【Pathology question】General Pathology part 2

DIRECTIONS: Each item below contains a question or incomplete statement followed by suggested responses. Select the one best response to each question.

51. A 9-year-old boy suddenly develops severe testicular pain. He is taken to the emergency room, where he is evaluated and immediately taken to surgery. There his left testis is found to be markedly hemorrhagic due to testicular torsion. This abnormality caused a hemorrhagic testicular infarction because of

    a. Arterial occlusion

    b. Septic infarction

    c. The collateral blood supply of the testis

    d. The dual blood supply of the testis

    e. Venous occlusion

ANS: E

Note:

Infarcts are localized areas of ischemic coagulative necrosis. 

They can be classified on the basis of their color into either red or white infarcts, or by the presence or absence of bacterial contamination into either septic or bland infarcts.

White infarcts: pale or anemic infarcts, are usually the result of arterial occlusion. 

• found in solid organs such as the heart, spleen, and kidneys. 

Red or hemorrhagic infarcts: May result from either arterial or venous occlusion. 

• occur in organs with a dual blood supply, such as the lung
• in organs with extensive collateral circulation, such as the small intestine and brain. 

These infarcts are hemorrhagic because there is bleeding into the necrotic area from the adjacent arteries and veins that remain patent. 

Hemorrhagic infarcts also occur in organs in which the venous outflow is obstructed (venous occlusion). Examples of this include torsion of the ovary or testis. In the latter, twisting of the spermatic cord occludes the venous outflow, but the arterial inflow remains patent because these arterial blood vessels have much thicker walls. This results in venous infarction. 

Testicular torsion is usually the result of physical trauma in an individual with a predisposing abnormality, such as abnormal development of the gubernaculum testis.

52. A young child who presents with megaloblastic anemia is found to have increased orotate in the urine due to a deficiency of orotate phosphoribosyl transferase. This enzyme deficiency decreases the synthesis of

    a. Glycogen

    b. Purines

    c. Pyrimidines

    d. Sphingomyelin

    e. Tyrosine

ANS: C

Note:

The synthesis of pyrimidines begins with the conversion of glutamine to carbamoyl phosphate. This step, which is the committed step in pyrimidine synthesis, is catalyzed by the enzyme carbamoyl phosphate synthetase II (CPSII) and requires 2ATP and CO2. After several biochemical steps orotate is formed; orotate is then converted to orotidine 5′-monophosphate (OMP) by the enzyme rotate phosphoribosyl transferase. Subsequently OMP is converted to uridine 5′-monophosphate (UMP) by the enzyme OMP decarboxylase. A deficiency of either of these two enzymes leads to a disorder called orotic aciduria, which is characterized by orotate in the urine, abnormal growth, and megaloblastic anemia. Next UMP is converted to CTP, while dUMP is converted by thymidylate synthase to dTMP. This latter step also involves folate and is inhibited by the folate analogue methotrexate, while thymidylate synthase is inhibited by the thymine analogue 5-flurouracil (5-FU). Finally, the ribonucleoside diphosphates (ADP, GDP, CDP, and UDP) are converted to deoxyribonucleoside diphosphates by ribonucleotide reductase, an enzyme that is inhibited by increased levels of dATP, as seen in individuals with the autosomal recessive (Swiss type) form of SCID, which is due to a deficiency of adenosine deaminase (ADA).

53. The combination of a primary defect, such as bilateral renal agenesis, along with its secondary structural change is best referred to by which one of the listed terms?

    a. Association

    b. Deformation

    c. Disruption

    d. Sequence

    e. Syndrome

ANS: D

Note:

There are several similar clinical terms that are used to describe various types of abnormal physical development. An association is a pattern of nonrandom anomalies with an unknown mechanism (e.g., VATER association). A deformation is an alteration of a normally formed body part by mechanical forces (e.g., oligohydramnios sequence). A disruption is a defect that results from interference in a normally developing process. 

Dysraphia refers to defects caused by failure of apposed structures to fuse (e.g., spina bifida). 

Dystopia refers to retention of an organ at a site during development (e.g., dystopic testes remaining in the inguinal canal, called cryptorchidism).

A malformation is a morphologic defect that results from an intrinsically abnormal developmental process (e.g., cleft lip or polydactyly).

A sequence is a recognized pattern that results from a single preexisting abnormality (e.g., oligohydramnios sequence). 

Syndrome refers to multiple anomalies having a recognizable pattern and known pathogenesis (e.g., Down’s syndrome).

54. As a general rule, familial disorders that involve abnormalities of structural proteins (rather than deficiencies of enzymes) and present during adulthood (rather than childhood) have what type of inheritance pattern?

    a. Autosomal dominant

    b. Autosomal recessive

    c. Mitochondrial

    d. X-linked dominant

    e. X-linked recessive

ANS: A

Note:

There are several general clinical differences between autosomal dominant (AD) disorders and autosomal recessive (AR) disorders. In general, AD mutations usually involve complex structural proteins or regulatory proteins, while AR disorders are more likely to result from abnormalities of proteins that function as enzymes. 

Examples of AD disorders involving abnormalities of structural proteins include Marfan’s syndrome (fibrillin), Ehlers-Danlos syndrome (collagen), osteogenesis imperfecta (collagen), and hereditary spherocytosis (spectrin). 

Examples of AD disorders involving abnormalities of regulatory proteins include familial hyperlipidemia (LDL receptor), von Willebrand’s disease (von Willebrand factor), and hereditary angioedema (C1 esterase inhibitor). 

Enzyme deficiencies are usually not associated with AD inheritance, because decreased levels of enzymes can usually be compensated for. 

Examples of AR disorders involving enzyme deficiencies include storage diseases and several amino acid diseases. Also note that, when compared with AD diseases, AR disorders tend to be more uniform in expression and the age of onset is frequently early in life. 

Examples of this latter fact include diseases of the blood (sickle cell anemia and thalassemia) and the infantile form of polycystic renal disease, which has an AR inheritance. In contrast, the adult form of polycystic renal disease has an AD pattern of inheritance.

55. A sex-linked recessive mode of inheritance exists in

    a. Myotonic dystrophy

    b. Limb-girdle dystrophy

    c. Facioscapulohumeral dystrophy

    d. Duchenne muscular dystrophy

    e. Polymyositis

ANS: D

Note:

Classification of the muscular dystrophies is based on the mode of inheritance and clinical features. Inheritance of the Duchenne type is by an X-linked recessive trait, with the gene located on the short arm of the X chromosome, although spontaneous mutations are fairly common. 

Autosomal dominant inheritance characterizes both myotonic dystrophy and the facioscapulohumeral type, while limb-girdle dystrophy is autosomal recessive. 

In Duchenne muscular dystrophy, males are affected and symptoms begin before the age of 4. Pelvic girdle muscles are affected, with resultant difficulty in walking, and this is followed by shoulder girdle weakness and eventual involvement of respiratory and cardiac muscles with death from respiratory failure before age 20. Histologic changes include rounded, atrophic fibers; hypertrophied fibers; degenerative and regenerative changes in adjacent myocytes; and necrotic fibers invaded by histiocytes. Elevation of serum creatine kinase is marked.

56. Assume that both parents are carriers for the abnormal gene that causes cystic fibrosis. If they have three children, what is the probability that ALL of their children will develop cystic fibrosis?

    a. 1⁄4 × 1⁄4 × 1⁄4

    b. 1⁄4 + 1⁄4 + 1⁄4

    c. 3⁄4 × 3⁄4 × 3⁄4

    d. 3⁄4 + 3⁄4 + 3⁄4

    e. 1 − (3⁄4 + 3⁄4 + 3⁄4)

ANS: A

Note:

The probability that a child will inherit a particular gene found on only one chromosome of a chromosome pair from one parent is 1 in 2 (e.g., 50%). Therefore, the probability that a child will inherit the cystic fibrosis (CF) gene from both parents and develop cystic fibrosis is 1 in 4 (e.g., 1⁄2 × 1⁄2). To calculate the probability that two or more events that are independent of each other will all occur, you must multiply the probabilities for each of these events together.

Therefore, the probability that three out of three children will each inherit two CF genes is 1⁄4 × 1⁄4 × 1⁄4.

57. The Hardy-Weinberg principle states that, given a frequency of a certain allele A of p and a frequency q of another allele a at the same locus on the same autosomal chromosome in a population with random mating (panmixia), then the number of heterozygous carriers is equal to

    a. p × p

    b. q × q

    c. p × q

    d. 2 × p × q

    e. (p × p) + (p × q)

ANS: D

Note:

The Hardy-Weinberg principle predicts population genotype frequencies based on gene frequencies. The principle, which assumes random mating, states that given gene frequencies p (for an allele A) and q (for another allele a), then the aa genotype (homozygous) = q × q and the Aa genotype (heterozygous carriers) = 2pq. The latter can also be written as ( p × q) + ( p × q).

58. A 6-year-old female is being evaluated for recurrent episodes of lightheadedness and sweating due to hypoglycemia. These symptoms are not improved by subcutaneous injection of epinephrine. Physical examination reveals an enlarged liver and a single subcutaneous xanthoma. An abdominal CT scan reveals enlargement of the liver along with bilateral enlargement of the kidneys. Laboratory examination reveals increased serum uric acid and cholesterol with decreased serum glucose levels. Following oral administration of fructose, there is no increase in blood glucose levels. A liver biopsy specimen reveals increased amounts of glycogen in hepatocytes, which also have decreased levels of glucose-6-phosphatase. What is the correct diagnosis?

    a. Andersen’s syndrome (type IV glycogen storage disease)

    b. Cori’s disease (type III glycogen storage disease)

    c. McArdle’s syndrome (type V glycogen storage disease)

    d. Pompe’s disease (type II glycogen storage disease)

    e. von Gierke’s disease (type I glycogen storage disease)

ANS: E

Note:

The glycogen storage diseases are due to defective metabolism of glycogen, and at least 11 syndromes stemming from genetic defects in the responsible enzymes have been described. Most of these glycogenoses are inherited as autosomal recessive disorders. 

von Gierke’s disease (type I) results from deficiency of glucose-6-phosphatase, the hepatic enzyme needed for conversion of G6P to glucose, with glycogen accumulation particularly in the enlarged liver and kidney and hypoglycemia. Diagnosis requires biopsy demonstration of excess liver glycogen plus either absent or low liver glucose-6-phosphatase activity, or a diabetic glucose tolerance curve, or hyperuricemia. von Gierke’s disease is the major hepatic or hepatorenal type of glycogenosis. 

Lysosomal glucosidase deficiency causes Pompe’s disease (type II). Glycogen storage is widespread but most prominent in the heart (cardiomegaly). In brancher glycogenosis (type IV) there is accumulation of amylopectin or abnormal glycogen in the liver, heart, skeletal muscle, and brain. The major myopathic form, McArdle’s disease (type V), is due to lack of muscle phosphorylase.

59. In tissues affected by the predominant form of Niemann-Pick disease, which one of the following is found at abnormally high levels?

a. Sphingomyelin

b. Sphingomyelinase

c. Kerasin

d. Acetyl coenzyme A

e. Ganglioside

ANS: A

Note:

Sphingomyelin, a lipid composed of phosphocholine and a ceramide, is characteristically found in abnormally high concentrations throughout the body tissues of patients who have any one of the forms of Niemann-Pick disease. 

Division of this disease into five categories is generally accepted: 

type A, the acute neuronopathic form, is the one that has the highest incidence. The lack of sphingomyelinase in type A is the metabolic defect that prevents the hydrolytic cleavage of sphingomyelin, which then accumulates in the brain. 

Patients who have the type A form usually show hepatosplenomegaly at 6 months of age, progressively lose motor functions and mental capabilities, and die during the third year of life.

