Section IV. Disorders of Development & Growth

This section deals with abnormalities that occur in cellular growth and development of the individual from conception to death. Chapter 15: Disorders of Development describes abnormalities occurring during fetal development, abnormalities of postnatal development, abnormalities of sexual development, and aging.

In addition, throughout life, cells grow, undergo mitotic division, differentiate, and die in a controlled fashion that maintains the normal size and structure of tissues. Abnormalities in these processes are described in Chapters 16, Chapters 17, Chapters 18, 19, with special emphasis on neoplasia (Chapters 17Chapters 18, 19).

The initial divisions of the fertilized ovum (zygote) create a mass of cells (blastocyst) consisting of an inner cell mass (the embryonic disk) surrounded by an outer layer (the trophoblast). The cells of the trophoblast actively penetrate the endometrium and form the placenta.

The cells of the embryonic disk are totipotential (ie, they have the capacity to produce all cells of the body). Initial differentiation into the three primary germ layers—ectoderm, mesoderm, and endoderm—ultimately gives rise to the organs of the body through division, organization, and differentiation. The mass of primitive cells from which an organ develops is known as the anlage. A fully developed organ is composed of highly differentiated cells committed to the performance of particular functions and having limited residual capacity for division. Most human organs are fully formed and functional at birth. Organs such as the heart complete development earlier in fetal life than others such as the lung, which reaches maturity after the thirty-fourth week. The brain shows considerable development after birth, attaining maturity at about age 7 years. Sexual development culminates at puberty.

Definitions

(Figure 15-1)

Agenesis

Failure of development of a primitive organ anlage in the embryo results in agenesis—complete absence of the organ. Agenesis of a vital organ such as the heart or brain leads to death of the fetus in utero. If the tissue is not vital or is one of a pair of organs, such as a kidney, the remainder of the embryo may develop normally.

Dysgenesis

Abnormal differentiation of the anlage leads to a structurally abnormal organ. For example, in renal dysgenesis, a mass of tissue composed of abnormal epithelium-lined cysts and mesenchymal tissues such as cartilage is found instead of a normal kidney (Figure 15-2). Dysgenesis sometimes affects only part of an organ.

Hypoplasia and Aplasia

When the anlage differentiates normally but growth or development ends prematurely, a structurally normal but small organ results (hypoplasia). In aplasia, the organ is completely absent. Aplasia can be distinguished from agenesis only if an undeveloped anlage or its vascular connections can be identified. In agenesis, there is no anlage or vascular pedicle.

Causes of Fetal Abnormalities

In most instances, the exact cause of fetal abnormalities is unknown. Known causes fall into two major groups: those affecting the genome and those acting mainly on the proliferating cells of the embryo or fetus. Almost any cause of injury to a child or adult (Table 15-1) may also act on the fetus. Although the fetus is in a sheltered environment, it is particularly susceptible to injury during times of rapid cell multiplication and primary differentiation of organs. In addition, normal growth of the fetus is critically dependent upon normal expression of genetic information and the integrity of the placenta and maternal blood flow. The most severe fetal abnormality is death, termed spontaneous abortion in the first 14 weeks and intrauterine death thereafter.

Fetal Abnormalities Caused by Genetic Disorders

The term mutation is used broadly to denote any stable heritable genetic change, whether or not it is associated with detectable structural abnormalities of the chromosomes.

Cytogenetics

Peripheral blood lymphocytes or skin fibroblasts are induced to divide and then arrested in metaphase with colchicine. The individual chromosomes, which become separated at metaphase, can then be identified by special staining techniques (banding with Giemsa stain or fluorescent dyes). The arrangement of an individual's chromosomes in the proper sequence is known as the karyotype (Figure 15-3). Cytogenetic methods can only detect changes in chromosomal number or major structural changes (chromosomal aberrations) that are sufficiently large to be seen by banding techniques (Figure 15-3; see also Figure 15-9). Such visible changes involve at least 1 million base pairs and may affect multiple genes. The clinical effects of such changes are therefore usually severe.

Molecular Genetics

This term embraces a number of related methods that incorporate recombinant deoxyribonucleic acid (DNA) technology and are able to detect a mutation (substitution or deletion) of even a single base pair. The classic approach commences with isolation of the gene product, followed by determination of the amino acid sequence and hence the messenger ribonucleic acid (mRNA), following which the gene is cloned and its chromosomal location identified. In the reverse approach, a disease locus (abnormal gene) is identified by mapping its location in relation to known marker genes (such as blood groups or various enzymes) through family linkage studies. Synthetic DNA probes can then be prepared. Under suitable conditions, these will bind with complementary DNA sequences on the chromosomes and can be visualized by labeling techniques (in situ hybridization, using radiographic, fluorescent, or enzymatic labels). Suitably configured probes permit visualization of whole chromosomes by targeting multiple repeat sequences (chromosome painting), or translocations, or even mutations involving a single nucleotide change following amplification of the region of interest by the polymerase chain reaction (PCR). An alternative simpler method of detecting mutations involves cutting the chromosomes into numerous fragments by the use of restriction enzymes. The resulting DNA fragments can then be displayed on a Southern blot. Changes in nucleotide sequence yield differently sized fragments (restriction fragment length polymorphism [RFLP]).

Chromosomal Aberrations

Normal Chromosomal Complement

The normal human cell has 46 chromosomes: 22 pairs of autosomes and two sex chromosomes (Figure 15-3). One of each of these homologous pairs of chromosomes is derived from each parent.

The autosomes are divided into seven groups (A–G) on the basis of the size and position of the centromeres (Figure 15-3).

The sex chromosomes are a pair of X chromosomes in the female and an X and a Y chromosome in the male. The genetic sex of an individual may be ascertained by examination of the karyotype, which is very accurate, or by examination of cells for the presence of a Barr body. When two X chromosomes are present in a cell, as in a normal female, one of them—the Barr body—becomes inactivated and condensed on the nuclear membrane. Absence of Barr bodies indicates that the cell has only one X chromosome (normal male: XY; Turner syndrome: XO). Barr bodies are most easily seen in a smear of squamous epithelial cells obtained by scraping the buccal mucosa. The Y chromosome can be identified in interphase nuclei by its strong fluorescence in ultraviolet light after it has been stained with quinacrine, and this is another means of establishing genetic sex.

Mechanisms of Chromosomal Aberrations

Nondisjunction in Meiosis

Nondisjunction is failure of paired homologous chromosomes to separate during the first meiotic division that leads to the production of gametes (ova and spermatozoa) (Figure 15-4). Thus, some gametes receive two and others receive none of the involved chromosome pair. After the second meiotic division, the resulting gametes will have 24 and 22 chromosomes. Such gametes are aneuploid (ie, the number of their chromosomes is not an exact multiple of 23, the haploid chromosome number for humans).

Union of an aneuploid gamete with a normal gamete leads to an aneuploid zygote that has either three of the involved chromosomes (trisomy) or only one (monosomy) (Figure 15-5).

Trisomy and monosomy involving the sex chromosomes are generally compatible with life, eg, Klinefelter syndrome (XXY) and Turner syndrome (XO). Autosomal monosomy, on the other hand, is associated with a profound loss of genetic material and is usually lethal. A few autosomal trisomies (21, 13, and 18) may be compatible with survival but are associated with severe abnormalities.

Nondisjunction in Mitosis

Nondisjunction of the early zygote during mitotic division produces mosaicism: the presence in an individual of two or more genetically different cell populations (Figure 15-5). In this type of nondisjunction (which may also occur during the second meiotic division), the two chromatids of a duplicated chromosome fail to divide. Mosaic individuals manifest phenotypic abnormalities that are intermediate between those associated with the two cell populations; eg, 45,X/46,XX is a Turner syndrome mosaic karyotype, and the individual's appearance will be somewhere between that of a normal female and those of an individual with classic Turner syndrome (45,XO).

Deletion

Deletion is loss of part of a chromosome after chromosomal breakage. Most deletions are lethal because a great deal of genetic material is lost. Deletions of the short arms of chromosomes 4 and 5 produce well-defined clinical syndromes (Wolf's syndrome and cri du chat syndrome, respectively). Partial deletions are common in malignant neoplastic cells (Chapters 18: Neoplasia: II. Mechanisms & Causes of Neoplasia and Chapter 19: Neoplasia: III. Biologic & Clinical Effects of Neoplasms).

Translocation

Translocation is the transfer of a broken segment of one chromosome to another chromosome. In balanced translocations, all genetic material is present and functional, and the individual is phenotypically normal.

The most common balanced translocation is transfer of the entire 21 chromosome to chromosome 14. Such an individual has 45 chromosomes, with absence of one each of chromosomes 14 and 21 and the presence of an abnormal, large chromosome containing the material of both chromosomes 14 and 21; assuming the patient is male, the karyotypic designation is 45,XY,t(14;21). The gametes produced by such an individual may be abnormal (Figure 15-6); offspring with monosomy 21 (incompatible with life) and translocation-type Down syndrome may result.

Other balanced translocations are being recognized as an important cause of habitual or repeated abortion. Still others occur in malignant tumors (Table 19-2). The Philadelphia chromosome (t[9;22]) in chronic granulocytic leukemia is the best-known example (Figure 19-3).

Other Chromosomal Rearrangements

Inversion and ring chromosome formation may occur after breakage or abnormal division of the centromere.

Single Base Changes

In addition, single changes (additions or deletions) in the composition of DNA bases result in misreading of the triplet code but cause no detectable structural changes in the chromosomes. These abnormalities constitute single gene disorders and are considered in a later section.

Note that an abnormality present in the germ line (gamete) will affect all of the cells of the body. This is typical of the major inherited disorders that will be described here and occurs also in some inherited tumors (eg, loss of a tumor suppressor gene in retinoblastoma; see Chapter 18: Neoplasia: II. Mechanisms & Causes of Neoplasia).

Genetic abnormalities that occur in other types of cancer are much more restricted in terms of the cells affected. These are discussed in Chapter 18: Neoplasia: II. Mechanisms & Causes of Neoplasia.

Causes of Chromosomal Aberrations

Most chromosomal defects occur at random without known cause, but in some cases a cause can be identified.

Increasing Maternal Age

Nondisjunction is associated with increasing maternal age, as is clearly shown in trisomy 21 (Down syndrome). The risk of trisomy 21, which is 1:1500 live births in women under 30 years of age, increases to 1:30 for women over 45 years of age. For this reason, routine chromosomal analysis of fetal cells obtained by amniocentesis is recommended for pregnancies occurring in women older than age 35 years. Increasing maternal age is also associated with other nondisjunction syndromes, eg, Klinefelter syndrome.

Ionizing Radiation

The incidence of chromosomal abnormalities is high in the survivors of the Nagasaki and Hiroshima atomic blasts. A safe low dose of ionizing radiation has not been established. Diagnostic abdominal x-rays should be avoided whenever possible in women who are pregnant or suspect they may be.

Drugs

Drugs and other chemical agents are an uncommon cause of structural chromosomal abnormalities. When used in early pregnancy, anticancer agents that interfere with DNA synthesis may cause chromosomal abnormalities that lead to fetal death. Many commonly used drugs, including aspirin, have been shown to cause karyotypic abnormalities in tissue culture; whether these drugs have this effect in vivo is unknown.

Common Autosomal Abnormalities

Down Syndrome (Trisomy 21)

Down syndrome is the most common autosomal disorder (1:700 live births overall). It results from the presence of three chromosome 21s, producing a characteristic clinical appearance (Figure 15-7). The infant has oblique palpebral fissures with a flat profile, upward-slanting eyes, and prominent epicanthal folds (a purported resemblance to Asian facial features, accounting for the older term mongolism). Severe mental retardation is a constant feature. Thirty percent of patients have congenital heart anomalies, most commonly ventricular septal defect. These children also have an increased susceptibility to infections, duodenal ulcers, and acute leukemia. Patients surviving into adulthood (50% or more) frequently develop presenile dementia with features of Alzheimer's disease. Beta amyloid protein is deposited in the lesions; interestingly, the beta amyloid gene is on chromosome 21.

Men with Down syndrome are generally infertile; women with the disease have borne children. The offspring of mothers with Down syndrome may be normal because the extra 21 chromosome is not transmitted to all gametes.

Three types of Down syndrome are recognized:

Nondisjunction Down Syndrome

Most cases (95%) of Down syndrome are due to this mechanism. These cases are associated with increasing maternal age (over age 35 years). The child has an extra 21 chromosome (47,XX,+21 or 47,XY,+21); the parents have normal karyotypes.

Translocation Down Syndrome

A few cases of Down syndrome (5%) are due to inheritance of a balanced translocation from one of the parents—commonly a 14,21 translocation (Figure 15-6), more rarely a 21,22 translocation. One parent carries the abnormal chromosome. The infant with Down syndrome has 46 chromosomes, one of which has the genetic material of both chromosomes 14 and 21. Translocation Down syndrome is not associated with increased maternal age but is familial.

Mosaic Down Syndrome

In this very rare type of Down syndrome, nondisjunction occurs during an early mitotic division in the developing embryo. Only one of two cell lines in the body shows trisomy for chromosome 21.

Edwards' Syndrome (Trisomy 18)

Trisomy 18 (47,XX/XY,+18) is rare. It produces severe defects, and few children survive beyond 1 year of age. Clinically, failure to thrive and severe mental retardation are accompanied by characteristic physical abnormalities such as rocker-bottom feet and clenched hands with overlapping fingers.

Patau's Syndrome (Trisomy 13)

Trisomy 13 (47,XX/XY,+13) is also rare. Most affected infants die soon after birth. Trisomy 13 is characterized by abnormal development of the forebrain (absent olfactory bulbs, fused frontal lobes, single ventricle) and midline facial structures (cleft lip, cleft palate, nasal defects, single central eye [cyclops]).

Cri Du Chat (Cat Cry) Syndrome

This disorder is caused by deletion of the short arm of chromosome 5. A mewing, cat-like cry is typical. Severe mental retardation and cardiac anomalies are common. Survival rates are slightly higher than those of patients with trisomy 18 or 13.

Microdeletions

Microdeletions of 13q14 (retinoblastoma gene) or 11p13 (Wilms tumor gene) are associated with a high incidence of specific childhood tumors (Chapter 18: Neoplasia: II. Mechanisms & Causes of Neoplasia). Other genes are also often deleted, leading to mental retardation and other changes in these patients.

Acquired Chromosomal Abnormalities

These occur quite commonly as somatic mutations in children and adults and are associated with a variety of neoplasms (Chapter 18: Neoplasia: II. Mechanisms & Causes of Neoplasia). The germ cells are usually not involved, and these anomalies are therefore not heritable.

Common Sex Chromosomal Abnormalities

Klinefelter Syndrome (Testicular Dysgenesis)

Klinefelter syndrome is common, with an incidence of 1:600 live male births. It is usually caused by nondisjunction of the X chromosome in the mother of the affected male child, resulting in an extra X chromosome (47,XXY) (Figures 15-8 and 15-9). More rarely, patients with Klinefelter syndrome have more than two X chromosomes (48,XXXY or 49,XXXXY).

