 This lesson will define neoplasia, distinguished between benign and malignant types, describe the classification and nomenclature of neoplasms, and illustrate some major histologic features and examples of neoplasia. There are six features which distinguish neoplasia from other forms of tissue growth. As with all rules, one should anticipate occasional exceptions. First, neoplasia results in the formation of a tissue mass, a neoplasm, or tumor. Although tumor literally refers to any kind of mass or swelling, the term is generally used to mean neoplasm. Tumors can grow to large, even enormous, size. Particularly when they arise in less obvious sites, variations in tumor size, location, and rate of growth can result in a large variety of clinical features. Even a small tumor can have profound effects upon the host. A neoplasm, one centimeter in diameter, arising in and obstructing the ampula of water, for example, can cause biliary obstruction, jaundice, and a variety of other symptoms. Second, neoplasia is generally considered to be an irreversible process. Third, neoplastic tissue tends to morphologically resemble its tissue of origin. This section is from a tumor of the thyroid gland. Histologically, there is a close resemblance to normal thyroid, with follicles lined by simple cuboidal epithelium and filled with colloid. The emphasis, however, should be placed on tens to, since some neoplasms show lesser degrees of morphologic resemblance to their tissue of origin. The histologic similarity of this thyroid tumor to normal thyroid tissue is not as obvious as in the previous one. Fourth, neoplastic tissue tends to functionally resemble its tissue of origin. Many neoplasms arising within the islet tissue of the pancreas not only resemble islet tissue with light microscopy. They also contain secretory granules ultra structurally, as demonstrable with electron microscopy. Like their non-neoplastic counterparts, some neoplastic islet cells secrete insulin. The amount of insulin produced by such tumors often exceeds the needs of the host. This results in hypoglycemia and, in turn, headaches, dizziness and other symptoms. Important clinical features of a tumor may result from its functional as well as its structural effects. Again, the emphasis is on tens to, since some neoplasms show little or no detectable evidence of tissue-specific functions. In addition, some neoplasms result in such non-specific systemic effects as catechia, fever, and increased susceptibility to infection. Fifth, neoplasms grow and function somewhat independently of the homeostatic mechanisms, which control normal tissue growth and function. This is referred to as autonomy. Once again, this feature must be qualified. Neoplasms are not, as they are sometimes portrayed, completely autonomous. Some breast cancers, for example, like normal breast, are sensitive to the effects of estrogen. Others are not. Growth of an estrogen-sensitive neoplasm might be arrested or reversed by anti-astrogen therapy, while an estrogen-resistant neoplasm would be expected to continue its growth. The estrogen-sensitive neoplasm is less autonomous than the estrogen-insensitive one. Such variation in autonomy has major prognostic and therapeutic implications. Sixth and last, neoplasms are rarely beneficial, are usually harmful, and sometimes are fatal to the host. Of particular significance to the host is whether the neoplasm is benign or malignant. Ultimately, this distinction depends upon the behavior of the tumor. In general, whether a neoplasm is benign or malignant can be determined by assessing its histologic features. It was pointed out previously that the thyroid tumor illustrated in this slide closely resembles normal thyroid tissue. In general, benign tumors are histologically identical to or closely resemble their tissue of origin. This is true functionally as well as structurally. This benign neoplasm arose in a parathyroid gland. It shows a close histologic resemblance to normal parathyroid gland, and like normal parathyroid, it secreted parathormone. Although benign neoplasms tend to be less autonomous than malignant ones, their growth is progressive, and they can function independently of the host's needs. Benign parathyroid tumors, for example, can, by secreting excessive amounts of parathormone, cause hyperparathyroidism. At lower magnification, the same parathyroid tumor is seen to be compressing the adjacent non-neoplastic glandular parenchyma and stroma. It has formed a discreet and well-demarcated mass. A benign neoplasm consists of a discreet tissue mass which continues to grow. Despite the fact that it may attain enormous size, it remains discreet and distinct from adjacent non-neoplastic tissue. The benign tumor, as it enlarges, compresses adjacent tissue, sometimes causing atrophy. The junction between a benign neoplasm and surrounding tissue may be converted into a fibrous connective