Figure 7-20 A liver studded with metastatic cancer.

Chapter 7 - Neoplasia

In the year 2000, there were 10 million new cases of cancer and 6 million cancer deaths worldwide.[1] [2] In the United States each year, almost 1.5 million individuals learn for the first

time that they have some type of cancer. Not included in these figures are more than 1 million new cases of the most common types of nonpigmented skin cancers and incipient, noninvasive cancers. Not only these noninvasive lesions but many invasive tumors as well can be cured. Nonetheless, according to American Cancer Society estimates, cancer caused approximately 556,000 deaths in 2003, corresponding to 1500 cancer deaths per day, accounting for about 23% of all deaths in the United States.[3] Some good news, however, has emerged: cancer mortality for both men and women in the United States declined during the last decade of the 20th century.[4] Thus, there has been progress, but the problem is still overwhelming. The discussion that follows deals with both benign tumors and cancers; the latter receive more attention. The focus is on the basic morphologic and biologic properties of tumors and on the present understanding of the molecular basis of carcinogenesis. We also discuss the interactions of the tumor with the host and the host response to tumors. Although the discussion of therapy is beyond the scope of this chapter, there are now dramatic improvements in therapeutic responses and 5-year survival rates with many forms of malignancy, notably the leukemias and lymphomas. A greater proportion of cancers is being cured or arrested today than ever before.

Definitions

Neoplasia literally means the process of "new growth," and a new growth is called a neoplasm. The term tumor was originally applied to the swelling caused by inflammation. Neoplasms also may induce swellings, but by long precedent, the non-neoplastic usage of tumor has passed into limbo; thus, the term is now equated with neoplasm.

Oncology (Greek oncos = tumor) is the study of tumors or neoplasms.

Cancer is the common term for all malignant tumors. Although the ancient origins of this term are somewhat uncertain, it probably derives from the Latin for crab, cancer—presumably because a cancer "adheres to any part that it seizes upon in an obstinate manner like the crab."

Although all physicians know what they mean when they use the term neoplasm, it has been surprisingly difficult to develop an accurate definition. The eminent British oncologist Willis[5] has come closest: "A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after cessation of the stimuli which evoked the change." We know that the persistence of tumors, even after the inciting stimulus is gone, results from heritable genetic alterations that are passed down to the progeny of the tumor cells. These genetic changes allow excessive and unregulated proliferation that becomes autonomous (independent of physiologic growth stimuli),

although tumors generally remain dependent on the host for their nutrition and blood supply. As we shall discuss later, the entire population of cells within a tumor arises from a single cell that has incurred genetic change, and hence tumors are said to be clonal.

Nomenclature

All tumors, benign and malignant, have two basic components: (1) proliferating neoplastic cells that constitute their parenchyma and (2) supportive stroma made up of connective tissue and blood vessels. Although parenchymal cells represent the proliferating "cutting edge" of neoplasms and so determine their behavior and pathologic consequences, the growth and evolution of neoplasms are critically dependent on their stroma. An adequate stromal blood supply is requisite, and the stromal connective tissue provides the framework for the parenchyma. In addition, there is cross-talk between tumor cells and stromal cells that appears to directly influence the growth of tumors. In some tumors, the stromal support is scant and so the neoplasm is soft and fleshy. Sometimes the parenchymal cells stimulate the formation of an abundant collagenous stroma, referred to as desmoplasia. Some tumors—for example, some cancers of the female breast—are stony hard or scirrhous. The nomenclature of tumors is, however, based on the parenchymal component.

Benign Tumors.

In general, benign tumors are designated by attaching the suffix -oma to the cell of origin. Tumors of mesenchymal cells generally follow this rule. For example, a benign tumor arising from fibroblastic cells is called a fibroma, a cartilaginous tumor is a chondroma, and a tumor of osteoblasts is an osteoma. In contrast, nomenclature of benign epithelial tumors is more complex. They are variously classified, some based on their cells of origin, others on microscopic architecture, and still others on their macroscopic patterns.

Adenoma is the term applied to a benign epithelial neoplasm that forms glandular patterns as well as to tumors derived from glands but not necessarily reproducing glandular patterns. On this basis, a benign epithelial neoplasm that arises from renal tubular cells growing in the form of numerous tightly clustered small glands would be termed an adenoma, as would a heterogeneous mass of adrenal cortical cells growing in no distinctive pattern. Benign epithelial neoplasms producing microscopically or macroscopically visible finger-like or warty projections from epithelial surfaces are referred to as papillomas ( Fig. 7-1 ).