The Y chromosome dictates testicular differentiation of the primitive gonad that results in a male phenotype. No abnormality is usually noted until puberty. The extra X chromosome interferes with normal development of the testis at puberty in some unknown manner. The testes remain small and typically do not produce spermatozoa (Figure 15-10). Patients are usually infertile. Testosterone levels are low, leading to failure of normal development of male secondary sexual characteristics. Patients tend to be tall (testosterone induces fusion of epiphyses) and of eunuchoid habitus with a high-pitched voice, small penis, and female distribution of hair (Figure 15-11). Gynecomastia (enlargement of breasts) may occur. Intelligence may be affected in a minority of cases.

The diagnosis of Klinefelter syndrome may be made by finding Barr bodies in a buccal scraping of a phenotypic male or by performing karyotypic analysis (Figure 15-9).

Turner Syndrome (Ovarian Dysgenesis)

Turner syndrome occurs in 1:2500 live female births. It is caused by nondisjunction of the X chromosome in either parent of an affected female, leading to absence of one X chromosome (45,XO; Figure 15-8). About half of patients with Turner syndrome show mosaicism (45,X/46,XX) owing to nondisjunction occurring in a postzygotic mitotic division. In a minority of cases, the second X chromosome is present but is grossly abnormal (isochromosome, partial deletion, etc).

Loss of the second X chromosome frequently causes fetal death, and many affected fetuses are aborted. Liveborn infants show lymphedema of the neck that persists into adulthood as a characteristic webbing of the neck (Figure 15-12). Congenital cardiac anomalies (most commonly coarctation of the aorta), short stature, obesity, and skeletal abnormalities (most typically an increase in the carrying angle of the forearm) are common. Intelligence is usually not affected.

In the presence of one X chromosome (and no Y chromosome), the primitive gonad develops as an ovary; the baby is phenotypically female but fails to develop at puberty. The absence of the second X chromosome causes failure of ovarian development at puberty. The ovaries remain small and lack primordial follicles (streak ovaries). Failure of estrogen secretion causes failure of the endometrial cycle (amenorrhea) and poor development of female secondary sex characteristics.

The diagnosis may be established by absence of Barr bodies in the buccal smear of a female and by karyotypic analysis.

XXX Syndrome (Superfemale)

The presence of a third X chromosome in a female causes the triple X disorder. Most patients are normal. A few show mental retardation, menstrual problems, and decreased fertility.

XYY Syndrome

The presence of an extra Y chromosome in a male causes XYY syndrome. Most patients appear normal. A minority may show aggressive behavior and mild mental retardation. The incidence is 1:1000 male births.

Fragile X Syndrome

This syndrome is associated with mental retardation in 80% of males who carry the abnormal chromosome but only 30% of females (perhaps due to preferential inactivation of the abnormal X chromosome). The abnormality consists of an unusually large number of repeat nucleotide triplets close to the tip of the long arm of the X chromosome (Xq27). Growth abnormalities may occur in addition to severe retardation. The frequency may be as high as 1:1000 in males and 1:2000 in females (see Table 15-4).

Single-Gene (Mendelian) Disorders

Dominant and Recessive Disorders

Diseases caused by a single abnormal gene are inherited in a manner predicted by mendelian laws. The pattern of inheritance depends on whether the abnormal gene is on a sex chromosome or an autosome and whether it is dominant or recessive.

If a gene has two alleles (alternative forms of the gene) A and a, three genotypes (AA, Aa, and aa) are possible. In homozygous genotypes (AA and aa) the two alleles are identical. In heterozygous genotypes (Aa), the alleles are different. The terms dominant and recessive denote the degree of expression of an allele. The mode of inheritance is dominant if only one abnormal allele is required for phenotypic expression of the disease (genotypes Aa, AA; Figure 15-13). A recessive trait, on the other hand, requires the presence of two abnormal alleles for expression of disease (genotype aa; Figure 15-14).

Analysis of the family history (pedigree) of an individual affected with a single-gene disease (proband; propositus or index case) is helpful in establishing the inheritance pattern of the disease.

Dominant Inheritance

If the A allele is abnormal, the disease is expressed in both the AA and the Aa genotypes (Figure 15-13). In diseases with dominant inheritance patterns, patients with the aa genotype are normal.

Recessive Inheritance

If the a allele is abnormal, however, the disease will occur only in the aa genotype (Figure 15-14). The person who is an Aa heterozygote for a recessive trait carries the abnormal gene but does not express the disease (heterozygous carrier of the trait). If the gene products of both the A and the a alleles can be detected in the Aa heterozygote, the disease is said to have a codominant mode of inheritance (ie, both alleles are expressed).

Autosomal Dominant Diseases

(Table 15-2.) Diseases with an autosomal dominant mode of inheritance have a characteristic family history (Figure 15-13; Table 15-3).

Many autosomal dominant diseases permit survival to adulthood. Transmission of the abnormal gene to the next generation only occurs following reproduction by affected individuals. Sporadic (nonfamilial) cases occur with varying frequency due to new mutations.

A characteristic of many autosomal dominant disorders is the variation in frequency with which the abnormal gene is manifested clinically as a disease (penetrance) and the degree of abnormality seen in different individuals (expressivity).

Autosomal Recessive Diseases

(Table 15-2.) Diseases with an autosomal recessive mode of inheritance also have a characteristic family history (Figure 15-14; Table 15-3).

Most autosomal recessive disorders are characterized by enzyme deficiency leading to biochemical defects that have come to be called inborn errors of metabolism. In the heterozygote (carrier), the level of a critical enzyme or other normal protein may be reduced, but not to the level where disease occurs (one gene still functions). In the homozygote, disease results from lack of a critical protein (eg, hemoglobin A in thalassemia), presence of an abnormal product (eg, sickle-cell hemoglobin (HbS) in sickle cell anemia), or accumulation of toxic metabolites in an enzymatic pathway due to absence of a critical enzyme (eg, the storage diseases). These disorders are often fatal in early life, although with treatment some patients survive to adulthood, eg, people with phenylketonuria can lead normal lives if phenylalanine is abolished from the diet.

Autosomal recessive traits are rare, and there is little chance of encountering the gene in an asymptomatic carrier in the general population. Many autosomal recessive diseases occur with greatest frequency in societies that discourage interracial mating. Tay-Sachs disease, for example, is virtually restricted to those of Ashkenazic Jewish ancestry. Very rare autosomal recessive diseases tend to occur in offspring of consanguineous matings when the parents have a common ancestor who carried the abnormal gene.

Sex Chromosome-Linked Diseases

(Table 15-4.) All sex chromosome-linked diseases are linked to the X chromosome and are characterized by an unequal incidence of the disease in the two sexes, in contrast to diseases linked to autosomes.

X-linked recessive diseases are common. The abnormal gene is usually expressed only in the male, who has only one X chromosome (Figure 15-15). X-linked recessive disorders are transmitted by asymptomatic female heterozygous carriers of the abnormal gene. On average, half of the male offspring of a mating between a carrier female and a normal male will manifest the disease. If an affected male mates with a normal female, all of the daughters will be carriers and the sons will be unaffected. If an affected male mates with a heterozygous carrier female, half of the sons and half of the daughters (homozygotes) on average will be affected. X-linked recessive diseases are often severe and commonly cause death early in life. Modern treatment, such as is available for hemophilia, has permitted survival of affected individuals to adult reproductive life.

X-linked dominant diseases are uncommon. Pseudohypoparathyroidism and hypophosphatemic rickets are the main examples. Because females have two X chromosomes, X-linked dominant diseases are more common in females.

Inborn Errors of Metabolism

These diseases are caused by an inherited single-gene abnormality that causes failure of synthesis of an enzyme and a subsequent block in a metabolic pathway. Enzyme deficiency results in abnormal amino acid, lipid, carbohydrate, or mucopolysaccharide metabolism with accumulation of the substrate and deficiency of the product of the enzymatic reaction. Cell damage may result from either mechanism. These diseases are all rare. As noted above (Table 15-2), most have an autosomal recessive mode of inheritance; a few are X-linked recessive diseases.

Abnormal Amino Acid Metabolism

(Table 15-5)

The inherited diseases associated with deficiency of enzymes involved in phenylalanine and tyrosine metabolism are good examples of inborn errors of metabolism (Figure 15-16). In phenylketonuria, the absence of phenylalanine hydroxylase prevents conversion of phenylalanine to tyrosine. This produces a tyrosine deficiency in the cell (with deficient melanin production and lack of pigmentation), as well as accumulation of phenylalanine, which is toxic to nerve cells (producing mental retardation). Phenylketonuria is an example of a biochemical abnormality that produces no specific morphologic change in affected cells. Diagnosis is made by detection of high levels of phenylalanine in the urine or serum. Treatment consists of removal of phenylalanine from the diet.

Abnormal Lipid Metabolism (Lipid Storage Diseases)

(Table 15-6)

The enzyme deficiencies listed in Table 15-6 all involve closely related pathways in the metabolism of sphingolipids. These deficiencies cause metabolic blocks that lead to accumulation of abnormal amounts of complex lipids in cells. Most of these enzymes are lysosomal, and abnormal lipid storage occurs within secondary lysosomes—hence the term lysosomal storage diseases. Except for Fabry's disease, which has an X-linked recessive inheritance pattern, these diseases are autosomal recessive in inheritance.

Storage of lipid occurs in different cells in the various diseases. Involvement of parenchymal cells causes degeneration and necrosis of these cells. When neurons are involved, as in Tay-Sachs disease and the infantile forms of Gaucher's disease and Niemann-Pick disease, severe mental retardation and death occur. Kidney failure occurs with renal involvement in Fabry's disease. In the milder adult forms of Gaucher's disease and Niemann-Pick disease, accumulation of lipid occurs in reticuloendothelial cells, producing enlargement of liver and spleen.

Diagnosis

The diagnosis can be made in several ways.

Clinical Features

In Tay-Sachs disease, lipid deposition in the macula of the retina produces a cherry-red spot visible on ophthalmoscopy. Diffuse skin lesions occur in Fabry's disease. Hepatosplenomegaly occurs in Gaucher's disease.

Microscopic Examination

Light microscopic examination of affected tissues such as brain, bone marrow, liver, and spleen (Figure 15-17) permits identification of the abnormal, lipid-distended cells. The affected cells in Tay-Sachs and Niemann-Pick disease have foamy cytoplasm. Gaucher's cells have a characteristic fibrillary (crinkled paper) cytoplasm.

Characteristic inclusions in the greatly distended lysosomes are demonstrated on electron microscopy. In Tay-Sachs disease, these are whorled; in Niemann-Pick disease, they appear as parallel lamellas (zebra bodies); and in Gaucher's disease the stored lipid is arranged in linear stacks.

Demonstration of the Enzyme Deficiency

The definitive diagnostic test is demonstration of the enzyme deficiency in cultured skin fibro-blasts.

Prevention and Treatment

Lipid storage diseases have no treatment. Prevention is achieved by genetic counseling.

Genetic Counseling

Heterozygous carriers of Tay-Sachs disease can be identified by serum enzyme assay. Screening of high-risk populations such as Ashkenazi Jews, with a carrier rate of 1:30 for the abnormal Tay-Sachs gene, enables identification of heterozygous carriers.

Amniocentesis

In high-risk pregnancies, amniocentesis permits identification of affected fetuses by demonstrating the enzyme deficiency in fetal fibroblasts.

Abnormal Glycogen Metabolism (Glycogen Storage Disease)

(Table 15-7.) Glycogen storage diseases are caused by deficiency of an enzyme involved in the metabolism of glycogen. Most of these diseases have an autosomal recessive mode of inheritance, with onset of disease in infancy or childhood. Interference with glycogen metabolism produces a variety of effects.

Accumulation of Glycogen

Glycogen accumulates in the cytoplasm and appears as granules that can be recognized on electron microscopy. In routinely fixed tissues, glycogen is dissolved by the aqueous formalin fixative; affected cells in routine slides appear distended and empty on examination by light microscopy (Figure 15-18). Demonstration of glycogen in cells requires fixation in alcohol and staining with Best's carmine or periodic acid-Schiff (PAS) reagent.

Dysfunction of Involved Cells

Hepatic involvement causes hepatomegaly, fibrosis, and liver failure; myocardial involvement causes heart failure.

Abnormal Glucose Delivery

With liver involvement (eg, type I), hypoglycemia occurs because breakdown of liver glycogen is the main source of blood glucose. With skeletal muscle involvement, lack of glucose in the cell causes muscle cramps and weakness.

Abnormal Mucopolysaccharide Metabolism (Mucopolysaccharidoses)

(Table 15-8.) The mucopolysaccharidoses are rare inherited lysosomal storage diseases in which deficiency of a lysosomal enzyme leads to the accumulation of mucopolysaccharides (glycosaminoglycans) in lysosomes in a variety of cells. All have an autosomal recessive pattern of inheritance except Hunter's syndrome, which is an X-linked recessive disease.

Accumulation of glycosaminoglycans in cells results in great enlargement of affected cells. Involvement of macrophages and endothelial cells leads to hepatosplenomegaly and deformities due to changes in skin and bones. Grotesque facial deformities occur (gargoylism is the alternative name for Hurler's syndrome). Affected cells are distended and, in routine preparations, demonstrate clear cytoplasm (balloon cells). Peripheral blood cells show glycosaminoglycan deposits as large purple cytoplasmic granules (Alder-Reilly bodies).

Dysfunction of affected parenchymal cells also occurs. Degeneration of involved neurons causes mental retardation; myocardial involvement causes heart failure.

Detection of Heterozygous Carrier State in Recessive Traits

Heterozygous carriers of a recessive trait, whether autosomal or X-linked, do not show evidence of clinical disease. In many disorders, however, biochemical abnormalities are present, permitting detection of the carrier state, which in turn makes possible genetic counseling and early diagnosis of affected offspring.

Hemophilia A is a good example of how heterozygous carriers are detected. Patients with hemophilia have low levels of factor VIII in the plasma. Female heterozygous carriers have plasma levels of factor VIII that fall between those of normal individuals and hemophiliac patients. The ratio between factor VIII clotting activity (low in hemophilia A) and factor VIII-related antigen (normal in hemophilia A) permits detection of over 90% of heterozygous carriers (see Chapter 27: Blood: IV. Bleeding Disorders).

Carrier detection is now possible in a large number of autosomal recessive diseases. Screening of populations for carriers is cost-effective only in families known to have the abnormal gene and in ethnic groups with a high incidence of the disease, eg, Tay-Sachs disease in individuals of Ashkenazi Jewish ancestry.

Polygenic (Multifactorial) Inheritance

Familial diseases such as atherosclerosis, high blood pressure, and diabetes mellitus are believed to be due at least in part to the presence of several abnormal genes. In atherosclerosis, two or more of the genes causing the different hyperlipidoses may interact to predispose to the disease (Chapter 20: The Blood Vessels). It is thought that this inherited predisposition for development of disease has an additive effect on environmental factors. A number of congenital disorders also show a familial but not strictly mendelian pattern. These include anencephaly, cleft palate, and Hirschsprung's disease.

Fetal Abnormalities Caused by External Agents (Teratogens)

Congenital anomalies (Table 15-9) due to abnormal development of the fetus affect about 2% of newborns and represent an important cause of neonatal morbidity and death. Most anomalies have no detectable chromosomal abnormality and are not inherited. Although a few teratogenic (monster-producing) agents have been identified, the cause of most congenital anomalies is unknown.

