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1. A 25-year-old man presents 1 week after discovering that
his left testicle is twice the normal size. Physical examination
reveals a nontender, testicular mass that cannot be transilluminated.
Serum levels of alpha-fetoprotein and human
chorionic gonadotropin are normal. A hemiorchiectomy is
performed, and histologic examination of the surgical specimen
shows embryonal carcinoma. Compared to normal
adult somatic cells, this germ cell neoplasm would most
likely show high levels of expression of which of the following
(A) Desmin
(B) Dystrophin
(C) Cytochrome c
(D) P selectin
(E) Telomerase


The answer is E: Telomerase.

Somatic cells do not normally
express telomerase, which is an enzyme that adds repetitive
sequences to maintain the length of the telomere. Thus, with
each round of somatic cell replication, the telomere shortens.
The length of telomeres may act as a “molecular clock” and
govern the lifespan of replicating cells. Because cancer cells
and embryonic cells express high levels of telomerase, the
reactivation of this enzyme may be important for maintaining
stem cell proliferation. Most human cancers show activation
of the gene for the catalytic subunit of telomerase: human
telomerase reverse transcriptase. P selectin (choice D) is a cell
adhesion molecule that mediates the margination of neutrophils
during acute infl ammation. The other choices are not
involved in malignant transformation.
Diagnosis: Embryonal carcinoma


A 25-year-old woman presents for a gynecologic examination.
The cervical Pap smear shows “koilocytic atypia” characterized
by perinuclear halos and wrinkled nuclei (shown in
the image). A cervical biopsy reveals invasive squamous cell
carcinoma. Molecular tests for human papillomavirus (HPV)
in the tumor cells are positive. Which of the following mechanisms
of disease best explains the role of HPV in the pathogenesis
of neoplasia in this patient?

A) Activation of cellular oncogenes
(B) Enhanced transcription of telomerase gene
(C) Episomal viral replication
(D) Inactivation of tumor suppressor proteins
(E) Insertional mutagenesis


The answer is D: Inactivation of tumor suppressor proteins.
Unlike RNA tumor viruses, whose oncogenes have
normal cellular counterparts, the transforming genes of DNA
viruses are not homologous with any cellular genes. This
conundrum was resolved with the discovery that the gene
products of oncogenic DNA viruses inactivate tumor suppressor
proteins. For example, proteins encoded by the E6 and
E7 genes of HPV16 bind p53 and pRb. The other choices are
involved in the pathogenesis of neoplasia, but they are not
specifi c for HPV.
Diagnosis: Cervical intraepithelial neoplasia, HPV infection


3. The patient described in Question 2 undergoes a hysterectomy.
In addition to a focus of invasive carcinoma, the pathologist
identifi es dysplastic squamous cells occupying the entire
thickness of the cervical epithelium, with no evidence of epithelial
maturation. The basal membrane in these areas appears
intact. Which of the following terms best describes this cervical
(A) Atypical hyperplasia
(B) Carcinoma in situ
(C) Carcinomatosis
(D) Complex hyperplasia
(E) Koilocytic atypia


The answer is B: Carcinoma in situ. Most carcinomas begin
as localized growths confi ned to the epithelium in which they
arise. As long as these early cancers do not penetrate the basement
membrane on which the epithelium rests, such tumors
are labeled carcinoma in situ. When the in situ tumor acquires
invasive potential and extends directly through the underlying
basement membrane, it is in a position to compromise
neighboring tissues and metastasize. Carcinomatosis (choice
C) is a clinical term used to describe widespread dissemination
of cancer. Koilocytosis (choice E) implies the presence of
squamous cells with perinuclear halos and nuclear changes. It
is indicative of human papillomavirus infection and carries an
increased risk of carcinoma. Atypical and complex hyperplasia
(choices A and D) refer to proliferative lesions of the glands
within the uterine endometrium.
Diagnosis: Cervical carcinoma, carcinoma in situ


4 A 62-year-old woman presents with a breast lump that she discovered
6 days ago. A breast biopsy shows lobular carcinoma
in situ. Compared to normal epithelial cells of the breast lobule,
these malignant cells would most likely show decreased
expression of which of the following proteins?
(A) Desmin
(B) E-cadherin
(C) Lysyl hydroxylase
(D) P selectin
(E) Telomerase