60. A 9-year-old boy is being evaluated for deafness. Physical examination reveals a child with short stature, coarse facial features (low, flat nose, thick lips, widely spaced teeth, facial fullness), a large tongue, and clear corneas. Laboratory examination reveals increased urinary levels of heparan sulfate and dermatan sulfate. Metachromatic granules (Reilly bodies) are found in leukocytes from a bone marrow biopsy. These leukocytes are also found to be deficient in iduronosulfate sulfatase. What is the correct diagnosis?

    a. Hunter’s disease

    b. Hurler’s disease

    c. I cell disease

    d. Metachromatic leukodystrophy

    e. Wolman’s disease

ANS: A

Note:

The mucopolysaccharidoses (MPSs) result from deficiencies of specific enzymes involved in the breakdown of glycosaminoglycans (GAGs), which are also called mucopolysaccharides. 

The seven major types of GAGs are hyaluronic acid, chondroitin sulfate, keratin sulfate, dermatan sulfate, heparan sulfate, and heparin. 

The MPSs are characterized by accumulation of partially degraded GAGs in multiple organs, including the liver, spleen, heart, and blood vessels. Accumulations of GAGs within leukocytes produce Alder-Reilly bodies, while accumulations within neurons can produce zebra bodies. 

The MPSs are also characterized by the excretion of excess acid mucopolysaccharides in the urine, a finding that helps to differentiate the MPSs from the mucolipidoses. 

Most of the MPSs are associated with coarse facial features, clouding of corneas, joint stiffness, and mental retardation. 

The characteristic appearance of patients with type IH MPS (Hurler’s syndrome), which results from a deficiency of alpha-L-iduronidase, has been described as “gargoylism.” These patients excrete excess dermatan sulfate and heparan sulfate, both of which are mucopolysaccharides, in the urine. 

Type II MPS (Hunter’s syndrome) is the only MPS that has an X-linked recessive type of inheritance. These patients have a much milder disease than Hurler’s syndrome patients, but they also secrete dermatan sulfate and heparan sulfate in the urine. 

Type IV MPS, known as Morquio’s syndrome, is characterized by short stature, aortic valvular disease, and normal intelligence. These patients are prone to development of subluxation of the spine, which can produce quadriplegia. They secrete keratan sulfate in the urine.

In contrast to the MPSs, the mucolipidoses (MLs) are characterized by abnormalities affecting both the mucopolysaccharidoses (MPSs) and the sphingolipidoses (SLs). Similar to the MPSs, the MLs involve abnormal bone development (dysostosis), while similar to some of the SLs, cherry red maculae and peripheral demyelination are also seen. The MLs, however, unlike the MPSs, do not involve excessive urinary excretion of acid mucopolysaccharides.

The metabolism of the carbohydrates in glycoproteins and glycolipids is abnormal in the MLs and results in excess accumulation of oligosaccharides. There are three main types of MLs: type I is sialidosis, type II is inclusion cell (I cell) disease, and type III is pseudo-Hurler’s disease.

Patients with type II ML lack the enzyme N-acetylglucosamine phosphotransferase, which catalyzes the first step in the formation of mannose-6-phosphate. Many lysosomal enzymes in these patients, such as acid hydrolases (which includes glycoprotein and ganglioside sialidases), do not reach the cellular lysosomes and are instead secreted into the plasma. 

The name I cell originated from the finding of cytoplasmic granular inclusions in affected patients’ fibroblasts when cultured in vitro and observed under a phase-contrast microscope. These cytoplasmic inclusions are lysosomes that are swollen with many different types of contents. I cell disease is a slowly progressive disease that starts at birth and is fatal in childhood. Treatment is symptomatic only.

61. A 45-year-old male presents with severe pain in both knee joints. At the time of surgery, his cartilage is found to have a dark blue-black color. Further evaluation reveals that the patient’s urine has darkened rapidly with time. The most likely diagnosis for this abnormality is

    a. Hyperphenylalaninemia

    b. Tyrosinemia

    c. Tyrosinase-positive oculocutaneous albinism

    d. Alkaptonuria

    e. Maple syrup urine disease

ANS: D

Note:

Several autosomal recessive disorders involve inborn errors of amino acid metabolism.

Alkaptonuria (ochronosis) is caused by the excess accumulation of homogentisic acid. This results from a block in the metabolism of the phenylalanine-tyrosine pathway, which is caused by a deficiency of homogentisic oxidase. Excess homogentisic acid causes the urine to turn dark upon standing after a period of time. It also causes a dark coloration of the scleras, tendons, and cartilage. After years, many patients develop a degenerative arthritis. 

Phenylketonuria (PKU), also called hyperphenylalaninemia, results from a deficiency of phenylalanine hydroxylase, an enzyme that oxidizes phenylalanine to tyrosine in the liver. 

Infants are normal at birth, but rising phenylalanine levels (hyperphenylalaninemia) result in irreversible brain damage. The excess phenylacetic acid in the urine results in a “mousy” odor. A lack of the enzyme fumarylacetoacetate hydrolase results in increased levels of tyrosine (tyrosinemia). Chronic forms of the disease are associated with cirrhosis of the liver, kidney dysfunction, and a high risk of developing hepatocellular carcinoma. 

Maple syrup urine disease is associated with an enzyme defect that causes the accumulation of branched-chain α-keto acid derivatives of isoleucine, leucine, and valine. 

Albinism refers to a group of disorders characterized by an abnormality of the synthesis of melanin. Two forms of oculocutaneous albinism are classified by the presence or absence of tyrosinase, which is the first enzyme in the conversion of tyrosine to melanin. 

Albinos are at a greatly increased risk for the development of squamous cell carcinomas in sun-exposed skin.

62. Which one of the listed processes is the most likely cause of an aneuploid karyotype?

    a. A reciprocal translocation between two acrocentric chromosomes

    b. Deletion of both ends of a chromosome with fusion of the damaged ends

    c. Division of the centromere along a transverse plane

    d. Failure of homologous chromosomes or paired chromatids to separate

    e. Two breaks within a single chromosome with reincorporating of the inverted segment

ANS: D

Note:

The normal human karyotype consists of 23 pairs of chromosomes, of which 22 are homologous pairs of autosomes and one pair is the sex chromosome. The number of chromosomes found in germ cells (23) is called the haploid number (n), while the number of chromosomes found in all of the remaining cells in the body (46) is called the diploid number (2n). Any exact multiple of the haploid number (n) is called euploid. Note that both haploid and diploid cells are euploid. Any number that is not an exact multiple of n is called aneuploid. Aneuploidy can result from nondisjunction (more commonly) or anaphase lag. Nondisjunction is the failure of paired chromosomes or chromatids to separate at anaphase, either during mitosis or meiosis. Nondisjunction during the first meiotic division is the mechanism responsible for the majority of cases of trisomy 21. In contrast, chromosome numbers such as 3n and 4n are called polypoid. 3n is called triploid, while 4n is called tetraploid. Do not confuse triploid with trisomy; the latter refers to the presence of three copies of one chromosome, which results in 47 chromosomes. Triploid karyotypes (69 chromosomes) are found in about 7% of miscarriages. Interestingly, they are also associated with abnormalities of the placenta, including cystic villi and partial hydatidiform moles. Both abnormalities can produce large placentas. Triploid karyotypes are usually due to double fertilization of a haploid ovum by two haploid sperm, that is, there is a total of 69 chromosomes, 46 of which are from the father.

A reciprocal translocation between two acrocentric chromosomes is characteristic of the Robertsonian translocation (centric fusion), which results in the formation of one large metacentric chromosome and a small chromosomal fragment, which is usually lost. Deletion of both ends of a chromosome with fusion of the damaged ends produces a ring chromosome, while abnormal division of the centromere along a transverse plane forms an isochromosome. Turner’s syndrome can result from an isochromosome of the X chromosome. Two breaks within a single chromosome with reincorporation of the inverted segment produces an inversion.

63. The first child of a couple has trisomy 21 (not the result of mosaicism), and they come to you wanting to know the risk of having another child with Down’s syndrome. The mother’s age is 23, and the father’s age is 25. Both appear normal and neither have had any unusual diseases. You analyze their karyotypes and find that the father’s karyotype is normal, but the mother has a Robertsonian translocation involving chromosome 21 (21q21q). Which one of the listed percentages is the best estimate of the chance that the next living child of this couple will have Down’s syndrome?

    a. 0%

    b. 15%

    c. 33%

    d. 50%

    e. 100%

ANS:

Note:

Nondisjunction during the first meiotic division is responsible for trisomy 21 in about 93% of patients with Down’s syndrome. Nondisjunction during mitosis of a somatic cell early during embryogenesis results in mosaicism in about 2% of patients with Down’s syndrome. 

Translocation of an extra long arm of chromosome 21 causes about 5% of Down’s syndrome cases. An important type of translocation, the Robertsonian translocation (centric fusion), involves two nonhomologous acrocentric chromosomes with the resultant formation of one large metacentric chromosome. Carriers of this type of translocation may also produce children with Down’s syndrome.

It is important to understand these different causes of Down’s syndrome in order to estimate the chance of recurrence if parents already have one child with Down’s syndrome. Overall, the risk of recurrence of trisomy 21 after one such child has been born to a family is about 1%. If the karyotypes of the parents are normal, then the recurrence rate is dependent upon the age of the mother. For mothers under the age of 30, the risk is about 1.4%. For mothers over the age of 30, the risk is the same as the agerelated maternal risk, which at age 30 is 1/900, at age 35 is 1/350, at age 40 is 1/100, and at age 40 and over is 1/25. The recurrence risk is different for a translocation Down’s syndrome, which may be either a 14q21q Robertsonian translocation or a 21q21q translocation. A carrier of a Robertsonian translocation involving chromosomes 14 and 21 has only 45 chromosomes and can theoretically produce six possible types of gametes. Of these, only three are potentially viable: one that is normal, one that is balanced, and one that is unbalanced, having both the translocated chromosome and a normal chromosome 21. The latter, when combined with a normal gamete, could produce a child with Down’s syndrome. Therefore, theoretically, the risk of a carrier of this type of Robertsonian translocation producing a child with Down’s syndrome would be 1 in 3. In practice, about 15% of the progeny of mothers with this type of translocation, and very few of the progeny of fathers with this type of translocation, develop Down’s syndrome. In contrast, carriers of a 21q21q translocation produce gametes that either have the translocated chromosome or lack any 21 chromosome. Progeny then can have either trisomy 21 or monosomy 21, but, since the latter is rarely viable, approximately 100% of progeny will have Down’s syndrome.

64. A male infant dies 1 day after birth. Gross examination at the time of autopsy reveals polydactyly, a cleft lip and palate, and a single, central eye (“cyclops”). Further examination reveals holoprosencephaly, consisting of fused frontal lobes with a single ventricle. Which of the listed chromosomal abnormalities is most consistent with these findings?

    a. Deletion 21

    b. Deletion 22

    c. Trisomy 13

    d. Trisomy 18

    e. Trisomy 21

ANS: C

Note:

The three most common trisomies causing human disease are trisomies 13, 18, and 21. 

Trisomy 13 (Patau’s syndrome) is characterized by forebrain and midline facial abnormalities. Patients can develop holoprosencephaly, which is characterized by fused frontal lobes and a single ventricle. Olfactory bulbs are also absent. The midline facial abnormalities that are seen with trisomy 13 include cleft lip, cleft palate, nasal defects, and a single central eye (“cyclops”). Other defects associated with Patau’s syndrome include polydactyly, rocker-bottom feet, and congenital heart diseases. 

Trisomy 18 (Edwards’ syndrome) is characterized by mental retardation, micrognathia (tiny jaw), low-set ears, rocker-bottom feet, and congenital heart diseases. Perhaps most characteristic is a clenched fist with overlapping fingers: the index finger overlying the third and fourth fingers, while the fifth finger overlaps the fourth. Edwards’ syndrome is also associated with polyhydramnios and a single umbilical artery.