Ionizing Radiation

In addition to its action on DNA and the genetic apparatus of the cell, ionizing radiation has direct toxic effects on other components of the developing fetus, and various congenital anomalies have been reported following irradiation during pregnancy. Because it is not known whether there is a safe low dose of radiation during pregnancy, abdominal x-rays should be avoided except when essential for diagnosis of diseases threatening the life of the mother or fetus.

Teratogenic Viral Infections

Rubella is the best-recognized teratogenic virus, ie, one that causes developmental defects. Transplacental infection of the fetus by the virus during the first trimester of pregnancy, when the fetal organs are developing, is associated with a high incidence of congenital anomalies. The risk is greatest (about 70%) in the first 8 weeks of pregnancy. Rubella virus interferes with protein synthesis in tissue culture. Rubella syndrome denotes the triad of congenital heart disease, deafness, and cataracts that is common in affected infants. Many other anomalies, including microcephaly, mental retardation, and microphthalmia, have been reported. The risk of rubella infection of fetuses has decreased dramatically since the introduction of rubella antibody testing and immunization.

The teratogenic effect of other viral infections in early pregnancy is uncertain. Congenital anomalies have been reported following many infections, including influenza, mumps, and varicella, but whether this is incidental or represents a teratogenic effect of these viruses is unknown.

Drugs

As with irradiation, the use of drugs of any sort during pregnancy should be discouraged except to save the life of the mother or when the benefits outweigh the risk to the fetus. No drug can be considered totally safe, especially during early pregnancy, and well-established drugs are preferred to newer ones. Although all drugs approved for use in the United States have undergone rigorous testing in pregnant animals, their safety in humans can be established only after many years of use. The significant congenital damage associated with use of thalidomide and diethylstilbestrol (now both discontinued) exemplify the risks of using newly approved drugs during pregnancy.

Thalidomide

Thalidomide is a mild sedative that was commonly used in Europe in the 1960s until it was shown by epidemiologic evidence to cause a distinctive fetal anomaly (phocomelia) when used in pregnancy. Failure of development of the limbs resulted in hands and feet that resemble the flippers of seals—short stumps closely attached to the trunk.

Diethylstilbestrol (DES)

Diethylstilbestrol is a synthetic estrogen used extensively between 1950 and 1960 to treat threatened abortion (miscarriage). Female offspring of women who took DES in pregnancy develop epithelial abnormalities of the vagina, including collections of mucous glands (vaginal adenosis) and, more seriously, clear cell adenocarcinoma.

Alcohol (Fetal Alcohol Syndrome)

Exposure of the fetus to alcohol during organogenesis in early pregnancy leads to congenital abnormalities, the extent of which correlates with the amount of alcohol consumed by the mother, who may not even know she is pregnant. Fetal alcohol syndrome occurs in one of every 1000 live births in the United States and in 30–50% of infants born to women who consume over 125 g of alcohol (about 450 mL of whisky) per day. Fetal alcohol syndrome is characterized by growth retardation, a characteristic abnormal facial appearance (short palpebral fissures, epicanthal folds, micrognathia, a thin upper lip), cardiac defects (commonly septal defects), vertebral anomalies (including spina bifida), and mental retardation with microcephaly and brain malformation.

Cigarette Smoking

Heavy smoking during pregnancy is associated with fetal growth retardation. To date, no teratogenic effects have been reported.

Normal Postnatal Development

The organs of the body vary considerably in degree of development and maturity at birth.

Most tissues (eg, skeletal muscle, bone, skin, gastrointestinal tract, endocrine glands) are fully developed and functional at birth and show growth during childhood. Liver and kidney are immature but sufficiently developed to function adequately after delivery, although many newborn infants develop transient mild jaundice as a result of immaturity of liver enzyme systems.

The lungs mature late in fetal life and are immature in premature infants—especially those born before 34 weeks of gestation. Maturity of the lungs is critical for survival in premature infants. Lung maturity of the fetus may be assessed by estimating the lecithin, sphingomyelin, and phosphatidylglycerol levels in amniotic fluid (eg, lipids associated with surfactant). As the lung matures—normally after 34 weeks—lecithin and phosphatidylglycerol appear in increasing amounts in amniotic fluid. Problems related to lung immaturity are very uncommon if the amniotic fluid lecithin:sphingomyelin ratio is over 2:1 or when significant amounts of phosphatidylglycerol are present.

The brain shows rapid growth and development after delivery, reaching full size and development in early childhood. Brain development after birth includes migration of primitive neuroectodermal cells and myelination in the central nervous system.

Lymphoid tissues show maximal growth during childhood, after which involution occurs.

Genital tissues (gonads, reproductive organs, and secondary sexual characteristics) reach full maturity during puberty.

Diseases of Infancy & Childhood

Postnatal growth and development may be interrupted by many disease processes. The frequency and nature of these diseases vary greatly during the different age groups recognized by physicians and statisticians (Table 15-10). Of the 10 leading causes of death in American infants (children under 1 year of age), 7 are complications of pregnancy, labor, or neonatal period (ie, the first 4 weeks of life). By far the most common cause of death for this age group is congenital anomalies. Overall, infant mortality rates are regarded as an indicator of the quality of medical care. Infant death rates are much higher in developing countries, and a significantly higher proportion of these deaths is due to infectious disease, malnutrition, and other largely preventable factors.

After the first year of life, the major causes of death change (Table 15-10). Infectious disease becomes more prominent: acquired immune deficiency syndrome (AIDS) was not recognized until 1981, but within a decade it had become one of the leading causes of death in American children. (AIDS is discussed in Chapter 7: Deficiencies of the Host Response and infectious diseases as a group in Chapters 13 and 14.) Benign and malignant neoplasms also become increasingly frequent causes of death in older children. For public-health officials, some of the most important information in Table 15-10 does not pertain to disease. For children aged 5 years and older, at least 2 of the top 4 causes of death are due to unintentional injury or violence (homicide or suicide). The leading cause of death for all American children older than 1 years in unintentional injury.

Disorders Associated with Low Birth Weight

The average American infant born at term (ie, between 38 and 42 weeks of gestation) weighs 2500–3999 g. Any infant with a birth weight of less than 2500 g is considered a low-birth-weight newborn. Term newborns who weigh less than 2500 g are considered small-for-gestational-age. Infants born prematurely are often low-birth-weight newborns. Factors other than prematurity that may compromise birth weight may be fetal, placental, or maternal in origin. Fetal factors include congenital anomalies and fetal infections. Placental insufficiency may be due to placental problems such as vascular lesions or infection. Placental insufficiency may also be due to numerous maternal factors—hypertension, cigarette smoking, narcotic and cocaine abuse, or alcohol abuse.

Disorders associated with low birth weight are generally the result of nutritional deprivation in utero (eg, placental insufficiency) or immaturity of organs. Such disorders are most common in infants born before 34 weeks of gestation. The risks increase as birth weight decreases and as gestational age decreases. Mortality and long-term outcome correlate with Apgar score. Apgar testing is performed at 1 and 5 minutes after delivery, and it assesses five key physiologic parameters (heart rate, respiratory effort, muscle tone, skin color, and reflex irritability). A low Apgar score (≤ 3) at 5 minutes suggests severe depression and correlates with a poor prognosis if the infant survives.

Respiratory Distress Syndrome (RDS)

Despite significant gains in the medical care of premature and low-birth-weight infants, RDS remains a leading cause of death in infants (Table 15-10). It most commonly affects infants under 34 weeks of gestational age and is caused by immaturity of type II pneumocytes, which fail to secrete adequate surfactant. Surfactant is a surface tension-reducing agent that performs the vital function of keeping alveoli expanded. Deficiency of surfactant causes alveolar collapse in the first hour after delivery following reasonably normal initial expansion of the lung, because the alveoli cannot remain expanded without the surface tension-reducing factor. Progressive respiratory distress, hypoxemia, and cyanosis occur. Alveolar collapse is associated with hypoxic necrosis of alveolar epithelium and exudation of protein-rich fluid into dilated alveolar ducts. This fluid forms eosinophilic hyaline membranes—a microscopic hallmark of the disease (see Chapter 34: The Lung: I. Structure & Function; Infections). RDS was once called hyaline membrane disease.

Treatment with artificial ventilation and oxygen has improved survival in RDS, but the overall mortality rate remains around 30%. Prolonged high-concentration oxygen therapy must be used with extreme caution because it is toxic to the lung (permanent interstitial fibrosis) and eyes (retrolental fibroplasia and blindness).

Intraventricular Hemorrhage

Intraventricular hemorrhage may occur in preterm infants with or without RDS. Hemorrhage begins in the periventricular region of the cerebral hemispheres and extends into the ventricular cavity. The cause of hemorrhage is unknown, but immaturity of the brain, poor support of the fragile vessels in this region by the subependymal tissue, increased fibrinolytic activity, and hypoxia are believed to contribute. Severe intraventricular hemorrhage carries a mortality rate of about 75%.

Necrotizing Enterocolitis

This is a dangerous complication of premature infants treated in neonatal intensive care units. It is characterized by extensive mucosal necrosis and ulceration involving the ileum and colon. The cause is unknown, although hypoxia and bacterial infection—notably Escherichia coli—probably contribute. Treatment commonly includes surgical resection of the involved intestine.

Perinatal Infections

In contrast to teratogenic infections such as rubella, which occur in early pregnancy, perinatal infections are caused by transplacental infection in late pregnancy or infection of the fetus by contagion during delivery. They present as infectious diseases in the neonatal period. TORCH complex is a general term for infections acquired in this way and is an acronym for toxoplasmosis, other (viruses), rubella, cytomegalovirus, and herpes simplex. To this list some would add syphilis (TORCHS).

Toxoplasma gondii and Cytomegalovirus Infections

These third-trimester fetal infections involve chiefly the brain and eyes. Extensive necrosis of the brain, most prominent in the periventricular region, is accompanied by dystrophic calcification and leads to microcephaly and mental retardation. The eyes show chorioretinitis, frequently associated with visual impairment.

Treponema pallidum Infection (Congenital Syphilis)

Syphilis is also a third-trimester transplacental infection of the fetus born to a mother with early active syphilis. When infection is severe, intrauterine death occurs. With lesser infections, congenital syphilis occurs (see Figure 54-2).

Rubella Virus Infection

Rubella infection in late pregnancy leads to severe infection of the fetus characterized by fever, petechial skin rash, and liver enlargement. The infantile immune system responds poorly to the virus, and affected infants frequently have prolonged infection with excretion of virus for several months after delivery.

Infections Acquired in the Birth Canal

Herpes simplex represents the most significant birth canal infection and occurs when the mother has active infection at the time of delivery. Fetal infection results either in severe viremia or encephalitis. The mortality rate is very high. Infants who recover commonly have severe permanent neurologic deficits. Active genital herpes infection of the mother is an absolute indication for cesarean section.

Other infections acquired during passage through an infected birth canal include gonorrhea and lymphogranuloma venereum, both of which cause severe conjunctivitis.

Sudden Infant Death Syndrome (SIDS; Crib Death)

The number of infant deaths due to SIDS has decreased significantly since parents were advised to place healthy babies on their side or back instead of on their abdomen. However, SIDS remains a major cause of death in infants (Table 15-10). SIDS is the sudden and unexpected death of a previously well infant in whom no cause of death is found at autopsy. SIDS occurs predominantly during sleep and has a maximum incidence in the age group from 2 to 4 months. While new hypotheses are put forward almost monthly, the cause is still unknown. An abnormality of the respiratory center that causes cessation of respiration during sleep appears the most likely cause.

Congenital Anomalies, Inborn Errors of Metabolism, & Hemolytic Disease of the Newborn

These are common problems during early childhood. The first two have been considered earlier in this chapter. Hemolytic disease of the newborn is discussed in Chapter 25: Blood: II. Hemolytic Anemias; Polycythemia.

Malignant Neoplasms

Malignant neoplasms, although much less common overall in children than in adults, account for over 10% of deaths in the age group from 5 to 14 years and 7% of deaths in children 1–4 years of age. Malignant neoplasms in children are primarily those of the lymphoid and hematopoietic cells (lymphomas and leukemias) and mesenchymal cells (sarcomas) (see Table 17-6).

Normal Sexual Development

Primary Sexual Development

The development of the gonads and genital organs in the embryo and fetus is directed by the sex chromosomes (Figure 15-19). Normal sexual development requires sequential interactions of chromosomes, genes, gonads, hormones, and receptors, with an associated sexual imprinting of the central nervous system, which governs subsequent sexual development.

Secondary Sexual Development

The development of secondary sexual characteristics and the production of gametes at puberty are initiated by gonadotropic hormones from the hypothalamic-pituitary axis. The testes produce spermatozoa and testosterone. The ovaries begin cyclic ovulation and secrete estrogen and progesterone. The sex hormones are responsible for development of secondary sexual characteristics. In the female, menstruation signifies the onset of reproductive capability (Chapter 52: The Ovaries & Uterine Tubes).

Abnormal Sexual Development

Abnormal primary sexual development leads to ambiguous genitalia (intersex) in infants. Abnormal secondary sexual development results in failure of production of gametes and sex hormones at puberty, with subsequent abnormalities of secondary sex characteristics. The principal types of abnormal sexual development are set forth in Table 15-11.

True Hermaphroditism

The term hermaphroditism is derived from Greek mythology—Hermes was a male messenger of the gods, and Aphrodite was the goddess of love. True hermaphroditism is a rare condition in which both testicular and ovarian tissue develop in the same individual. The genetic makeup of true hermaphrodites varies; many individuals are 46,XX or 46,XY, but some show mosaicism: 46,XX/46,XY. The exact mechanism underlying hermaphroditism is uncertain, but the disorder may be associated with transfer to another chromosome of that part of the Y modulator gene that dictates testicular development.

Pseudohermaphroditism

Pseudohermaphroditism is relatively common. In pseudohermaphroditic individuals, the gonads correspond to the genetic sex, but abnormal development of the external genitalia causes difficulty in determining sex in the newborn. Classification as a male or female pseudohermaphrodite is based on the individual's genetic sex.

The penis of a male with extreme hypospadias (opening of the urethra on the ventral aspect of the penis [Chapter 51: The Testis, Prostate, & Penis]) may resemble a female urethra and clitoris. Failure of testicular descent, when associated with failure of fusion of the scrotum in a male, may result in an appearance that resembles the female external genitalia.

Ambiguous genitalia may occur in females with congenital adrenal hyperplasia (see Chapter 60: The Adrenal Cortex & Medulla). Congenital absence of an enzyme in the synthetic pathway for adrenal steroids leads to overproduction of adrenal androgenic hormones. In the female, this may cause clitoral hypertrophy so marked that the clitoris is mistaken for a penis. A female with this disorder may resemble a male with undescended testes and hypospadias, and there may be initial confusion about the infant's sex.