The answer is B: E-cadherin. Cadherins are Ca2+-dependent
transmembrane glycoproteins that mediated cell–cell adhesion.
E-cadherin is expressed on the surface of all epithelia
and mediates cell adhesion by “zipper-like” interactions.
Overall, cadherins suppress invasion and metastasis. Thus, it
is perhaps not surprising that the expression of E-cadherin is
reduced in most carcinomas. Desmin (choice A) is an intermediate
fi lament protein found in cells of mesenchymal origin.
Lysyl hydroxylase (choice C) is involved in the posttranslational
modifi cation of collagen. P selectin is a cell adhesion
molecule that mediates the margination of neutrophils during
acute infl ammation. Telomerase (choice E) is increased in certain
Diagnosis: Breast cancer


5 An 80-year-old man complains of lower abdominal pain,
increasing weakness, and fatigue. He has lost 16 lb (7.3 kg)
in the past 6 months. The prostate-specifi c antigen test is
elevated (8.5 ng/mL). Rectal examination reveals an enlarged
and nodular prostate. A needle biopsy of the prostate discloses
invasive prostatic adenocarcinoma. Histologic grading of
this patient’s carcinoma is based primarily on which of the
following criteria?
(A) Capsular involvement
(B) Extent of regional lymph nodes involvement
(C) Pulmonary metastases
(D) Resemblance to normal tissue of origin
(E) Volume of prostate involved by tumor


The answer is D: Resemblance to normal tissue of origin. To
establish criteria for therapy, many cancers are classifi ed
according to histologic grading schemes or by staging protocols
that describe the extent of spread. Cancer grading refl ects
cellular characteristics. Low-grade tumors are well differentiated,
whereas high-grade tumors lack differentiated features
(anaplasia). The general correlation between cytologic grade
and the behavior of a neoplasm is not invariable. Indeed, there
are many examples of tumors of low cytologic grades that
exhibit substantial malignant properties. The other choices
pertain to cancer staging.
Diagnosis: Prostate cancer


A 50-year-old woman presents with a lump in her breast.
A 4-cm fi rm and fi xed mass is noted on breast examination.
Excisional biopsy reveals malignant cells that form glandlike
structures and solid nests, surrounded by a dense collagenous
stroma. A connective tissue stain (trichrome) of
the biopsy is shown in the image. Which of the following
descriptive terms best describes the blue areas observed in
this specimen?

(A) Colloid carcinoma
(B) Comedocarcinoma
(C) Desmoplastic change
(D) Medullary carcinoma
(E) Papillomatosis


The answer is C: Desmoplastic change. Secondary descriptors
are used to refer to a tumor’s morphologic and functional
characteristics. Papillomatosis (choice E) describes frond-like structures. Medullary (choice D) signifi es a soft cellular tumor,
whereas scirrhous or desmoplastic implies dense fi brous
stroma. Colloid carcinomas (choice A) secrete abundant
mucus. Comedocarcinoma (choice B) is an intraductal neoplasm
in which necrotic material can be expressed from the
Diagnosis: Breast cancer


7 A 65-year-old man complains of muscle weakness and a dry
cough for 4 months. He has smoked two packs of cigarettes
daily for 45 years. A chest X-ray shows a 4-cm central, left
lung mass. Laboratory studies reveal hyperglycemia and
hypertension. A transbronchial biopsy is diagnosed as small
cell carcinoma. Metastases to the liver are detected by CT scan.
Which of the following might account for the development of
hyperglycemia and hypertension in this patient?
(A) Adrenal metastases
(B) Paraneoplastic syndrome
(C) Pituitary adenoma
(D) Pituitary metastases
(E) Thrombosis of the renal artery


The answer is B: Paraneoplastic syndrome. Cancers may produce
remote effects, collectively termed paraneoplastic syndromes.
For example, the secretion of corticotropin (ACTH)
by a tumor leads to clinical features of Cushing syndrome,
including hyperglycemia and hypertension. Corticotropin
production is most commonly seen with cancers of the lung,
particularly small cell carcinoma. Adrenal and pituitary metastases
(choices A and D) would lead to loss of adrenal function
(Addison disease). Although pituitary adenoma (choice C) is
a possible cause of Cushing syndrome, this choice would be
unlikely in a patient with lung cancer.
Diagnosis: Small cell carcinoma of lung, paraneoplastic