Trisomy 21 (Down’s syndrome) is the most common chromosomal abnormality and is an important cause of mental retardation. Children with Down’s syndrome invariably have severe mental retardation, which progressively declines with advancing age. Patients have characteristic facial features that include a flat facial profile, oblique palpebral fissures, and epicanthal folds; a horizontal palmar crease; and a decreased muscle tone at birth that leads to a “floppy baby.” About one-third of these children also have congenital heart defects, most commonly ventricular septal defects and AV canal defects. There is also a marked increase in the incidence of acute leukemia, usually acute lymphoblastic leukemia, in children with Down’s syndrome who are younger than 3 years of age. There is almost a 100% incidence of Alzheimer’s disease in patients with Down’s syndrome by the age of 35. Changes in the brains of patients with Down’s syndrome similar to those seen in the brains of patients with Alzheimer’s disease include senile plaques and neurofibrillary tangles. Patients with Down’s syndrome also have an increased incidence of infections, GI obstruction, and duodenal ulcers.

Deletions involving chromosome 22 (e.g., 22q11) are associated with both DiGeorge’s syndrome and the velocardiofacial (VCF) syndrome. 

DiGeorge’s syndrome is associated with absence of the thymus, which leads to cell-mediated immune deficiencies, and absence of the parathyroids, which leads to hypocalcemia. 

VCF syndrome is associated with palate (velum) abnormalities and dysfunction of the T cells. 

DiGeorge’s syndrome and VCF syndrome may represent spectrums of the same abnormality.

In fact, the acronym CATCH-22 refers to the signs of the 22q11 deletion syndrome: cardiac abnormality, abnormal face, T cell defect secondary to thymic hypoplasia, cleft palate, and hypocalcemia secondary to hypoparathyroidism.

65. A 2-month-old girl presents with a soft, high-pitched, mewing cry and is found to have microcephaly, low-set ears and hypertelorism, and several congenital heart defects. The chromosomal abnormality that is most likely to produce these symptoms is

    a. 46,XX,4p−

    b. 46,XX,5p−

    c. 46,XX,13q−

    d. 46,XX,15q−

    e. 46,XX,17p−

ANS: B

Note:

Several genetic diseases are characterized by a deletion of part of an autosomal chromosome. 

The 5p− syndrome is also called the cri-du-chat syndrome, as affected infants characteristically have a high-pitched cry similar to that of a kitten. Additional findings in this disorder include severe mental retardation, microcephaly, and congenital heart disease. 

4p−, also called Wolf-Hirschhorn syndrome, is characterized by pre- and postnatal growth retardation and severe hypotonia. Affected infants have many defects including micrognathia and a prominent forehead. 

The 11p− syndrome is characterized by the congenital absence of the iris (aniridia) and is often accompanied by Wilms tumor of the kidney. 

The 13q− syndrome is associated with the loss of the Rb suppressor gene and the development of retinoblastoma. 

Deletions involving chromosome 15 (15q−) may result in either Prader-Willi syndrome or Angelman’s syndrome depending on whether the defect involves the paternal or the maternal chromosome (genetic imprinting). 

17p−, also known as Smith-Margens syndrome, is associated with self-destructive behavior.

66. A 6-year-old female with a fair complexion is being evaluated for severe mental retardation and seizures. She is found to have a stiff, ataxic gait characterized by jerky movements. She also displays laughter at inappropriate times. What is the correct diagnosis?

    a. Beckwith-Wiedemann syndrome

    b. Prader-Willi syndrome

    c. Angelman’s syndrome

    d. Smith-Margens syndrome

    e. Wolf-Hirschhorn syndrome

ANS: C

Note:

Genetic imprinting refers to the fact that different diseases may result from the same chromosomal deletion depending on whether that deletion specifically involves either the maternal chromosome or the paternal chromosome. This finding is in sharp contrast to the classic concept of Mendelian inheritance, which states that the phenotype of a certain allele is independent of whether the chromosome is the maternal or the paternal chromosome.

The best example of genetic imprinting involves deletions involving chromosome 15 (15q−). If the deletion involves the maternal chromosome, then Angelman’s syndrome results, while deletions involving the paternal chromosome result in Prader-Willi syndrome. Angelman’s syndrome is characterized by severe mental retardation, seizures, a stiff ataxic gait with jerky movements, inappropriate laughter, and occasional oculocutaneous albinism. Because of the combination of ataxic gait and inappropriate laughter, these patients are sometimes referred to as “happy puppets.” Prader-Willi syndrome is characterized by short stature, obesity, mild to moderate mental retardation, small hands and feet, and hypogonadism, which is characterized in males by cryptorchidism and micropenis and in females by hypoplastic labia.

The cause of genetic imprinting is not known, but it may relate to the degree of methylation of genes. Genes that are more highly methylated are less likely to be transcribed into messenger RNA. Note that a loss of chromosome 15 can also occur if two parental chromosomes of the same type are derived from the same parent. This condition is called uniparental disomy, whereas the normal condition is called biparental disomy. Inheritance of the same (duplicated) chromosome is called isodisomy, while inheritance of homologues from the same parent is called heterodisomy. To illustrate this concept, consider paternal uniparental disomy of chromosome 15. This refers to inheriting two copies of paternal chromosome 15 and no maternal chromosome 15. Therefore, this is essentially the same as a deletion of maternal chromosome 15, which produces Angelman’s syndrome.

Inheriting two copies of paternal chromosome 11 results in Beckwith-Wiedemann syndrome. This is not a trisomy, as the maternal chromosome is lost, and therefore this would be a paternal uniparental disomy for chromosome 11. This syndrome is characterized by exomphalos, macroglossia, and gigantism (EMG). Patients also develop hypoglycemia because the genes for insulin and insulinlike growth factors are located in this region. Smith-Margens syndrome (17p−) is associated with self-destructive behavior, while Wolf-Hirschhorn syndrome (4p−) is characterized by growth retardation, severe hypotonia, and micrognathia.

67. A 19-year-old female of average intelligence and short stature is being evaluated for amenorrhea. Taking a history, you discover that she has never menstruated. Physical examination reveals that she has a shield-shaped chest and her elbows turn outward when her arms are at her sides. She has a “thick neck” and you notice the absence of secondary female characteristics. Serum estrogen levels are found to be decreased, while both FSH and LH levels are increased. What is the correct diagnosis?

    a. Fragile X syndrome

    b. Klinefelter’s syndrome

    c. Multi-X syndrome

    d. Turner’s syndrome

    e. XYY syndrome

ANS: D

Note:

Turner’s syndrome (hypogonadism in phenotypic females) is an important cause of primary amenorrhea. Characteristics of this syndrome include small stature due to a lack of a growth spurt during adolescence, a webbed neck, and multiple skeletal abnormalities that include a wide carrying angle of the arms where the elbow is out (cubitus valgus), a “shield-shaped” chest, and a high-arched palate. Individuals with Turner’s syndrome are phenotypic females, but they fail to develop secondary characteristics at puberty. Patients have streak gonads, histologic sections of which reveal atrophic, fibrous strands and are devoid of ova and follicles. These hypermaturing ovaries produce decreased estrogen levels, resulting in primary amenorrhea with no menarche. About one-half of patients develop hypothyroidism due to autoantibodies against thyroid hormone. Mental retardation is not associated with Turner’s syndrome. Most cases of Turner’s syndrome are associated with a 45,XO karyotype, which has no Barr body, but other causes of Turner’s syndrome include isochromosome X and mosaicism.

An XYY karyotype, which most often results from nondisjunction at the second meiosis during spermatogenesis, produces individuals who are phenotypically normal except that they may be tall and have severe acne (cystic acne). The relationship of the extra Y to behavior is controversial, but these individuals do have problems with motor and language development. Multi-X females are normal, except there is an increased tendency toward mental retardation that is proportional to the number of X chromosomes that are present.

68. A 17-year-old individual who is phenotypically female presents for workup of primary amenorrhea and is found to have an XY karyotype. The most likely diagnosis is

    a. Androgen insensitivity syndrome

    b. Deficiency of 5-α-reductase

    c. Kallmann’s syndrome

    d. Mixed gonadal dysgenesis

    e. Turner’s syndrome

ANS: A

Note:

Sexual ambiguity arises when there is disagreement between the various ways of determining sex. Genetic sex is determined by the presence or absence of a Y chromosome. Gonadal sex is based upon the histologic appearance of the gonads. Ductal sex depends on the presence of derivatives of the Müllerian or Wolffian ducts. Phenotypic or genital sex is based on the appearance of the external genitalia. True hermaphroditism refers to the presence of both ovarian and testicular tissue. Pseudohermaphroditism is a disagreement between the phenotypic and gonadal sex. A female pseudohermaphrodite has ovaries but external male genitalia, while a male pseudohermaphrodite has testicular tissue, resulting from an XY genital sex karyotype, but female external genitalia. Female pseudohermaphroditism results from excessive exposure to androgens during early gestation; most often this is the result of congenital adrenal hyperplasia. Male pseudohermaphroditism results from defective virilization of the male embryo, most commonly caused by complete androgen insensitivity syndrome, also called testicular feminization.

Kallmann’s syndrome results from a lack of embryonic migration of cells from the olfactory bulb to the hypothalamus and is characterized by primary amenorrhea, lack of secondary sex characteristics, and decreased sense of smell (hyposmia). Laboratory findings include decreased GnRH, LH, and FSH. Mixed gonadal dysgenesis consists of one well-defined testis and a contralateral streak ovary. It is a cause of ambiguous genitalia in the newborn. Turner’s syndrome, which has a 45,XO karyotype, is characterized by a female phenotype and bilateral streak ovaries.

69. Which immunoglobulins are characteristically present on mature (virgin) B cells, which are B lymphocytes that have not yet been exposed to the appropriate antigen?

    a. IgA and IgE

    b. IgD and IgA

    c. IgE and IgG

    d. IgG and IgM

    e. IgM and IgD

ANS: E

Note:

Both B lymphocytes and T lymphocytes have definite sequences of maturation that are characterized by gene rearrangement and the acquisition of surface markers. These cells originate from a common lymphoid stem cell that is characterized by the intranuclear enzyme terminal deoxynucleotidyl transferase (TdT) and the surface antigens CD34 and CD38. The first definable stage of B cell maturation occurs as the cell begins the process of producing immunoglobulin (Ig). The heavy chain genes, which are located on chromosome 14, are first rearranged, but because this occurs before the rearrangement of the light chain genes, complete immunoglobulin is not yet expressed on the cell surface. Instead μ heavy chain genes are rearranged first, and are found within the cytoplasm. This defines these developing cells as being pre-B cells. These cells also demonstrate surface CD10 (CALLA) and the pan–B cell markers CD19, CD20, and CD22. Next these developing B cells begin to synthesize light chains. κ light chain genes are found on chromosome 2 and are rearranged first. If something goes wrong in this process, then the λ light chain genes on chromosome 22 are rearranged; otherwise they stay in their germline configuration. The synthesized light chains then combine with the intracytoplasmic μ heavy chains to form complete IgM, which is then transported to the surface, forming surface IgM (sIgM). These cells, which have also acquired CD21 but have lost TdT and CD10, are called immature B cells. Next these developing B cells produce IgD, which is also expressed on the cell surface (sIgD). These cells with surface IgM and IgD are called mature B cells. They are also called “virgin” B cells because these cells have not encountered any foreign antigen. (Note that all of the preceding steps occur in the bone marrow of the developing fetus.)

Later in life, binding of foreign antigen to membrane bound surface Ig results in activation of the B cell, which then becomes either a memory cell or a plasma cell. Before B cells become plasma cells, there may be a class switch (isotype switch) to a particular surface immunoglobulin that the plasma cell will then secrete. This activation occurs within germinal centers, where morphologically B cells are classified as being small cleaved lymphocytes, large cleaved lymphocytes, small noncleaved lymphocytes (with prominent nucleoli), or large noncleaved lymphocytes (with prominent nucleoli). Prior to forming plasma cells, these activated B lymphocytes are called B immunoblasts. Plasma cells are characterized by cytoplasmic immunoglobulin and surface plasma cell antigen 1 (PCA-1). In contrast, memory B lymphocytes, which histologically look like unremarkable small lymphocytes, have surface immunoglobulin of the IgG, IgA, or IgE type. They are found within lymphoid follicles.