Testicular Feminization Syndrome

An individual with testicular feminization syndrome is a genetic male (46,XY) but phenotypically a female. This syndrome is caused by an inherited (X-linked recessive) absence of receptors for androgens on the cells of the end-organs of androgen action (end-organ insensitivity). Failure of androgen action leads to failure of testicular descent, with formation of female external genitalia, including a vagina. At puberty, individuals develop female secondary sex characteristics because of the unopposed action of adrenal estrogenic hormones, and they appear to be normal young females. The absence of the uterus—an organ derived from the müllerian duct, which regresses under the influence of müllerian duct regression factor that is secreted and acts normally in patients with testicular feminization—results in failure of menstruation and infertility. Patients also lack body hair in either the typical adult female or typical adult male distribution.

Chromosomal analysis (which shows a normal male karyotype) is diagnostic. It is important in the treatment of these patients to remove the undescended testes, which have an increased incidence of malignant neoplasms. Psychologically, it is important to permit the patient to lead her life as an infertile woman.

Klinefelter syndrome and Turner syndrome represent chromosomal aberrations that have been described previously (see Figures 15-9 to 15-12).

Aging is the final phase of human development and may be defined as the aggregate of structural changes that occur with the passage of time; it is characterized by progressive inability to sustain vital functions, with death the eventual result. The life expectancy of humans varies from country to country (it is high in countries with well-developed systems of medicine and health care delivery, as in the Scandinavian countries, and lower in developing nations). It is generally higher in females than males. In the United States, the average male life expectancy at birth is between 70 and 75 years; for females, between 75 and 80 years.

There is a steady loss of function in various critical organs with age. Extrapolation from such observations would indicate that humans have a finite biologic life span of 90–110 years, so that even if cardiovascular diseases and cancer were eradicated, the current average life expectancy would increase by only a few years.

Hypotheses of Aging

Several different hypotheses have been proposed to explain aging, but no one of them is entirely satisfactory, and it is probable that aging is due to a combination of several processes.

Programmed Aging Hypothesis

According to this hypothesis, the genome of every cell is programmed at conception to cease mitotic division after a certain time. This has been demonstrated by normal fibroblasts and other cells in tissue culture, which undergo a finite number (40–60) of divisions. Programmed cessation of mitotic division does not explain the attrition in permanent (irreversibly postmitotic) cells such as neurons and muscle cells. To explain loss of these cells, proponents suggest that such cells are also programmed to make errors in transcription of nucleic acid that lead to cell death.

Evidence supporting the theory of programmed aging derives from observations of identical twins, who show remakably similar life spans, and from rare diseases that are characterized by acceleration of the aging process. These include Down syndrome and progeria. In infantile progeria, a young child resembles a wizened old person, with loss of hair, fusion of epiphyses, atherosclerosis, and arterial calcification. The life span in Down syndrome and progeria is variable but always shortened.

DNA Damage Hypothesis

According to this hypothesis, aging is the result of DNA damage, due either to somatic mutations or to failure of DNA repair mechanisms in aging cells. DNA changes lead to errors in ribonucleic acid (RNA) transcription and in that way cause defects in cellular synthesis of protein. Although these changes undoubtedly occur in aging cells, they could just as easily be the result of the aging process rather than the cause.

Neuroendocrine Hypothesis

This hypothesis holds that the aging process is programmed into brain cells at birth and that these cells direct the process by means of hormonal and neural influences. Proponents point to the control of puberty, which is initiated by the hypothalamus via pituitary hormones, as evidence that the brain can be programmed to function in this manner. Experiments in rats provide some supportive evidence in that removal of the pituitary increases life span.

Immune Hypothesis

A decline in immunologic reactivity occurs with increasing age, which predisposes to development of infections, autoimmune diseases, and neoplasia in elderly persons. This hypothesis postulates that such progressive immunologic dysfunction is inevitable and that it is responsible for limitations on life span. In experimental animals, immunologic manipulations such as thymic transplants have been shown to increase life span. On the other hand, if they are kept in a microbe-free environment, mice with thymic aplasia and marked immune deficiency live as long as normal mice.

Free Radical Hypothesis

Aging is accompanied by the accumulation of lipofuscin in cells—mainly in the heart, liver, and brain. Lipofuscin is derived from the action of oxygen-based free radicals on plasma membranes of cellular organelles by lipid peroxidation. While lipofuscin itself is harmless, it provides evidence for a general increase in free radical injury of cells as the individual ages. This is due probably to decreased activity of enzymes such as superoxide dismutase that normally inactivate free radicals. Because free radicals can cause cell death, increasing free radical injury as the individual ages may contribute to increasing cell loss and the aging process.

Cumulative Injury Hypothesis

It has been suggested that aging may merely represent the aggregate effect of pathologic insults sustained during the life of the individual. If this were true, eradication of disease would lead to a greatly increased life expectancy. All available evidence suggests, however, that it is not true, and maximum life expectancy (90–100 years) is not greatly different now from what it was 100 years ago.

Changes Associated with Aging

(Table 15-12)

Morphologic Changes

As life expectancy increases, the study of aging (gerontology) becomes increasingly important. It is crucial to distinguish changes that are part of the aging process from diseases that are common in older individuals. Changes associated with aging are inevitable; on the other hand, diseases associated with aging should be aggressively treated to permit the individual to function at the highest possible level.

Cellular Changes

Cell Loss

Changes in metabolism lead to decreased cell size and number and to atrophy of organs. Cell loss occurs in all tissues but is most evident in organs composed of permanent (irreversibly postmitotic) cells such as the brain and heart, in which replacement of lost cells does not occur. Cell loss in the brain is selective, with the greatest loss occurring in the basal ganglia, substantia nigra, and hippocampus.

Organelle Changes

The endoplasmic reticulum of aged cells is often disorganized, and its usual close relationship with ribosomes is lost. Free ribosomes are present in greater numbers than normal, with resulting abnormalities of protein synthesis. The activity of many enzymes is decreased.

Mitochondria of aged cells show abnormalities in size, shape, and cristae. These, coupled with decreased levels of cytochrome C reductase, decrease the efficiency of energy production.

An increased rate of organelle breakdown in aged cells is associated with the presence of increased numbers of phagolysosomal vacuoles in the cells and the deposition of lipofuscin (Chapter 1: Cell Degeneration & Necrosis)—a brown pigment believed to be derived from degraded organelle membranes—particularly evident in the heart, brain, and liver.

Specialized cytoplasmic structures are often abnormal in aged cells. Myofibrils in muscle cells show decreased contractility. Nerve cells show decreased synthesis of acetylcholine. Poor function of cytoskeletal microfilaments in macrophages leads to decreased efficiency of phagocytosis. Hormone receptors on the cell surface become abnormal, resulting in inefficient action of hormones such as insulin.

DNA Abnormalities

DNA abnormalities are mainly the result of a progressive failure of cellular DNA repair mechanisms. Failure of DNA repair can potentially affect any cellular function and frequently leads to cell death.

Connective Tissue Changes

Weakening of fibrous tissues, in association with intermittent muscle spasm, may increase the incidence of diverticula in the colon. Weakening of the abdominal and pelvic walls leads to abdominal hernias (inguinal, umbilical, diaphragmatic) and prolapse of organs (uterus, rectum) through the pelvic floor.

Deposition of abnormal substances in connective tissue is common in old age and makes the line between disease and simple aging difficult to define. Calcification of the media of muscular arteries is common and usually without clinical significance. Deposition of amyloid (senile amyloidosis) may occur in the heart, brain, and many other organs; clinical disease may result.

Elastic Tissue Changes

Changes in elastic tissue of the body result in loss of elasticity and wrinkling of the skin. This occurs first in the sun-exposed regions of the body. Loss of elasticity in large arteries such as the aorta leads to decreased distensibility. The systolic pressure increases with age because of the aorta's decreased ability to accommodate cardiac output. Loss of elastic tissue in the lungs is associated with destruction and dilation of alveoli (senile emphysema).

Ground Substance Changes

Changes in the ground substance of tissues result in various abnormalities. In the lens, for example, these changes are associated with the development of opacities (cataracts), which usually impair vision. Cataract formation may be accelerated by disease, eg, diabetes mellitus. The lens also loses its accommodative power with age, so that visual changes—most commonly presbyopia (far-sightedness)—occur, and the individual cannot see objects in the near distance.

Cartilage and Bone Changes

Changes in articular cartilage lead to erosions and fibrillations. The end result is osteoarthrosis (Chapter 68: Diseases of Joints & Connective Tissue). Osteoarthrosis is most common in weight-bearing joints of the spine and the lower extremities, suggesting that wear and tear is an aggravating factor.

Loss of bone (osteoporosis) is also a manifestation of aging. It is characterized by loss of both bone matrix and mineral, with resulting thinning of bones. Compression of vertebrae causes a decrease in total height. If collapse of vertebral bodies occurs, abnormal curvature (kyphosis) results. Elderly people are therefore often represented in caricature as short and bent over. Osteoporosis in the long bones predisposes to fractures, particularly in the neck of the femur. Osteoporosis is more common in postmenopausal women because of lack of the anabolic effects of estrogens, and estrogen replacement therapy delays onset of the disease. Lack of physical exercise (especially weight-bearing exercise) accelerates the onset and progression of osteoporosis.

Hair Changes

In elderly people, the hair becomes thin and sparse and loses its pigment. These characteristic changes are due to progressive failure of hair follicles to produce both keratin-like hair protein and pigment.

Reproductive System Changes

Menopause signifies the end of reproductive life in women. Cessation of ovulation results in decreased ovarian hormone levels, endometrial atrophy, cessation of menses, atrophy of the reproductive system, and increased secretion of pituitary gonadotropins by removal of feedback inhibition. Increased follicle-stimulating hormone (FSH) levels are thought to be responsible for some menopausal symptoms, eg, hot flushes. Menopause usually occurs between age 40 and 50 years.

Although testicular function declines with age, the existence of a corresponding climacteric in men (so-called male menopause) is controversial.

Changes in Host Defense Mechanisms

The thymus begins to atrophy even in childhood. Some authorities maintain that this is the earliest form of aging or even a direct cause of aging—a belief that may account for the use of injections of embryonic thymus extracts in an attempt to retard the aging process.

Abnormal immune function in the elderly predisposes to development of infections (Figure 15-20). Viral infections of the respiratory tract and bacterial infections of the respiratory and urinary tracts and skin are common. The incidence of tuberculosis is increased and the disease is more virulent in the elderly. Pneumonia is a common cause of death. Older individuals frequently develop autoantibodies and show an increased incidence of autoimmune diseases such as pernicious anemia, Hashimoto's thyroiditis, and Addison's disease. Cancer is predominantly a disease of older individuals and may in part be related to the decreased ability of the immune system to rid the body of cancer cells.

Diseases Associated with Aging

Older individuals are susceptible to many different diseases that affect virtually every organ of the body (Table 15-12). It is important to identify diseases responsible for clinical symptoms in elderly patients in order to maximize personal independence and quality of life.

The cells of the body continue to grow, divide, and differentiate throughout life. Normally, growth and differentiation are controlled in such a way as to maintain the normal structure of a particular tissue. In tissues characterized by continuous cell loss (skin, intestinal mucosa, blood), labile stem cells continuously undergo mitosis to replace lost cells. Stem cells frequently differentiate from a primitive to a mature form during this process—eg, normoblasts in bone marrow become the erythrocytes of the peripheral blood. In the skin, as superficial keratinized cells are shed from the surface, basal cells proliferate at a suitable rate to replace them. The newly produced basal cells move upward, differentiating into squamous cells that undergo nuclear and cytoplasmic changes to become the superficial cornified layer of cells. When the epidermal turnover rate is normal, the skin appears normal on histologic examination; but if the rate is greatly increased, as occurs in psoriasis, cells do not fully mature, and abnormalities are seen both on gross examination and at the histologic level.

Control of Growth

The growth of a tissue reflects the net balance of cell proliferation on the one hand and cell differentiation, leading to cell death, on the other. The rate of proliferation is determined by the time of passage through the cell cycle and by the interplay of a variety of growth factors with their corresponding receptors, the production of which is regulated by the interaction of growth control genes. Many of the cellular proto-oncogenes that have been identified as playing a potential role in the induction of cancer (Chapter 18: Neoplasia: II. Mechanisms & Causes of Neoplasia) encode for growth factors for receptors.

The principal categories of growth factors are listed in Table 16–1.

Definitions

Abnormal cellular growth may result in either a decrease or an increase in the mass of the involved tissue (see Figure 16-4).

Atrophy is a decrease in the size of a tissue or organ, resulting from a decrease either in the size of individual cells or in the number of cells composing the tissue. Note that atrophy, which is a decrease in size of a normally formed organ, is distinct from agenesis, aplasia, and hypoplasia, which are abnormalities of organ development.

Hypertrophy is an increase in the size of a tissue due to increased size of individual cells (Table 16-2). It occurs in tissues made up of permanent cells, in which a demand for increased metabolic activity cannot be met through cell multiplication.

Hyperplasia is an increase in the size of a tissue as a result of increased numbers of component cells (Table 16-2). It is the principal mechanism accounting for increased size in tissues composed of labile and stable cells.

Not uncommonly, increased size of a tissue is due to a combination of hypertrophy and hyperplasia.

Causes of Atrophy

Decrease in the size of a cell results from a reduction in the amount of cytoplasm and the number of cytoplasmic organelles; it is usually associated with diminished metabolism. Degenerating organelles are taken up in lysosomal vacuoles for enzymatic degradation (autophagy). Residual organelle membranes often accumulate in the cytoplasm as brown lipofuscin pigment. A decrease in cell number results from an imbalance of cell proliferation and death over a long period.

Atrophy of Disuse

Atrophy of disuse occurs in immobilized skeletal muscle and bone, as when a fractured limb is put in a cast or when a patient is restricted to complete bed rest. Skeletal muscle atrophies rapidly with disuse. Initially, there is a rapid decrease in cell size that is readily reversible when activity is resumed. With more prolonged immobilization, muscle fibers decrease in number as well as in size. Because skeletal muscle can regenerate only to a very limited extent, restoration of muscle size after loss of muscle fibers can only occur through compensatory hypertrophy of the surviving fibers, which often requires a long rehabilitation period. Bone atrophy results when bone resorption occurs more rapidly than bone formation; it is characterized by decreased size of the trabeculae (decreased mass), leading to osteoporosis of disuse.

Denervation Atrophy

Skeletal muscle is dependent on its nerve supply for normal function and structure. Damage to the lower motor neuron at any point between the cell body in the spinal cord and the motor end plate leads to rapid atrophy of the muscle fibers supplied by that nerve. When denervation is temporary, physical therapy and electrical stimulation of the muscle are important to prevent muscle fiber loss and ensure that normal function can be restored when nerve function is reestablished. Many primary muscle diseases (eg, the genetically determined dystrophies) also show irregular atrophy of muscle fibers.

Atrophy Due to Loss of Trophic Hormones

The endometrium, breast, and many endocrine glands are dependent on trophic hormones for normal cellular growth, and withdrawal of these hormones leads to atrophy. When estrogen secretion by the ovary decreases at menopause, there is physiologic atrophy of the endometrium, vaginal epithelium, and breast. Pituitary disease associated with decreased secretion of pituitary trophic hormones results in atrophy of the thyroid, adrenals, and gonads. High-dose adrenal corticosteroid therapy, which is sometimes used for immunosuppression, causes atrophy of the adrenal glands because it suppresses pituitary corticotropin (adrenocorticotropic hormone [ACTH]) secretion. Such patients soon lose the ability to secrete cortisol and become dependent on exogenous steroids. Withdrawal of steroid therapy in such patients must be gradual enough to permit regeneration of the atrophied adrenal.