8 A 60-year-old man presents with a 4-month history of increasing
weight loss, wheezing, and shortness of breath. He has
smoked two packs of cigarettes a day for 40 years. His past
medical history is signifi cant for emphysema and chronic
bronchitis. A chest X-ray shows a 10-cm mass in the left lung.
Bronchoscopy discloses obstruction of the left main stem
bronchus. A biopsy is obtained (shown in the image). Immunohistochemical
studies of this biopsy specimen would most
likely show strong expression of which of the following tumor

(A) Alpha-fetoprotein
(B) Calretinin
(C) Carcinoembryonic antigen
(D) Cytokeratins
(E) Synaptophysin

The answer is D: Cytokeratins. Tumor markers are products
of malignant neoplasms that can be detected in cells or body
fl uids. Useful tumor markers include immunoglobulins, fetal
proteins, enzymes, hormones, and cytoskeletal proteins. Carcinomas
uniformly express cytokeratins, which are intermediate
fi laments. Alpha-fetoprotein (choice A) is a marker for
yolk sac carcinoma and hepatocellular carcinoma. Calretinin
(choice B) provides a marker for mesothelioma. Carcinoembryonic
antigen (choice C) is a marker for colon carcinoma
and many other malignancies. Synaptophysin (choice E) is a
marker for neuroendocrine tumors, including small cell carcinoma
of the lung.
Diagnosis: Squamous cell carcinoma of lung


9 Which of the following potent carcinogens was most likely
involved in the pathogenesis of lung cancer in the patient
described in Question 8?
(A) Afl atoxin B1
(B) Asbestos
(C) Azo dyes
(D) Polycyclic aromatic hydrocarbons
(E) Vinyl chloride


The answer is D: Polycyclic aromatic hydrocarbons. Polycyclic
aromatic hydrocarbons, originally derived from coal tar, are
among the most extensively studied carcinogens. These compounds
produce cancers at the site of application. Since polycyclic
hydrocarbons have been identifi ed in cigarette smoke,
it has been suggested (but not proved) that they are involved
in the pathogenesis of lung cancer. Afl atoxin B1 (choice A), a
natural product of the fungus Aspergillus fl avus, is among the
most potent liver carcinogens. Asbestos (choice B), a mineral,
is associated with mesothelioma and adenocarcinoma of lung.
Industrial workers exposed to high levels of vinyl chloride
(choice E) in the ambient atmosphere developed angiosarcomas
of the liver.
Diagnosis: Squamous cell carcinoma of lung


10 A 33-year-old woman discovers a lump in her left breast on
self-examination. Her mother and sister both had breast cancer.
A mammogram demonstrates an ill-defi ned density in
the outer quadrant of the left breast, with microcalcifi cations.
Needle aspiration reveals the presence of malignant, ductal
epithelial cells. Genetic screening identifi es a mutation in
BRCA1. In addition to cell cycle control, BRCA1 protein promotes
which of the following cellular functions?
(A) Apoptosis
(B) Cell adhesion
(C) DNA repair
(D) Gene transcription
(E) Transmembrane signaling


The answer is C: DNA repair. Breast (BR) cancer (CA) susceptibility
genes (BRCA1 and BRCA2) encode tumor suppressor
proteins involved in checkpoint functions related to progression
of the cell cycle into S phase. BRCA1 and BRCA2 proteins
also promote DNA repair by binding to RAD51, a molecule
that mediates DNA double-strand repair breaks. The other
choices may be abnormal in neoplasia, but they are not primarily
affected by BRCA1.
Diagnosis: Breast cancer


11 A 60-year-old man who worked for 30 years in a chemical
factory complains of blood in his urine. Urine cytology
discloses dysplastic cells. A bladder biopsy demonstrates
transitional cell carcinoma. Which of the following carcinogens
was most likely involved in the pathogenesis of bladder
cancer in this patient?
(A) Aniline dyes
(B) Arsenic
(C) Benzene
(D) Cisplatinum
(E) Vinyl chloride


The answer is A: Aniline dyes. Transitional cell carcinoma is
the most common malignant tumor of the urinary bladder,
and the incidence of bladder cancer is increased in aniline dye
workers. These azo dyes are converted to water-soluble carcinogens
in the liver. They are excreted in the urine, where
they primarily affect the transitional epithelium of the bladder.
Benzene exposure (choice C) is associated with leukemia.
Vinyl chloride exposure (choice E) has been associated with
hepatic angiosarcomas.
Diagnosis: Transitional cell carcinoma of bladder