70. What type of antibody is produced first against a bacterial infection, is very effective at activating complement, and is too large to cross the placenta?

    a. IgG

    b. IgM

    c. IgD

    d. IgE

    e. IgA

ANS: B
Note:

Immunoglobulins (Igs) are the product of plasma cells, the effector cells of B lymphocyte activation. Igs are composed of light chains and heavy chains, each of which are composed of a variable region and a constant region. The variable regions of both of these chains form the antigenbinding region of Ig, which is called the Fab portion. The portion of Ig that binds complement is called the Fc portion. Not only can the Fc portion of Ig bind to complement, but it can bind to cells that have Fc receptors. There are two types of light chains and five types of heavy chains. The two light chains are the κ chain, the genes of which are located on chromosome 2, and the λ chain, the genes of which are located on chromosome 22. The heavy chains are M, D, A, E, and G, the genes of all of these being on chromosome 14. The combination of one type of light chain with a particular heavy chain forms each of the five types of immunoglobulin.

The most abundant Ig in the serum (80%) is IgG. It is secreted in the second response to certain antigens, but it does not predominate early during the first response. IgG can cross the placenta, and it is the major protective immunoglobulin in the neonate. IgG can also activate complement, participate in antibody-dependent cell-mediated cytotoxicity (ADCC), neutralize toxins or viruses, and function as an opsonin. 

IgM, which constitutes about 5 to 10% of the Ig in the serum, is secreted in the first exposure to antigen (primary immune response). The monomeric form of IgM is found on the surface of some B cells, while the pentameric form is found in the serum and cannot cross the placenta. IgM is very effective at activating complement. 

IgD, which forms less than 1% of serum Ig, is found on the cell surface of some B cells and functions in the activation of these B cells. 

IgE, also known as reaginic antibody, is found on the plasma membrane of mast cells and basophils and participates in type I hypersensitivity reactions, such as allergies, asthma, and anaphylaxis. IgE is used to fight parasitic infections. 

IgA, which constitutes about 10 to 15% of serum Ig, exists as a monomer in the serum and a dimer in glandular secretions. IgA is synthesized by mucosal plasma cells of the GI tract, lung, and urinary tract—thus making it the immunoglobulin of “secretory immunity”—and is found in saliva, sweat, nasal secretion, and tears. It is secreted as a dimer bound to a secretory piece that stabilizes the molecule against proteolysis.

71. Which one of the following sequences correctly describes the usual temporal sequence of T-lymphocyte maturation within the cortex and medulla of the thymus?

    a. Double negative → double positive → single positive

    b. Double negative → single positive → double positive

    c. Double positive → double negative → single positive

    d. Double positive → single positive → double negative

    e. Single positive → double positive → double negative

ANS:

Note: 

T cells arise from precursor cells in the bone marrow that migrate to the thymus and mature. Like B cells, T cells originate from a common lymphoid stem cell that includes intranuclear terminal deoxynucleotidyl transferase (TdT) and surface antigens CD34 and CD38. This stage of development occurs prior to the migration of the developing cell to the thymus and is called the prethymus stage. There are three stages of maturation within the thymus. Stage I occurs in the outer cortex of the thymus, where the developing T lymphocytes (thymocytes) obtain the surface antigen CD7 followed by CD2 and CD5. These stage I (or early) thymocytes lack both CD4 or CD8 and are called double-negative cells. These cells make up about 10% of the thymocytes in the thymus. The next step in development, which starts in the cortex and continues into the medulla, involves generation of an intact T cell receptor (TCR) on the cell surface. The TCR is a heterodimer, usually made up of an α and a β chain, each having a variable (antigen-binding) region and a constant region, analogous to the immunoglobulin molecule. Early in the formation of TCR, called stage II, the intermediate (common) thymocytes acquire both CD4 and CD8 molecules and are called double-positive T cells. They are the majority of thymocytes in the thymus (80%). Stage III occurs in the medulla, where the T cells lose either the CD4 or the CD8 antigen. These mature thymocytes, which are single-positive cells, make up about 15% of the thymus thymocytes. Post-thymus T cells are either CD4+ or CD8+. CD4+ cells function as helper cells, while CD8+ cells function as cytotoxic cells. In normal, healthy individuals, the helper/suppressor ratio (e.g., CD4/CD8 ratio) in the peripheral blood is about 2:1. That is, about 40% of peripheral lymphocytes are helper cells and 20% of peripheral lymphocytes are cytotoxic T cells.

72. Which cytokine is produced mainly by TH1 cells and stimulates cell mediated immunity by stimulating cytokine-driven proliferation of CD8+ cytotoxic T cells?

    a. α-interferon

    b. γ-interferon

    c. Interleukin 1

    d. Interleukin 2

    e. Interleukin 3

ANS: D

Note:

The cytokines are soluble mediators of immune reactions that are released from immune cells. Products of lymphocytes are called lymphokines, while products of monocytes or macrophages are called monokines. Two of the more important cells that secrete cytokines are two subsets of T helper lymphocytes, namely TH1 cells and TH2 cells. TH1 cells secrete several types of cytokines, including interleukin 2 (IL-2), γ-IFN, and lymphotoxin (β-TNF). IL-2, secreted by CD4+ TH1 cells, has autocrine effects to increase IL-2 receptors. It also stimulates NK cells (antibody-dependent cell-mediated immunity) and CD8+ T cells (cell-mediated immunity). TH2 cells also secrete several types of cytokines, including IL-4, IL-5, IL-6, and IL-10. IL-4 simulates TH2 cells while at the same time inhibiting TH1 cells. This combination inhibits cell-mediated immunity and favors humoral immunity. In addition, IL-4 regulates heavy chain class switch to IgE. IL-5 increases the numbers and function of eosinophils. IL-6 is the most potent stimulator for acutephase reactant production by the liver. Additionally, it stimulates B cells, and synergistically with IL-1 it stimulates T cells. IL-10 inhibits TH1 cells (cellmediated immunity), NK cells, and macrophages.

In contrast, IL-1 is produced by many types of cells, including macrophages, antigen-presenting cells (APCs), and other somatic cells. The functions of IL-1 include autocrine effects on the APCs and paracrine effects on T cells. Effects of IL-1 on the APCs include increased expression of adhesion molecules, γ-IFN receptors, and class II antigens. Effects of IL-1 on T cells include increased IL-2 secretion and increased expression of receptors for IL-2 and γ-IFN. Other effects of IL-1 are important in acute inflammation and include stimulation of neutrophils and B cells, production of fever, and increased production of acute-phase reactants. IL-3, also known as multi-CSF, stimulates pluripotential stem cells. Interferon α is an antiviral interferon, while interferon γ is an immune interferon. Interferon γ is the most potent activator of macrophages. These activated macrophages (epithelioid cells) produce granulomas. Effects of interferon γ also include increased class I antigen expression on all somatic cells, increased class II antigen expression on APCs, and induction of high endothelial venules.

73. In antigen recognition by cytotoxic T lymphocytes, the T cell receptor recognizes antigens bound to

    a. Class I antigens

    b. Class II antigens

    c. Class III antigens

    d. C3b

    e. Fc portion of IgG

ANS: A

Note:

CD8+ cytotoxic T lymphocytes can recognize a foreign antigen only if that antigen is complexed to self-class I antigens. In general these class I molecules bind to proteins synthesized within the cell; one example is the cellular production of viral antigens. The CD8 molecule of the cytotoxic T cell binds to the nonpolymorphic portion of the class I molecule, while the T cell receptor on the surface of the T lymphocyte binds to a complex formed by the peptide fragment of the antigen and the class I antigen. In contrast, CD4+ helper T lymphocytes can recognize a foreign antigen only if that antigen is complexed to self-class II antigens. In general, class II antigens present foreign antigens that have been processed within the cell in endosomes or lysosomes; one example is bacteria. Macrophages and neutrophils are active phagocytes and have receptors for the Fc portion of IgG and C3b; both of these substances are important opsonins. Macrophages also ingest and present antigens to T cells in conjunction with surface class II antigens.

74. There is a strong association between ankylosing spondylitis and

    a. HLA-B27

    b. HLA-DR3

    c. HLA-DR4

    d. HLA-A3

    e. HLA-BW47

ANS: A
Note:

A variety of different diseases have an association with certain HLA types. The exact mechanism of this association is unknown. These diseases can be grouped into three broad categories: 

• inflammatory diseases, such as ankylosing spondylitis (associated with HLA-B27); 
• inherited errors of metabolism, such as hemochromatosis (associated with HLA-A3); 
• autoimmune diseases, which are usually associated with the DR locus. 

Two examples of the latter are the associations of rheumatoid arthritis with DR4 and of insulindependent diabetes with DR3/DR4. Ankylosing spondylitis is one type of spondyloarthropathy that lacks the rheumatoid factor found in rheumatoid arthritis. Other seronegative spondyloarthropathies include Reiter’s syndrome, psoriatic arthritis, and enteropathic arthritis. All of these are associated with an increased incidence of HLA-B27. Ankylosing spondylitis, also known as rheumatoid spondylitis or Marie-Strümpell disease, is a chronic inflammatory disease that primarily affects the sacroiliac joints of adult males.

75. Ten minutes after being stung by a wasp, a 30-year-old male develops multiple patches of red, irregular skin lesions over his entire body. These lesions (urticaria) are pruritic, and new crops of lesions occur every day. This response is primarily the result of liberation of specific vasoactive substances by the action of

    a. Activated T lymphocytes on smooth muscle cells

    b. IgA on basophils and mast cells

    c. IgA on lymphocytes and eosinophils

    d. IgE on basophils and mast cells

    e. IgE on lymphocytes and eosinophils

ANS: D

Note:

Hypersensitivity diseases are caused by immune mechanisms. They are classified into four different categories based on the immune mechanisms involved. 

Type I hypersensitivity reactions involve IgE (reaginic) antibodies that have been bound to the surface of mast cells and basophils. These IgE antibodies are formed by a T cell–dependent process. An allergen initially binds to antigen-presenting cells, which then stimulate TH2 cells to secrete interleukin 4 (IL-4), IL-5, and IL-6. IL-5 stimulates the production of eosinophils, while IL-4 stimulates B cells to transform into plasma cells and produce IgE. This IgE then attaches to mast cells and basophils, because these cells have cell surface receptors for the Fc portion of IgE. When these “armed” mast cells or basophils are reexposed to the allergen, the antigen bridges two IgE molecules and causes mast cells to release preformed (primary) mediators. This antigen-to-antibody binding also causes these cells to synthesize secondary mediators.

The reactions that occur as a result of the primary mediators of type I hypersensitivity are rapidly occurring, since the mediators have already been made and are present within the granules of mast cells. These substances include biogenic amines, such as histamine, chemotactic factors, enzymes, and proteoglycans. Histamine causes increased vascular permeability, vasodilation, and bronchial smooth muscle contraction. The chemotactic factors are chemotactic for eosinophils and neutrophils. Mast cells also produce new products (secondary mediators) via a series of reactions within the cell membrane that lead to the generation of lipid mediators and cytokines. The lipid mediators are generated from arachidonic acid. Membrane receptors bound to IgE activate phospholipase A2, which then cleaves membrane phospholipids into arachidonic acid. Lipoxygenase produces leukotrienes, including LTB4 and leukotrienes C4, D4, and E4. These last three leukotrienes are the most potent vasoactive and spasmogenic agents known. They used to be called slow reactive substance of anaphylaxis (SRS-A). Prostaglandin D2, which is produced via the enzyme cyclooxygenase, is abundant in lung mast cells. It causes bronchospasm and increased mucus production.

Type I reactions may be either local or systemic. Local reactions include urticaria (hives), angioedema, allergic rhinitis (hay fever), conjunctivitis, food allergies, and allergic bronchial asthma. Systemic reactions usually follow parenteral administration of antigen, such as with drug reactions (penicillin) or insect stings. The amount of antigen may be very small. Symptoms include vomiting, cramps, diarrhea, itching, wheezing, and shortness of breath, and death may occur within minutes. The main treatment is epinephrine.

