Chapter 16. Disorders of Cellular Growth, Differentiation, & Maturation

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.