12. A 60-year-old man presents with an ulcerated, encrusted,
and infi ltrating lesion on the sun-exposed dorsal aspect of a
fi nger (shown in the image). A biopsy reveals squamous cell
carcinoma. The metastatic potential of this neoplasm would
be enhanced by upregulation of the gene for which of the following


The answer is E: Plasminogen activator. Malignant cells and
stromal cells associated with cancers elaborate a variety of proteases
that degrade basement membrane components. Such
enzymes include the urokinase-type plasminogen activator
(u-PA) and matrix metalloproteinases. u-PA converts serum
plasminogen to plasmin, a serine protease that degrades
laminin and activates type IV procollagenase. Changes in the
expression of u-PA, the u-PA receptor, and PA inhibitors have
been reported in different cancers. Metastatic cells would be
expected to show reduced expression of collagens (choice A)
and cadherins (choice C). Desmin (choice B) is found in cells
of mesenchymal origin.
Diagnosis: Squamous cell carcinoma of skin


13 A 45-year-old man presents with a 9-month history of a
reddish nodule on his foot. Biopsy of the nodule discloses
a poorly demarcated lesion composed of fi broblasts and
endothelial-like cells lining vascular spaces. Further work-up
identifi es similar lesions in the lymph nodes and liver. The
tumor cells contain sequences of human herpesvirus-8
(HHV-8). This patient most likely has which of the following
(A) Acquired immunodefi ciency
(B) Ataxia telangiectasia
(C) Li-Fraumeni syndrome
(D) Neurofi bromatosis type I
(E) Xeroderma pigmentosum


The answer is A: Acquired immunodefi ciency. Kaposi sarcoma
is the most common neoplasm associated with
acquired immunodefi ciency syndrome (AIDS). The neoplastic
cells contain sequences of a novel virus, HHV-8, which
is also known as Kaposi sarcoma–associated herpesvirus. In
addition to infecting the spindle cells of Kaposi sarcoma,
HHV-8 is lymphotropic and has been implicated in two
uncommon B-cell lymphoid malignancies, namely, primary
effusion lymphoma and multicentric Castleman disease.
Like other DNA viruses, the HHV-8 genome encodes proteins
that interfere with the p53 and pRb tumor suppressor
pathways. The other choices are hereditary conditions
associated with cancer; however, these patients do not typically
acquire Kaposi sarcoma. The predominant malignancy
seen in patients with ataxia telangiectasia (choice B) is lymphoma/
Diagnosis: Kaposi sarcoma, AIDS


14 During a routine checkup, a 50-year-old man is found to
have blood in his urine. He is otherwise in excellent health.
An abdominal CT scan reveals a 2-cm right renal mass. You
inform the patient that staging of this tumor is key to selecting
treatment and evaluating prognosis. Which of the following is
the most important staging factor for this patient?
(A) Histologic grade of the tumor
(B) Metastases to regional lymph nodes
(C) Proliferative capacity of the tumor cells
(D) Somatic mutations in the p53 tumor suppressor gene
(E) Tumor cell karyotype (aneuploidy)


The answer is B: Metastases to regional lymph nodes. The
choice of surgical approach or treatment modalities is infl uenced
more by the stage of a cancer than by its cytologic
grade. The signifi cant criteria used for staging vary with
different organs. Commonly used criteria include (1) tumor
size, (2) extent of local growth, (3) presence of lymph node
metastases, and (4) presence of distant metastases. The other
choices refl ect grade of the tumor.
Diagnosis: Renal cell carcinoma


15 A 68-year-old man who has worked in a shipyard and manufacturing
plant all his adult life complains of a 4-month history
of chest discomfort, malaise, fever, night sweats, and weight
loss. A chest X-ray reveals a large pleural effusion. The patient
dies 5 months later of cardiorespiratory failure. The lung at
autopsy is shown in the image. This malignant neoplasm is associated with environmental exposure to which of the following