Those that form large cystic masses, as in the ovary, are referred to as cystadenomas.

Figure 7-1Papilloma of the colon with finger-like projections into the lumen. (Courtesy of Dr. Trace Worrell, University of Texas Southwestern Medical School, Dallas, TX.)

Figure 7-2Colonic polyp. A, This benign glandular tumor (adenoma) is projecting into the colonic lumen and is attached to the mucosa by a distinct stalk. B, Gross appearance of several colonic polyps.

Figure 7-3This mixed tumor of the parotid gland contains epithelial cells forming ducts and myxoid stroma that resembles cartilage. (Courtesy of Dr. Trace Worrell, University of Texas Southwestern Medical School, Dallas, TX.)

Figure 7-4 A, Gross appearance of an opened cystic teratoma of the ovary. Note the presence of hair, sebaceous material, and tooth. B, A microscopic view of a similar tumor shows skin, sebaceous glands, fat cells, and a tract of neural tissue (arrow).

TABLE 7-1-- Nomenclature of Tumors

have primitive-appearing, unspecialized cells. In general, benign tumors are well differentiated ( Fig. 7-6 ). The neoplastic cell in a benign smooth muscle tumor—a leiomyoma—so closely resembles the normal cell that it may be impossible to recognize it as a tumor by microscopic examination of individual cells. Only the massing of these cells into a nodule discloses the neoplastic nature of the lesion. One may get so close to the tree that one loses sight of the forest.

Malignant neoplasms, in contrast, range from well differentiated to undifferentiated. Malignant neoplasms composed of undifferentiated cells are said to be anaplastic. Lack of differentiation, or anaplasia, is considered a hallmark of malignant transformation. Anaplasia literally means "to form backward," implying a reversion from a high level of differentiation to a lower level. There is substantial evidence, however, that most cancers do not represent "reverse differentiation" of mature normal cells but, in fact, arise from stem cells that are present in all specialized tissues. The well-differentiated cancer ( Fig. 7-7 ) evolves from maturation or specialization of undifferentiated cells as they proliferate, whereas the undifferentiated malignant tumor derives from proliferation without complete maturation of the transformed cells. Lack of differentiation, or anaplasia, is marked by a number of morphologic changes.

• Pleomorphism. Both the cells and the nuclei characteristically display pleomorphism—variation in size and shape ( Fig. 7-8 ). Cells may be found that are many times larger than their neighbors, and other cells may be extremely small and primitive appearing.

• Abnormal nuclear morphology. Characteristically the nuclei contain an abundance of DNA and are extremely dark staining (hyperchromatic). The nuclei are disproportionately large for the cell, and the nucleus-to-cytoplasm ratio may approach 1:1 instead of the normal 1:4 or 1:6. The nuclear shape is very variable, and the chromatin is often coarsely clumped and distributed along the nuclear membrane. Large nucleoli are usually present in these nuclei.

• Mitoses. As compared with benign tumors and some well-differentiated malignant neoplasms, undifferentiated tumors usually possess large numbers of mitoses, reflecting the higher proliferative activity of the parenchymal cells. The presence of mitoses, however, does not necessarily indicate that a tumor is malignant or that the tissue is neoplastic.

Many normal tissues exhibiting rapid turnover, such as bone marrow, have numerous mitoses, and non-neoplastic proliferations such as hyperplasias contain many cells in mitosis.

More important as a morphologic feature of malignant neoplasia are atypical, bizarre mitotic figures, sometimes producing tripolar, quadripolar, or multipolar spindles ( Fig. 7-9 ).

• Loss of polarity. In addition to the cytologic abnormalities, the orientation of anaplastic cells is markedly disturbed (i.e., they lose normal polarity). Sheets or large masses of tumor cells grow in an anarchic, disorganized fashion.

• Other changes. Another feature of anaplasia is the formation of tumor giant cells, some possessing only a single huge polymorphic nucleus and others having two or more nuclei.

These giant cells are not to be confused with inflammatory Langhans or foreign body giant cells, which are derived from macrophages and contain many small, normal-appearing nuclei. In the cancer giant cell, the nuclei are hyperchromatic and large in relation to the cell. Although growing tumor cells obviously require a blood supply, often the vascular stroma is scant, and in many anaplastic tumors, large central areas undergo ischemic necrosis.

Figure 7-5Leiomyoma of the uterus. This benign, well-differentiated tumor contains interlacing bundles of neoplastic smooth muscle cells that are virtually identical in appearance to normal smooth muscle cells in the myometrium.

