PART I
Basic Considerations
CHAPTER 10
Oncology
BASIC SCIENCE QUESTIONS
1. What is the most common cancer in the world?
A. Breast
B. Gastric
C. Lung
D. Liver
Answer: C
Lung cancer is the leading cancer in the world, accounting for 1.35 million new cases and 1.15 million deaths per year. Breast cancer is now the second most common cause of cancer (1.15 million cases per year) followed by gastric cancer (934,000 cases), colorectal cancer (1.03 million cases), and liver cancer (626,000 case). (See Schwartz 9th ed., p. 237.)
2. Approximately how many people die of cancer annually in the United States?
A. 100,000
B. 500,000
C. 2,000,000
D. 5,000,000
Answer: B
In the year 2008, an estimated 1.44 million new cancer cases were diagnosed in the United States. In addition, over a million cases of basal and squamous cell carcinomas of the skin, 54,020 cases of melanoma in situ, and 67,770 cases of carcinoma in situ of the breast were predicted. Furthermore, an estimated 565,650 people were expected to die of cancer in the United States in the same year. Cancer deaths accounted for 23% of all deaths in the United States in 2005, second only to deaths from heart disease. (See Schwartz 9th ed., p. 236.)
3. The incidence of breast cancer is highest in developed nations with the exception of
A. France
B. England
C. Japan
D. Australia
Answer: C
The incidence of breast cancer is high in all of the most highly developed regions except Japan, including the United States and Canada, Australia, and Northern and Western Europe, ranging from 82.5 to 99.4 per 100,000 women per year. (See Schwartz 9th ed., p. 238.)
4. Which of the following is associated with an increased incidence of liver cancer?
A. Salted food
B. Infection with Hepatitis A
C. Exposure to aflatoxin
D. Helicobacter pylori
Answer: C
In contrast to colon cancers, 82% of liver cancers occur in developing countries. The incidence of liver cancer is especially high in China (37.9 per 100,000 men), whereas it is relatively low in North and South America and Europe (2.6 to 6.2 per 100,000 men). Worldwide, the major risk factors for liver cancer are infection with hepatitis B and C viruses and consumption of foods contaminated with aflatoxin. Hepatitis B immunization in children has recently been shown to reduce the incidence of liver cancer. (See Schwartz 9th ed., p. 238.)
5. Which of the following is NOT one of the six cell alterations that permit malignant growth to occur in cells?
A. Self-sufficiency of growth signals
B. Predisposition to apoptosis
C. Angiogenesis
D. Invasion and metastasis
Answer: B
Although there are >100 types of cancer, it has been proposed that there are six essential alterations in cell physiology that dictate malignant growth: self-sufficiency of growth signals, insensitivity to growth-inhibitory signals, evasion of apoptosis (programmed cell death), potential for limitless replication, angiogenesis, and invasion and metastasis (Fig. 10-1). (See Schwartz 9th ed., p. 239.)
FIG. 10-1. Acquired capabilities of cancer. (Modified with permission from Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 100:57, 2000. Copyright © Elsevier.)
6. Which of the following occurs in abnormally proliferating, transformed cells?
A. Anchorage-dependent growth
B. Immortalization
C. Increased contact inhibition
D. Increased cell-cell adherence
Answer: B
In normal cells, cell growth and proliferation are under strict control. In cancer cells, cells become unresponsive to normal growth controls, which leads to uncontrolled growth and proliferation. Human cells require several genetic changes for neoplastic transformation. Cell type–specific differences also exist for tumorigenic transformation. Abnormally proliferating, transformed cells outgrow normal cells in the culture dish (i.e., in vitro) and commonly display several abnormal characteristics. These include loss of contact inhibition (i.e., cells continue to proliferate after a confluent monolayer is formed); an altered appearance and poor adherence to other cells or to the substratum; loss of anchorage dependence for growth; immortalization; and gain of tumorigenicity (i.e., the ability to give rise to tumors when injected into an appropriate host). (See Schwartz 9th ed., p. 240.)