A) Afl atoxin B1
(B) Asbestos
(C) Beryllium
(D) Ionizing radiation
(E) Silica


The answer is B: Asbestos. The characteristic tumor associated
with asbestos exposure is mesothelioma of the pleural
and peritoneal cavities. This cancer has been reported to
occur in 2% to 3% of heavily exposed workers. The pipe fi tters
in shipyards were the most exposed workers. Many of
these workers developed mesotheliomas 20 to 40 years after
exposure. It is reasonable to surmise that mesotheliomas of
both the pleura and the peritoneum refl ect the close contact of these membranes with asbestos fi bers transported to them
by lymphatic channels. Like the polycyclic aromatic hydrocarbons,
afl atoxin B1 (choice A) can bind covalently to DNA
and is among the most potent liver carcinogens recognized.
Beryllium (choice C) and silica (choice E) cause lung disease,
but they are not carcinogenic.
Diagnosis: Mesothelioma


16 A 58-year-old woman with colon cancer presents with
3 months of increasing shortness of breath. A chest X-ray
reveals numerous, bilateral, round masses in both lungs. Histologic
examination of an open-lung biopsy discloses malignant
gland-like structures, which are nearly identical to the
colon primary. Which of the following changes in cell behavior
was the fi rst step in the process leading to tumor metastasis
from the colon to the lung in this patient?
(A) Arrest within the circulating blood or lymph
(B) Exit from the circulation into a new tissue
(C) Invasion of the underlying basement membrane
(D) Penetration of vascular or lymphatic channels
(E) Stimulation of angiogenesis within the pulmonary


The answer is C: Invasion of the underlying basement
membrane. The first event in tumor cell invasion is breach
of the basement membrane that separates an epithelium from
the underlying mesenchyme. After invading the interstitial tissue,
malignant cells penetrate lymphatic or vascular channels
(choice D). In the lymph nodes, communications between the
lymphatics and venous tributaries allow malignant cells access
to the systemic circulation. The other choices are important
for tumor metastases, but they occur later than basement
membrane invasion.
Diagnosis: Adenocarcinoma of colon


17 A 68-year-old man complains of recent changes in bowel
habits and blood-tinged stools. Colonoscopy reveals a 3-cm
mass in the sigmoid colon. Biopsy of the mass shows infi ltrating
malignant glands. These neoplastic cells have most likely
acquired a set of mutations that cause which of the following
changes in cell behavior?
(A) Decreased cellular motility
(B) Enhanced stem cell differentiation
(C) Increased cell-cell adhesion
(D) Increased susceptibility to apoptosis
(E) Loss of cell cycle restriction point control


The answer is E: Loss of cell cycle restriction point control.
Cancer cells often display loss of cell cycle restriction
point control through mechanisms such as overexpression
of cyclin D1, loss of Cdk inhibitors, or inactivation of the
pRb or p53 proteins. The p53 gene is deleted or mutated in
75% of cases of colorectal cancer and frequently mutated in
numerous other tumors. The p53 protein is a negative regulator
of cell division. Inactivating mutations of p53 cause loss of
cell cycle restriction point control and allow cells with damaged
DNA to progress through the cell cycle. Malignant cells
have increased cellular motility (see choice A), reduced stem
cell differentiation (see choice B), decreased cell adhesion
(see choice C), and decreased susceptibility to apoptosis (see
choice D).
Diagnosis: Adenocarcinoma of colon


18 A 35-year-old woman complains of nipple discharge and irregular
menses of 5 months duration. Physical examination reveals a
milky discharge from both nipples. MRI shows an enlargement
of the anterior pituitary. Which of the following is the most likely
histologic diagnosis of this patient’s pituitary tumor?
(A) Adenoma
(B) Choristoma
(C) Hamartoma
(D) Papilloma
(E) Teratoma


The answer is A: Adenoma. Benign tumors arising from a
glandular epithelium are termed adenomas. Patients with a
prolactin-secreting pituitary adenoma present with amenorrhea
and galactorrhea. Ectopic islands of normal tissue are
called choristomas (choice B). Localized, disordered differentiation
during development results in a hamartoma (choice C).
Papillomas (choice D) do not occur in the pituitary. Benign
tumors that arise from germ cells and contain all three germ
layers are termed teratomas (choice E).
Diagnosis: Pituitary adenoma, prolactinoma


19 A 52-year-old woman presents with a 1-year history of upper
truncal obesity and moderate depression. Physical examination
shows hirsutism and moon facies. A CT scan of the thorax displays
a hilar mass. A transbronchial lung biopsy discloses small
cell carcinoma. Electron microscopy of this patient’s lung tumor
will most likely reveal which of the following cytologic features?
(A) Councilman bodies
(B) Hyperplasia of endoplasmic reticulum
(C) Mitochondrial calcifi cation
(D) Myelin fi gures in lysosomes
(E) Neuroendocrine granules