76. After receiving incompatible blood, a patient develops a transfusion reaction in the form of back pain, fever, shortness of breath, and hematuria. This type of immunologic reaction is classified as a

    a. Systemic anaphylactic reaction

    b. Systemic immune complex reaction

    c. Delayed type hypersensitivity reaction

    d. Complement-mediated cytotoxicity reaction

    e. T cell–mediated cytotoxicity reaction

ANS: D

Note:

A blood transfusion reaction is a type II hypersensitivity reaction that is mediated by antibodies reacting against antigens present on the surface of blood group antigens or irregular antigens present on the donor’s red blood cells. Type II hypersensitivity reactions result from attachment of antibodies to changed cell surface antigens or to normal cell surface antigens. Complement-mediated cytotoxicity occurs when IgM or IgG binds to a cell surface antigen with complement activation and consequent cell membrane damage or lysis. Blood transfusion reactions and autoimmune hemolytic anemia are examples of this form. Systemic anaphylaxis is a type I hypersensitivity reaction in which mast cells or basophils that are bound to IgE antibodies are reexposed to an allergen, which leads to a release of vasoactive amines that causes edema and broncho- and vasoconstriction. Sudden death can occur. Systemic immune complex reactions are found in type III reactions and are due to circulating antibodies that form complexes upon reexposure to an antigen (such as foreign serum), which then activates complement. This process is followed by chemotaxis and aggregation of neutrophils, which leads to release of lysosomal enzymes and eventual necrosis of tissue and cells. Serum sickness and Arthus reactions are examples of type III reactions. Delayed type hypersensitivity is type IV and is due to previously sensitized T lymphocytes, which release lymphokines upon reexposure to the antigen. This takes time—perhaps up to several days following exposure. The tuberculin reaction is the best-known example. T cell–mediated cytotoxicity leads to lysis of cells by cytotoxic T cells in response to tumor cells, allogenic tissue, and virus-infected cells. These cells have CD8 antigens on their surfaces.

77. Which one of the following histologic or immunofluorescent findings is most indicative of a delayed type hypersensitivity reaction?

    a. A linear immunofluorescence pattern in the wall of the esophagus

    b. Caseating granulomas in hilar lymph nodes

    c. Councilman (apoptotic) bodies in the liver

    d. Fibrinoid necrosis around dermal blood vessels

    e. Numerous eosinophils in a nasal polyp

ANS: B

Note:

Type IV hypersensitivity reactions do not involve antibody formation, and instead are mediated by T cells (cell-mediated hypersensitivity). There are two subtypes of type IV hypersensitivity reactions, one of which involves CD4+ cells [delayed type hypersensitivity (DTH)] and the other of which involves CD8+ cells (cellmediated cytotoxicity). Upon first exposure to the antigen in DTH reactions, macrophages ingest the antigen and process it in association with class II antigens (HLA-D) to these helper cells (CD4). Upon reexposure to the antigen, these CD4+ cells are activated and secrete biologically active factors (the lymphokines). Specifically, CD4 TH1 cells are activated and secrete interferon γ, interleukin 2, and TNF-α. Interferon γ activates macrophages (epithelioid cells) and forms granulomas (caseating or non-caseating). Interleukin 2 activates other CD4 cells, while TNF-α causes endothelial cells to increase production of prostacyclin and ELAM-1. The classic example of a DTH reaction is the tuberculin skin test (Mantoux reaction). A local area of erythema and induration peaks at about 48 h following intracutaneous injection of tuberculin. Granulomatous inflammation (with epithelioid cells), poison ivy reactions, and contact dermatitis are types of delayed type hypersensitivity. Contact dermatitis is often the result of sensitivity to nickel, which can be found in some watchbands. With T cell–mediated cytotoxicity, sensitized T cells (CD8) by themselves kill antigen-bearing target cells. These cells are called cytotoxic T lymphocytes (CTLs). These CTLs, directed against modified surface HLA antigens, play a role in viral infections, tumors, and graft rejection.

A linear immunofluorescence pattern is consistent with a type II hypersensitivity reaction, while a granular pattern is seen with a type III hypersensitivity reaction. The latter may also reveal fibrinoid necrosis around blood vessels, while eosinophils in an allergic nasal polyp are an example of a type I hypersensitivity reaction.

78. An allograft is a graft between

    a. A human and an animal

    b. Two individuals of different species

    c. Two individuals of the same species

    d. Two individuals of the same inbred strain

    e. Identical twins

ANS: C

Note:

An allograft is also called a homograft and refers to a graft between members of the same species. An autograft is a tissue graft taken from one site and placed in a different site in the same individual. Isografts are grafts between individuals from an inbred strain of animals. A graft between individuals of two different species is a xenograft or heterograft.

79. Minutes after a donor kidney is connected to the recipient’s blood vessels, the transplanted kidney turns blue, becomes flaccid, excretes a few drops of bloody urine, and has to be removed. Histologic examination of the kidney reveals neutrophils within arterioles, glomeruli, and peritubular capillaries. Immunoglobulin and complement are found to be deposited in blood vessel walls. This type of transplant rejection is due primarily to

    a. Donor cytotoxic T lymphocytes that are directed against host antigens

    b. Host cytotoxic T lymphocytes that are directed against donor antigens

    c. Donor natural killer cells that are directed against host antigens

    d. Preformed donor antibodies that are directed against host antigens

    e. Preformed host antibodies that are directed against donor antigens

ANS: E

Note:

The rejection of organ transplants involves both humoral and cell-mediated immunologic reactions. Hyperacute rejection, due to preformed host antibodies that are directed against antigens of the graft, occurs within minutes after transplantation. Histologically, neutrophils are found within the glomerulus and peritubular capillaries. These changes illustrate an antigen-antibody reaction at the vascular endothelium, similar to the Arthus reaction. Acute rejection may occur within days or much longer after transplantation. It is called acute because once it begins, the changes progress rapidly. Acute rejection can result from vasculitis or interstitial lymphocytic infiltration. The vasculitis is the result of humoral rejection (acute rejection vasculitis), while the interstitial mononuclear infiltrate is the result of cellular rejection (acute cellular rejection). Acute cellular rejection is responsive to immunosuppressive therapy, but acute rejection vasculitis is not. Subacute rejection vasculitis occurs during the first few months after transplantation and is characterized by the proliferation of fibroblasts and macrophages in the tunica intima of arteries. In chronic rejection, tubular atrophy, mononuclear interstitial infiltration, and vascular changes are found. The vascular changes are probably the result of the proliferative arteritis seen in acute and subacute stages. The vascular obliteration leads to interstitial fibrosis and tubular atrophy, resulting in loss of renal function.

In contrast, graft-versus-host (GVH) disease occurs when immunocompetent lymphocytes from the donor, usually from bone marrow or liver, attack the recipient’s tissue. GVH may be acute or chronic. Acute GVH is manifested by changes in the skin (dermatitis), the intestines (diarrhea, malabsorption), and the liver (jaundice). Chronic GVH produces changes in the skin (fibrosis) that are similar to the skin changes seen in patients with progressive systemic sclerosis.

80. An autoantibody that reacts to immunoglobulin (e.g., an anti-IgG autoantibody) is most characteristic of

    a. Bullous pemphigoid

    b. Diabetes mellitus

    c. Goodpasture’s disease

    d. Pemphigus vulgaris

    e. Rheumatoid arthritis

ANS: E

Note:

Autoantibodies can be directed against antigens in the nucleus or cytoplasm, or they can be directed against certain cells, proteins, structural antigens, or receptors. Autoantibodies against nuclear antigens (antinuclear antibodies or ANAs) are can be grouped into several categories. Antibodies may be directed against DNA, histones, nonhistone proteins bound to RNA, or nucleolar antigens. Antibodies to double-stranded DNA are specific for patients with SLE. Non-DNA nuclear components, called extractable nuclear antigens, include Sm antigen, ribonucleoprotein, SS-A and SS-B reactive antigens, and Scl-70. Autoantibodies to Smith antigen are specific for patients with SLE, antibodies to Scl-70 are specific for patients with progressive systemic sclerosis, and antibodies to either SS-A or SS-B or specific for patients with Sjögren’s syndrome. Anticentromere antibodies are found in patients with systemic sclerosis, especially in a subset of patients with the CREST syndrome.

Antimitochondrial antibodies are found in the majority of patients with primary biliary cirrhosis. Anti-smooth-muscle antibodies are characteristic of lupoid autoimmune hepatitis. Antineutrophil cytoplasmic antibodies (ANCAs) may be directed against myeloperoxidase or proteinase 3. The former produces a perinuclear pattern (P-ANCAs) and is seen in some patients with Wegener’s granulomatosis, but more often is associated with microscopic polyarteritis nodosa. The latter type of ANCA produces a cytoplasmic pattern (C-ANCAs) and is seen mainly in patients with Wegener’s granulomatosis. Antibodies to parietal cells of the stomach and intrinsic factor are seen in pernicious anemia, while antibodies to the microvasculature of muscle are seen in dermatomyositis. Autoantibodies to IgG (called rheumatoid factor) are present in patients with rheumatoid arthritis. This type of antibody may also be seen in patients with other types of autoimmune diseases. Antibodies to thyroglobulin are seen in Hashimoto’s thyroiditis, while antibodies against type IV collagen, which is found in the basement membranes of the lung and glomerulus, are seen in Goodpasture’s disease. Antibodies to antigens found in the intercellular space of the epidermis are seen with pemphigus vulgaris, while antibodies to antigens found in the epidermal basement membrane are seen with bullous pemphigoid. Acetylcholine receptor antibodies are seen with myasthenia gravis, thyroid hormone receptor antibodies are seen with Grave’s disease, and insulin receptor antibodies are seen with diabetes mellitus.

81. Anti-double-stranded DNA antibodies are most likely to be found in which one of the listed individuals?

    a. A 28-year-old female with arthritis and a bimalar photosensitive, erythematous rash on her face

    b. A 65-year-old female who develops Congo red–positive extracellular deposits in her liver

    c. A 29-year-old female who presents with trouble swallowing and sclerodactyly

    d. A 35-year-old female who presents with dry eyes, a dry mouth, and enlarged salivary glands

    e. A 47-year-old female who presents with periorbital lilac discoloration and erythema on the dorsal portions of her hands

ANS: A

Note:

Systemic lupus erythematosus (SLE) is a chronic, remitting and relapsing, often febrile multisystem disorder that predominantly affects the skin, kidneys, serosal membranes, and joints. Histologic sections of affected areas reveal vascular lesions with fibrinoid deposits consisting of accumulations of pink-staining homogeneous masses of fibrin, immunoglobulins, and other plasma proteins. SLE has a strong female predominance (10:1), and the disease usually arises in the second and third decades. There is a positive association between SLE and HLA-DR2 and DR3. Some drugs, especially procainamide and hydralazine, cause an SLE-like syndrome. Patients with hereditary C2 or C4 deficiencies also develop a lupuslike syndrome. Patients with SLE have marked B cell hyperactivity. This leads to a polyclonal production of antibodies to self and nonself antigens. Several autoantibodies to both nuclear and cytoplasmic cell components have been found, but antinuclear antibodies (ANAs) are the hallmark of SLE. Most of the visceral lesions in SLE result from the deposition of immune complexes; this is an example of a type III hypersensitivity reaction. The classic lesion involving the skin is an erythematous lesion over the bridge of the nose producing a “butterfly” pattern. Sunlight makes the rash worse. Histologically there is liquefactive degeneration of the basal layer of the epidermis with a perivascular lymphoid infiltrate. Deposits of immunoglobulin and complement can be demonstrated at the dermoepidermal junction. Finding immunoglobulin deposits in uninvolved skin is considered highly specific for SLE; this is called the lupus band test. The most common symptom is caused by involvement of the joints (arthritis), which produces a nonerosive synovitis. The heart may also be involved in patients with SLE. Small vegetations may develop on the heart valves and are called Libman-Sacks endocarditis. The major cause of death in patients with SLE is involvement of the kidneys leading to renal failure. There are deposits of DNA–anti-DNA complexes within the glomeruli. These deposits are found within the mesangium as well as in subendothelial and subepithelial locations. The subendothelial deposits produce wire-loop lesions and are particularly important. Other sites of involvement include the CNS, which may be life threatening, and serous membranes, which can produce pleuritis and pleural effusions.