7. A “field effect” is best described as
A. The effect of oncogene amplification in a cell on the adjacent cells
B. The effect of loss of tumor-suppressor gene function in a cell on the adjacent cells
C. Increased oncogene amplification or loss of tumor-suppressor gene function in a group of cells
D. The effect of radiation on a tumor
Answer: C
Tumorigenesis is proposed to have three steps: initiation, promotion and progression. Initiating events such as gain of function of genes known as oncogenes or loss of function of genes known as tumor-suppressor genes may lead a single cell to acquire a distinct growth advantage. Although tumors usually arise from a single cell or clone, it is thought that sometimes not a single cell but rather a large number of cells in a target organ may have undergone the initiating genetic event; thus many normal-appearing cells may have an elevated malignant potential. This is referred to as a field effect. The initiating events are usually genetic and occur as deletions of tumor-suppressor genes or amplification of oncogenes. Subsequent events can lead to accumulations of additional deleterious mutations in the clone. (See Schwartz 9th ed., p. 240.)
8. Malignant cells are LEAST likely to be in which of the following stages of the cell cycle?
A. S phase
B. G0 phase
C. G1 phase
D. M phase
Answer: B
Malignant cells are cells that do not enter the G0 stage (quiescent stage) after proliferation.
The proliferative advantage of tumor cells is a result of their ability to bypass quiescence. Cancer cells often show alterations in signal transduction pathways that lead to proliferation in response to external signals. Mutations or alterations in the expression of cell-cycle proteins, growth factors, growth factor receptors, intracellular signal transduction proteins, and nuclear transcription factors all can lead to disturbance of the basic regulatory mechanisms that control the cell cycle, allowing unregulated cell growth and proliferation. The cell cycle is divided into four phases (Fig. 10-2). During the synthetic or S phase, the cell generates a single copy of its genetic material, whereas in the mitotic or M phase, the cellular components are partitioned between two daughter cells. The G1 and G2 phases represent gap phases during which the cells prepare themselves for completion of the S and M phases, respectively. When cells cease proliferation, they exit the cell cycle and enter the quiescent state referred to as G0. In human tumor cell-cycle regulators like INK4A, INK4B, and KIP1 are frequently mutated or altered in expression. These alterations underscore the importance of cell-cycle regulation in the prevention of human cancers. (See Schwartz 9th ed., p. 240.)
FIG. 10-2. Schematic representation of the phases of the cell cycle. Mitogenic growth factors can drive a quiescent cell from G0 into the cell cycle. Once the cell cycle passes beyond the restriction point, mitogens are no longer required for progression into and through S phase. The DNA is replicated in S phase, and the chromosomes are condensed and segregated in mitosis. In early G1 phase, certain signals can drive a cell to exit the cell cycle and enter a quiescent phase. Cell-cycle checkpoints have been identified in G1, S, G2, and M phases. CDK = cyclin-dependent kinase. (Adapted from Kastan M, Skapek S: Molecular biology of cancer: The cell cycle, in DeVita V, Hellman S, Rosenberg S (eds): Cancer: Principles and Practice of Oncology, 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2005.)
9. Which of the following is a proto-oncogene that is activated to promote malignant growth by gene amplification?
A. BRCA 1
B. ras
C. HER2/neu
D. p53
Answer: C
Normal cellular genes that contribute to cancer when abnormal are called oncogenes. The normal counterpart of such a gene is referred to as a proto-oncogene. Oncogenes are usually designated by three-letter abbreviations, such as myc or ras. Oncogenes are further designated by the prefix “v-” for virus or “c-” for cell or chromosome, corresponding to the origin of the oncogene when it was first detected. Proto-oncogenes can be activated (show increased activity) or overexpressed (expressed at increased protein levels) by translocation (e.g., abl), promoter insertion (e.g., c-myc), mutation (e.g.,ras), or amplification (e.g., HER2/neu). More than 100 oncogenes have been identified. (See Schwartz 9th ed., p. 241.)
10. HER2, also known as neu, is an oncogene that promotes malignant potential by
A. Forming a hetrodimer with other EGFR members
B. Increasing cell proliferation and growth
C. Suppressing apoptosis
D. All of the above
Answer: D
HER2 can interact with different members of the EGFR family and regulate mitogenic and survival signaling (Fig 10-3). (See Schwartz 9th ed., p. 242.)
