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1.40 y/o man with hx of IV drug abuse. Physical shows needle track in left antecubital fossa. He has mild scleral icterus. Serologic studies show HBsAg and anti-HCV positive. He develops hepatocellular carcinoma 15 yrs later. Which of the following viral characteristics best explains why this pt. developed hepatocellular carcinoma?

C) Viral-induced injury followed by extensive hepatocyte regeneration

(C) Although the hepatitis B virus (HBV) and hepatitis C virus (HCV) genomes do not encode for any transforming
proteins, the regenerating hepatocytes are more likely to develop mutations, such as inactivation of p53. HBV does not
have a consistent site of integration in the liver cell nuclei, and it does not contain viral oncogenes. Many DNA viruses,
such as human papillomavirus, inactivate tumor suppressor genes, but there is no convincing evidence that HBV or HCV
can bind to p53 or RB proteins. Also, the HBV-encoded regulatory element, called HBx, disrupts normal growth of infected
hepatocytes. Neither HBV nor HCV infects immune cells.


A 48-year-old woman notices a lump in her left breast. On physical examination, the physician palpates a firm, nonmovable, 2-cm mass in the upper outer quadrant of the left breast. There are enlarged, firm, nontender lymph nodes in the left axilla. A fine-needle aspiration biopsy is performed, and the cells present are consistent with carcinoma. A mastectomy with axillary lymph node dissection is performed, and carcinoma is present in two of eight axillary nodes. Which of the following factors is most likely responsible for the lymph node metastases?

A) increased laminin receptors on tumor receptor cells

(A) Several pathologic mechanisms play a role in the development of tumor metastases. The tumor cells first must
become discohesive and detach from the primary site and then attach elsewhere to become metastases. Tumor cells tend
to have many more laminin receptors than do normal cells, allowing them to attach more readily to basement membranes
at distant sites. Keratin is a marker of epithelial differentiation, not metastatic ability. A reduction in apoptosis allows
greater proliferation, but not metastases. Monoclonality is a feature of neoplasia, but further tumor heterogeneity helps to
increase the chance for metastases to occur. Inflammation probably does not play a major role in metastasis


A 30-year-old woman who has had multiple sexual partners sees her physician because she has had vaginal bleeding and discharge for the past 5 days. On physical examination, she is afebrile. Pelvic examination shows an ulcerated lesion arising from the squamocolumnar junction of the uterine cervix. A cervical biopsy is performed. Microscopic examination reveals an invasive tumor containing areas of squamous epithelium, with pearls of keratin. In situ hybridization shows the presence of human papillomavirus type 16 (HPV-16) DNA within the tumor cells. Which of the following molecular abnormalities in this tumor is most likely related to infection with HPV-16?

D) Functional inactivation of the RB1 protein


(D) The oncogenic potential of human papillomavirus (HPV), a sexually transmissible agent, is related to products of two
early viral genes—E6 and E7. E7 binds to RB protein to cause displacement of normally sequestered transcription factors,
which nullifies tumor suppressor activity of the RB protein. E6 binds to and inactivates the p53 gene product. Trapping of
GTP-bound RAS protein can occur in many tumors but is not related to HPV infection. Laminin receptor expression
correlates with metastatic potential of a malignant neoplasm. Inability to repair DNA damage plays a role in some colon
and skin cancers. Increased epidermal growth factor receptor expression is a feature seen in many pulmonary squamous
cell carcinomas, and the related ERBB2 (HER2) receptor is seen in some breast carcinomas.


4. An experiment involving carcinoma cells grown in culture studies the antitumor surveillance effects of the innate immune system. These carcinoma cells fail to express MHC class I antigens. It is observed, however, that carcinoma cells are lysed in the presence of one type of immune cell that has been activated by IL-2. Which of the following immune cells is most likely to function in this manner?

□ (A) CD4+ lymphocyte

□ (B) CD8+ lymphocyte

□ (C) Macrophage

□ (D) Neutrophil □

(E) NK cell □

(F) Plasma cell

NK cells

(E) Several types of immune cells can recognize and help destroy tumor cells. Tumor antigens that are displayed via
MHC class I molecules can be recognized by cytotoxic CD8+ cells. Many cancers do not display their antigens well,
however, and when MHC class I molecules are not displayed, NK cells are triggered to target these cells for lysis.
Macrophages may work in concert with CD8+ cells and NK cells to phagocytize and kill tumor cells when up-regulated by
interferon-γ. CD4+ “helper” cells do not play a direct anticancer role. Neutrophils are ineffective against cancer cells, but
may be attracted to areas of tumor necrosis. Plasma cells may produce antibodies directed against tumor antigens, but
such antibodies are ineffective in controlling tumors.