In contrast, Congo red–positive extracellular deposits in the liver are diagnostic of amyloidosis; trouble swallowing with sclerodactyly is suggestive of progressive systemic sclerosis; the combination of dry eyes, a dry mouth, and enlarged salivary glands is suggestive of Sjögren’s syndrome; and periorbital lilac discoloration with erythema on the dorsal portion of her hands is suggestive of dermatomyositis. 

82. A 36-year-old female presents with increased trouble swallowing. Physical examination finds hypertension and sclerodactyly. A skin biopsy reveals dermal fibrosis with an absence of adnexal structures, while laboratory examination finds an autoantibody against DNA topoisomerase (anti-Scl-70). What is the best diagnosis for this individual?

    a. Dermatomyositis

    b. Mixed connective tissue disorder

    c. Progressive systemic sclerosis

    d. Sjögren’s syndrome

    e. Systemic lupus erythematosus

ANS: C

Note:

The combination of trouble swallowing, hypertension, and sclerosis of the skin should raise the possibility of progressive systemic sclerosis (scleroderma), a multisystem disease that involves the cardiovascular, gastrointestinal, cutaneous, musculoskeletal, pulmonary, and renal systems through progressive interstitial fibrosis. Small arterioles in the aforementioned systems show obliteration caused by intimal hyperplasia accompanied by progressive interstitial fibrosis. Evidence implicates a lymphocyte overdrive of fibroblasts to produce an excess of rather normal collagen. Eventually myocardial fibrosis, pulmonary fibrosis, and terminal renal failure ensue. Over half of these patients have dysphagia with solid food caused by distal esophageal narrowing.

83. An 87-year-old male develops worsening heart failure. Workup reveals decreased left ventricular filling due to decreased compliance of the left ventricle. Two months later the patient dies, and postmortem sections reveal deposits of eosinophilic, Congo red–positive material in the interstitium of his heart. When viewed under polarized light, this material displays an apple-green birefringence. What is the correct diagnosis?

    a. Amyloidosis

    b. Glycogenosis

    c. Hemochromatosis

    d. Sarcoidosis

    e. Senile atrophy

ANS: A

Note:

Amyloid is a generic term that describes special properties of any protein having a tertiary structure that produces a β-pleated sheet. Amyloid stains brown with iodine (“starchlike”). Histologically, the deposits always begin between or outside of cells. Eventually the amyloid deposits may strangle the cells, leading to atrophy or cell death. The histologic diagnosis of amyloid is based solely on its special staining characteristics. It stains pink with the routine hematoxylin and eosin stain, but, with Congo red stain, amyloid stains dark red and has an apple-green birefringence when viewed under polarized light.

There are many different types of proteins that stain as amyloid, and these are associated with a wide variety of diseases. These diseases may be either systemic, such as with immune dyscrasias, reactive diseases, or hemodialysis, or they may be localized, such as with senile or endocrine disorders.

Immune dyscrasias, such as multiple myeloma or B cell lymphomas, secrete amyloid light (AL) chains, while reactive systemic diseases secrete amyloid-associated (AA) protein. This protein is a polypeptide derived from serum amyloid-associated protein, which is produced in the liver. Systemic deposits of AA protein complicate various chronic infections and inflammatory processes, most commonly rheumatoid arthritis, other connective tissue diseases, bronchiectasis, and inflammatory bowel disease.

Patients on chronic hemodialysis may develop amyloid deposits consisting of β2-microglobulin. Patients with senile cardiac disease may develop amyloid deposits in the heart consisting of amyloid transthyretin (ATTR), while patients with senile cerebral disease, such as Alzheimer’s disease, may develop amyloid deposits in the brain consisting of β2-amyloid protein. Do not confuse β2-amyloid protein with β2-microglobulin, a component of the MHC class I molecule. Patients with medullary carcinoma of the thyroid, a malignancy of the calcitonin-secreting parafollicular C cells of the thyroid, characteristically have amyloid deposits of procalcitonin within the tumor. Patients with type II diabetes mellitus may have amyloid deposits within pancreatic islets consisting of islet amyloid polypeptide.

84. A 28-year-old woman’s first son dies at 7 months of age due to severe combined immunodeficiency disease (SCID). Subsequent workup reveals a mutation in the gene for the common γ chain of the interleukin 2 receptor (IL2RG). Lymphocyte and red cell adenosine deaminase (ADA) levels are within normal limits. Workup during the woman’s second pregnancy reveals that the fetus has the same abnormality found in her first son. Bone marrow is obtained from the 29-year-old father and is enriched with CD34+ cells (hematopoietic cell progenitors). It is then injected intraperitoneally by percutaneous, ultrasound-guided injection at 16, 17.5, and 18.5 weeks of gestation. At 11 months of life, the second child is found to be clinically normal. What is the mode of inheritance of this patient’s disease?

    a. Autosomal dominant

    b. Autosomal recessive

    c. Mitochondrial

    d. X-linked dominant

    e. X-linked recessive

ANS: E

Note:

Patients with severe combined immunodeficiency disease (SCID) have defects of lymphoid stem cells involving both T cells and B cells. These patients have severe abnormalities of immunologic function with lymphopenia. They are at risk for infection with all types of infectious agents, including bacteria, mycobacteria, fungi, viruses, and parasites. Patients have a skin rash at birth, possibly due to a graft-versus-host reaction from maternal lymphocytes. Patients are particularly prone to chronic diarrhea, due to rotavirus and bacteria, and to oral candidiasis. About 50% of patients with the autosomal recessive form (Swiss type) lack the enzyme adenosine deaminase (ADA) in their red cells and leukocytes. This leads to accumulation of adenosine triphosphate and deoxyadenosine triphosphate, both of which are toxic to lymphocytes. The other form of SCID is an X-linked form due to a defect in the IL-2 receptor.

85. Individuals homozygous for defective CCR5 are resistant to infection by

    a. CMV

    b. EBV

    c. HHV-6

    d. HHV-8

    e. HIV

ANS: E

Note:

Acquired immunodeficiency syndrome (AIDS) is caused by infection with the human immunodeficiency virus (HIV), which is an RNA retrovirus. The major genes of HIV are gag, pol, and env. gag encodes for precursor protein p55, which is processed by viral protease into other components that include p24 (the major core protein) and p7 (nucleocapsid). pol encodes viral enzymes including protease, reverse transcriptase, and integrase. Reverse transcriptase is an RNA-dependent DNA polymerase that converts viral RNA to DNA so it can be integrated into the host DNA. env encodes for envelope proteins, including gp120 and gp41. Levels of antibodies to gp120 are used to monitor the course of infection, while levels of p24 are used to measure virus load in the blood. HIV enters certain cells by binding to CD4 protein. The molecule on HIV that mediates this attachment is gp120 (a glycoprotein with a molecular weight of 120 kD). An additional ligand that is a cytokine receptor is also necessary for entry into cells. For example, after binding to CD4, new recognition sites on gp120 must bind to CCR5, which is the receptor for β-chemokine. Therefore, individuals homozygous for defective CCR5 are resistant to infection by HIV. After being infected with HIV, the CD4+ lymphocytes die. This results in a characteristic decrease in the peripheral CD4/DC8 cell ratio (which is normally about 2:1). CD4 is also present on other types of cells that may be reservoirs of HIV, including monocytes, macrophages, microglial cell of CNS, follicular dendritic cells of lymph nodes, and Langerhans cells of skin. In contrast to HIV, herpesviruses are large, encapsulated viruses that contain double-stranded DNA. Types of herpesviruses include HSV-1, HSV-2, varicella-zoster virus (VZV), CMV, human herpesvirus 6 (HHV-6, which causes a benign skin rash in infants), HHV-7, EBV, and HHV-8 (which causes Kaposi’s sarcoma).

86. A 52-year-old male presents with symptoms of gastric pain after eating. During workup, a 3-cm mass is found in the wall of the stomach. This mass is resected and histologic examination reveals a tumor composed of cells having elongated, spindle-shaped nuclei. The tumor does not connect to the overlying epithelium and is found only in the wall of the stomach. This tumor most likely originated from

    a. Adipocytes

    b. Endothelial cells

    c. Glandular epithelial cells

    d. Smooth muscle cells

    e. Squamous epithelial cells

ANS: D

Note:

The names given to tumors are based on the parenchymal component of the tumor, which consists of the proliferating neoplastic cells. In general, benign tumors are designated by using the suffix -oma attached to a name describing either the cell of origin of the tumor or the gross or microscopic appearance of the tumor. 

Examples of benign tumors whose names are based on their microscopic appearance include adenomas, which have a uniform proliferation of glandular epithelial cells; 

papilloma, which are tumors that form finger-like projections; 

fibromas, which are composed of a uniform proliferation of fibrous tissue; 

leiomyomas, which originate from smooth muscle cells and have elongated, spindleshaped nuclei; 

hemangiomas, which are formed from a uniform proliferation of endothelial cells; and lipomas, which originate from adipocytes. 

The suffix -oma is unfortunately still applied to some tumors that are not benign. Examples of this misnaming include melanomas, lymphomas, and seminomas.

87. A 64-year-old male presents with symptoms of anemia. On workup, you discover that the patient has been losing blood from the GI tract secondary to a tumor mass in his colon. The pathology report from a biopsy specimen indicates that this mass is an invasive adenocarcinoma. Which one of the listed descriptions best describes the most likely histologic appearance of this tumor?

    a. A uniform proliferation of fibrous tissue

    b. A disorganized mass of proliferating fibroblasts and blood vessels

    c. A disorganized mass of cells forming keratin

    d. A uniform proliferation of glandular structures

    e. A disorganized mass of cells forming glandular structures

ANS: E

Note:

Malignant tumors are generally classified as being either carcinomas or sarcomas. Carcinomas are malignant tumors of epithelial origin, while sarcomas are malignant tumors of mesenchymal tissue. 

Examples of malignant epithelial tumors (carcinomas) include adenocarcinomas, which consist of a disorganized mass of malignant cells that form glandular structures, and squamous cell carcinomas, which consist of a disorganized mass of malignant cells that produce keratin. 

Examples of malignant mesenchymal tumors include rhabdomyosarcoma, leiomyosarcomas, fibrosarcomas, and liposarcomas. One clue that a tumor has developed from skeletal muscle, such as a rhabdomyosarcoma, is the presence of cross-striations. These individual cells, seen histologically, are called strap cells. The wall of the stomach consists of smooth muscle, and a tumor that originates from these smooth-muscle cells will consist of proliferating cells with elongated, spindle-shaped nuclei. 

If a tumor of this type is benign it is called a leiomyoma, while if it is malignant it is called a leiomyosarcoma. This distinction is based on the number of mitoses that are present and the degree of atypia displayed by the neoplastic cells.

88. A 35-year-old male presents with the new onset of a “bulge” in his left inguinal area. After performing a physical examination, you diagnose the bulge to be an inguinal hernia. You refer the patient to a surgeon, who repairs the hernia and sends the resected hernia sac to the pathology laboratory along with some adipose tissue, which he calls a “lipoma of the cord.” The pathology resident examines the tissue grossly and microscopically and decides that it is not a neoplastic lipoma, but instead is nonneoplastic normal adipose tissue. Which one of the following features would have been present had the lesion been a lipoma rather than normal adipose tissue?

    a. Anaplasia

    b. Fibrous capsule

    c. Numerous mitoses

    d. Prominent nucleoli

    e. Uniform population of cells

ANS: B

Note:

Several gross and microscopic features help to differentiate benign neoplasms from malignant neoplasms. 