Atrophy Due to Lack of Nutrients

Severe protein-calorie malnutrition (marasmus) results in the utilization of body tissues such as skeletal muscle as a source of energy and protein after other sources such as adipose stores have been exhausted. Marked muscle atrophy is seen in marasmus.

A decrease in blood supply (ischemia) to a tissue as a result of arterial disease results in atrophy of the tissue due to progressive cell loss. Cerebrovascular disease, for example, is associated with cerebral atrophy, including neuronal loss.

Senile Atrophy

Cell loss is one of the morphologic changes of the aging process. It is most apparent in tissues populated by permanent cells, eg, the brain and heart. Atrophy due to aging is frequently compounded by atrophy due to coexisting factors such as ischemia.

Pressure Atrophy

Prolonged compression of tissue causes atrophy. A large, encapsulated benign neoplasm in the spinal canal may produce atrophy in both the spinal cord it compresses and the surrounding vertebrae. It is likely that such atrophy results from compression of small blood vessels, resulting in ischemia, and not from the direct effect of pressure on cells.

Causes of Hypertrophy & Hyperplasia

Hypertrophy results from increased amounts of cytoplasm and cytoplasmic organelles in cells. In secretory cells, the synthetic apparatus—including the endoplasmic reticulum, ribosomes, and the Golgi zone—becomes prominent. In contractile cells such as muscle fibers, there is an increase in size of cytoplasmic myofibrils. Hyperplasia results when cells of a tissue are stimulated to undergo mitotic division, thereby increasing the number of cells.

Physiologic Hypertrophy and Hyperplasia

Hypertrophy and hyperplasia may occur as an adaptation to increased demand (Table 16-2; Figures 16-1, 16-2, and 16-3). Hypertrophy and hyperplasia are controlled responses reflecting increased demand; if the demand is removed, the tissues revert toward normal.

Pathologic Hypertrophy and Hyperplasia

Abnormal hypertrophy and hyperplasia occur in the absence of an appropriate stimulus of increased functional demand. Myocardial hypertrophy, if it occurs without recognizable cause (eg, in the absence of hypertension or valvular or congenital heart disease), is considered an example of pathologic hypertrophy. Such hypertrophy is frequently associated with abnormal cardiac function, producing cardiomyopathy (Chapter 23: The Heart: III. Myocardium & Pericardium).

Endometrial hyperplasia is an important result of increased estrogen stimulation, particularly when estrogens are not opposed by progesterone secretion, as typically occurs near menopause. It is associated with irregular, often excessive uterine bleeding (Chapter 53: The Uterus, Vagina, & Vulva). The presence of excessive trophic hormones causes hyperplasia of the target organs, eg, excessive secretion of ACTH causes bilateral adrenal hyperplasia. The hyperplastic target organs frequently show increased function. In the case of the adrenal gland, there is increased cortisol secretion (Cushing's syndrome; Chapter 60: The Adrenal Cortex & Medulla).

Thyroid hyperplasia (goiter; Graves' disease) results from increased thyroid-stimulating hormone (TSH) stimulation of the thyroid or from the action of autoantibodies that are able to bind to TSH receptors in thyroid cell membranes (Chapter 58: The Thyroid Gland).

Hyperplasia of the prostategland is common in older men and is due to hyperplasia of both the glandular and the stromal elements. The cause is not known, although it is believed that waning androgen levels may be responsible (Chapter 51: The Testis, Prostate, & Penis).

(Table 16-3)

Metaplasia is an abnormality of cellular differentiation in which one type of mature cell is replaced by a different type of mature cell—and the latter is not normal for the tissue involved. Metaplasia results from abnormal differentiation of stem cells (Figures 16-4, 16-5, and 16-6). The new, metaplastic tissue is structurally normal, however, so the regular cellular organization is maintained. Metaplasia is reversible.

Metaplasia most commonly involves epithelium. As the germinative stem cells multiply to replace cells shed at the surface, they differentiate in a manner that is abnormal for that location, resulting in epithelium of a type different from that usually present. Epithelial metaplasia is thus a manifestation of the varied potential for differentiation in stem cells and typically occurs following chronic physical or chemical irritation.

In squamous metaplasia—the most common type of epithelial metaplasia—nonsquamous pseudostratified columnar or cuboidal epithelium is replaced by a normal-appearing stratified squamous epithelium. Squamous metaplasia is common in the endocervix and the bronchial mucosa (Figure 16-5); it occurs less frequently in the endometrium and urinary bladder.

Glandular metaplasia occurs in the esophagus, where the normal squamous epithelium is replaced by a glandular, mucus-secreting epithelium (either gastric or intestinal in type), usually as a result of acid reflux into the esophagus (see Barrett's esophagus, Chapter 37: The Esophagus). Metaplasia may also occur in the stomach and intestine, where the mucosa of one part is replaced by that of another, eg, replacement of gastric mucosa with intestinal mucosa (intestinal metaplasia) or vice versa (gastric metaplasia). It may also affect the germinal epithelium of the ovary, as in the formation of serous and mucinous cysts.

Metaplasia rarely occurs in mesenchymal tissue and is best exemplified by osseous metaplasia in scars and other fibroblastic proliferations. Metaplasia in mesenchymal tissue is the same as epithelial metaplasia in representing the potential for diverse differentiation of mesenchymal stem cells.

Most metaplasia is of little clinical significance, although important functional deficits may result in some areas; loss of cilia and of mucus production in the bronchi may predispose to development of infection. Metaplastic tissue is structurally normal and itself carries no increased risk of development of cancer. However, dysplastic changes are often present as well (Figure 16-6), and cancer does occur in metaplastic epithelia under such circumstances. Squamous carcinoma develops in metaplastic squamous epithelium in the bronchus, and adenocarcinoma may arise in the esophagus from metaplastic glandular epithelium.

Characteristics of Dysplasia

Dysplasia is an abnormality of both differentiation and maturation. Use of the term dysplasia should be restricted to abnormalities of cell growth with the characteristics described below and illustrated by Figures 16-4 to 16-9. Loose application of the term dysplasia to denote any cell or tissue that does not appear quite normal is to be discouraged.

Nuclear Abnormalities

Dysplasia is characterized by increased size of the nucleus, both absolute and relative to the amount of cytoplasm (increased nuclear:cytoplasmic ratio); increased chromatin content (hyperchromatism); abnormal chromatin distribution (coarse clumping); and nuclear membrane irregularities such as thickening and wrinkling.

Cytoplasmic Abnormalities

Cytoplasmic abnormalities in dysplasia result from failure of normal differentiation, eg, lack of keratinization in squamous cells and lack of mucin in glandular epithelium.

Increased Rate of Cell Multiplication

In squamous epithelium, an increased rate of cellular multiplication is characterized by the presence of mitotic figures in many layers of the epithelium—in contrast to the normal state, in which mitosis is limited to the basal layer. Individual mitoses are morphologically normal in dysplasia.

Disordered Maturation

Dysplastic epithelial cells retain a resemblance to basal stem cells as they move upward in the epithelium; normal differentiation (keratin production) fails to occur. Dysplasia is usually graded as mild, moderate, or severe.

Significance of Dysplasia

When it is defined in this manner, epithelial dysplasia is a premalignant lesion, associated with an increased risk of development of cancer. In simple terms, dysplasia is one step short of cancer—with cancer a general term for invasive, aggressive growths that are more properly called malignant neoplasms. The process of neoplasia and the many different kinds of neoplasms are the subject of the next three chapters. In the uterine cervix, the relationship of dysplasia to cervical cancer is so intimate that the term cervical intraepithelial neoplasia (CIN) is used synonymously with the term dysplasia (Figure 16-9). For this reason, we include the discussion of carcinoma in situ at this point—recognizing, however, that carcinoma in situ is a true neoplasm with all of the features of malignant neoplasms except invasiveness, which will be described in the next chapter. Severe dysplasia of the cervix and carcinoma in situ of the cervix have the same clinical significance and are treated similarly. In effect, the terms are equivalent.

The risk of developing invasive cancer varies with (1) the grade of dysplasia—the more severe, the greater the risk; (2) the duration of dysplasia—the longer the duration, the greater the risk; and (3) the site of dysplasia. Dysplasia in the urinary bladder is associated with a more imminent risk of cancer than is cervical dysplasia, in which several years may elapse before invasive carcinoma develops.

Differences between Dysplasia & Cancer

Dysplasia and carcinoma in situ differ from true cancer in two important respects: invasiveness and reversibility.

Lack of Invasiveness

The abnormal cellular proliferation in dysplasia and carcinoma in situ does not invade the basement membrane. Because the epithelium contains neither lymphatics nor blood vessels, the proliferating cells do not spread from the epithelium. Complete removal of the dysplastic area is therefore curative. Cancer, in contrast, invades the basement membrane and spreads from the local (primary) site via lymphatics and blood vessels, so that excision of the primary site may not be curative.

Reversibility

Dysplastic tissue, particularly that affected by the milder grades of dysplasia, may sometimes spontaneously return to normal—unlike cancer, which is an irreversible process. Severe dysplasia may be irreversible.

Diagnosis of Dysplasia

Gross Examination

Epithelial dysplasia, including carcinoma in situ, is usually asymptomatic, and in many cases gross examination of the mucosa shows no abnormality. Dysplasia can sometimes be identified through special examination techniques (eg, colposcopy for cervical dysplasia, fluorescent bronchoscopy for bronchial dysplasia). The Schiller test for cervical dysplasia exploits the lack of cellular differentiation of the dysplastic epithelium; when the cervix is painted with iodine solution, normal squamous epithelium turns brown owing to its glycogen content; dysplastic epithelium remains unstained.

Microscopic Examination

The diagnosis of dysplasia is made by microscopic examination of samples from asymptomatic patients. Cytologic findings (in cell smears) must be confirmed by biopsy. Smears are made from material scraped from the epithelium for cytologic diagnosis (Figure 16-8); tissue obtained by biopsy is necessary for histologic diagnosis (Figures 16-6 and 16-7). Microscopic examination of the nuclear and cytoplasmic features of dysplastic tissue provides evidence for both diagnosis and grading of dysplasia. The criteria for cytologic diagnosis of dysplasia are well established for the cervix, urinary bladder, and lung. In other sites, such as the gastrointestinal tract and breast, it may be difficult to distinguish dysplasia from other epithelial changes associated with inflammation and regeneration (repair and regeneration involve cell proliferation, so that variable degrees of cellular disorganization may occur; such changes are often grouped under the less precise term atypia).

Routine cytologic screening of Papanicolaou cervical smears has permitted early detection and treatment of cervical dysplasia. Widespread use of Pap smears has contributed to the striking decline in incidence of cancer of the uterine cervix in the past 20 years. The results of cytologic screening in other sites have not been as encouraging. Although dysplasia can be recognized in lung (sputum smears), bladder (urine smears), stomach (gastric brushings), and colon (colonic lavage), complete removal of all dysplastic epithelium from these tissues is much more difficult. As a result, routine screening for dysplasia in these tissues is not recommended, and early recognition of dysplasia has had little impact on the statistics for incidence of cancer in these sites.

Neoplasia (Latin, new growth) is an abnormality of cellular differentiation, maturation, and control of growth. Neoplasms are commonly recognized by the formation of masses of abnormal tissue (tumors). The term tumor can be applied to any swelling—and in that context is one of the cardinal signs of inflammation—but today it is used most commonly to denote suspected neoplasm. Neoplasms are benign or malignant depending on several features, chiefly the ability of malignant neoplasms to spread from the site of origin. Benign neoplasms grow but remain localized. Cancer denotes a malignant neoplasm (the term is thought to derive from the way in which the tumor grips the surrounding tissues with claw-like extensions, much like a crab).

Although a neoplasm may not be difficult to recognize, the process of neoplasia is hard to define. The definition of neoplasm proposed in the early 1950s by Rupert Willis, a British pathologist, is probably the best: “A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the surrounding normal tissues and persists in the same excessive manner after cessation of the stimuli that evoked the change.” This definition is analyzed in greater detail in Chapter 18: Neoplasia: II. Mechanisms & Causes of Neoplasia.

Although all neoplasms possess certain characteristics in common—particularly the capacity for uncontrolled continuous growth (Chapter 19: Neoplasia: III. Biologic & Clinical Effects of Neoplasms)—they vary enormously in their gross and microscopic features. The clinical presentation, behavior, effects, response to therapy (Chapter 19: Neoplasia: III. Biologic & Clinical Effects of Neoplasms), and etiology (Chapter 18: Neoplasia: II. Mechanisms & Causes of Neoplasia) are likewise diverse.

For these reasons, the classification of neoplasms has major implications for prognosis and therapy. Approaches to the classification of neoplasms are summarized in Table 17-1.

Types of Biologic Behavior

The biologic behavior of neoplasms constitutes a spectrum (Figure 17-1) with two extremes:

Benign

At one extreme, benign neoplasms grow slowly and do not invade surrounding tissues or spread to distant sites (ie, no metastasis). Such neoplasms are rarely life-threatening but may become so because of hormone secretion or critical location, eg, a benign neoplasm can cause death if it arises in a cranial nerve and compresses the medulla.

Malignant

At the other extreme are malignant neoplasms, which grow rapidly, infiltrate and destroy surrounding tissues, and metastasize throughout the body, often with lethal results.

Intermediate

Between these two extremes is a smaller third group of neoplasms that are locally invasive but have low metastatic potential. Such neoplasms are called locally aggressive neoplasms or low-grade malignant neoplasms. An example is basal cell carcinoma of the skin.

Prediction of Biologic Behaviorby Pathologic Examination

Treatment of neoplasms is based upon their biologic behavior. Benign neoplasms are cured by excision of the tumor. Locally aggressive neoplasms must be treated by excising the tumor along with a wide margin of surrounding tissue to ensure that infiltrating cells are removed. Malignant neoplasms require local wide removal, frequently including regional lymph nodes as well as systemic treatment for neoplastic cells that may have metastasized.

The pathologist classifies a neoplasm as benign or malignant on the basis of histologic and cytologic features in association with the cumulative clinicopathologic experience gained with various types of neoplasms. There are no absolute criteria for distinguishing benign from malignant neoplasms, and the characteristics listed in Table 17-2 serve as general guidelines only.

Rate of Growth

Malignant neoplasms generally grow more rapidly than benign ones, but there is no critical rate that distinguishes malignant from benign. Assessment of the growth rate is based upon clinical information (eg, change in size of the mass in serial examinations). On microscopic examination, the number of mitotic figures and the metabolically active appearance of nuclei (enlarged, dispersed chromatin, large nucleoli) correlate positively with the growth rate of the neoplasm.