A 44-year-old woman sees her physician because she feels lumps in the right axilla. The physician notes right axillary
lymphadenopathy on physical examination. The nodes are painless but firm. Which of the following is the most likely
□ (A) Ductal carcinoma of the breast
□ (B) Acute mastitis with breast abscess
□ (C) Leiomyosarcoma of the uterus
□ (D) Cerebral glioblastoma multiforme
□ (E) Squamous dysplasia of the larynx


A) Ductal carcinoma of the breast


A) Lymphatic spread, especially to regional lymph nodes draining from the primary site, is typical of a carcinoma.
Infection from a breast abscess can spread to the lymph nodes, but the resulting nodal enlargement is typically associated
with pain—a cardinal sign of acute inflammation. Sarcomas uncommonly metastasize to lymph nodes. Central nervous
system (CNS) malignancies rarely metastasize outside of the CNS. Dysplasias do not metastasize because they are not


A 20-year-old man has a raised, irregular, pigmented lesion on his forearm that has increased in size and become more
irregular in color over the past 4 months. Physical examination shows a 0.5 × 1.2 cm black-to-brown lesion with irregular
borders. An excisional biopsy specimen shows a malignant melanoma that extends into the reticular dermis. Family history
indicates that the patient's paternal uncle died of metastatic melanoma that spread to the liver after excision of a primary
lesion on the foot. His grandfather required enucleation of the left eye because of a “dark brown” mass in the eyeball.
Which of the following genes is most likely to have undergone mutation to produce these findings?
□ (A) BCL2 (anti-apoptosis gene)
□ (B) C-MYC (transcription factor gene)
□ (C) IL2 (growth factor gene)
□ (D) Lyn (tyrosine kinase gene)
□ (E) p16 (cell cycle inhibition)
□ (F) p53 (DNA damage response gene)
□ (G) PDGF (growth factor overexpression)


p16 - cell cycle inhibition


(E) This patient has a family history of malignant melanoma. Familial tumors often are associated with inheritance of a
defective copy of one of several tumor suppressor genes. In the case of melanomas, the implicated gene is called p16, or
INK4a. The product of the p16 gene is an inhibitor of cyclin-dependent kinases. With loss of control over cyclin-dependent
kinases, the cell cycle cannot be regulated, favoring neoplastic transformation. BCL2 is present in some lymphoid
neoplasms. The C-MYC gene is mutated in various carcinomas, but is not known to be specifically associated with
melanomas. The IL2 mutation is associated with some T cell neoplasms. The Lyn mutation is seen in some
immunodeficiency states. p53 mutations occur in many cancers, but not specifically in familial melanomas. PDGF can be
overexpressed in some central nervous system gliomas and some osteosarcomas


A 32-year-old woman has experienced dull pelvic pain for the past 2 months. Physical examination shows a right adnexal
mass. An abdominal ultrasound scan shows a 7.5-cm cystic ovarian mass. The mass is surgically excised. The surface of
the mass is smooth, and it is nonadherent to surrounding pelvic structures. On gross examination, the mass is cystic and
filled with hair. Microscopically, squamous epithelium, tall columnar glandular epithelium, cartilage, and fibrous connective
tissue are present. Which of the following is the most likely diagnosis?
□ (A) Adenocarcinoma
□ (B) Fibroadenoma
□ (C) Glioma
□ (D) Hamartoma
□ (E) Mesothelioma
□ (F) Rhabdomyosarcoma
□ (G) Teratoma



(G) A teratoma is a neoplasm derived from totipotential germ cells that differentiate into tissues that represent all three germ layers: ectoderm, endoderm, and mesoderm. When the elements all are well differentiated, the neoplasm is “mature”
(benign). Adenocarcinomas have malignant-appearing glandular elements. Fibroadenomas have a benign glandular and
stromal component; they are common in the breast. Gliomas are found in the central nervous system. Hamartomas contain
a mixture of cell types common to a tissue site; the lung is one site for this uncommon lesion. A mesothelioma arises from
the lining of thoracic and abdominal body cavities. A rhabdomyosarcoma comprises cells that poorly resemble striated
muscle; most arise in soft tissues.


A 30-year-old man has a 15-year history of increasing numbers of multiple benign skin nodules. On physical
examination, the firm nodules average 0.5 to 1 cm and appear to be subcutaneous. Further examination shows numerous
oval 1- to 5-cm pigmented skin lesions. Ophthalmoscopic examination shows hamartomatous nodules on the iris. A biopsy
specimen of one skin nodule shows a neoplasm that is attached to a peripheral nerve. Which of the following mechanisms
of transformation is most likely related to the mutation that this patient has inherited?
□ (A) Persistent activation of the RAS gene
□ (B) Increased production of epidermal growth factor
□ (C) Decreased susceptibility to apoptosis
□ (D) Impaired functioning of mismatch repair genes
□ (E) Inactivation of the RB gene


A) persistent activation of the RAS gene


(A) This patient has clinical features of neurofibromatosis type 1. The NF1 gene encodes a GTPase-activating protein
that facilitates the conversion of active (GTP-bound) RAS to inactive (GDP-bound) RAS. Loss of NF1 prevents such
conversion and traps RAS in the active signal-transmitting stage. All other listed mechanisms also are involved in
carcinogenesis, but in different tumors.