Figure 7-6Benign tumor (adenoma) of the thyroid. Note the normal-looking (well-differentiated), colloid-filled thyroid follicles. (Courtesy of Dr. Trace Worrell, University of Texas Southwestern Medical School, Dallas, TX.)

Figure 7-7Malignant tumor (adenocarcinoma) of the colon. Note that compared with the well-formed and normal-looking glands characteristic of a benign tumor (see Fig. 7-6 ), the cancerous glands are irregular in shape and size and do not resemble the normal colonic glands. This tumor is considered differentiated because gland formation can be seen. The malignant glands have invaded the muscular layer of the colon. (Courtesy of Dr. Trace Worrell, University of Texas Southwestern Medical School, Dallas, TX.)

Figure 7-8Anaplastic tumor of the skeletal muscle (rhabdomyosarcoma). Note the marked cellular and nuclear pleomorphism, hyperchromatic nuclei, and tumor giant cells. (Courtesy of Dr. Trace Worrell, University of Texas Southwestern Medical School, Dallas, TX.)

Figure 7-9Anaplastic tumor showing cellular and nuclear variation in size and shape. The prominent cell in the center field has an abnormal tripolar spindle.

Figure 7-10Well-differentiated squamous cell carcinoma of the skin. The tumor cells are strikingly similar to normal squamous epithelial cells, with intercellular bridges and nests of keratin pearls (arrow). (Courtesy of Dr. Trace Worrell, University of Texas Southwestern Medical School, Dallas, TX.)

Figure 7-11 A, Carcinoma in situ. This low-power view shows that the entire thickness of the epithelium is replaced by atypical dysplastic cells. There is no orderly differentiation of squamous cells. The basement membrane is intact and there is no tumor in the subepithelial stroma. B, A high-power view of another region shows failure of normal differentiation, marked nuclear and cellular pleomorphism, and numerous mitotic figures extending toward the surface. The basement membrane (below) is not seen in this section.

Figure 7-12Biology of tumor growth. The left panel depicts minimal estimates of tumor cell doublings that precede the formation of a clinically detectable tumor mass. It is evident that by the time a solid tumor is detected, it has already completed a major portion of its life cycle as measured by cell doublings. The right panel illustrates clonal evolution of tumors and generation of tumor cell heterogeneity. A new subclone arise from the descendants of the original transformed cell, and with progressive growth the tumor mass becomes enriched for those variants that are more adept at evading host defenses and are likely to be more aggressive. (Adapted from Tannock IF: Biology of tumor growth. Hosp Pract 18:81, 1983.)

Figure 7-13Schematic representation of tumor growth. As the cell population expands, a progressively higher percentage of tumor cells leaves the replicative pool by reversion to G0, differentiation, and death.

Figure 7-14Fibroadenoma of the breast. The tan-colored, encapsulated small tumor is sharply demarcated from the whiter breast tissue.

Figure 7-15Microscopic view of fibroadenoma of the breast seen in Figure 7-14 . The fibrous capsule (right) delimits the tumor from the surrounding tissue. (Courtesy of Dr. Trace Worrell, University of Texas Southwestern Medical School, Dallas, TX.)

Figure 7-16Cut section of an invasive ductal carcinoma of the breast. The lesion is retracted, infiltrating the surrounding breast substance, and would be stony hard on palpation.

Figure 7-17The microscopic view of the breast carcinoma seen in Figure 7-16 illustrates the invasion of breast stroma and fat by nests and cords of tumor cells (compare with fibroadenoma shown in Fig. 7-15 ). The absence of a well-defined capsule should be noted. (Courtesy of Dr. Trace Worrell, University of Texas Southwestern Medical School, Dallas, TX.)

Figure 7-18Colon carcinoma invading pericolonic adipose tissue. (Courtesy of Dr. Melissa Upton, University of Washington, Seattle, WA.)

Figure 7-19Axillary lymph node with metastatic breast carcinoma. The subcapsular sinus (top) is distended with tumor cells. Nests of tumor cells have also invaded the subcapsular cortex. Courtesy of Dr. Trace Worrell, University of Texas Southwestern Medical School, Dallas, TX.)

Figure 7-20 A liver studded with metastatic cancer.

Figure 7-21Microscopic view of liver metastasis. A pancreatic adenocarcinoma has formed a metastatic nodule in the liver. (Courtesy of Dr. Trace Worrell, University of Texas Southwestern Medical School, Dallax, TX.)

Figure 7-22Comparison between a benign tumor of the myometrium (leiomyoma) and a malignant tumor of similar origin (leiomyosarcoma).