FIG. 10-3. Selected HER2 signaling pathways. HER2 can interact with different members of the HER family and activate mitogenic and antiapoptotic pathways. 4E-BP1 = eIF4E binding protein 1; CREB = cyclic adenosine monophosphate element binding; eIF4E = eukaryotic initiation factor 4E; EZH = enhancer of zeste homolog; FAK = focal adhesion kinase; Fas-L = Fas ligand; GSK3 = glycogen synthase kinase-3; HER = human epidermal growth receptor; IKK = IκB kinase; ILK= integrin-linked kinase; IP3 = inositol triphosphate; IκB = inhibitor of NF-κB; MAPK = mitogen-activated protein kinase; MDM2 = mouse double minute 2 homologue; MEK = mitogen-activated protein/extracellular signal regulated kinase kinase; MEKK = MEK kinase; mTOR = mammalian target of rapamycin; NF-κB = nuclear factor κB; PI3K = phosphoinositide-3 kinase; PLC-γ = phospholipase Cγ; SAPK = stress-activated protein kinase; SEK = SAPK/extracellular signal regulated kinase kinase; TSC = tuberous sclerosis complex. (Modified with permission from Meric-Bernstam F, Hung MC: Advances in targeting human epidermal growth factor receptor-2 signaling for cancer therapy. Clin Cancer Res 12:6326, 2006.)
11. What percentage of malignant tumors have activating mutations in one of the ras genes?
A. 1%
B. 5%
C. 20%
D. 70%
Answer: C
Approximately 20% of all tumors have activating mutations in one of the ras genes. The frequency of ras mutations varies widely by cancer type (e.g., 90% of pancreatic cancers, but 5% of breast cancers). Tumors that lack ras mutations, however, may undergo activation of the ras signaling pathway by other mechanisms, such as growth factor receptor activation, loss of GAP, or activation of raseffectors. (See Schwartz 9th ed., p. 243.)
12. Which of the following stimulates the extrinsic (death receptor) apoptotic pathway?
A. Tumor necrosis factor
B. DNA damage
C. Release of cytochrome C from the mitochondria
D. BcL-2 activcation
Answer: A
The effectors of apoptosis are a family of proteases called caspases (cysteine-dependent and aspartate-directed proteases). The initiator caspases (e.g., 8, 9, and 10), which are upstream, cleave the downstream executioner caspases (e.g., 3, 6, and 7) that carry out the destructive functions of apoptosis.
Two principal molecular pathways signal apoptosis by cleaving the initiator caspases with the potential for crosstalk: the mitochondrial pathway and the death receptor pathway. In the mitochondrial (or intrinsic) pathway, death results from the release of cytochrome c from the mitochondria.
The mitochondrial pathway can be stimulated by many factors, including DNA damage, reactive oxygen species, or the withdrawal of survival factors. The permeability of the mitochondrial membrane determines whether the apoptotic pathway will proceed. The Bcl-2 family of regulatory proteins includes proapoptotic proteins (e.g., Bax, Bad, and Bak) and antiapoptotic proteins (e.g., Bcl-2 and Bcl-xL). The activity of the Bcl-2 proteins is centered on the mitochondria, where they regulate membrane permeability.
The second principal apoptotic pathway is the death receptor pathway, sometimes referred to as the extrinsic pathway. Cell-surface death receptors include Fas/APO1/CD95, tumor necrosis factor receptor 1, and KILL-ER/DR5, which bind their ligands Fas-L, tumor necrosis factor (TNF), and TNF-related apoptosis-inducing ligand (TRAIL), respectively. When the receptors are bound by their ligands, they form a death-inducing signaling complex (DISC). (See Schwartz 9th ed., p. 243.)