A study of patients treated with chemotherapy protocols for cancer shows that 10% of them subsequently develop a
second cancer, a much higher incidence compared with a control group not receiving chemotherapy. These chemotherapy
protocols included the alkylating agent cyclophosphamide. What is the most likely mechanism of action by this alkylating
agent for development of the subsequent carcinomas in these treated cancer patients?
□ (A) Activation of protein kinase C
□ (B) Activation of endogenous viruses
□ (C) Blockage of TGF-β pathways
□ (D) Direct DNA damage
□ (E) Inhibition of DNA repair
□ (F) Inhibition of telomerase


d) direct DNA damage


(D) Chemical carcinogens have highly reactive electrophile groups that can directly damage DNA, leading to mutations.
Direct-acting agents, such as alkylating chemotherapy drugs, do not require conversion to a carcinogen. Some agents,
such as polycyclic hydrocarbons, require metabolic conversion to a carcinogen and are called indirect-acting agents.
Phorbol esters are examples of promoters of chemical carcinogenesis that cause tumor promotion by activating protein
kinase C. This enzyme phosphorylates several substrates in signal transduction pathways, including those activated by
growth factors, and the cells divide. Forced cell division predisposes the accumulation of mutations in cells previously
damaged by exposure to a mutagenic agent (initiator). The TGF-β pathways work via growth inhibition. Proteins such as
p53 that function in DNA repair pathways can become nonfunctional through mutation. Viral infections such as hepatitis B
and C tend to promote growth by binding to p53 and inactivating its protective function. Telomerase activity is not affected
by carcinogens.


50-year-old woman undergoes screening colonoscopy as part of a routine health maintenance workup. An isolated 1-
cm pedunculated polyp is found in the sigmoid colon. The excised polyp histologically shows well-differentiated glands
with no invasion of the stalk. Which of the following investigational research procedures can distinguish most clearly
whether the polyp represents hyperplasia of the colonic mucosa or a tubular adenoma?
□ (A) Histochemical staining for mucin
□ (B) Flow cytometry to determine the frequency of cells in the S phase
□ (C) Determination of clonality by pattern of X chromosome inactivation
□ (D) Immunoperoxidase staining for keratin
□ (E) Immunoperoxidase staining for factor VIII


C) Determination of clonality by pattern of X chromosome inactivation


(C) A true neoplasm is a monoclonal proliferation of cells, whereas a reactive proliferation of cells is not monoclonal.
Reactive and neoplastic cellular proliferations may have similar histochemical and immunohistochemical staining patterns
based on the type of cells that are present. Flow cytometry is effective at indicating the DNA content, aneuploidy, and
growth fraction, but does not indicate clonality


A 66-year-old woman has worked all of her life on a small family farm on the Kanto plain near Tokyo. She has had no
previous major illnesses, but has been feeling increasingly tired and weak for the past year. On physical examination, she
Robbins & Cotran Review of Pathology Pg. 101
is afebrile, but appears pale. Laboratory studies show hemoglobin, 11.3 g/dL; hematocrit, 33.8%; platelet count,
205,200/mm3; and WBC count, 64,000/mm3. Immunophenotyping yields the findings shown in the figure. Assuming that the
dominant cell population is clonal, which of the following viral agents is most likely involved in this patient's disease
□ (A) Human papillomavirus
□ (B) HIV-1
□ (C) Epstein-Barr virus
□ (D) Human T cell lymphotropic virus type 1
□ (E) Hepatitis B virus

d) Human T cell lymphotropic virus type 1


(D) The largest cell population, determined to be clonal, is marking for CD4. This patient has a T cell leukemia, which
develops in approximately 1% of individuals infected with human T cell lymphotropic virus type 1. Human papillomavirus is
best known for causing squamous epithelial dysplasias and carcinomas. HIV-1 infection causes AIDS. Infection with
Epstein-Barr virus is associated with various cancers, including Burkitt lymphoma and nasopharyngeal carcinoma.
Infection with hepatitis B virus may result in hepatic cirrhosis, in which hepatocellular carcinoma may arise.


A 50-year-old woman saw her physician after noticing a mass in the right breast. Physical examination showed a 2-cm
mass fixed to the underlying tissues beneath the areola and three firm, nontender, lymph nodes palpable in the right axilla.
There was no family history of cancer. An excisional breast biopsy was performed, and microscopic examination showed a
well-differentiated ductal carcinoma. Over the next 6 months, additional lymph nodes became enlarged, and CT scans
showed nodules in the lung, liver, and brain. The patient died 9 months after diagnosis. Which of the following molecular
abnormalities is most likely to be found in this setting?
□ (A) Inactivation of one BRCA1 gene copy
□ (B) Deletion of one p53 gene copy
□ (C) Amplification of the ERBB2 (HER2) gene
□ (D) Deletion of an RB gene locus
□ (E) Fusion of BCR and C-ABL genes


c) Amplification of the ERBB2 (HER2) gene


C) Increased expression of ERBB2 (HER2) can be detected immunohistochemically in the biopsy specimen. One third
of breast cancers may show this change. Such amplification is associated with a poorer prognosis. Detection of a specific
gene product in the tissue has value for determination of prognosis. BRCA1 and p53 mutations, if inherited in the germ
line, can predispose the patient to breast cancer and other tumors. With BRCA1, there is family history of breast cancer,
and p53 mutation predisposes to many types of cancers. An inherited deletion of RB gene predisposes to retinoblastoma.
The BCR-ABL fusion product, seen in chronic myeloid leukemia, results from t(9;22).