The answer is E: Neuroendocrine granules. Neuroendocrine
tumors may synthesize a number of hormones. The presence
of small, membrane-bound granules with a dense core is a feature
of these neoplasms. Dense granules are visible by electron
microscopy. In this way, electron microscopy may aid in the
diagnosis of poorly differentiated cancers, whose classifi cation
is problematic by light microscopy. Carcinomas often exhibit
desmosomes and specialized junctional complexes, which
are structures that are not typical of sarcomas or lymphomas.
Myelin fi gures (choice D) are seen in patients with inherited
lysosomal storage disease. Councilman bodies (choice A) are
apoptotic hepatocytes (acidophilic bodies).
Diagnosis: Small cell carcinoma of lung, paraneoplastic


20 Cytogenetic studies in a 40-year-old woman with follicular
lymphoma demonstrate a t(14;18) chromosomal translocation
involving the bcl-2 gene. Constitutive expression of the protein
encoded by the bcl-2 gene inhibits which of the following
processes in this patient’s transformed lymphocytes?
(A) Apoptosis
(B) DNA excision repair
(C) G1-to-S cell cycle progression
(D) Oxidative phosphorylation
(E) Protein (N-linked) glycosylation


The answer is A: Apoptosis. Many human cancers show
abnormalities in the control of apoptosis. For example, follicular
B-cell lymphomas display a characteristic chromosomal
translocation in which the bcl-2 gene is brought under
the transcriptional control of the immunoglobulin light-chain
gene promoter, thereby causing overexpression of bcl-2. As a
result of the antiapoptotic properties of bcl-2, the neoplastic
clone accumulates in lymph nodes. Since its demonstration
in follicular lymphomas, bcl-2 expression has been observed
in a variety of other human cancers. None of the other choices
describes the function of bcl-2.
Diagnosis: Follicular lymphoma


21. A 60-year-old man presents with a 6-month history of increasing
weight loss and fatigue. Physical examination reveals conspicuous
hepatomegaly. An abdominal CT scan reveals multiple
“canon ball” nodules in the liver (shown in the image). A CTguided
biopsy reveals a mucous-secreting adenocarcinoma.
This patient’s metastatic liver cancer most likely originated in
which of the following anatomic locations?

(A) Adrenal medulla
(B) Bone marrow
(C) Brain
(D) Pancreas
(E) Urinary bladder


The answer is D: Pancreas. Radiologic evidence of “canon
ball” lesions in the liver or lung suggests metastatic cancer.
The liver is involved in a third of all metastatic cancers, including
half of those of the gastrointestinal tract, breast, and lung.
Other tumors that characteristically metastasize to the liver
are pancreatic carcinoma and malignant melanoma. Liver
metastases are the most common cause of massive hepatomegaly.
Visible secretions of tumor cells, such as mucin or
serous fl uid, provide important clues for tumor diagnosis.
Mucin-secreting glandular epithelium and mucin-secreting
adenocarcinoma are expected in the pancreas. None of the
other organs are composed of glandular epithelial cells or produce
Diagnosis: Metastatic cancer


22 A 59-year-old woman presents with increasing pigmentation
of the skin. Physical examination shows hyperkeratosis and
hyperpigmentation of the axilla, neck, fl exures, and anogenital
region. Endocrinologic studies reveal normal serum levels
of adrenal corticosteroids and glucocorticoids. If this patient’s
skin pigmentation represents a paraneoplastic syndrome, the
primary tumor would most likely be found in which of the
following anatomic locations?
(A) Bladder
(B) Cervix
(C) Esophagus
(D) Pleura
(E) Stomach

The answer is E: Stomach. Acanthosis nigricans is a cutaneous
disorder marked by hyperkeratosis and pigmentation
of the axilla, neck, fl exures, and anogenital region. It is of
particular interest because more than half of patients with
acanthosis nigricans have cancer. Over 90% of cases occur in
association with gastrointestinal carcinomas (primarily stomach
cancer). The other tumors are uncommon causes of acanthosis
Diagnosis: Paraneoplastic syndrome, acanthosis nigricans