tissue capsule. The terms malignant neoplasm, malignant tumor, and cancer are synonymous. The histologic and cytologic features of cancer are summarized by the term anaplasia. These features include derangement of the normal tissue architecture, the crowding of its cells, their lack of orientation termed dyspilarity, and their heterogeneity in size and shape termed pleomorphism. The cytologic features of anaplasia include an increased nuclear cytoplasmic ratio, nuclear pleomorphism, clumping and increased staining of nuclear chromatin, and enlarged and increased numbers of nucleoli. This section shows juxtaposed normal and cancerous colonic mucosa. The non-neoplastic epithelium is evenly distributed and oriented along the basement membrane. Its cells and nuclei are uniform in size and shape, and it shows the features of a highly differentiated tissue. The cancerous tissue is dyspilaric, pleomorphic, poorly differentiated, and shows the cytologic features of anaplasia. A section from another cancer also shows the features of anaplasia. While here we can compare the histologic and cytologic features of benign and malignant tumors arising in the adrenal cortex. Malignant neoplasms often contain numerous mitotic cells. These are typically abnormal, such as the tripolar mitosis in the slide. Such mitotic aberrations account for some of the karyotypic abnormalities found in most cancers. Bizarre, multi-nucleated cells are also seen in some cancers, especially those which are highly anaplastic. In the pathogenesis of cancer, normal tissues do not suddenly become anaplastic. The term dysplasia refers to a pre-malignant state in which a tissue demonstrates histologic and cytologic features which are intermediate between normal and anaplastic. Dysplasia is considered to be at least potentially reversible. The sequence of histologic changes from normal to dysplastic to cancer has been most clearly demonstrated in serial biopsies of the uterine cervix. This section shows the normal stratified squamous epithelium of the exo cervix. The cells show progressive maturation from the deep layer of normal, less differentiated basal cells to the superficial layer of flattened and highly differentiated squamous cells. In this section of dysplastic exo cervix, there has been some loss of these progressive maturational changes. Many cells, especially in the deeper portions, have become somewhat dyspolaric and less stratified. There is some pleomorphism, and the nuclear cytoplasmic ratio is increased. In other words, some of the features of anaplasia are present, at least in the deeper layers. On the other hand, the changes are mild. A gradient of maturation is still evident, especially in the more superficial portions. In this section, the changes have become more severe and extensive, involving virtually the entire thickness of the cervical epithelium. They are now of sufficient magnitude to warrant a diagnosis of cancer. Note, however, that the basement membrane is still intact. This means that the cancer is still in situ. That is, it has not invaded the underlying stroma. A comparison of normal cervix, dysplastic cervix, and cervix with in situ cancer highlights their differences. In addition to the previously noted features, note that mitosis are relatively infrequent and limited to the basal areas in the normal cervix, while they are frequent and found throughout the entire thickness of the cancer. The dysplastic cervix shows an intermediate number and distribution of mitosis. It should be noted that although the designation of cancer implies an irreversible process, in situ cancers of the cervix are an exception, in that they have occasionally been observed to undergo spontaneous regression. On the other hand, if untreated, an in situ cancer is likely to break through the basement membrane and invade subjacent stroma. Invasion and metastasis, the spread of the neoplasm to distant sites, are the definitive features of malignancy. When the pathologist describes a neoplasm as anoplastic, the implication is that it is capable of invading and metastasizing. Most cancers appear to invade early in their growth. Unlike benign tumors which simply push adjacent tissues out of the way, malignant tumors grow into the adjacent tissue. The border of a growing malignant neoplasm is reminiscent of the astrologic crab, hence the term cancer. Malignant cells invade singly or in small groups. These breast cancer cells have infiltrated adjacent adipose and fibrous connective tissue stroma in the breast. A cancer originating in the colonic mucosa may form a mass which protrudes into the lumen, but which also invades deeply into the submucosal, muscular and serosal layers of the intestinal wall. Eventually the growing and invading cancer may penetrate the organ's external surface and extend into adjacent structures and organs, incorporating them into a fixed mass of cancerous tissue. Cancer cells