Chapter 17. Neoplasia: I. Classification, Nomenclature, & Epidemiology of Neoplasms

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).