In a family of five children, a 12-year-old girl and a 14-year-old boy have been affected by skin nodules that have
developed over the past 5 years. On physical examination, both children are of appropriate height and weight. The skin
lesions are 1- to 3-cm maculopapular nodules that are erythematous to brown-colored and have areas of ulceration.
Biopsy specimens of the skin lesions show squamous cell carcinoma. The children have no history of recurrent infections,
and their parents and other relatives are unaffected. Which of the following mechanisms is most likely to produce
neoplasia in these children?
□ (A) Infection with human papillomavirus
□ (B) Failure of nucleotide excision repair of DNA
□ (C) Ingestion of food contaminated with Aspergillus flavus
□ (D) Inactivation of p53
□ (E) Chromosomal translocation


B) Failure of nucleotide excision repair of DNA


(B) The children described in the question have an autosomal recessive condition known as xeroderma pigmentosum.
Affected individuals have extreme photosensitivity, with a 2000-fold increase in the risk of skin cancers. The DNA damage
is initiated by exposure to ultraviolet light; however, nucleotide excision repair cannot occur normally in xeroderma
pigmentosum. Human papillomavirus is a sexually transmitted disease that is associated with the development of genital
squamous cell carcinomas. Aspergillus flavus, found on moldy peanuts and other foods, produces the potent hepatic
carcinogen aflatoxin B1. Inactivation of the p53 tumor suppressor gene is found in many sporadic human cancers and in
some familial cancers, but these cancers are not limited to the skin. Chromosomal translocations are often involved in the
development of hematologic malignancies, although they are not often seen in skin cancers


A 55-year-old man visits the physician because of hemoptysis and worsening cough. On physical examination,
wheezes are auscultated over the right lung posteriorly. A chest radiograph shows a 6-cm perihilar mass on the right. A
fine-needle aspiration biopsy yields cells consistent with non–small cell bronchogenic carcinoma. Molecular analysis of the
neoplastic cells shows a p53 gene mutation. Which of the following mechanisms has most likely produced the neoplastic
□ (A) Inability to hydrolyze GTP
□ (B) Microsatellite instability
□ (C) Lack of necrosis
□ (D) Loss of cell cycle arrest
□ (E) Transcriptional activation

d) Loss of cell cycle arrest


(D) The p53 mutation involving both alleles is one of the most common genetic mutations in human cancers, including
the most common—lung, colon, and breast cancers. The loss of this tumor suppressor indicates that the cell cycle is not
properly arrested in the late G1 phase; when DNA damage occurs, DNA repair cannot be completed before the cell
proliferates. Inability to hydrolyze GTP is a result of RAS oncogene activation. Microsatellite instability occurs with
mutation in genes, such as hMSH2, that repair DNA damage. BCL2 mutation is one of the best-known mechanisms for
apoptotic arrest in neoplasms. Transcriptional activation is a feature of the MYC proto-oncogene.


A 5-year-old child has difficulty with vision in the right eye. On physical examination, there is leukokoria of the right eye,
consistent with a mass in the posterior chamber. MR imaging shows a mass that nearly fills the globe. The child
undergoes enucleation of the right eye. Molecular analysis of the neoplastic cells indicates absence of both copies of a
tumor suppressor gene that controls the transition from the G1 to the S phase of the cell cycle. Which of the following
genes is most likely to have the mechanism of action that produced this neoplasm?
□ (B) BCL2
□ (C) hMSH2
□ (D) K-RAS
□ (E) NF1
□ (F) p53
□ (G) RB




(G) The RB gene is a classic example of the two-hit mechanism for loss of tumor suppression. About 60% of these
tumors are sporadic. Others are familial, and there is inheritance of a mutated copy of the RB gene. Loss of the second
copy in retinoblasts leads to the occurrence of retinoblastoma in childhood. Researchers do not know why patients who
inherit a mutant RB gene through the germline develop retinoblastoma rather than other types of tumors. The RB gene
controls the G1 to S transition of the cell cycle; with loss of both copies, this important checkpoint in the cell cycle is lost.
The BCR-ABL fusion gene in chronic myelogenous leukemia is an example of overexpression of a gene product producing
neoplasia. The BCL2 gene is an inhibitor of apoptosis. The hMSH2 gene is present in most cases of hereditary
nonpolyposis colon cancer and functions in DNA repair. Many cancers have the K-RAS gene, which acts as an oncogene.
The NF1 gene product acts as a tumor suppressor; this is a component of neurofibromatosis (which usually does not
involve the eye), and the neoplasms typically appear at a later age. Many cancers have the p53 tumor suppressor gene
mutation, but this is not typical of childhood ocular neoplasms.