23 A 65-year-old man dies after a protracted battle with metastatic
colon carcinoma. At autopsy, the liver is fi lled with
multiple nodules of cancer, many of which display central
necrosis (umbilication). Which of the following best explains
the pathogenesis of tumor umbilication in this patient?
(A) Biphasic tumor
(B) Chronic infl ammation
(C) Granulomatous infl ammation
(D) Ischemia and infarction
(E) Stimulation of angiogenesis


The answer is D: Ischemia and infarction. Angiogenesis is a
requirement for the continued growth of cancers, whether primary
or metastatic. In the absence of new vessels to supply the
nutrients and remove waste products, malignant tumors do
not grow larger than 1 to 2 mm in diameter. In general, causes
of tumor cell death in situ include (1) programmed cell death
(apoptosis); (2) inadequate blood supply, with consequent
ischemia; (3) a paucity of nutrients; and (4) vulnerability to
specifi c and nonspecifi c host defenses. The CT scan provided
for Question 21 shows central necrosis (umbilication) in most
of the metastatic tumor nodules. None of the other choices are
likely causes of tumor necrosis.
Diagnosis: Metastatic cancer


24 A 59-year-old man complains of progressive weakness. He
reports that his stools are very dark. Physical examination
demonstrates fullness in the right lower quadrant. Laboratory
studies show iron defi ciency anemia, with a serum hemoglobin
level of 7.4 g/dL. Stool specimens are positive for occult
blood. Colonoscopy discloses an ulcerating lesion of the
cecum. Which of the following serum tumor markers is most
likely to be useful for following this patient after surgery?
(A) Alpha-fetoprotein
(B) Carcinoembryonic antigen
(C) Chorionic gonadotropin
(D) Chromogranin
(E) Coagulation factor VIII


The answer is B: Carcinoembryonic antigen (CEA). Colorectal
cancer is asymptomatic in its initial stages. As the tumor
grows, the most common sign is occult blood in feces,
especially when the tumor is in the proximal portion of the
colon. Chronic, asymptomatic bleeding typically causes
iron- defi ciency anemia. Adenocarcinomas of the colon usually
express CEA, a glycoprotein that is released into the circulation
and serves as a serologic marker for these tumors. CEA is also found in association with malignant tumors of
the pancreas, lung, and ovary. AFP (choice A) is expressed by
hepatocellular carcinoma and yolk sac tumors. Chromogranin
(choice D) is expressed by neuroendocrine tumors. Chorionic
gonadotropin (choice C) is secreted by choriocarcinoma.
Diagnosis: Colon cancer


25 Laboratory studies of the surgical specimen obtained from the
patient described in Question 24 demonstrate hypermethylation
of the p53 gene. Which of the following best characterizes
this biochemical change in the neoplastic cells?
(A) Epigenetic modifi cation
(B) Gene amplifi cation
(C) Insertional mutagenesis
(D) Nonreciprocal translocation
(E) Protooncogene mutation


The answer is A: Epigenetic modifi cation. Hypermethylation
of many tumor suppressor and DNA repair genes has been
demonstrated in human tumors. The pathways controlled by
these genes are, therefore, suppressed. For example, the normal
p53 gene can be inactivated by hypermethylation. Thus,
aberrant methylation of tumor suppressor genes may be an
epigenetic mechanism for a “second hit,” leading to loss of
heterozygosity. Unlike genetic changes in cancer, epigenetic
changes are reversible, and a search for drugs that infl uence
DNA methylation is under way. The other choices are unrelated
to DNA methylation.
Diagnosis: Colon cancer


26 A 20-year-old woman has an ovarian tumor removed. The
surgical specimen is 10 cm in diameter and cystic. The cystic
cavity is found to contain black hair and sebaceous material.
Histologic examination of the cyst wall reveals a variety of
benign differentiated tissues, including skin, cartilage, brain,
and mucinous glandular epithelium. What is the diagnosis?
(A) Adenoma
(B) Chondroma
(C) Hamartoma
(D) Teratocarcinoma
(E) Teratoma


The answer is E: Teratoma. Teratomas are benign tumors
composed of tissues derived from all three primary germ layers:
ectoderm, mesoderm, and endoderm. They are most common
in the ovary but also occur in the testis and extragonadal
sites. Teratocarcinomas (choice D) are malignant tumors that
harbor embryonal carcinoma stem cells. Adenoma (choice A)
is a benign tumor of epithelial origin. Chondroma (choice B)
is a benign cartilaginous tumor. Hamartoma (choice C) is disorganized
normal tissue.
Diagnosis: Mature teratoma