typically invade such thin walled vessels as small veins, venules, capillaries and lymphatics. In this longitudinal section of a systemic vein, the invading cancer has grown into the lumen, forming anitis from which cancer cells and clumps can break off and become emboli. The passage of cancer cells via lymphatics to lymph nodes and via blood vessels to other organs and structures and their subsequent implantation and growth in those sites is referred to as metastasis. In addition to lymph nodes, liver, lung, bone and bone marrow and brain are common sites for metastasis. Virtually any organ or anatomic structure can be involved, however. Seeding is still another means by which some cancers spread. In some forms of ovarian cancer, for example, malignant cells are shed into the peritoneal fluid. These cells may be carried by the fluid to distant sites on the peritoneal surface, where they can implant and form new foci of cancer growth. The classification and the naming of most neoplasms reflect their tissue of origin, whether a neoplasm is benign or malignant, and sometimes additional features. The great majority of neoplasms may be divided into four types, epithelial and non-epithelial, and blastomas and teratomas. Benign epithelial neoplasms are generally classified as adenomas, polyps, or papillomas. Malignant epithelial neoplasms are termed carcinomas. Adenomas are benign epithelial neoplasms which arise in solid organs, such as liver, kidney and thyroid. Typically, they are composed of glandular structures. Since they are benign, adenomas remain discrete, pushing and compressing the surrounding tissue rather than invading it. Similarly, since they are benign, adenomas tend to show a close histological resemblance to their tissue of origin. This adenoma, which arose in the renal cortex, is very similar to normal renal tubular epithelium. Other adenomas may show more variant histologic patterns. They can, for example, be papillary or cystic. Variant patterns continue to show the histologic and cytologic features of benignity. Polyps are benign epithelial neoplasms which arise from the linings of such organs as the intestine. They are typically mushroom-shaped, with their head and stalk covered by epithelium. Their core consists of non-neoplastic connective tissue stroma. The glands and cells of an adenomatous polyp are generally more crowded than those of the normal colon. Nevertheless, there is a close resemblance to normal colonic mucosa. Papillomas are similar to polyps, except that they tend to be finger-like rather than mushroom-shaped. Sometimes the papilloma consists of multiple finger-like projections. Malignant epithelial neoplasms are termed carcinomas. Like benign epithelial neoplasms, carcinomas can arise in solid organs or from epithelial surfaces. The carcinoma in this open segment of colon has invaded the deeper portions of the intestinal wall. Carcinomas, while retaining some of the histologic features of their tissue of origin, are clearly anoplastic. Adenocarcinomas are carcinomas in which gland-like structures are present. This adenocarcinoma of the colon shows some attempt at gland formation. Other carcinomas, like adenomas, may be papillary or cystic. The degree to which adenocarcinomas, as well as other carcinomas and malignant neoplasms, resemble their tissue of origin is indicated by modifiers, such as well-differentiated, moderately-differentiated, and poorly-differentiated. This adenocarcinoma, for example, might be described as moderately or even poorly-differentiated. In general, more highly-differentiated or low-grade cancers tend to have a better prognosis than poorly-differentiated or high-grade cancers. This is a section from a squamous cell carcinoma of the skin. The darker pink areas are dense aggregates of a major squamous cell product, keratin. The features of both partial squamous differentiation and overt anaplasia are present. The cancer is moderately well-differentiated. This transitional cell carcinoma of the bladder closely resembles non-neoplastic bladder epithelium. Although it is a relatively well-differentiated carcinoma, experience with histologically similar bladder tumors allows the pathologist to predict malignant behavior. The second major category of neoplasms is the non-epithelial tumors. These are generally of mesenchymal or mesodermal origin. Non-epithelial neoplasms are generally designated by a prefix which indicates their histologic type and a suffix which indicates whether they are benign or malignant. The suffix oma generally means benign, while sarcoma means malignant. This section is from a well-demarcated tumor in the wall of the uterine fundus. Histologically, it consists of smooth muscle, which is virtually identical to that of normal myometrium. The prefix liomyo indicates smooth muscle and the suffix oma benignity. This neoplasm is a liomyoma. An invasive tumor was present in a similar