13. Which of the following is INCORRECT?
A. A feature of malignant cells is invasion
B. In situ cancer lies above the basement membrane
C. Invasion involves changes in adhesion, motility, and proteolysis of extracellular matrix
D. E-cadherin molecules increase invasion
Answer: C
A feature of malignant cells is their ability to invade the surrounding normal tissue. Tumors in which the malignant cells appear to lie exclusively above the basement membrane are referred to as in situ cancer, whereas tumors in which the malignant cells are demonstrated to breach the basement membrane, penetrating into surrounding stroma, are termed invasive cancer. The ability to invade involves changes in adhesion, initiation of motility, and proteolysis of the extracellular matrix (ECM). Cell-to-cell adhesion in normal cells involves interactions between cell-surface proteins. Calcium adhesion molecules of the cadherin family (E-cadherin, P-cadherin, and N-cadherin) are thought to enhance the cells’ ability to bind to one another and suppress invasion. (See Schwartz 9th
ed., p. 244.)
14. Which of the following is NOT a gene associated with hereditary cancer
A. FBN1
B. CDH1
C. HER2
D. RET
Answer: A
FBN1 is the gene associated with Marfan’s syndrome and in not associated with malignancy. CDH1, HER2, and RET are associated with hereditary cancers. (See Schwartz 9th ed., p. 247, and Table 10-1.)
TABLE 10-1 Genes associated with hereditary cancer
15. Certain breast cancer subtypes preferably spread to certain organs. This is an example of
A. Tumor dormancy
B. “Seed and soil” theory
C. Lymphatic spread
D. In situ carcinoma
Answer: B
One explanation for the tendency of cancer subtypes to spread to certain organs is mechanical and is based on the different circulatory drainage patterns of the tumors. When different tumor types and their preferred metastasis sites were compared, 66% of organ-specific metastases were explained on the basis of blood flow alone. The other explanation for preferential metastasis is what is referred to as the ‘seed and soil’ theory, the dependence of the seed (the cancer cell) on the soil (the secondary organ). According to this theory, once cells have reached a secondary organ, their growth efficiency in that organ is based on the compatibility of the cancer cell’s biology with its new microenvironment. (See Schwartz 9th ed., p. 245.)
16. Mutations in the Rb1 gene were first associated with
A. Breast cancer
B. Colorectal cancer
C. Rhabdomyosarcoma
D. Retinoblastoma
Answer: D
The retinoblastoma gene rb1 was the first tumor suppressor to be cloned. The rb1 gene product, the Rb protein, is a regulator of transcription that controls the cell cycle, differentiation, and apoptosis in normal development. Retinoblastoma is a pediatric retinal tumor. Most of these tumors are detected within the first 7 years of life. Bilateral disease usually is diagnosed earlier, at an average age of 12 months. There is a higher incidence of second extraocular primary tumors, especially sarcomas, malignant melanomas, and malignant neoplasms of the brain and meninges in patients with germline mutations. In addition to hereditary retinoblastoma, Rb protein is commonly inactivated directly by mutation in many sporadic tumors. Moreover, other molecules in the Rb pathway, such as p16 and cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), have been identified in a number of sporadic tumors, which suggests that the Rb pathway is critical in malignant transformation. (See Schwartz 9thed., p. 246.)
17. APC (adenomatosis polyposis coli tumor-suppressor gene) is abnormal in what percentage of sporadic (nonsyndromic) colon cancer?
A. 5%
B. 15%
C. 50%
D. 80%
Answer: D
The product of the adenomatous polyposis coli tumor-suppressor gene (APC) is widely expressed in many tissues and plays an important role in cell-cell interactions, cell adhesion, regulation of β-catenin, and maintenance of cytoskeletal microtubules. Alterations in APC lead to dysregulation of several physiologic processes that govern colonic epithelial cell homeostasis, including cell-cycle progression, migration, differentiation, and apoptosis. Mutations in the APC gene have been identified in FAP and in 80% of sporadic colorectal cancers. Furthermore, APC mutations are the earliest known genetic alterations in colorectal cancer progression, which emphasizes its importance in cancer initiation. The germline mutations in APC may arise from point mutations, insertions, or deletions that lead to a premature stop codon and a truncated, functionally inactive protein. The risk of developing specific manifestations of FAP is correlated with the position of the FAP mutations, a phenomenon referred to as genotype-phenotype correlation. For example, desmoids usually are associated with mutations between codons 1403 and 1578. (See Schwartz 9th ed., p. 248.)