27 A 42-year-old man presents with upper gastrointestinal bleeding.
Upper endoscopy and biopsy reveal gastric adenocarcinoma.
Which country of the world has the highest incidence
of this malignant neoplasm?
(A) Argentina
(B) Canada
(C) Japan
(D) Mexico
(E) United States




28 An 8-year-old girl with numerous hypopigmented, ulcerated,
and crusted patches on her face and forearms develops
an indurated, crater-like, skin nodule on the back of her left
hand. Biopsy of this skin nodule discloses a squamous cell carcinoma.
Molecular biology studies reveal that this patient has
germline mutations in the gene encoding a nucleotide excision
repair enzyme. What is the appropriate diagnosis?
(A) Ataxia telangiectasia
(B) Hereditary albinism
(C) Li-Fraumeni syndrome
(D) Neurofi bromatosis, type I
(E) Xeroderma pigmentosum


The answer is E: Xeroderma pigmentosum. Xeroderma
pigmentosum is an autosomal recessive disease in which
increased sensitivity to sunlight is accompanied by a high
incidence of skin cancers, including basal cell carcinoma,
squamous cell carcinoma, and malignant melanoma. Several
xeroderma pigmentosum genes are involved in nucleotide
excision of ultraviolet-damaged DNA. Li-Fraumeni syndrome
(choice C) refers to an inherited predisposition to develop
cancers in many organs due to germline mutations of p53.
Ataxia telangiectasia (choice A) features cerebellar degeneration,
immunologic abnormalities, and a predisposition to
cancer. The mutated gene codes for a nuclear phosphoprotein
involved in regulation of the cell cycle and DNA repair.
Patients with hereditary albinism (choice B) are also at high
risk for development of squamous cell carcinoma of the skin,
but they do not have a defect in DNA excision repair. Patients
with neurofi bromatosis (choice D) develop benign cutaneous
neurofi bromas.
Diagnosis: Xeroderma pigmentosum


29 A 59-year-old woman complains of “feeling light-headed” and losing
5 kg (11 lb) in the last month. A CBC reveals a normocytic,
normochromic anemia. The patient subsequently dies of metastatic
cancer. Based on current epidemiologic data for cancer-associated
mortality in women, which of the following is the most likely primary
site for this patient’s malignant neoplasm?
(A) Brain
(B) Breast
(C) Colon
(D) Lung
(E) Urinary bladder


The answer is D: Lung. Lung carcinoma is the cause of most
cancer-related deaths in the United States and Western Europe
in men and women. The second most common cause of death
from cancer in women is breast cancer (choice B). One of the
most common fi ndings in patients with cancer is anemia,
but the mechanism for this paraneoplastic syndrome is not
clear. The anemia is usually normocytic and normochromic,
although iron defi ciency anemia is common in cancers that
bleed into the gastrointestinal tract.
Diagnosis: Lung cancer


30 The parents of a 6-month-old girl palpate a mass on the
left side of the child’s abdomen. Urinalysis shows high levels
of vanillylmandelic acid. A CT scan reveals an abdominal
tumor and bony metastases. The primary tumor is surgically
resected. Histologic examination of the surgical specimen discloses
neuroblastoma. Evaluation of the N-myc protooncogene
in this child’s tumor will most likely demonstrate which of the
following genetic changes?
(A) Chromosomal translocation
(B) Exon deletion
(C) Expansion of a trinucleotide repeat
(D) Frameshift mutation
(E) Gene amplifi cation


The answer is E: Gene amplifi cation. Chromosomal alterations
that result in an increased number of copies of a gene
have been found primarily in solid tumors. Such aberrations
are recognized as (1) homogeneous staining regions (HSRs);
(2) abnormal banding regions on chromosomes; or (3) double
minutes, which are visualized as small, paired cytoplasmic
bodies. In some cases, gene amplifi cation has been shown to
involve protooncogenes. For example, HSRs may be seen in
neuroblastomas and are all derived from the N-myc protooncogene.
The presence of N-myc HSRs is associated with up to
700-fold amplifi cation of this gene and is a marker of advanced
disease with a poor prognosis. Although the other choices are
mechanisms for protooncogene activation, they do not cause
upregulation of N-myc in patients with neuroblastoma.
Diagnosis: Neuroblastoma