A 60-year-old man comes to his physician because he has noted a mass in his neck that has increased rapidly in size
over the past 2 months. On physical examination, a firm, nontender, 10-cm mass in the left lateral posterior neck that
appears to be fused to cervical lymph nodes is palpated. Hepatosplenomegaly is noted. A head CT scan reveals a mass in
the Waldeyer ring near the pharynx. A biopsy of the neck mass is performed, and on microscopic examination the biopsy
specimen shows abnormal lymphoid cells with many mitotic figures and many apoptotic nuclei. The patient is treated with
a cocktail of cell cycle–acting chemotherapeutic agents. The cervical and oral masses shrink dramatically over the next
month. Based on his history and response to treatment, the tumor cells are most likely to have which of the following
□ (A) Limited capacity to metastasize
□ (B) Polyclonality
□ (C) Poor vascularity
□ (D) High growth fraction
□ (E) Strong expression of tumor antigens


D) High growth fraction


(D) Some neoplasms, including certain lymphomas, have a high proportion of cells in the replicative pool (i.e., have
high growth fraction). They grow rapidly and respond rapidly to drugs that kill dividing cells. Monoclonality rather than
polyclonality is typical of malignant tumors. Similarly, poor vascularity would not favor rapid growth. Tumors that are highly
antigenic are likely to be controlled by the immune system and not to be rapidly growing.


A 58-year-old woman has experienced an increasing feeling of fullness in the neck for the past 3 months, and she has
noted a 3-kg weight loss during that time. On physical examination, there is a firm, fixed mass in a 3 × 5 cm area in the
right side of the neck. CT scan shows a solid mass in the region of the right lobe of the thyroid gland. A biopsy of the mass
is performed; the microscopic appearance of the specimen is shown in the figure. All areas of the tumor have similar
morphology. Which of the following terms best describes this neoplasm?
□ (A) Adenoma
□ (B) Well-differentiated adenocarcinoma
□ (C) Squamous cell carcinoma
Robbins & Cotran Review of Pathology Pg. 103
□ (D) Leiomyoma
□ (E) Anaplastic carcinoma

E) Aplastic carcinoma


(E) The cells shown in the figure show marked pleomorphism and hyperchromatism (anaplasia). A bizarre tripolar
mitotic figure is present. This degree of anaplasia is consistent with a malignancy. An adenoma is a benign tumor of
glandular origin. Adenocarcinomas and squamous cell carcinomas show differentiation into glandular or squamous tissues.
Leiomyomas are benign mesenchymal tumors of smooth muscle origin.


59-year-old man has recently noticed blood in his urine. Cystoscopy shows a 4-cm exophytic mass involving the right
bladder mucosa near the trigone. Biopsy specimens are obtained, and the patient undergoes a radical cystectomy.
Examination of the excised specimen shows that a grade IV urothelial cell carcinoma has infiltrated the bladder wall. Which
of the following statements regarding these findings is most appropriate?
□ (A) The neoplasm is a metastasis
□ (B) The patient has a poorly differentiated neoplasm
□ (C) A paraneoplastic syndrome is likely
□ (D) The stage of the neoplasm is low
□ (E) The patient is probably cured of the cancer


B) Pt. has a poorly differentiated neoplasm


(B) Cancer grading systems are typically denoted by I to III or I to IV, and increase with worse differentiation (more
anaplasia). A transitional cell carcinoma would be expected at this site. Bladder cancers are not commonly associated with
paraneoplastic syndromes. Infiltration through the wall indicates a high stage. The cure rate for this high-grade, high-stage
cancer is poor. Determination of the presence of metastases is part of staging, not grading.


An epidemiologic study analyzes health care benefits of cancer screening techniques applied to a population. Which of
the following diagnostic screening techniques used in health care is most likely to have had the greatest impact on
reduction in cancer deaths in developed nations?
□ (A) Chest radiograph
□ (B) Stool guaiac
□ (C) Pap smear
□ (D) Serum carcinoembryonic antigen assay
□ (E) Urinalysis


C) Pap smear


(C) Because Pap smear screening can detect dysplasias and in situ carcinomas that can be treated before
progression to invasive lesions, deaths from cervical carcinoma have steadily decreased since this screening method
became widely available in the last half of the 20th century. A chest radiograph is an insensitive technique for detecting
early lung cancers. Use of stool guaiac has had a minimal effect on rates of death from colorectal carcinomas, but
physicians are cautioned not to indicate “rectal deferred” on the physical examination report, and hence contribute to the
problem. Serum tumor markers have not proved useful as general screening techniques, although they are useful in
selected circumstances. Urine cytology is better than urinalysis for detection of urothelial malignancies, but it does not
have a high sensitivity