CLINICAL QUESTIONS
1. Which of the following is thought to have contributed to a decrease in the worldwide mortality rate of gastric cancer?
A. Lower intake of fruits
B. Better food preservation
C. Routine laboratory monitoring
D. More effective therapy after diagnosis
Answer: B
The incidence of stomach cancer varies significantly among different regions of the world. The age-adjusted incidence is highest in Japan (62.1 per 100,000 men, 26.1 per 100,000 women). In comparison, the rates are much lower in North America (7.4 per 100,000 (4.4 to 3.4 per 100,000 men, 2.5 to 3.6 per 100,000 women). The difference in risk by country is presumed to be primarily due to differences in dietary factors. The risk is increased by high consumption of preserved salted foods such as meats and pickles, and decreased by high intake of fruits and vegetables. There also is some international variation in the incidence of infection with Helicobacter pylori, which is known to play a major role in gastric cancer development. Fortunately, a steady decline is being observed in the incidence and mortality rates of gastric cancer. This may be related to improvements in preservation and storage of foods as well as due to changes in the prevalence of H. pylori. (See Schwartz 9th ed., p. 237.)
2. A patient with breast cancer is considered to be cancer free (no further risk of primary recurrence or metastatic tumor) after
A. 3 years
B. 5 years
C. 10 years
D. Never
Answer: D
Metastases can sometimes arise several years after the treatment of primary tumors. For example, although most breast cancer recurrences occur within the first 10 years after the initial treatment and recurrences are rare after 20 years, breast cancer recurrences have been reported decades after the original tumor. This phenomenon is referred to as dormancy, and it remains one of the biggest challenges in cancer biology. Persistence of solitary cancer cells in a secondary site such as the liver or bone marrow is one possible contributor to dormancy. Another explanation of dormancy is that cells remain viable in a quiescent state and then become reactivated by a physiologically perturbing event. Interestingly, primary tumor removal has been proposed to be a potentially perturbing factor. An alternate explanation is that cells establish preangiogenic metastases in which they continue to proliferate but that the proliferative rate is balanced by the apoptotic rate. Therefore, when these small metastases acquire the ability to become vascularized, substantial tumor growth can be achieved at the metastatic site, leading to clinical detection. (See Schwartz 9th ed., p. 245.)
3. Which of the following is the most common etiology of Li-Fraumeni syndrome?
A. Exposure to aflatoxin
B. Exposure to radiation
C. Mutation in the p53 gene
D. Mutation in the BRCA1 gene
Answer: C
Li-Fraumeni syndrome (LFS) was first defined on the basis of observed clustering of malignancies, including early-onset breast cancer, soft tissue sarcomas, brain tumors, adrenocortical tumors, and leukemia. Criteria for classic LFS in an individual (the proband) include (a) a bone or soft tissue sarcoma when younger than 45 years, (b) a first-degree relative with cancer before age 45 years, and (c) another first- or second-degree relative with either a sarcoma diagnosed at any age or any cancer diagnosed before age 45 years. Approximately 70% of LFS families have been shown to have germline mutations in the tumor-suppressor gene p53. Breast carcinoma, soft tissue sarcoma, osteosarcoma, brain tumors, adrenocortical carcinoma, Wilms’ tumor, and phyllodes tumor of the breast are strongly associated; pancreatic cancer is moderately associated; and leukemia and neuroblastoma are weakly associated with germline p53 mutations. Mutations of p53 have not been detected in approximately 30% of LFS families, and it is hypothesized that genetic alterations in other proteins interacting with p53 function may play a role in these families. (See Schwartz 9th ed., p. 246.)