TABLE 7-2-- Comparisons between Benign and Malignant Tumors

reasons discussed later, they do not indicate the inevitable development of metastases.

The distinguishing features of benign and malignant tumors discussed in this overview are summarized in Table 7-2 and Figure 7-22 . With this background on the structure and behaviour of neoplasms, we now discuss the origin of tumors, starting with insights gained from the epidemiology of cancer and followed by the molecular basis of carcinogenesis.

Epidemiology

Because cancer is a disorder of cell growth and behavior, its ultimate cause has to be defined at the cellular and subcellular levels. Study of cancer patterns in populations, however, can contribute substantially to knowledge about the origins of cancer. For example, the concept that chemicals can cause cancer arose from the astute observations of Sir Percival Pott, who related the increased incidence of scrotal cancer in chimney sweeps to chronic exposure to soot. Thus, major insights into the cause of cancer can be obtained by epidemiologic studies that relate particular environmental, hereditary, and cultural influences to the occurrence of malignant neoplasms. In addition, certain diseases associated with an increased risk of developing cancer can provide insights into the pathogenesis of malignancy. Therefore, in the following discussion, we first summarize the overall incidence of cancer to provide an insight into the magnitude of the cancer problem, and then review a number of factors relating to both the patient and the environment that influence predisposition to cancer.

CANCER INCIDENCE

In some measure, an individual's likelihood of developing a cancer is expressed by national incidence and mortality rates. For example, residents of the United States have about a one in five chance of dying of cancer. There were, it is estimated, about 556,000 deaths from cancer in 2003, representing 23% of all mortality,[3] a frequency surpassed only by deaths caused by cardiovascular diseases. These data do not include an additional 1 million, for the most part readily curable, non-melanoma cancers of the skin and 100,000 cases of carcinoma in situ, largely of the uterine cervix but also of the breast. The major organ sites affected and the estimated frequency of cancer deaths are shown in Figure 7-23 . The most common tumors in men are prostate, lung, and colorectal cancers. In women, cancers of the breast, lung, and colon and rectum are the most frequent. Cancers of the lung, female breast, prostate, and colon/rectum constitute more than 50% of cancer diagnoses and cancer deaths in the U.S. population.[15] of the colon and in virtually 100% of cases are fated to develop a carcinoma of the colon by age 50. Other autosomal dominant cancer syndromes are the Li-Fraumeni syndrome resulting from germ line mutations of the p53 gene, multiple endocrine neoplasia types 1 and 2 (MEN-1 and MEN-2), and hereditary nonpolyposis colon cancer (HNPCC), a condition caused by inactivation of a mismatch repair gene (also listed below among repair defects).

Figure 7-23Cancer incidence and mortality by site and sex. Excludes basal cell and squamous cell skin cancers and in situ carcinomas, except urinary bladder. (Adapted from Jemal A, et al: Cancer statistics, 2003. CA Cancer J Clin 53:5, 2003.)

Figure 7-24Age-adjusted cancer death rates for selected sites in the United States, adjusted for the 2000 U.S. population. (Adapted from Jemal A, et al: Cancer statistics, 2003. CA Cancer J Clin 53:5, 2003.)

Figure 7-25The change in incidence of various cancers with migration from Japan to the United States provides evidence that the occurrence of cancers is related to components of the environment that differ in the two countries. The incidence of each kind of cancer is expressed as the ratio of the death rate in the population being considered to that in a hypothetical population of California whites with the same age distribution; the death rates for whites are thus defined as 1. The death rates among immigrants and immigrants' sons tend consistently toward California norms. (From Cairns J: The cancer problem. In Readings from Scientific American—Cancer Biology. New York, WH Freeman, 1986, p. 13.)

TABLE 7-3-- Occupational Cancers

Modified from Stellman JM, Stellman SD: Cancer and workplace. CA Cancer J Clin 46:70, 1996.

There are several features that characterize inherited cancer syndromes:

• In each syndrome, tumors involve specific sites and tissues, although they may involve more than one site. For example, in MEN-2, caused by a mutation of the RET protooncogene, thyroid, parathyroid, and adrenals are involved. There is no increase in predisposition to cancers in general.

• Tumors within this group are often associated with a specific marker phenotype. For example, there may be multiple benign tumors in the affected tissue, as occurs in familial polyposis of the colon and in MEN. Sometimes, there are abnormalities in tissue that are not the target of transformation (e.g., Lisch nodules and café-au-lait spots in neurofibromatosis type 1; see Chapter 5 ).

• As in other autosomal dominant conditions, both incomplete penetrance and variable expressivity occur.

Date: 2016-04-22; view: 812