During a routine health maintenance examination, a 46-year-old man is found to have an enlarged, nontender
supraclavicular lymph node that is palpable on physical examination. The 2-cm node is excised. Histologically, the nodal
architecture is effaced by a monomorphous population of small lymphocytes. Which of the following procedures would best
confirm that the patient has a malignancy?
□ (A) Peripheral WBC count and differential cell count
□ (B) Flow cytometry of nodal tissue for DNA content
□ (C) Electron microscopy to determine cellular ultrastructure
□ (D) Southern blot analysis to show monoclonality
□ (E) Determination of the serum lactate dehydrogenase level


d) Southern blot analysis to show monoclonality


(D) Monoclonality is the hallmark of a malignancy. In the diagnosis of a leukemia, the WBC count is helpful, but not
definitive. The DNA content analysis alone cannot define a malignancy; Southern blot analysis for T-cell or B-cell receptor
gene rearrangements can define monoclonality. Electron microscopy is an adjunct to diagnosis of the type of tumor.
Lactate dehydrogenase levels are often increased with lymphoid proliferations, but are not diagnostic of the type of


21. An epidemiologic study investigates the potential cellular molecular alterations that may contribute to the development
of cancers in a population. Data analyzed from resected colonic lesions show that changes are occurring that show the
evolution of a sporadic colonic adenoma into an invasive carcinoma. Which of the following best describes the mechanism
producing these changes?
□ (A) Activation of proto-oncogenes by chromosomal translocation
□ (B) Stepwise accumulation of multiple proto-oncogene and tumor suppressor gene mutations
□ (C) Extensive regeneration of tissues increasing the mutation rate in regenerating cells
□ (D) Inheritance of defects in DNA repair genes that increase the susceptibility to develop cancer
□ (E) Overexpression of growth factor receptor genes

b) Stepwise accumulation of multiple protooncogene and tumor suppressor gene mutations


(B) Development of colonic adenocarcinoma typically takes years, during which time numerous mutations occur within
the mucosa, including mutations involving such genes as APC (adenomatous polyposis coli), K-RAS, and p53. The
accumulation of mutations, rather than their occurrence in a specific order, is most important in the development of a
carcinoma. Activation of proto-oncogenes, extensive regeneration, faulty DNA repair genes, and amplification of growth
factor receptor genes all contribute to the development of malignancies, but they are not sufficient by themselves to
produce a carcinoma from an adenoma of the colon.


22. A 49-year-old man has a lump near his right shoulder that has been increasing in size for the past 8 months. On
Robbins & Cotran Review of Pathology Pg. 104
physical examination, the physician palpates a 4-cm, firm, nontender mass in the right supraclavicular region. The mass is
excised, and microscopically it is diagnosed as follicular lymphoma. Karyotypic analysis of the cells shows a chromosomal
translocation, t(14;18), involving the immunoglobulin heavy-chain gene. Which of the following genes is most likely to have
undergone mutation to produce these findings?
□ (A) APC (tumor suppressor gene)
□ (B) BCL1 (cyclin gene)
□ (C) BCL2 (anti-apoptosis gene)
□ (D) BRCA1 (DNA repair gene)
□ (E) C-MYC (transcription factor gene)
□ (F) ERBB2 (growth factor receptor gene)
□ (G) IL2 (growth factor gene)
□ (H) K-RAS (GTP-binding protein gene)
□ (I) p53 (DNA damage response gene)

c) BCL2 (anti-apoptosis gene)


C) This is an example of chromosomal translocation that brings BCL2, an anti-apoptosis gene, close to another gene
(immunoglobulin heavy-chain gene). The BCL2 gene becomes subject to continuous stimulation by the adjacent enhancer
element of the immunoglobulin gene, leading to overexpression. The APC gene is mutated in sporadic colon cancers and
cancers associated with familial polyposis coli. The BCL1 gene is mutated in mantle zone lymphoma, with t(11;14) that
brings the cyclin gene on chromosome 11 to the immunoglobulin enhancer gene on chromosome 14. The BRCA1 and
ERBB2 gene mutations are seen in some breast cancers. The IL2 mutation may be present in some T cell neoplasms. KRAS
and p53 mutations are present in many cancers, but not typically lymphoid malignancies.


23. A Pap smear obtained from a 29-year-old woman during a routine health maintenance examination is abnormal. She is
currently asymptomatic, but has a history of multiple sexual partners. Cervical biopsy specimens are obtained. The
representative microscopic appearance of a specimen is shown in the figure. Which of the following is the most likely
□ (A) Adenocarcinoma
□ (B) Carcinoma in situ
□ (C) Dysplasia
□ (D) Hamartoma
□ (E) Melanoma
□ (F) Mesothelioma
□ (G) Small-cell anaplastic carcinoma
□ (H) Squamous cell carcinoma