4. What percentage of breast cancers are hereditary?
A. 1%
B. 5-10%
C. 30%
D. 50%
Answer: B
It is estimated that 5 to 10% of breast cancers are hereditary. Of women with early-onset breast cancer (aged 40 years or younger), nearly 10% have a germline mutation in one of the breast cancer genesBRCA1 or BRCA2. Mutation carriers are more prevalent among women who have a first- or second-degree relative with premenopausal breast cancer or ovarian cancer at any age. The likelihood of aBRCA mutation is higher in patients who belong to a population in which founder mutations may be prevalent, such as in the Ashkenazi Jewish population. (See Schwartz 9th ed., p. 248.)
5. The risk of developing breast cancer by age 70 for a woman with a BRCA1 mutation is approximately
A. 10%
B. 20%
C. 30%
D. 40%
Answer: D
For a female BRCA1 mutation carrier, the cumulative risks of developing breast cancer and ovarian cancer by age 70 have been estimated to be 87 and 44%, respectively. The cumulative risks of breast cancer and ovarian cancer by age 70 in families with BRCA2 mutation have been estimated to be 84 and 27%, respectively. Although male breast cancer can occur with either BRCA1 or BRCA2 mutation, the majority of families (76%) with both male and female breast cancer have mutations in BRCA2. (See Schwartz 9th ed., p. 248.)
6. BRCA2 mutations are associate with all of the following EXCEPT
A. Gastric cancer
B. Lung cancer
C. Ovarian cancer
D. Prostate cancer
Answer: B
Besides breast and ovarian cancer, BRCA1 and BRCA2 mutations may be associated with increased risks for several other cancers. BRCA1 mutations confer a fourfold increased risk for colon cancer and threefold increased risk for prostate cancer. BRCA2 mutations confer a fivefold increased risk for prostate cancer, sevenfold in men younger than 65 years. Furthermore, BRCA2 mutations confer a fivefold increased risk for gallbladder and bile duct cancers, fourfold increased risk for pancreatic cancer, and threefold increased risk for gastric cancer and malignant melanoma. (See Schwartz 9th ed., p. 248.)
7. A patient with Lynch syndrome 2 is at increased risk for
A. Carcinoma of the endometrium
B. Secretory carcinoma of the breast
C. Osteosarcoma
D. Melanoma
Answer: A
Hereditary nonpolyposis colorectal cancer (HNPCC), also referred to as Lynch syndrome, is an autosomal dominant hereditary cancer syndrome that predisposes to a wide spectrum of cancers, including colorectal cancer without polyposis. Some have proposed that HNPCC consists of at least two syndromes: Lynch syndrome 1, which entails hereditary predisposition for colorectal cancer with early age of onset (approximately age 44 years) and an excess of synchronous and metachronous colonic cancers; and Lynch syndrome 2, featuring a similar colonic phenotype accompanied by a high risk for carcinoma of the endometrium, transitional cell carcinoma of the ureter and renal pelvis, and carcinomas of the stomach, small bowel, ovary, and pancreas. The diagnostic criteria for HNPCC are referred to as the Amsterdam criteria, or the 3-2-1-0 rule. The classic Amsterdam criteria were revised to include other HNPCC-related cancers (Table 10-2). (See Schwartz 9th ed., p. 248.)
TABLE 10-2 Revised criteria for hereditary nonpolyposis colon cancer (HNPCC) (Amsterdam criteria II)
Three or more relatives with an HNPCC-associated cancer (colorectal cancer, endometrial cancer, cancer of the small bowel, ureter, or renal pelvis), one of whom is a first-degree relative of the other two
At least two successive generations affected
At least one case diagnosed before age 50 y
Familial adenomatous polyposis excluded
Tumors verified by pathologic examination
Source: Modified with permission from Vasen HF, Watson P, Mecklin JP, et al: New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the international Collarbone group on HNPCC. Gastroenterology 116:1453, 1999. Copyright © Elsevier.
