell renal cell carcinoma,

pheochromocytomas, and pancreatic neuroendocrine tumors. Arising from a germline mutation of the

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