h) squamous cell carcinoma


(H) Notice on the figure that the disorderly, atypical epithelial cells involve the entire thickness of the epithelium and
extend through the underlying basement membrane, a process known as invasion. The ectocervix and the squamous
metaplasia of endocervix give rise to squamous cell carcinoma. Carcinoma in situ is confined to the epithelium; if the
basement membrane is breached, the lesion is no longer in situ, but rather invasive. An adenocarcinoma is a malignant
neoplasm arising from glandular epithelium, such as the endocervix or endometrium, not the ectocervix. A dysplastic
process could precede development of carcinoma in situ and squamous carcinoma; dysplasia involves only part of the
thickness of the epithelium. A hamartoma contains a mixture of cell types common to a tissue site. Melanomas are
malignant and tend to enlarge quickly; many are darkly pigmented. The benign counterpart to the melanoma is the nevus,
which is quite common; nevi are usually light brown. A mesothelioma arises from the mesodermally derived lining of
thoracic and abdominal body cavities. Small-cell anaplastic carcinomas of the lung are aggressive neoplasms that are
unlikely to be diagnosed in situ.



An epidemiologic study of cancer deaths recorded in the last half of the 20th century is conducted. The number of
deaths for one particular type of cancer has been decreasing in developed nations, despite the absence of widespread
screening programs. Which of the following neoplasms was most likely to be identified by this study?
□ (A) Angiosarcoma of the liver
□ (B) Gastric adenocarcinoma
□ (C) Glioma of the brain
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□ (D) Leukemia
□ (E) Lymphoma of the lymph nodes
□ (F) Pancreatic adenocarcinoma




b) gastric adenocarcinoma

(B) The decrease in the number of gastric cancers may be related to reduced numbers of dietary carcinogens or a
decrease in the prevalence of Helicobacter pylori infection; however, the exact reason is obscure. Angiosarcomas of the
liver are quite rare; they are epidemiologically linked to vinyl chloride exposure. Cerebral gliomas are not as common as
carcinomas; an urban legend links them to cell phone use, but legitimate epidemiologic studies have not made this link.
Leukemias and lymphomas are not as common as carcinomas. Pancreatic adenocarcinoma is the sixth most common
cause of cancer deaths in men and women, and the death rate is typically double the incidence because the prognosis for
pancreatic cancer is so poor.


25. A 26-year-old woman has a lump in the left breast. On physical examination, the physician finds an irregular, firm, 2-cm
mass in the upper inner quadrant of the breast. No axillary adenopathy is noted. A fine-needle aspirate of the mass shows
carcinoma. The patient's 30-year-old sister was recently diagnosed with ovarian cancer, and 3 years ago her maternal
aunt was diagnosed with ductal carcinoma of the breast and had a mastectomy. Which of the following genes is most likely
to have undergone mutation to produce these findings?
□ (A) BCL2 (anti-apoptosis gene)
□ (B) BRCA1 (DNA repair gene)
□ (C) EGF (epidermal growth factor gene)
□ (D) ERBB2 (growth factor receptor gene)
□ (E) HST1 (fibroblast growth factor gene)
□ (F) IL2 (growth factor gene)
□ (G) K-RAS (GTP-binding protein gene)
□ (H) Lyn (tyrosine kinase gene)




b) BRCA1 (DNA gene repair)


(B) Approximately 5% to 10% of breast cancers are familial, and 80% of these cases result from mutations in the
BRCA1 and BRCA2 genes. Onset of these familial cancers occurs earlier in life than the sporadic cancers. The protein
products of these genes are involved in DNA repair. BCL2 is overexpressed in some lymphoid neoplasms. ERBB2
overexpression is present in some sporadic breast cancers; other EGF alterations can be seen in lung, bladder,
gastrointestinal, ovarian, and brain neoplasms. The HST1 mutation is seen in some gastric cancers. IL2 overexpression is
associated with some T cell neoplasms. K-RAS overexpression is seen in many cancers, including some breast cancers,
but the early age of onset and family history in this case strongly suggest BRCA mutations. The Lyn mutation is seen in
some immunodeficiency states.


26. A 51-year-old man who works in a factory that produces plastic pipe has experienced weight loss, nausea, and

vomiting over the past 4 months. On physical examination, he has tenderness to palpation in the right upper quadrant of
the abdomen, and the liver span is increased. Laboratory findings include serum alkaline phosphatase, 405 U/L; AST,
45 U/L; ALT, 30 U/L; and total bilirubin, 0.9 mg/dL. An abdominal CT scan shows a 12-cm mass in the right lobe of the
liver. A liver biopsy is performed, and microscopic examination shows an angiosarcoma. The patient has most likely been
exposed to which of the following agents?
□ (A) Arsenic
□ (B) Asbestos
□ (C) Benzene
□ (D) Beryllium
□ (E) Nickel
□ (F) Vinyl chloride
□ (G) Naphthalene




f) vinyl chloride


(F) Vinyl chloride is a rare cause of liver cancer. This causal relationship was easy to show, however, because hepatic
Robbins & Cotran Review of Pathology Pg. 119
angiosarcoma is a rare neoplasm. Arsenic is a risk factor for skin cancer. Asbestos exposure is linked to pleural malignant
mesothelioma and to bronchogenic carcinomas in smokers. Benzene exposure is linked to leukemias. Beryllium exposure
can produce interstitial lung disease and lung cancer. Nickel exposure increases the risk of respiratory tract cancers.
Exposure to naphthalene compounds is a risk factor for cancer of the urinary tract.