Benign neoplasms grow slowly with an expansile growth pattern that often forms a fibrous capsule. This histologic feature can also be useful in distinguishing a benign neoplastic lipoma from normal nonneoplastic adipose tissue. Benign neoplasms characteristically remain localized and do not metastasize. Histologically, benign neoplastic cells tend to be uniform and well differentiated; that is, they appear similar to their tissue of origin. This histologic feature may not distinguish between benign neoplasms and normal tissue. 

In contrast to benign tumors, malignant neoplasms grow rapidly in a crablike pattern and are capable of metastasizing. Histologically, the malignant cells are pleomorphic because they differ from one another in size and shape. These cells have hyperchromatic nuclei and an increased nuclear-to-cytoplasmic ratio.

Malignant cells tend to have nucleoli, and mitoses may be frequent. These two features only indicate rapidly proliferating cells and can also be seen in reactive or reparative processes. The mitoses in malignancies, however, tend to be atypical, such as tripolar mitoses. 

Malignant tumors are graded by their degree of differentiation as well differentiated, moderately differentiated, or poorly differentiated. 

Marked pleomorphism is described as anaplasia. This histologic feature is usually seen in poorly differentiated or undifferentiated malignancies.

89. Which one of the listed numbered sequences best illustrates the postulated sequence of events that precedes the formation of an infiltrating squamous cell carcinoma of the cervix?

        1 = Carcinoma in situ

        2 = Invasive carcinoma

        3 = Mild dysplasia

        4 = Moderate dysplasia

        5 = Severe dysplasia

        6 = Squamous metaplasia

    a. 3, then 4, then 5, then 1, then 6, then 2

    b. 3, then 4, then 5, then 6, then 1, then 2

    c. 5, then 4, then 3, then 1, then 6, then 2

    d. 6, then 3, then 4, then 5, then 1, then 2

    e. 6, then 4, then 3, then 5, then 2, then 1

ANS: D

Note:

Some epithelial malignancies (carcinomas) are preceded by disordered growth (dysplasia) of the epithelium. One example of this is the development of squamous cell carcinoma of the uterine cervix. The normal cervix is lined by a stratified layer of squamous epithelium, while the endocervix is composed of mucussecreting columnar epithelial cells. In response to chronic inflammation, the columnar epithelial cells change to stratified squamous epithelial cells. This change—squamous metaplasia—is characterized histologically by normal-appearing stratified squamous epithelium overlying endocervical glands. Next, infection with human papillomavirus (HPV) causes dysplastic changes within the epithelium. These dysplastic changes are characterized by disorganized stratified squamous epithelium with mitoses located above the basal layers of the epithelium. The cells themselves are pleomorphic and have hyperchromatic nuclei. The intraepithelial dysplasia is divided into three types based on the degree of dysplasia present and the location of mitoses. In mild dysplasia there are mitoses in the basal onethird of the epithelium; in moderate dysplasia mitoses occur in the middle one-third of the epithelium; and in severe dysplasia there are mitoses in the upper one-third of the epithelium. When the dysplastic changes involve the full thickness of the epithelium, it is referred to as carcinoma in situ (CIS). Next, the neoplastic cells start to invade the underlying tissue, forming an invasive squamous cell carcinoma.

90. During a routine physical examination, a 49-year-old male is found to have a 2.5-cm “coin lesion” in the upper lobe of his left lung. The lesion is removed surgically, and histologic sections reveal sheets of malignant cells with clear cytoplasm (clear cell carcinoma). This lung lesion is most likely a metastasis from the

    a. Appendix

    b. Breast

    c. Kidney

    d. Pancreas

    e. Stomach

ANS: C

Note:

The most common histologic type of cancer at a given site generally reflects the normal histology of that site. For example, squamous cell carcinomas arise in organs that are normally lined by stratified squamous epithelium. That is, sites associated with the development of squamous cell carcinoma include the skin, lung, esophagus, and cervix. Adenocarcinomas arise from glandular epithelium, and therefore sites associated with the development of adenocarcinoma include the lung, colon, stomach, prostate, and endometrium. Sites for transitional cell carcinoma include the urinary bladder and kidney (renal pelvis). Two types of cancer associated with special sites include clear cell carcinoma and signet cell carcinoma. Sites for clear cell carcinoma include the kidney (renal cortex) and vagina, the latter being associated with previous diethylstilbestrol (DES) exposure, while signet cell carcinoma is seen in the stomach and ovaries. In this malignancy the cells infiltrate individually instead of forming recognizable glandular structures. Each individual cell is filled with a large drop of mucin, which pushes the nucleus to the side, giving it the appearance of a signet ring.

91. v-oncs are a type of oncogene that are most characteristically found within

    a. Acute-transforming viruses

    b. Fungi and parasites

    c. Gram-negative bacteria

    d. Gram-positive bacteria

    e. Slow-transforming viruses

ANS: A

Note:

Many cancers originate in association with the abnormal activation of cellular proto-oncogenes (p-oncs), which are cellular genes that promote normal growth and differentiation. The protein product of a proto-oncogene is often a growth factor, a growth factor receptor, or a protein kinase. A cellular proto-oncogene may function as a cellular oncogene (c-onc) if it produces more of its protein product than it normally should. These normal cellular proto-oncogenes may become oncogenic (tumor-forming) by several mechanisms, including gene mutations, translocations, amplification, or interaction with viruses. Increased transcription of proto-oncogenes can result from the integration of viral controller sequences into cellular DNA; this process is associated with retroviruses. 

These RNA viruses are characterized by having three specific genes: gag (which codes for core protein), pol (which codes for the polymerase reverse transcriptase), and env (which codes for the envelope protein). In addition, these genes are flanked by long terminal repeat units (LTRs), which can turn on genes that are located near to the LTRs. These LTRs can turn on nearby p-oncs (making them c-oncs) by either a slow process of a fast process. The fast way involves first incorporating these proto-oncogenes into the genome of acute-transforming retroviruses by a process called retroviral transduction. These oncogenes are transduced (captured) by the virus through a chance recombination with the DNA of a normal host cell. These gene sequences within these viruses, now called viral oncogenes (v-oncs), are capable of rapid induction of tumors because, being located within the viral genome, they are always located near the LTRs. This process is called acute transformation. It is important to note also that these acute-transforming viruses do not contain the pol gene, so they cannot replicate on their own. Proto-oncogenes may also become oncogenic via slow-transforming viruses, which by chance can be inserted near a proto-oncogene. These viruses may either induce a structural change in the cellular gene (converting it into a cellular oncogene, or c-onc), or the retroviral promoters may turn on the cellular gene (by means of the viral LTRs). This process is called insertional mutagenesis.

92. Point mutations of the oncogene c-ras can result in the inability of the product of this oncogene to bind with

    a. GAP

    b. p210

    c. p53

    d. pRb

    e. WT1

ANS: A

Note:

Oncoproteins, which are the protein products of oncogenes, are signal-transducing proteins that are located on the inner leaflet of the plasma membrane. They can be grouped into two major categories: guanosine triphosphate (GTP)–binding proteins and non-receptor-associated tyrosine kinases.

GTP-binding proteins include the ras family and the G proteins. Mutation of the ras gene is the single most common abnormality of dominant oncogenes in human tumors and is found in about one-third of all human tumors. 

Normal ras protein (p21) flips back and forth between an activated, signal-transmitting form and an inactive state. In the inactive state, p21 binds GDP, but when cells are stimulated by growth factors, p21 becomes activated by exchanging GDP for GTP, and it can then stimulate MAP kinases and protein kinase C. In normal cells the activated sinaltransmitting stage of ras protein bound to GTP is transient because its intrinsic GTPase activity hydrolyzes GTP to GDP, which returns it to its inactive state. The GTPase activity of normal ras protein is accelerated by GTPase-activating proteins (GAPs), which function as brakes to prevent uncontrolled ras activity. Mutant ras proteins bind GAP, but their GTPase activity is not increased, trapping the mutant proteins in their excited, GTP-bound form.

93. A 4-year-old African boy develops a rapidly enlarging mass that involves the right side of his face. Biopsies of this lesion reveal a prominent “starry sky” pattern produced by proliferating small, noncleaved malignant lymphocytes. Based on this microscopic appearance, the diagnosis of Burkitt’s lymphoma is made. This neoplasm is associated with chromosomal translocations that involve

    a. bcl-2

    b. c-abl

    c. c-myc

    d. erb-B

    e. N-myc

ANS: C

Note:

There are several mechanisms through which proto-oncogenes (p-oncs) can become oncogenic (c-oncs). Normal cellular genes (proto-oncogenes) may become oncogenic by being incorporated into the viral genome (forming v-oncs), or they may be activated by other processes to form cellular oncogenes (c-oncs). These other processes include gene mutations, chromosomal translocations, and gene amplifications. Gene mutations, such as point mutations, are associated with the formation of cancers by mutant c-ras oncogenes. Chromosomal translocations are associated with the development of many types of cancers, one example of which is Burkitt’s lymphoma. The most common translocation associated with Burkitt’s lymphoma is t(8;14), in which the c-myc oncogene on chromosome 8 is brought in contact with the immunoglobulin heavy chain gene on chromosome 14. Two other examples of chromosomal translocations are the association of chronic myelocytic leukemia (CML) with t(9;22), which is the Philadelphia chromosome, and the association of follicular lymphoma with the translocation t(18;14). The former involves the proto-oncogene c-abl, which is rearranged in proximity to a break point cluster region (bcr) on chromosome 22. The resultant chimeric c-abl/bcr gene encodes a protein with tyrosine kinase activity. The t(18;14) translocation involves the bcl-2 oncogene on chromosome 18. Expression of the oncogene bcl-2 is associated with the prevention of apoptosis in germinal centers. Examples of associations that involve gene amplification include N-myc and neuroblastoma, c-neu and breast cancer, and erb-B and breast and ovarian cancer. Gene amplifications can be demonstrated by finding doublet minutes or homogenous staining regions.

94. The product of the p53 antioncogene is a nuclear protein that regulates DNA replication and prevents the proliferation of cells with damaged DNA by stopping their cell cycle

    a. Between G1 and S

    b. Between G2 and M

    c. Between M and G1

    d. Between S and G2

    e. During G3

ANS: A

Note:

In contrast to proto-oncogenes, which are genes that encode for proteins stimulating cell growth, cancer suppressor genes (antioncogenes) encode for proteins that suppress cell growth. Examples of tumor suppressor genes are Rb (associated with retinoblastoma), p53, APC, NF1, DCC, and WT1. In general, these tumor suppressor genes encode proteins that can function as cell surface molecules, regulators of signal transduction, or regulators of nuclear transcription. The DCC gene codes for a cell surface molecule that can transmit negative signals such as contact inhibition. NF1 is associated with regulating signal transduction. It codes for a GAP that binds to a ras protein and then increases GTPase activity, which inactivates ras product. Loss of normal NF1 functioning causes ras to be trapped in an active state. Genes that regulate nuclear transcription include Rb, p53, and WT1. Products of these genes are found within the nucleus and are involved in regulation of the cell cycle. The product of the Rb gene is a nuclear phosphoprotein that regulates the cell cycle at several points. It exists as an active unphosphorylated form (pRb) and an inactive phosphorylated form (pRb-P). The active unphosphorylated form (pRb) normally stops the cell cycle at G1 going to S. It does this by binding to transcription factors such as the product of c-myc and the E2F protein. When pRb is phosphorylated, the cell can enter S and complete the cell cycle. Inactivation of the pRb stop signal causes the cell to continually cycle and undergo repeated mitosis. The product of the p53 gene is also a nuclear protein that regulates DNA replication. The normal p53 prevents the replication of cells with damaged DNA. It does this by pausing cells during G1 (before S), giving the cells time to repair the damaged DNA. The p53 gene, located on chromosome 17, is the single most common target for genetic alterations in human cancers. It is found in many cases of colon, breast, and lung cancers. Mutations in the adenomatous polyposis coli (APC) gene lead to the development of tumors that may progress to adenocarcinomas of the colon, while deletion of WT1, located on chromosome 11, is associated with the development of Wilms tumor, a childhood neoplasm of the kidney.