Size

The size of a neoplasm usually has no bearing on its biologic behavior. Many benign neoplasms become very large; conversely, highly malignant neoplasms may be lethal by virtue of extensive dissemination even though the original primary tumor is still small. In a few neoplasms, however, size is the deciding factor in distinguishing benign from malignant growths. A carcinoid tumor of the appendix is considered benign unless it is larger than 2 cm, in which case it is regarded as malignant; this distinction is based on the observation that the risk of metastasis increases with increasing size of the primary neoplasm and that appendiceal carcinoid tumors less than 2 cm in diameter do not metastasize. Benign and malignant carcinoid tumors are histologically identical.

Degree of Differentiation

When the term differentiation is used to describe neoplasms, it denotes the degree to which a neoplastic cell resembles the normal mature cells of the tissue in question; this meaning is distinct from the more general use of the word to describe passage of a cell down a particular maturation pathway. Benign neoplasms are usually fully (well) differentiated, ie, they closely resemble normal tissue (Figure 17-2). Malignant neoplasms, on the other hand, show variable degrees of differentiation and frequently demonstrate little resemblance to normal tissue (ie, they are poorly differentiated). In anaplasia, the neoplastic cells have no morphologic resemblance whatsoever to normal tissue. Malignant neoplasms are also usually more cellular, have a higher mitotic rate, and display the cytologic features of malignancy (Table 17-2). The importance of these individual criteria varies with different neoplasms. For example, the mitotic rate is the major factor distinguishing benign from malignant smooth muscle neoplasms in the uterus; in many other neoplasms, the mitotic rate is of little relevance. Similarly, pheochromocytoma, a neoplasm of the adrenal medulla, may show extreme cytologic abnormalities without demonstrating malignant behavior.

Changes in Deoxyribonucleic Acid (DNA)

Neoplasms are associated with abnormalities in their DNA content; this abnormality increases with the degree of malignancy. The degree of hyperchromatism (increased staining of the nucleus) provides a crude assessment of DNA content on microscopic examination; malignant cells are hyperchromatic. When measured precisely by flow cytometry, the DNA content of malignant cells correlates well with the degree of malignancy in malignant lymphoma, bladder neoplasms, and astrocytic neoplasms. Cytogenetic studies demonstrating aneuploidy and polyploidy also are indicative of malignancy. Molecular techniques that demonstrate clonal deletions, translocations, or abnormalities of oncogene expression (Chapter 18: Neoplasia: II. Mechanisms & Causes of Neoplasia) are of increasing value.

Infiltration and Invasion

Benign neoplasms are generally noninfiltrative and are surrounded by a capsule of compressed and fibrotic normal tissue. Malignant neoplasms, on the other hand, have infiltrating margins. Many exceptions to this rule exist, and some benign neoplasms—eg, granular cell tumor, dermatofibroma, and carcinoid tumors—lack a capsule and have an infiltrative margin.

Metastasis

The occurrence of metastasis (noncontiguous or distant growth of tumor; Chapter 18: Neoplasia: II. Mechanisms & Causes of Neoplasia) is absolute evidence of malignancy. The major reason for distinguishing benign from malignant neoplasms is to be able to predict their ability to metastasize before they do so.

Gross and microscopic examination of a neoplasm usually enables a trained pathologist to classify most neoplasms as benign or malignant. In some instances, however, this identification is difficult, and the only reliable evidence of a neoplasm's biologic behavior is the occurrence of metastasis; about 90% of pheochromocytomas are benign, but there are no reliable criteria for identifying the 10% that will metastasize.

Neoplasms are classified and named chiefly on the basis of their presumed cell of origin. These cells have different potentials for further development into various cell types (Tables 17-3 and 17-4).

Neoplasms of Totipotent Cells

The prototype of the totipotent cell—ie, a cell that is capable of differentiating (maturing) into any cell type in the body—is the zygote, which gives rise to the embryo, and the eventual fetus. In postnatal life, the only totipotent cells in the body are the germ cells. These are most commonly found in the gonads but also occur in the retroperitoneum, mediastinum, and pineal region.

Germ cell neoplasms (Figure 17-3) may remain with minimal differentiation as a mass of malignant primitive germ cells (seminoma and embryonal carcinoma) or may develop into a variety of tissues, including trophoblast (choriocarcinoma), yolk sac (yolk sac carcinoma), or somatic structures (teratoma) (Table 17-4). Mixtures of different tissues frequently coexist in a single neoplasm.

Teratomas show somatic differentiation and contain elements of all three germ layers: endoderm, ectoderm, and mesoderm. Thus, brain, respiratory and intestinal mucosa, cartilage, bone, skin, teeth, or hair may be seen in the neoplasm. The constituent tissues are not limited to those normally present in the area of origin. One older hypothesis held that teratomas represented a maldeveloped included twin (twin within a twin), but teratomas differ from fetuses in that the various tissues are largely disorganized. Testicular teratomas are diploid or aneuploid, with both X and Y chromosomes; they appear to arise before the first meiotic division and contain the same heterozygous pairs of alleles as are found in the normal host cells. In the ovary, teratomas are usually 46,XX but frequently show homozygous allelic pairs, suggesting an origin after the first meiotic division.

Teratomas are classified as mature (well-differentiated and composed of adult-type tissues) or immature (made up of fetal-type tissues). Immature teratomas are malignant, whereas mature teratomas vary in their biologic potential. Most mature teratomas are benign, eg, mature teratoma of the ovary (dermoid cyst) (Chapter 52: The Ovaries & Uterine Tubes). Mature testicular teratomas are benign when they occur in childhood but are usually malignant in adult testes. In teratomas, the distinction between benign and malignant incorporates unusual criteria such as maturity of constituent tissues, site of occurrence, and age of the patient.

Neoplasms of Embryonic Pluripotent Cells

Pluripotent cells can mature into several different cell types, and the corresponding neoplasms have the potential for formation of diverse structural elements; neoplasms of the renal anlage cells (nephroblastoma) commonly differentiate into structures resembling renal tubules and less often into rudiments of muscle, cartilage, and bone. These neoplasms are generally called embryomas or blastomas (Figure 17-4).

Embryonic pluripotent cells are found only in the fetal period and during the first few years of postnatal life. The corresponding neoplasms usually occur in early childhood and only rarely in adults.

Blastomas may be completely undifferentiated—ie, are composed of small, malignant, primitive-appearing, hyperchromatic cells—or may show evidence of differentiation, eg, the presence of primitive renal tubules in nephroblastoma or of ganglion cells in neuroblastoma. Evidence of differentiation generally signifies less malignant biologic behavior.

Neoplasms of Differentiated Cells

Differentiated, adult-type cells make up most of the cells in the body in postnatal life. They show a restricted potential for differentiation, as seen when they undergo metaplasia. Most human neoplasms are derived from differentiated cells.

The classification and nomenclature of these neoplasms (Table 17-4) combine several of the approaches set out in Table 17-1: the distinction between benign and malignant; the division into epithelial and mesenchymal; the cell or tissue of origin; the site; and other descriptive features.

Nomenclature of Neoplasms of Differentiated Cells

(Figure 17-5.)

Epithelial Neoplasms

A benign epithelial neoplasm is called an adenoma if it arises within a gland (eg, thyroid adenoma, colonic adenoma) or a papilloma (Latin, papilla = nipple) when arising from an epithelial surface. Papillomas may arise from squamous, glandular, or transitional epithelium (eg, squamous papilloma, intraductal papilloma of the breast, and transitional cell papilloma, respectively). Not uncommonly, descriptive adjectives are incorporated in the nomenclature; eg, colonic adenomas may be villous or tubular.

Malignant epithelial neoplasms are called carcinomas (adenocarcinomas if derived from glandular epithelia; squamous carcinoma and transitional cell carcinoma if originating in those kinds of epithelia). Names may also include the organ of origin and often an adjective as well, eg, clear cell adenocarcinoma of the kidney, papillary adenocarcinoma of the thyroid, verrucous squamous carcinoma of the larynx.

Mesenchymal Neoplasms

Benign mesenchymal neoplasms are named after the cell of origin (a Greek or Latin word is used) followed by the suffix -oma (Table 17-4). The names of these tumors may contain the organ of origin and an adjective, eg, cavernous hemangioma of the liver.

Malignant mesenchymal neoplasms are named after the cell of origin, to which is added the suffix -sarcoma. Again, adjectives are commonly used; liposarcomas are classified as sclerosing, myxoid, round cell, or pleomorphic.

Exceptions to These Rules

This simple scheme is complicated by several neoplasms that do not fit in.

Neoplasms That Sound Benign But Are Really Malignant

The names of some malignant neoplasms are formed by adding the suffix -oma to the cell of origin, eg, lymphoma (lymphocyte), plasmacytoma (plasma cell), melanoma (melanocyte), glioma (glial cell), and astrocytoma (astrocyte). The adjective malignant should be used—malignant lymphoma, malignant melanoma—but if it is not, these neoplasms are assumed to be malignant because there is no benign lymphoma, melanoma, glioma, etc.

Neoplasms That Sound Malignant But Are Really Benign

Two rare bone neoplasms, osteoblastoma and chondroblastoma, may sound malignant because of the suffix -blastoma but are in fact benign neoplasms derived from osteoblasts and chondroblasts present in adult bone.

Leukemias

Neoplasms of blood-forming organs are called leukemias. These disorders are all considered malignant, although some exhibit a slower clinical course than others (Chapter 26: Blood: III. the White Blood Cells). Leukemias are classified on the basis of their clinical course (acute or chronic) and cell of origin (lymphocytic, granulocytic [myelocytic], monocytic, etc). Leukemias are characterized by the presence of neoplastic cells in bone marrow and peripheral blood; they rarely produce localized tumors.

Mixed Tumors

Neoplasms composed of more than one neoplastic cell type are called mixed tumors. Malignant mixed tumors may have two epithelial components, as in adenosquamous carcinoma; two mesenchymal components, as in malignant fibrous histiocytoma; or an epithelial and a mesenchymal component, as in carcinosarcoma of the lung and malignant mixed müllerian tumor of the uterus.

The existence of mixed tumors poses certain conceptual problems: Are they neoplasms derived from two separate cell lines that coincidentally became neoplastic at the same time, or are they neoplasms of a single multipotent cell type that then differentiates along more than one pathway? The latter is considered more likely.

In the case of benign mixed tumors such as fibroadenoma of the breast, most investigators believe that only the epithelial (adenoma) component is neoplastic and that fibrous tissue represents some form of reaction to the adenoma cells.

Neoplasms Whose Cell of Origin Is Unknown

When the cell of origin is unknown, the name of the person who first described the neoplasm is commonly used to name the tumor (Table 17-5). As the histogenesis of these neoplasms is clarified, the name is often changed: Wilms' tumor is now called nephroblastoma, and Grawitz's tumor is better known as renal adenocarcinoma. Some neoplasms of uncertain histogenesis are named descriptively, eg, granular cell tumor (from Schwann cells?), alveolar soft part sarcoma (from rhabdomyoblasts?).

Hamartomas & Choristomas

Hamartomas and choristomas are tumor-like growths thought to be the result of developmental anomalies. They are not true neoplasms (ie, they do not show continuous excessive growth). The tumors are abnormal, disorganized, proliferating masses of several different adult cell types.

A hamartoma is composed of tissues that are normally present in the organ in which the tumor arises; a hamartoma of the lung consists of a disorganized mass of bronchial epithelium and cartilage that may become so large that it presents as a lung mass. Its growth is coordinated with that of the lung itself.

A choristoma resembles a hamartoma but contains tissues that are not normally present in its site of origin. A disorderly mass of smooth muscle and pancreatic acini and ducts in the wall of the stomach is properly called a choristoma. A gastric choristoma such as this may present as an intramural mass that is clinically indistinguishable from a benign neoplasm.

Incidence & Mortality Rates

Cancer is the second overall leading cause of death (after ischemic heart disease) in the United States: It causes approximately 500,000 deaths annually (25% of all deaths). The incidence continues to rise, probably reflecting the increasing average age of the population.

There are many reasons why the incidence of cancer varies tremendously in different populations and different areas. Epidemiologic study of cancer distribution often sheds light on the etiologic factors. Thorough knowledge of the incidence and pattern of cancer in the local population is important for the clinician evaluating the possibility of cancer in a given patient.

Both the incidence (Figure 17-6) and the death rate (Figure 17-7) of cancer must be considered. The latter reflects both the incidence and the success of diagnosis and therapy. For instance, skin cancer is by far the most common cancer in the United States (> 500,000 cases per year) but is usually diagnosed early and cured by excision; the death rate from skin cancer is thus low and does not figure prominently in the overall cancer death rate statistics. (Note that in Figures 17-6 and 17-7 skin cancer other than melanoma has been specifically excluded and does not appear in the overall cancer incidence statistics.)

Major Factors Affecting Incidence

The presence or absence of any of the many factors influencing the incidence of cancer must be established during history taking and physical examination of a patient thought to have cancer.

Sex

Prostate cancer in men and uterine cancer and breast cancer in women are obviously sex-specific. In other types of cancer, the reasons for the difference in incidence between the sexes are less evident. For example, cancer of the oropharynx, esophagus, and stomach is more than twice as common in men, but cancers of the gallbladder and thyroid and malignant melanoma are more frequent in women. Both bladder and lung cancer are more common in men, partly because of greater occupational exposure (dye and rubber industries for bladder cancer, mining and asbestos for lung cancer) and smoking habits. Recent figures show that the rate of lung cancer in women is fast approaching that in men as smoking habits of women match those of men (in the United States but not everywhere).

Age

The frequency of occurrence of most types of cancer varies greatly at different ages.

Carcinoma is rare in children, but some leukemias, primitive neoplasms (blastomas) (Figure 17-4) of the brain, kidney, and adrenal, malignant lymphomas, and some types of connective tissue tumors are relatively common (Table 17-6). Most of these childhood neoplasms grow rapidly and are composed of small, very primitive cells with large, hyperchromatic nuclei, scant cytoplasm, and a high mitotic rate.

In adults, carcinomas make up the largest group of malignant tumors; they result from neoplastic change occurring in mature adult-type epithelial tissues. Sarcomas occur in adults but are less common than carcinomas.

Neoplasms of the hematopoietic and lymphoid cells (leukemias and lymphomas) occur at all ages. The incidence of different types of these neoplasms varies with age; acute lymphoblastic leukemia is common in children, whereas chronic lympho-cytic leukemia occurs more often in the elderly (Chapter 26: Blood: III. the White Blood Cells).

Occupational, Social, and Geographic Factors

Occupational factors have been mentioned with reference to an increased risk of bladder cancer in workers in the dye industry and lung cancer in certain miners. These aspects are discussed more fully in Chapter 18: Neoplasia: II. Mechanisms & Causes of Neoplasia and usually correlate with increased exposure to carcinogens. Because the risk is so high in certain industries, an occupational history is an essential part of a full medical examination.

Similarly, such social habits as cigarette smoking (lung cancer)—and to a lesser extent pipe and cigar smoking, snuff taking, and tobacco chewing (cancer of the oropharynx)—represent risk factors for development of several types of cancer, and the physician must evaluate the amount of exposure to these factors during history taking.