8. Cowden syndrome is associated with an increased incidence of
A. Thyroid cancer
B. Adrenal cancer
C. Colorectal cancer
D. Gastric cancer
Answer: A
Somatic deletions or mutations in the tumor-suppressor gene PTEN (phosphatase and tensin homologue deleted on chromosome 10) have been observed in a number of glioma and breast, prostate, and renal carcinoma cell lines and several primary tumor specimens. PTEN also is referred to as the gene mutated in multiple advanced cancers 1 (MMAC1). PTEN was identified as the susceptibility gene for the autosomal dominant syndrome Cowden disease (CD) or multiple hamartoma syndrome. Trichilemmomas, benign tumors of the hair follicle infundibulum, and mucocutaneous papillomatosis are pathognomonic of CD. Other common features include thyroid adenomas and multinodular goiters, breast fibroadenomas, and hamartomatous GI polyps. The diagnosis of CD is made when an individual or family has a combination of pathognomonic major and/or minor criteria proposed by the International Cowden Consortium (Table 10-3). CD is associated with an increased risk of breast and thyroid cancers. Breast cancer develops in 25 to 50% of affected women. (See Schwartz 9th ed., p. 249.)
TABLE 10-3 Cowden disease diagnostic criteria
Pathognomonic criteria
Mucocutaneous lesions
Facial trichilemmomas
Acral keratoses
Papillomatous lesions
Mucosal lesions
Major criteria
Breast cancer
Thyroid cancer, especially follicular thyroid carcinoma type
Macrocephaly (≥97th percentile)
Lhermitte-Duclos disease
Endometrial carcinoma
Minor criteria
Other thyroid lesions (e.g., goiter)
Mental retardation (intelligence quotient ≤75)
GI hamartomas
Fibrocystic disease of the breast
Lipomas
Fibromas
Genitourinary tumors (e.g., uterine fibroids) or malformation
operational diagnosis in an individual
Mucocutaneous lesions alone if there are:
Six or more facial papules, of which three or more must be trichilemmoma, or
Cutaneous facial papules and oral mucosal papillomatosis, or
Oral mucosal papillomatosis and acral keratoses, or
Palmoplantar keratoses, six or more
Two major criteria, but one must be macrocephaly or Lhermitte-Duclos disease
One major and three minor criteria
Four minor criteria
Source: Modified with permission from Eng C: Will the real Cowden syndrome please stand up: revised diagnostic criteria. J med Genet 37:828, 2000. With permission from the BMJ Publishing Group.
9. Patients with hereditary melanoma due to a p16 mutation are also at higher risk for
A. Thyroid cancer
B. Pancreatic cancer
C. Colorectal cancer
D. Breast cancer
Answer: B
The gene P16, also known as INK4A, CDKN1, CDKN2A, and MTS1, is a tumor suppressor that acts by binding CDK4 and CDK6 and that is required for phosphorylation of Rb and subsequent cell-cycle progression. Studies suggest that germline mutations in p16 can be found in 20% of melanoma-prone families. Mutations in p16 that alter its ability to inhibit the catalytic activity of the CDK4-CDK6/cyclin D complex not only increase the risk of melanoma by 75-fold but also increase the risk of pancreatic cancer by 22-fold. (See Schwartz 9th ed., p. 249.)
10. Which of the following chemical carcinogens has been associated with angiosarcoma of the liver?
A. Benzene
B. Diethylstilbestrol
C. Vinyl chloride
D. Coal tar
Answer: C
(See Schwartz 9th ed., p. 250, and Table 10-4 below.)
TABLE 10-4 Selected IARC group 1 chemical carcinogensa
11. Exposure to coal tar is associated with which of the following cancers?
A. Bladder cancer
B. Nasopharyngeal cancer
C. Scrotal cancer
D. Breast cancer
Answer: C
(See Schwartz 9th ed., p. 251, and Table 10-5.)
12. Epstein Barr virus (EBV) is associated with which of the following cancers?
A. Nasopharyngeal carcinoma
B. Non-Hodgkin’s lymphoma
C. Adult T-cell leukemia
D. Kaposi’s sarcoma
Answer: A
(See Schwartz 9th ed., p. 251, and Table 10-5.)
TABLE 10-5 Selected viral carcinogensa
13. Which of the following is the most significant risk factor for invasive breast cancer when screening a patient for risk?
A. >2 first-degree relatives with breast cancer
B. 2 previous breast biopsies in a patient 50 years of age
C. Age 12 at menarche
D. Atypical hyperplasia in a previous breast biopsy
Answer: A
(See Schwartz 9th ed., p. 253, and Table 10-6.)