95. A 76-year-old male farmer presents with a 2-cm mass on the left side of his forehead. A biopsy reveals squamous cell carcinoma. Which one of the following causes the formation of pyrimidine dimers in DNA and is associated with the formation of squamous cell carcinoma?

    a. Aflatoxin B1

    b. Vinyl chloride

    c. UVC

    d. UVB

    e. Epstein-Barr virus

ANS: D

Note:

Ultraviolet rays are associated with the formation of skin cancers, including squamous cell carcinoma, basal cell carcinoma, and malignant melanoma. The ultraviolet portion of the spectrum (ultraviolet rays) is divided into three wavelength ranges: UVA (320 to 400 nm), UVB (280 to 320 nm), and UVC (200 to 280 nm). UVB is the wavelength range that is responsible for the induction of skin cancers. The carcinogenic property of UVB is related to the formation of pyrimidine dimers in DNA. UVC, although a potent mutagen, is not significant because it is filtered out by the ozone layer around the earth.

Some DNA viruses and RNA viruses are associated with the development of dysplasia and malignancy. For example, infection with human papillomavirus (HPV), especially types 16 and 18, is associated with cervical dysplasia; Epstein-Barr virus (EBV) is associated with Burkitt’s lymphoma and nasopharyngeal carcinoma; hepatitis B virus (HBV) and hepatitis C virus (HCV) are associated with primary hepatocellular carcinoma; and HHV-8 is associated with Kaposi’s sarcoma. HTLV-I is an RNA retrovirus that is associated with the formation of a peculiar type of hematologic malignancy called adult T cell leukemia/lymphoma. These patients have malignant cells in their lymph nodes and blood. This malignancy is endemic in southern Japan and the Caribbean region.

96. A 17-year-old male presents with a lesion on his face that measures approximately 1.5 cm in its greatest dimension. He has a history of numerous similar skin lesions that have occurred mainly in sun-exposed areas. The present lesion is biopsied and reveals an invasive squamous cell carcinoma. This patient most probably has one type of a group of inherited diseases associated with unstable DNA and increased incidence of carcinoma.

What is the diagnosis for this patient?

    a. Xeroderma pigmentosa

    b. Wiskott-Aldrich syndrome

    c. Familial polyposis

    d. Sturge-Weber syndrome

    e. Multiple endocrine neoplasia type I (MEN I)

ANS: A

Note:

Hereditary factors are important in the development of many types of cancers. They are particularly important in several inherited neoplasia syndromes. The autosomal recessive DNA-chromosomal instability syndromes include ataxia-telangiectasia, Bloom’s syndrome, Fanconi’s anemia, and xeroderma pigmentosa. These disorders have in common abnormalities involving the normal repair of DNA. Patients with xeroderma pigmentosa have defective endonuclease activity, which normally repairs the pyrimidine dimers found in DNA damaged by ultraviolet (UV) light. These patients have an increased incidence of skin cancers, including basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. 

Wiskott-Aldrich syndrome, characterized by thrombocytopenia and eczema, is an immunodeficiency disease associated with an increased incidence of lymphomas and acute leukemias. 

Familial polyposis is characterized by the formation of numerous neoplastic adenomatous colon polyps. These individuals have a 100% risk of developing colorectal carcinoma unless surgery is performed. 

Sturge-Weber syndrome is a rare congenital disorder associated with venous angiomatous masses in the leptomeninges and ipsilateral port-wine nevi of the face. 

Multiple endocrine neoplasia (MEN) syndrome type 1 (Wermer’s syndrome) refers to the combination of adenomas of the pituitary, adenomas or hyperplasia of the parathyroid glands, and islet cell tumors of the pancreas.

97. Gastric carcinoma is most common in which one of the listed geographic locations?

    a. Canada

    b. France

    c. Japan

    d. United Kingdom

    e. United States

ANS: C

Note:

There are marked differences in the incidence of various types of cancer in different parts of the world. The highest rates for gastric carcinoma are found in Japan, Chile, China, and Russia, while it is much less common in the United States, the United Kingdom, Canada, and France. 

The high rates for gastric cancer in Japan might be related to dietary factors, such as eating smoked and salted foods. Other examples of geographic variations in the incidence of neoplasms include nasopharyngeal carcinoma, liver cancer, and trophoblastic disease. 

Nasopharyngeal carcinoma, associated with the Epstein-Barr virus, is rare in most parts of the world, except for parts of the Far East, especially China. Liver cancer is associated with both hepatitis B infection and high levels of aflatoxin B1. It is endemic in large parts of Africa and Asia. Trophoblastic diseases, including choriocarcinoma, have high rates of occurrence in the Pacific rim areas of Asia. In contrast, Asian populations have a very low incidence of prostate cancer.

98. A 57-year-old male presents with signs of fatigue that are the result of anemia. Workup reveals that his anemia is the result of bleeding from a colon cancer located in the sigmoid colon. The lesion is resected and at the time of surgery no metastatic disease is found. Which of the listed markers would be most useful for future follow-up of this patient for the evaluation of possible metastatic disease from his colon cancer?

    a. α fetoprotein (AFP)

    b. Carcinoembryonic antigen (CEA)

    c. Chloroacetate esterase (CAE)

    d. Human chorionic gonadotropin (hCG)

    e. Prostate-specific antigen (PSA)

ANS: B

Note:

Tumor markers are a diverse group of biochemical substances associated with the presence of some tumors. These tumor markers include hormones, oncofetal antigens, isozymes, proteins, mucins, and glycoproteins. Carcinoembryonic antigen (CEA) is a glycoprotein associated with many cancers including adenocarcinomas of the colon, pancreas, lung, stomach, and breast. It is used clinically to follow up patients with certain malignancies, such as colon cancer, and to evaluate them for recurrence or metastases. Human chorionic gonadotropin (hCG) is a hormone associated with trophoblastic tumors, especially choriocarcinoma. α fetoprotein (AFP) is a glycoprotein synthesized by the yolk sac and the fetal liver and is associated with yolk sac tumors of the testes and liver cell carcinomas. Prostatespecific antigen (PSA) and prostatic acid phosphatase (PAP) are associated with cancer of the prostate. Chloroacetate esterase (CAE), not to be confused with CEA, is a histochemical stain used in the differentiation of acute leukemias. It is not considered to be a tumor marker.

99. A 23-year-old female presents with the recent onset of vaginal discharge. Physical examination reveals multiple clear vesicles on her vulva and vagina. A smear of material obtained from one of these vesicles reveals several multinucleated giant cells with intranuclear inclusions and groundglass nuclei. These vesicles are most likely the result of an infection with

    a. Cytomegalovirus (CMV)

    b. Herpes simplex virus (HSV)

    c. Human papillomavirus (HPV)

    d. Candida albicans

    e. Trichomonas vaginalis

ANS:

Note:

The cytopathic effect of viruses is often a clue to the diagnosis of the type of infection that is present. There are several types of herpesviruses, which are relatively large, double-stranded DNA viruses. Infection by herpes simplex virus (HSV) or varicella-zoster virus (VZV) is recognized by nuclear homogenization (ground-glass nuclei), intranuclear inclusions (Cowdry type A bodies), and the formation of multinucleated cells. 

Herpes simplex type 2, a sexually transmitted viral disease, results in the formation of vesicles that ulcerate and cause burning, itching, and pain. These lesions heal spontaneously, but the virus remains dormant in the lumbar and sacral ganglia. Recurrent infections may occur, and transmission to the newborn during delivery is a feared complication that may be fatal to the infant. Shingles and chickenpox are caused by herpes zoster, which is identical to varicella. 

Cytomegalovirus (CMV) causes both the nucleus and the cytoplasm of infected cells to become enlarged. Infected cells have large, purple intranuclear inclusions surrounded by a clear halo and smaller, less prominent basophilic intracytoplasmic inclusions.

Adenoviruses can produce similar inclusions, but the infected cells are not enlarged. Adenoviruses also produce characteristic smudge cells in infected respiratory epithelial cells. 

Human papillomavirus (HPV) infection may produce a characteristic effect that is called koilocytosis. Histologic examination reveals enlarged squamous epithelial cells that have shrunken nuclei (“raisinoid”) within large cytoplasmic vacuoles. 

Candidiasis is the most common fungal infection of the vagina and is especially common in patients who have diabetes or take oral contraceptives. Candida infection causes vulvar itching and produces a white discharge. Microscopic examination of the vaginal discharge reveals yeast and pseudohyphae. T. vaginalis, a large, pear-shaped, flagellated protozoan, causes severe vaginal itching with dysuria. It produces a thick yellow-gray discharge.

100. A 19-year-old man living in New Mexico presents to a local clinic after a 1-day history of fever, myalgia, chills, headache, and malaise. He complains of vomiting, diarrhea, abdominal pain, tachypnea, and a productive cough. His white cell count is elevated with an increase in the number of bands. Atypical lymphocytes are also found in the peripheral blood. He is treated with antibiotics, but the next day he develops acute respiratory failure with cardiopulmonary arrest and dies. Postmortem examination of the lungs reveals intraalveolar edema, rare hyaline membranes, and a few interstitial lymphoid aggregates. The most likely cause of this patient’s illness is infection with

    a. Ebola virus

    b. Dengue fever virus

    c. Hantavirus

    d. Yellow fever virus

    e. Alphavirus

ANS: C

Note:

The Hantavirus genus belongs to the Bunyaviridae family and includes the causative agent of a group of diseases that occur throughout Europe and Asia and are referred to as hemorrhagic fever with renal syndrome. The characteristic features of this syndrome are hematologic abnormalities, renal involvement, and increased vascular permeability. Respiratory involvement is generally minimal in these diseases. Although several species of rodents in the United States are known to be infected with Hantavirus, no human cases were reported until an outbreak of severe, often fatal respiratory illness occurred in the United States in May 1993 in the Four Corners area of New Mexico, Arizona, Colorado, and Utah. This illness resulted from a new member of the genus Hantavirus that caused a severe disease characterized by a prodromal fever, myalgia, pulmonary edema, and hypotension. The main distinguishing feature of this illness, which is called Hantavirus pulmonary syndrome, is noncardiogenic pulmonary edema resulting from increased permeability of the pulmonary capillaries. Laboratory features common to both Hantavirus pulmonary syndrome and hemorrhagic fever with renal syndrome include leukocytosis, atypical lymphocytes, thrombocytopenia, coagulopathy, and decreased serum protein concentrations. Abdominal pain, which can mimic an acute abdomen, may be found in both Hantavirus pulmonary syndrome and hemorrhagic fever with renal syndrome.

Dengue fever virus is a type of flavivirus; flaviviruses which are similar to alphaviruses. Dengue fever (breakbone fever) is initially similar to influenza but then progresses to a rash, muscle pain, joint pain, and bone pain. It can produce a potentially fatal hemorrhagic disorder. Yellow fever virus, which causes yellow fever, is another flavivirus. It is spread by a mosquito and produces characteristic coagulative necrosis of liver acinar zone 2 (midzonal necrosis). The necrotic hepatocytes produced by the process of apoptosis in the absence of inflammation result in Councilman bodies. Because of liver failure, patients become jaundiced (hence the term yellow fever) and may vomit clotted blood (“black vomit”). Another flavivirus is the cause of St. Louis encephalitis, which is spread by the Culex mosquito. Alphaviruses, a type of togavirus, are similar to flaviviruses. They are the prototypical arboviruses, which are arthropod-born viruses. Clinical diseases include eastern equine encephalitis (EEE), western equine encephalitis (WEE), and Venezuelan equine encephalitis (VEE). Ebola virus is a member of the Filoviridae family that causes a severe hemorrhagic fever. Outbreaks occur in Africa and typically make the national news.