Epidemiologic studies also show that a patient's sexual and childbearing histories are important. Women who have borne several children and have breast-fed them have a significantly lower incidence of breast cancer than women who elect not to breast-feed or who are nulliparous. (Nuns have a high incidence of breast cancer.) Conversely, nuns have a lower incidence of cervical cancer, which appears to be most common among women who begin sexual activity early—particularly those with multiple partners. Circumcised men have a much lower incidence of carcinoma of the penis than their uncircumcised counterparts, and some studies have suggested that carcinoma of the uterine cervix is more common in women whose sexual partners have not been circumcised. Various explanations include the finding that smegma is carcinogenic in mice; associations of cervical carcinoma with standards of sexual hygiene and herpesvirus and papovavirus infections (Chapter 53: The Uterus, Vagina, & Vulva) have also been reported.

Geographic variations in the overall incidence of cancer and in the incidence of specific types of cancer also occur from one country to another (Table 17-7), from one city to another, and from urban to rural areas (Figures 17-8 and 17-9). Detailed epidemiologic case control studies have sometimes uncovered associations with high-risk occupations, diet, environmental carcinogens, or endemic viruses; other occurrences remain unexplained. For example, the high incidence of stomach cancer in Japan (Figure 17-8) has been related to diet (smoked raw fish). This type of cancer does not appear to be genetically determined, because Japanese emigrating to the United States show within a single generation the lower incidence of stomach cancer demonstrated by native-born Americans. However, marked differences in the mortality rate of stomach cancer exist even within different parts of the United States for unknown reasons. (Areas with high gastric cancer mortality death rates in the north central United States are associated with populations of northern European descent.) The factors involved clearly differ from those playing a role in lung cancer, because the distribution of deaths due to this disease is very different, although there is some association with asbestos exposure in mining or shipyards.

Marked variation in cancer incidence in different countries has in some cases provided important clues to the possible causative role of viruses and immune stimulation. The distribution of Burkitt's lymphoma, infection with Epstein-Barr virus, and malaria in Africa provides the best-known example of an association between a neoplasm and infection. A close association also exists between liver cell carcinoma and the incidence of hepatitis B virus carriers in a population (Figure 17-9).

Family History

A few cancers have a simple pattern of genetic inheritance (Chapter 18: Neoplasia: II. Mechanisms & Causes of Neoplasia)—and those that do are so striking that they warrant careful study of relatives of known cases (eg, retinoblastoma, polyposis coli and carcinoma of the colon, medullary carcinoma of the thyroid).

For other cancers, the genetic link is not as strong (eg, breast cancer) or is almost nonexistent (eg, lung cancer). It must also be understood that familial occurrence of neoplasms may represent the action of similar environmental factors rather than a genetic predisposition.

Cancer families with a high incidence of cancer have also been described. In such cases the cancer is usually of a particular type but may be of different types; colon, endometrial, and breast cancer occur in some families. Cancer in such families may skip generations, suggesting the possible interplay both of recessive genetic mechanisms and of environmental factors.

History of Associated Diseases

Perhaps the most important finding in the history of a patient with suspected cancer is a record of diagnosis or treatment of previous cancer. A positive history of cancer greatly increases the chances that the current illness represents either a metastasis (which may be delayed many years) or a second primary tumor. Statistics show that patients who have had cancer—even if the lesion was totally excised—have a much higher incidence of a second cancer, particularly in the same tissue. For example, cancer in one breast increases the chances of cancer in the opposite breast, and one occurrence of colon cancer necessitates repeated routine examinations to detect the development of another colon cancer. Second cancers of a different type—particularly leukemia and sarcomas—also occur as a complication of chemotherapy and radiation used to treat the first cancer.

In addition, certain disorders that in themselves are nonneoplastic carry an associated higher risk of development of cancer and are considered preneoplastic diseases. These diseases are uncommon, but together they constitute a significant group of risk factors (Table 17-8).

Trends in Cancer Incidence

The relative incidence of different types of cancer and their mortality rates vary over time and reflect both changes in incidence of various cancers and improvement in diagnosis and therapy, respectively (Figures 17-10, 17-11, 17-12, and 17-13).

Neoplasia is an abnormality of cell growth and multiplication characterized by the following features: (1) excessive cellular proliferation that typically but not invariably produces an abnormal mass, or tumor; (2) uncoordinated growth occurring without any apparent purpose; and (3) persistence of excessive cell proliferation and growth even after the inciting stimulus that evoked the change has been removed—ie, neoplasia is an irreversible process.

At a molecular level, neoplasia is a disorder of growth regulatory genes (proto-oncogenes and tumor suppressor genes). It develops in a multistep fashion, such that different neoplasms, even of the same histologic type, may show different genetic changes.

Several hypotheses have been advanced to explain neoplasia, many of them reflecting or in response to advances in the basic sciences current at the time. For example, hypotheses of the viral cause of neoplasia coincided with the demonstration of transmission of certain animal neoplasms by ultrafiltrable agents (Rous sarcoma, 1908; Shope papilloma, 1933; Bittner milk factor, 1935). Immunologic hypotheses came to the fore after experiments involving tumor transplantation in animals (Ehrlich, 1908; immune surveillance, Burnet, 1950s). Deoxyribonucleic acid (DNA) mutations as a cause of neoplasia were proposed after the discovery of DNA structure and function (Watson and Crick, 1950s). Several of these hypotheses have enjoyed a phase of respectability, followed by a period of discreditation and then reemergence in modified form.

Two general types of origins have been proposed for neoplasms.

Monoclonal Origin

According to the concept of monoclonal origin, the initial neoplastic change affects a single cell, which then multiplies and gives rise to the neoplasm. The monoclonal origin of neoplasms has been clearly shown in neoplasms of B lymphocytes (B-cell lymphomas and plasma-cell myelomas) that produce immunoglobulin and in some other tumor types by isoenzyme studies (Figure 18-1).

Note that as a neoplasm progresses, further subclones may evolve from the initial clone as a result of additional ongoing genetic changes (multiple hits; see below).

Field Origin

A carcinogenic agent acting on a large number of similar cells may produce a field of potentially neoplastic cells. Neoplasms may then arise from one or more cells within this field. In many cases the result is several discrete neoplasms, each of which derives from a separate clonal precursor. The field change may be regarded as the first of 2 or more sequential steps that lead to overt cancer (multiple hits; see below).

Multifocal (neoplastic field) neoplasms occur in skin, urothelium, liver, breast, and colon. Recognizing that a neoplasm is of field origin has practical implications because one neoplasm in any of these sites should alert the clinician to the possibility of a second similar neoplasm. In the breast, for example, cancer in one breast carries a risk of cancer in the opposite breast that is about 10 times higher than that of the general population.

The Lag Period

A constant feature of all known agents that cause neoplasms is the interval (lag period) between exposure and development of the neoplasm. In survivors of the atomic bomb blasts of Hiroshima and Nagasaki, the largest number of cases of leukemia occurred about 10 years after the event, and some cancers developed as late as 20 years afterward. In shipyard workers exposed to asbestos during World War II, neoplasms attributed to asbestos were rare within 15 years of exposure. However, new cases were identified through the 1970s even though exposure stopped in the 1940s. In utero exposure to diethylstilbestrol may give rise to vaginal cancer 15 or more years after birth. These types of long lag periods may account for the difficulty in identifying carcinogenic agents for common neoplasms.

During the lag period, the altered cell may not show any structural or functional abnormality; for example, an epidermal cell that has been exposed to a carcinogen looks and functions the same as surrounding cells. Subtle changes are present in such cells, particularly in the genome, but these may not be apparent morphologically.

Multiple Hits & Multiple Factors

Knudson proposed that carcinogenesis requires two hits. The first event is initiation (Figure 18-2), and the carcinogen causing it is the initiator. The second event, which induces neoplastic growth, is promotion, and the agent is the promoter. It is now believed that in fact multiple hits occur (five or more), that multiple factors may cause these hits, and that each hit produces a change in the genome of the affected cell that is transmitted to its progeny (ie, the neoplastic clone). The period between the first hit and the development of clinically apparent cancer is the lag period.

The role of the Bittner milk factor (a ribonucleic acid [RNA] virus) in mouse mammary carcinoma (Figure 18-3), the genesis of African Burkitt's lymphoma in humans (Figure 18-4), and the sequential changes leading to colon cancer (see Figure 18-12) clearly illustrate that cancer arises through the interaction of many factors.

Oncogenes & Tumor Suppressor Genes

There are two main categories of genes that regulate cell growth, and the abnormal action of either or both may lead to neoplasia. Proto-oncogenes (cellular oncogenes: c-onc) code for a variety of growth factors, receptors, and signal-relay or transcription factors (Table 18-1), which act in concert to control entry into the cell cycle (eg, the growth promoter effect). The action of these genes is opposed by the action of tumor suppressor genes, which serve to down-regulate the cell cycle. A net increase in the production of stimulatory (promoter) factors, a decrease in inhibitory (suppressor) growth factors, or the production of functionally abnormal factors may lead to uncontrolled cell growth.

The neoplastic cell is then the result of several such changes interacting in summative fashion (multiple hits). Hits may result from inherited genetic abnormalities, spontaneous mutations, or the actions of external agents that may affect the gene. These mutagens* include chemical carcinogens, ionizing radiation, and viruses (which introduce new DNA; see below). The effect of these agents is exacerbated by incompetent DNA repair mechanisms such as mutation of the genes that oversee the fidelity of DNA duplication (mismatch repair; Table 18-2). Defective repair is common in the elderly and in persons with certain inherited conditions (such as xeroderma pigmentosum [sunlight; skin cancer], Bloom's syndrome (defective DNA ligase; several tumor types), and ataxia-telangiectasia (lymphomas). In persons with these conditions, a first hit (eg, defective repair mechanisms) is inherited and is already present in every cell in the body.

Mutagens are agents that produce mutations. Oncogens or carcinogens frequently act by producing mutations that result in cancer.

Neoplasia Associated with Constant Genetic Abnormalities

As techniques for chromosomal analysis extend beyond the gene to study of single nucleotides, so genetic abnormalities are being uncovered in many tumors (see Table 19-2), and the roles of the affected genes in normal growth and tumorigenesis are being elucidated.

The pedigree of families with a high incidence of retinoblastoma shows inheritance of an abnormal chromosome 13 with a partially deleted long arm; it is postulated that the missing genetic material may be involved in the normal control of retinal cells. It is thought that retinoblastoma develops in these patients when the residual normal chromosome 13 undergoes a similar deletion or mutation. This concept was the basis for Knudson's two-hit hypothesis.

Over 90% of patients with chronic granulocytic leukemia show a reciprocal translocation of genetic material between chromosome 22 and chromosome 9 (Philadelphia chromosome, Ph1). The translocation of the c-abl oncogene from chromosome 9 to 22 leads to production of a novel growth-regulating protein (a tyrosine protein kinase with a molecular weight of 210) and neoplastic proliferation of granulocytes.

Mechanisms of Gene Activation & Inactivation

It has been suggested that neoplastic transformation occurs as a result of activation (or derepression) of growth promoter genes (proto-oncogenes) or inactivation or loss of suppressor genes. Activation is a functional concept whereby the normal action of growth regulation is diverted into oncogenesis. The resultant activated proto-oncogene is referred to as an activated oncogene (or a mutant oncogene, if structurally changed), or simply as a cellular oncogene (c-onc). Activation and inactivation may occur through several mechanisms (Figure 18-5): (1) mutation, including single nucleotide loss (frameshift) or substitution (nonsense or missense codon), codon loss, gene deletion or more major chromosomal loss; (2) translocation to a different part of the genome where regulatory influences may favor inappropriate expression or repression; (3) insertion of an oncogenic virus at an adjacent site (see Figure 18-9); (4) amplification (production of multiple copies of the proto-oncogenes), which appear as additional chromosome bands or extra DNA fragments (double minutes); (5) introduction of viral oncogenes (see Figure 18-9); or (6) derepression (loss of suppressor control).

Viral Oncogene Hypothesis

Certain RNA viruses contain nucleic acid sequences that are complementary to a proto-oncogene and can (by reverse transcriptase) produce a viral DNA sequence that is essentially identical, lacking only the introns of the animal host cell. These sequences are termed viral oncogenes (v-onc). Many, perhaps all, of the oncogenic RNA retroviruses contain such sequences (Table 18-3), and they are found in the corresponding neoplasms. Currently, it is thought that the RNA oncogenic virus acquired its v-onc sequence by incorporation of the cellular oncogene from animal cells by a recombination-like mechanism (Figure 18-6).

DNA oncogenic viruses do not appear to contain intrinsic DNA sequences (cellular oncogenes) analogous to viral oncogenes of RNA viruses. Instead, DNA viruses appear to exert their oncogenic effect by blocking the action of supressor-gene protein products (see below).

Epigenetic Hypothesis

According to the epigenetic hypothesis, the fundamental cellular alteration occurs not in the genetic apparatus of the cell but rather in the regulation of gene e xpression, specifically the protein products of growth regulatory genes. The various patterns of gene expression that characterize tissue differentiation are thought to be maintained by heritable epigenetic mechanisms.

The main evidence for the role of epigenetic mechanisms in neoplasia comes from cancers produced by chemicals that have no known effect on the genetic apparatus of the cell. It is postulated that these chemicals may serve as promoters by binding various growth regulatory proteins, thus rendering them inactive.

Hypothesis of Failure of Immune Surveillance

The hypothesis of immune surveillance encompasses several concepts: (1) Neoplastic changes frequently occur in the cells of the body. (2) As a result of alteration in their DNA, neoplastic cells produce new molecules (neoantigens, tumor-associated antigens; see Figure 19-1). (3) The immune system of the body recognizes these neoantigens as foreign (Figure 18-7) and mounts a cytotoxic immune response that destroys the neoplastic cells. (4) Neoplastic cells produce clinically detectable neoplasms only if they escape recognition and destruction by the immune system.

This hypothesis of immune surveillance was popular in the 1950s largely because it provided a raison d'tre for the then recently discovered phenomenon of cell-mediated immunity. Evidence supporting the existence of immune surveillance is based on observations of a higher incidence of neoplasia in many immunodeficiency states and in transplant recipients receiving immunosuppressive drugs. The observation that cancer is a disease of the elderly may then be attributed to progressive failure of immune surveillance in the face of an increased frequency of neoplastic events resulting from the defective DNA repair that accompanies aging.

Challenges to this hypothesis are based on several findings: (1) T cell-deficient strains of mice do not show higher rates of neoplasia; (2) immunodeficient humans or those who have undergone transplant operations develop mainly lymphomas and not a full spectrum of different cancers, as would be expected; (3) thymectomized humans do not show an increased incidence of neoplasia; and (4) although many tumors do possess tumor-associated antigens and an immune response can often be demonstrated, the response is clearly ineffective at the time of clinical expression of the cancer.

The complexity of interactions between the immune system and tumors is depicted in Figure 18-7.

An agent that causes neoplasms is an oncogenic agent; an agent causing a malignant neoplasm (cancer) is a carcinogenic agent.

Carcinogens are substances that are known to cause cancer or at least produce an increased incidence of cancer in an animal or human population. Many carcinogens have been identified in experimental animals, but because of dose-related effects and the metabolic differences among species, the relevance of these studies to humans is not always clear. The following discussion will consider mainly those carcinogens of known importance to humans. It is important to stress that (1) the cause of most common human cancers is unknown; (2) most cases of cancer are probably multifactorial in origin; and (3) except for cigarette smoking, the agents discussed below have been implicated in only a small percentage of cases.