TABLE 10-6 Assessment of risk for invasive breast cancer
14. For average-risk patients, routine cancer screening is recommended for all but the following disease?
A. Breast cancer
B. Colorectal cancer
C. Cervical cancer
D. Pancreatic cancer
Answer: D
(See Schwartz 9th ed., p. 254, and Table 10-7.)
TABLE 10-7 American Cancer Society recommendations for early detection of cancer in average-risk, asymptomatic individuals
15. Tumor staging for most epithelial cancers includes all of the following EXCEPT
A. Tumor size
B. Tumor mutations
C. Nodal involvement
D. Distant spread
Answer: B
Standardization of staging systems is essential to allow comparison of results from different studies from different institutions and worldwide. The staging systems proposed by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer (International Union Against Cancer, or UICC) are among the most widely accepted staging systems. Both the AJCC and the UICC have adopted a shared tumor, node, and metastasis (TNM) staging system that defines the cancer in terms of the anatomic extent of disease and is based on assessment of three components: the size of the primary tumor (T), the presence (or absence) and extent of nodal metastases (N), and the presence (or absence) and extent of distant metastases (M). (See Schwartz 9th ed., p. 254.)
16. Which of the following tumor marker-disease associations is NOT correct?
A. PSA and prostate cancer
B. CEA and colon cancer
C. CA19-9 and pancreatic cancer
D. AFP and breast cancer
Answer: D
(See Schwartz 9th ed., p. 255, and Table 10-8.)
TABLE 10-8 Sensitivity and specificity of some common tumor markers
17. Which of the following is an alkylating agent?
A. Cyclophosphamide
B. Doxorubicin
C. Pactitaxel
D. Vincristine
Answer: A
Alkylating agents are cell-cycle–nonspecific agents, that is, they are able to kill cells in any phase of the cell cycle. They act by cross-linking the two strands of the DNA helix or by causing other direct damage to the DNA. The damage to the DNA prevents cell division and, if severe enough, leads to apoptosis. The alkylating agents are composed of three main subgroups: classic alkylators, nitrosoureas, and miscellaneous DNA-binding agents (Table 10-9). (See Schwartz 9th ed., p. 261.)
TABLE 10-9 Classification of chemotherapeutic agents
Alkylating agents
Classic alkylating agents
Busulfan
Chlorambucil
Cyclophosphamide
Ifosfamide
Mechlorethamine (nitrogen mustard)
Melphalan
Mitomycin C
Triethylene thiophosphoramide (thiotepa)
Nitrosoureas
Carmustine (BCNU)
Lomustine (CCNU)
Semustine (MeCCNU)
Streptozocin
Miscellaneous DNA-binding agents
Carboplatin
Cisplatin
Dacarbazine (DTIC)
Hexamethylmelamine
Procarbazine
Antitumor antibiotics
Bleomycin
Dactinomycin (actinomycin D)
Daunorubicin
Doxorubicin
Idarubicin
Plicamycin (mithramycin)
Antimetabolites
Folate analogues
Methotrexate
Purine analogues
Azathioprine
Mercaptopurine
Thioguanine
Cladribine (2-chlorodeoxyadenosine)
Fludarabine
Pentostatin
Pyrimidine analogues
Capecitabine
Cytarabine
Floxuridine
Gemcitabine
Ribonucleotide reductase inhibitors
Hydroxyurea
Plant alkaloids
Vinca alkaloids
Vinblastine
Vincristine
Vindesine
Vinorelbine
Epipodophyllotoxins
Etoposide
Teniposide
Taxanes
Paclitaxel
Docetaxel
Miscellaneous agents
Asparaginase
Estramustine
Mitotane
18. Which of the following molecularly targeted therapies is directed against the HER2 gene?
A. Cetuximab
B. Sunitinib
C. Trastuzumab
D. Temsirolimus
Answer: C
(See Schwartz 9th ed., p. 263, and Table 10-10.)
TABLE 10-10 Selected FDA-approved targeted therapies