27. A 39-year-old woman underwent a routine health maintenance examination for the first time in many years. A Pap

smear was obtained, and the result reported was abnormal. On pelvic examination, a red, slightly raised, 1-cm lesion on
the anterior ectocervix at the 2-o’clock position was excised and biopsied. The microscopic appearance on medium-power
magnification is shown in the figure. Which of the following statements best characterizes the patient's condition?
Robbins & Cotran Review of Pathology Pg. 106
□ (A) A primary site should be sought
□ (B) This is a high-grade lesion
□ (C) The cell of origin is a fibroblast
□ (D) A chest radiograph would show nodules
□ (E) Local excision would be curative




e) local excision would be curative


(E) The figure shows an in situ carcinoma of the squamous cervical epithelium with neoplastic growth above the
basement membrane. Such cancers, limited to the epithelium, are noninvasive, and local excision has a 100% cure rate. In
situ lesions do not give rise to metastases. Lesions limited to the epithelium are low grade. Because it originated in the
epithelium, this neoplasm is not derived from fibroblasts.


28. A 61-year-old woman has felt a lump in her breast for the past 2 months. On physical examination, there is a firm, 2-cm

mass in the right breast. An excisional biopsy specimen of the mass shows carcinoma. Immunoperoxidase stains for
protease cathepsin D and matrix metalloproteinase-9 are performed on the microscopic tissue section and show
pronounced cytoplasmic staining in the tumor cells. Which of the following characteristics is most likely to be predicted by
this marker?
□ (A) Angiogenesis
□ (B) Invasiveness
□ (C) Differentiation
□ (D) Heterogeneity
□ (E) Aneuploidy




b) invasiveness


(B) The elaboration of various enzymes by tumor cells aids in degradation of extracellular matrix and invasiveness.
Cathepsin D is a cysteine proteinase that cleaves various substrates, such as fibronectin and laminin. High levels of this
enzyme in tumor cells are associated with greater invasiveness. Angiogenesis can be mediated by basic fibroblast growth
factor and vascular endothelial cell growth factor. Differentiation, heterogeneity, and aneuploidy are regulated by protooncogenes
and tumor suppressor genes.


29. A 22-year-old woman, who works as a secretary for an accounting firm, has noted a palpable nodule on the side of her

neck for the past 3 months. On physical examination, there is a 2-cm, firm, nontender nodule involving the right lobe of the
thyroid gland. A fine-needle aspiration biopsy specimen of the nodule shows cells consistent with carcinoma of the thyroid.
No other family members are affected by this disorder. Which of the following would be considered most relevant in the
woman's past medical history?
□ (A) Chronic alcoholism
□ (B) Ataxia telangiectasia
□ (C) Radiation therapy in childhood
□ (D) Blunt trauma from a fall
□ (E) Exposure to arsenic compounds




c) radiation therapy in childhood


(C) Radiation is oncogenic. Cancers of thyroid and bone often develop after radiation exposure; leukemias also can
occur. Hepatocellular carcinomas can arise in cirrhosis caused by chronic alcoholism. Ataxia telangiectasia is an inherited
syndrome that carries an increased risk of development of leukemias and lymphomas. Trauma is not a risk factor for
development of cancer, although traumatic episodes often are recalled and irrationally associated with subsequent health
problems. Arsenic exposure, which is uncommon, leads to lung and skin cancers.


30. An epidemiologic study is performed to assess risks for cervical carcinoma. The cells from cervical lesions in a
population of women are analyzed. Binding of certain viral proteins to pRB is found in patients in whom dysplastic cells are
present. Viral proteins from which of the following are most likely to bind pRB, increasing the risk for dysplasia?
□ (A) Cytomegalovirus
□ (B) Epstein-Barr virus
□ (C) Herpes simplex virus
□ (D) Hepatitis B virus
□ (E) HIV
□ (F) Human papillomavirus
□ (G) JC papovavirus


f) HPV


(F) Human papillomavirus (HPV) types 16, 18, and 31 encode proteins that bind p53 with high affinity, resulting in loss
of tumor suppressor activity. Seventy-five percent to nearly 100% of squamous epithelial dysplasias and carcinomas of the
cervix are associated with HPV infection. Cytomegalovirus and herpes simplex virus do not participate directly in
carcinogenesis. Epstein-Barr virus is associated with some malignant lymphomas and nasopharyngeal carcinomas.
Hepatitis B virus is associated with hepatocellular carcinomas arising in the setting of regeneration in chronic liver injury.
HIV does not affect pRB, but the loss of immune regulation promotes development of lymphomas and Kaposi sarcoma.
The JC papovavirus is associated with development of progressive multifocal leukoencephalopathy.