Ref Robbins 7/e p273_274;9/e p271 CHARACTERISTICS OF BENIGN AND MALIGNANT NEOPLASMS Nothing is more impoant to the patient with a tumor than being told: "It is benign." In general, benign tumors appear to be genetically "simple," harboring fewer muta- tions than cancers, and genetically stable, changing little in genotype over time. The latter feature probably explains why benign tumors such as lipomas and leiomyomas transform to malignancies rarely, if at all. In practice, the determination of benign versus malignant is made with remarkable accuracy using long-established clinical and anatomic criteria, but some neoplasms defy easy character- ization. Ceain features may indicate innocence, and others may indicate malignancy. Such problems are not the rule, however, and there are four fundamental features by which benign and malignant tumors can be distinguished: dif- ferentiation and anaplasia, rate of growth, local invasion, and metastasis. Differentiation and Anaplasia Differentiation and anaplasia are characteristics seen only in the parenchymal cells that constitute the transformed elements of neoplasms. The differentiation of parenchymal tumor cells refers to the extent to which they resemble their normal forebears morphologically and functionally. * Benign neoplasms are composed of well-differentiated cells that closely resemble their normal counterpas. A lipoma is made up of mature fat cells laden with cytoplasmic lipid vacuoles, and a chondroma is made up of mature cailage cells that synthesize their usual cailaginous matrix--evidence of morphologic and functional differentiation. In well-differentiated benign tumors, mitoses are usually rare and are of normal configuration. * Malignant neoplasms are characterized by a wide range of parenchymal cell differentiation, from sur- prisingly well differentiated (Fig. 5-3) to completel undifferentiated. For example, well-differentiated ade- nocarcinomas of the thyroid may contain normal- appearing follicles. Such tumors sometimes may be difficult to distinguish from benign proliferations. Between the two extremes lie tumors loosely referred to as moderately well differentiated. The stroma carrying the blood supply is crucial to the growth of tumors but does not aid in the separation of benign from malignant ones. The amount of stromal connective tissue does deter- mine, however, the consistency of a neoplasm. Ceain cancers induce a dense, abundant fibrous stroma (des- moplasia), making them hard, so-called scirrhous tumors. * Malignant neoplasms that are composed of undiffer- entiated cells are said to be anaplastic. Lack of differen- tiation, or anaplasia, is considered a hallmark of malignancy. The term anaplasia literally means "back- ward formation"--implying dedifferentiation, or loss of the structural and functional differentiation of normal cells. It is now known, however, that at least some cancers arise from stem cells in tissues; in these tumors, failure of differentiation, rather than dedifferentiation of specialized cells, accounts for their undifferentiated appearance. Recent studies also indicate that in some cases, dedifferentiation of apparently mature cells does occur during carcinogenesis. Anaplastic cells display marked pleomorphism (i.e., variation in size and shape) (Fig. 5-4). Often the nuclei are extremely hyperchromatic (dark-staining) and large resulting in an increased nuclear-to-cytoplasmic ratio that may approach 1: 1 instead of the normal 1: 4 or 1 :6. Giant cells that are considerably larger than their neighbors may be formed and possess either one enormous nucleus or several nuclei. Anaplastic nuclei are variable and bizarre in size and shape. The chromatin is coarse and clumped, and nucle- oli may be of astounding size. More impoant, mitoses often are numerous and distinctly atypical; anarchic multi- ple spindles may produce tripolar or quadripolar mitotic figures (Fig. 5-5). Also, anaplastic cells usually fail to develop recognizable patterns of orientation to one another (i.e., they lose normal polarity). They may grow Figure 5-3 Well-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 (arrow). (Couesy of Dr. Trace Worrell, Depament of Pathology, University of Texas Southwestern Medical School, Dallas, Texas.) Figure 5-4 Anaplastic tumor of the skeletal muscle (rhabdomyosar- coma). Note the marked cellular and nuclear pleomorphism, hyperchro- matic nuclei, and tumor giant cells. (Couesy of Dr. Trace Worrell, Depa in sheets, with total loss of communal structures, such as glands or stratified squamous architecture. The more differentiated the tumor cell, the more com- pletely it retains the functional capabilities of its normal counterpas. Benign neoplasms and even well-differenti- ated cancers of endocrine glands frequently elaborate the hormones characteristic of their origin. Well-differentiated squamous cell carcinomas produce keratin (Fig. 5-3), just as well-differentiated hepatocellular carcinomas secrete bile. In other instances, unanticipated functions emerge. Some cancers may elaborate fetal proteins not produced by comparable cells in the adult. Cancers of nonendocrine origin may produce so-called ectopic hormones. For example, ceain lung carcinomas may produce adrenocor- ticotropic hormone (ACTH), parathyroid hormone-like hormone, insulin, glucagon, and others. More is said about these phenomena later. Despite exceptions, the more rapidly growing and the more anaplastic a tumor, the less likely it is to have specialized functional activity. Of relevance in the discussion of differentiation and ana- plasia is dysplasia, referring to disorderly but non-neoplastic proliferation. Dysplasia is encountered principally in epi- thelial lesions. It is a loss in the uniformity of individual cells and in their architectural orientation. Dysplastic cells exhibit considerable pleomorphism and often possess hyperchro- matic nuclei that are abnormally large for the size of the cell. Mitotic figures are more abundant than usual and frequently appear in abnormal locations within the epithe- lium. In dysplastic stratified squamous epithelium, mitoses are not confined to the basal layers, where they normally occur, but may be seen at all levels and even in surface cells. There is considerable architectural anarchy. For example, the usual progressive maturation of tall cells in the basal layer to flattened squames on the surface may be lost and replaced by a disordered scrambling of dark basal- appearing cells (Fig. 5-6). When dysplastic changes are marked and involve the entire thickness of the epithelium, the lesion is referred to as carcinoma in situ, a preinvasive stage of cancer (Chapter 18). Although dysplastic changes often are found adjacent to foci of malignant transforma- tion, and long-term studies of cigarette smokers show that epithelial dysplasia almost invariably antedates the appear- ance of cancer, the term dysplasia is not synonymous with cancer; mild to moderate dysplasias that do not involve the entire thickness of the epithelium sometimes regress completely, par- ticularly if inciting causes are removed.