The importance of environmental carcinogens must not be minimized simply because they may not yet have been identified. The marked geographic variation in the incidence of different cancers (Chapter 17: Neoplasia: I. Classification, Nomenclature, & Epidemiology of Neoplasms) is thought to result more from the action of different carcinogens than from variations in genetic makeup. If this belief is valid, then still unidentified environmental agents probably play a major role in causing about 95% of human cancers.

Chemical Oncogenesis

(Table 18-4)

It is difficult to assess the possible carcinogenic effects of the many industrial, agricultural, and household chemicals present in low levels throughout the environment. A significant hazard is also posed by disposal of industrial waste, which may contaminate drinking water and offshore coastal waters (and marine life).

One of the major problems associated with the identification of chemical carcinogens is the long lag phase, sometimes 20 or more years between exposure and the development of cancer. Unless the effects produced are dramatic, it is difficult to establish the carcinogenicity of any particular chemical in view of the huge number of substances to which people are exposed during their lives. Table 18-5 summarizes the clinical approach and experimental assays used to detect potential carcinogens.

Most chemical carcinogens act by producing changes in DNA, including abnormal base alkylation, deletions (partial), strand breakages, and cross-linkages. A small number act by epigenetic mechanisms, ie, they cause changes in growth-regulating proteins without producing genetic changes. Still others may act synergistically with viruses (derepressing oncogenes) or may serve as promoters for other carcinogens.

Chemical carcinogens that act locally at the site of application without having to undergo metabolic change in the body are called proximate or direct-acting carcinogens. Other chemicals produce cancer only after they are converted into metabolically active compounds within the body; these are termed procarcinogens, and the active carcinogenic compounds that are produced are called ultimate carcinogens.

The potency of carcinogens also varies greatly, at least in experimental systems, expressed as the amount that must be given to induce cancer on a regular basis (ie, reproducibly). Thus, saccharin requires 10 g/kg/d (a huge dose—low-potency carcinogen); 2-naphthylamine, 10−1 g/kg/d; benzidine, 10−2 g/kg/d; and aflatoxin B1, 10−6 g/kg/d (making aflatoxin B1 the most potent known carcinogen).

Polycyclic Hydrocarbons

The first recognized carcinogen in humans was soot, the tarry residue of coal combustion. Sir Percivall Pott established in 1775 that soot was the agent responsible for scrotal cancer in London chimney sweeps. Soot from the chimneys tended to collect in the rugose scrotal skin and cause cancer. Much later, it was shown that the active carcinogens in soot and coal tar were a group of polycyclic hydrocarbons, the most active of which were benzoαpyrene and dibenzanthracene. Application of small amounts of these polycyclic hydrocarbons to the skin of experimental animals regularly cause skin cancer.

Cigarette Smoking

Cigarette smoking—and to a lesser extent cigar and pipe smoking—is associated with an increased risk of cancer of the lung, bladder, oropharynx, and esophagus. Smoking filtered cigarettes and newer low-nicotine and low-tar cigarettes decreases the risk only slightly. There is also strong evidence that the risk of cancer associated with smoking is not limited to the smoker but may extend to nonsmoking family members, coworkers, and others in close physical proximity to the smoke for long periods (eg, effect of second-hand smoke). It has been estimated that smoking accounts for more cancer deaths than all other known carcinogens combined.

Cigarette smoke contains numerous carcinogens, the most important of which are probably polycyclic hydrocarbons (tars). Although these are direct-acting carcinogens in the skin, they act as procarcinogens in producing lung and bladder cancer. Inhaled polycyclic hydrocarbons are converted in the liver to an epoxide by a microsomal enzyme, aryl hydrocarbon hydroxylase. This epoxide (the ultimate carcinogen) is an active compound that combines with guanine in DNA, leading to neoplastic transformation. Smokers who develop lung cancer have been shown to have significantly higher levels of aryl hydrocarbon hydroxylase than nonsmokers or smokers who fail to develop cancer. The reported risk of developing cancer has varied in different studies, but it is about ten times higher in someone who smokes a pack of cigarettes a day for 10 years (10 pack years) than in a nonsmoker. If a smoker stops smoking, the risk drops almost to that of a nonsmoker after about 10 years of abstinence.

Aromatic Amines

Exposure to aromatic amines such as benzidine and naphthylamine is associated with an increased incidence of bladder cancer (first recognized in workers in the leather and dye industries). Similar compounds have been used in many pathology and research laboratories; their use is closely controlled by the Food and Drug Administration (FDA), but as with radiation, there is no safe threshold of exposure.

Aromatic amines are procarcinogens that enter the body through the skin, lungs, or intestine and exert their carcinogenic effects predominantly in the urinary bladder. In the body they are converted to carcinogenic metabolites that are excreted in the urine. Retention of urine in the bladder maximizes the carcinogenic effect on the bladder mucosa.

Different species vary in their susceptibility to the effects of aromatic amines: Humans and dogs are quite susceptible; rats and rabbits, much less so. This variation reinforces the point that procarcinogens (which must be converted in the body to ultimate carcinogens) may have different effects in different species because of different metabolic processes. This is a serious flaw in all animal studies that attempt to establish lack of carcinogenicity of new drugs to be used in humans.

Cyclamates and Saccharin

These compounds are artificial sweeteners once widely used by patients with diabetes mellitus. Administration of large amounts of these compounds caused bladder cancer in experimental animals. No carcinogenic effect has been demonstrated in humans, and it is not even known whether humans metabolize these compounds to produce ultimate carcinogens.

Azo Dyes

These dyes were extensively used as food coloring agents (scarlet red and butter yellow) until they were shown to cause liver tumors in rats. They have since been withdrawn from commercial use. Less potent relatives, such as trypan blue and Evans blue, remain in use as histologic stains.

Aflatoxin

Aflatoxin, a toxic metabolite produced by the fungus Aspergillus flavus, is thought to be an important cause of liver cancer in humans. The fungus grows on improperly stored food, particularly grain, groundnuts, and peanuts, producing aflatoxin. In Africa, dietary intake of large amounts of aflatoxin has been shown to correlate with a high incidence of hepatocellular carcinoma. Ingested aflatoxin is oxidized in the liver to an ultimate carcinogen that binds with guanine in the DNA of hepatic cells. In large amounts, the toxin causes acute liver-cell necrosis followed by regenerative hyperplasia and possibly cancer. When lesser amounts (minute amounts, as this is a very potent carcinogen) are ingested over a long period, the carcinogenic effect predominates. There is increasing evidence that aflatoxin induces mutations of P53, leading to loss of tumor supressor function.

Nitrosamines

Small amounts of these compounds have been shown to be carcinogenic in experimental animals. Their ability to react with both nucleic acids and cytoplasmic macromolecules provides a theoretic basis for their carcinogenic action, but their role in human carcinogenesis is uncertain.

Nitrosamines are derived mainly from conversion of nitrites in the stomach. Nitrites are ubiquitous in food because of their common use as preservatives, mainly in processed meats, ham, bacon, sausage, and so forth. The direct local action of nitrosamines is thought to be an important cause of esophageal and gastric cancer. The markedly decreased incidence of gastric cancer in the last 2 decades in the United States is believed to be due mainly to better refrigeration of food, which has decreased the need for chemical preservatives. The high incidence of gastric cancer in Japan is thought to be related more to high intake of smoked fish (containing polycyclic hydrocarbons) than to high nitrosamine levels.

Betel Leaf

Chewing of betel leaf or betel nut in Sri Lanka and parts of India is responsible for an extremely high incidence of cancers of the oral cavity. The carcinogenic agent has not been identified but is believed to be present either in the Areca (betel) nut or in the crushed limestone or tobacco that is commonly chewed along with the betel leaf.

Anticancer Drugs

Certain drugs used in the treatment of cancer (alkylating agents, such as cyclophosphamide, chlorambucil, busulfan, and thiotepa) interfere with nucleic acid synthesis in normal cells and in cancer cells and may cause oncogenic mutations. Leukemia is the most common neoplastic complication of cancer chemotherapy and is a significant problem in patients in whom cure of the primary tumor has been achieved.

Asbestos

Asbestos has been widely used as an insulating material and fire retardant and is found in almost all buildings constructed in the United States between 1940 and 1970. The greatest individual exposure to asbestos occurred in shipyard workers during World War II.

Asbestos is inhaled into the lung, where it produces fibrosis and chronic lung disease. Crocidolite, the variety of asbestos having the finest diameter fibers (< 0.25 mm), presents the greatest hazard. Asbestosis also leads to fibrous proliferation in the pleura, where it results in fibrous plaques that are a reliable radiologic indicator of previous asbestos exposure. Diffuse pulmonary fibrosis also occurs (Chapter 35: The Lung: II. Toxic, Immunologic, & Vascular Diseases). Asbestos is associated with two types of cancer.

Malignant Mesothelioma

This uncommon neoplasm is derived from mesothelial cells, mainly in the pleura but also in the peritoneum and pericardium. Nearly all patients who develop malignant mesothelioma give a history of asbestos exposure.

Bronchogenic Carcinoma

Patients with asbestos exposure have a risk of lung cancer about twice that of the general population; this risk is greatly magnified by smoking (Figure 18-8). Although it is not as specifically associated with asbestosis as is mesothelioma, lung cancer is the most common malignant neoplasm in patients with a history of asbestos exposure.

It has been established that the risk of malignant mesothelioma and lung cancer is not limited solely to individuals with high levels of exposure to asbestos. Family members and even individuals living in communities where asbestos industries exist carry an increased risk of developing cancer. Recognition of this fact has resulted in claims for compensation by many individuals with low levels of direct exposure.

Other Industrial Carcinogens

Many other cancer-causing agents have been identified. Miners exposed to heavy metals such as nickel, chromium, and cadmium show an increased incidence of lung cancer. Arsenic exposure, which may occur in agricultural workers exposed to arsenic-containing pesticides, is associated with a high incidence of skin cancer and a lesser risk of lung cancer. Vinyl chloride, a gas used in the manufacture of polyvinyl chloride (PVC), has been shown to be associated with a malignant vascular neoplasm (angiosarcoma) of the liver, mainly in experimental animals.

Radiation Oncogenesis

(See also Chapter 11: Disorders Due to Physical Agents)

Several different types of radiation cause cancer, most probably by direct effects on DNA or possibly by activation of cellular oncogenes.

Ultraviolet Radiation

Solar ultraviolet radiation is associated with different kinds of skin cancer, including squamous carcinoma, basal cell carcinoma, and malignant melanoma. Neoplasms of the skin are especially common in fair-skinned individuals whose occupations expose them to sunlight; farmers in Queensland, Australia, have an extremely high incidence of melanoma. Skin cancer is overall the most common type of cancer in the United States. The incidence of ultraviolet radiation-induced skin cancer, including melanoma, is low in darker-skinned races because of the protective effect of melanin pigment.

Ultraviolet light is believed to induce formation of linkages between pyrimidine bases on the DNA molecule. In normal individuals, this altered DNA molecule is rapidly repaired. Carcinoma occurs when DNA repair mechanisms do not operate efficiently, as occurs in older individuals and in people with xeroderma pigmentosum. Skin cancer due to exposure to sunlight is thus a disorder seen most often in the elderly.

X-Ray Radiation

Early radiologists who were exposed to x-rays of low penetration developed radiation dermatitis with a high incidence of skin cancer. As x-rays capable of greater penetration were developed, the second generation of radiologists suffered an increased incidence of leukemia. Present-day radiologists are at minimal risk for cancer because of highly effective protective measures against x-rays.

In the 1950s it was believed that thymic enlargement caused respiratory obstruction in infants (this was later proved to be untrue; a large thymus is normal in infants). Infants experiencing respiratory distress therefore underwent radiation therapy of the neck to decrease thymic size; many developed papillary thyroid cancer 15–25 years later.

One complication of radiotherapy for cancer is the occurrence of additional radiation-induced malignant neoplasms, commonly sarcomas, that appear 10–30 years after radiation therapy.

Diagnostic x-rays use such small doses of radiation that no increased risk of cancer is believed to be associated with their use. A possible exception is abdominal x-rays during pregnancy, which may slightly increase the incidence of leukemia in the fetus.

Radioisotopes

The carcinogenic effect of radioactive materials was first recognized when many cases of osteosarcoma occurred among factory workers who used radium-containing paints to produce luminous watch faces. It was found that these workers shaped their brushes to a point with their tongues and lips, thereby ingesting dangerous amounts of radium. Radioactive radium is metabolized in the body in much the same way as calcium and is therefore deposited in bone, where it induces osteosarcoma.

Occupational exposure to radioactive minerals in the mines of central Europe and the western United States is associated with an increased incidence of lung cancer.

Thorotrast, a radiologic dye containing radioactive thorium, was used in diagnostic radiology between 1930 and 1955. Thorotrast is deposited in the liver and increases the risk for several types of liver cancer, including angiosarcoma, liver cell carcinoma, and cholangiocarcinoma (cancer of the bile ducts).

Radioactive iodine, which is used to treat nonneoplastic thyroid disease, is associated with an increased risk of cancer developing 15–25 years after treatment; the risk is weighed against the nature of the primary disease, the therapeutic benefits, and the patient's age.

Nuclear Fallout

Three groups of people have been exposed to nuclear fallout. The Japanese in Hiroshima and Nagasaki who survived the atomic bomb blasts have shown a greatly increased incidence of cancer, including leukemia and carcinoma of the breast, lung, and thyroid. Inhabitants of the Marshall Islands were accidentally exposed to fallout during atmospheric testing of a nuclear device in the southern Pacific Ocean. The fallout was rich in radioactive iodine and resulted in a high incidence of thyroid neoplasms in those exposed. The accident at the Chernobyl nuclear power plant in the Ukraine in 1986 also released radioactive iodine into the atmosphere and resulted in the exposure of several thousand people to radioactive contamination.

To put this in perspective, it has been estimated that all radiation derived from x-rays, therapeutic isotopes, nuclear power plants, and the like currently accounts for less than 1% of the total radiation exposure of the population; the remainder comes from radioactive rocks, the earth itself, and cosmic rays (ie, unavoidable background radiation).

Viral Oncogenesis

Both DNA viruses and RNA viruses can cause neoplasia (Table 18-6). DNA viruses insert their nucleic acid directly into the genome of the host cell. Normally, virus replication ensues. In the oncogenic DNA viruses, replication is sporadic or absent. However, viral products may still be formed with 2 observed effects: inactivation of tumor suppressor-gene proteins (p53, Rb), or enhancement of oncogene action (see below). RNA viruses require RNA-directed DNA polymerase (reverse transcriptase), an enzyme that causes production of a DNA copy of the RNA viral genome; this DNA copy (provirus) can then be inserted in the host genome. Some RNA viruses contain a built-in oncogene that directly activates the cell; others insert adjacent to an endogenous cellular oncogene, which is thereby activated (Figure 18-9; see also Table 18-3 and the discussion of oncogenes earlier in this chapter). Insertion of the viral DNA sequence into the host genome is a highly complex process requiring several viral enzymes that cleave the host DNA, insert the viral DNA, and then repair the break.