location in another patient. Histologically, although a resemblance to smooth muscle is evident, so are the features of anaplasia. The prefix is still liomyo, but the suffix is now sarcoma, indicating malignancy. This is a liomyosarcoma. A discrete mass was removed from the subcutaneous tissue of the forearm. It consists of histologically unremarkable adipose tissue. This neoplasm is a lipoma. Another mass removed from the subcutaneous tissue of the buttock consists of anaplastic adipose tissue. It is a liposarcoma. The histologic features of benign and malignant neoplasms of cartilage, a chondroma and a chondrosarcoma can be compared in this slide. There are a variety of other non-epithelial neoplasms for which the same principles of nomenclature apply. The epithelial and non-epithelial neoplasms discussed thus far are generally composed of a single type of tissue. Blastomas and teratomas contain more than one type of tissue. Blastomas are a group of generally malignant neoplasms which consist of tissues resembling the embryonic counterpart of the organ in which the tumor originates. In addition, a blastoma can also contain other tissues into which the organ's embryonic onlogin are capable of differentiating. This somewhat convoluted definition is clarified by a specific example, the blastoma which arises in the kidney. This is the nephroblastoma or Wilms tumor. Nephroblastomas typically occur in infants and young children. They may reach enormous size before they are detected. This one was removed from a two-year-old boy. A remnant of kidney is seen at the inferior pole of the mass. Histologically, a nephroblastoma may consist of any of the tissues into which the embryonic mesodermal onlog of the kidney can differentiate. This section shows nests of primitive renal precursor cells or blastoma and tubular-like derivatives reminiscent of embryonic kidney. Another area contains a structure which resembles a primitive glomerulus. Still another area consists of skeletal muscle. This is not surprising considering the mesodermal nature of the renal onlaga. A trichrome stain shows red striated skeletal muscle and blue collagenous stroma. There are a variety of other blastomas which arise in other organs. They too resemble the embryonic onlaga of their respective organs. Blastomas are therefore considered to be multi-potent in terms of their ability to form various tissues. Teratomas are the fourth major type of neoplasm. This group includes a variety of benign and malignant neoplasms which are derived from germ cells. Most arise in the gonads, but they may occur in other locations as well, usually in the midline of the body. Since they arise from totipotent germ cells, teratomas are at least potentially capable of differentiating into tissues derived from all three embryonic germ layers, as well as extra embryonic trophoblastic tissues. Thus, while the great majority of epithelial and non-epithelial neoplasms may be regarded as histogenetically unipotent and blastomas as multipotent, teratomas are theoretically at least totipotent. This section is from a benign teratoma of the ovary which contained a dozen different types of tissue. Seen here are skin, cartilage, pancreas and respiratory epithelium. The high degree of differentiation in this benign teratoma is evident at higher magnification in its cutaneous and cartilaginous components. Another area shows cerebellar-like tissue. The neurons are well differentiated and resemble those of the normal Purkinje layer. Still another area in this teratoma demonstrates an attempt to form an eye. Retinal and pigmented components are evident. Sometimes teratomas differentiate along a single embryonic germ line. The ovarian dermoid cyst is a common example. This opened dermoid cyst contains hair, sebum and a tooth. Microscopically, the wall of the cyst is composed of well-differentiated skin complete with numerous sebaceous glands and a superficial layer of keratin. Malignant teratomas are often termed teratocarsanomas. Teratocarsanomas contain, in addition to various differentiated tissues, a population of totipotent malignant germ cells termed embryonal cells. The embryonal cells are the progenitors of the differentiated elements of the teratocarsanoma. This section from a teratocarsanoma shows a spectrum ranging from embryonal cells on the left to partially differentiated tissues in the center to well-differentiated cartilage on the right. The highly anaplastic, poorly differentiated character of malignant embryonal cells is seen in this slide. Malignant teratomas may also contain tissue which resembles derivatives of extra embryonic trophoblasts. These include choreocarsanoma, which resembles placental choreonic villi, and yolk sac carcinoma, which resembles endodermal sinus tissue of the embryonic yolk sac. Embryonal cell, teratomatous, yolk sac, and choreocarsanomatous tissue may all be found in a single malignant teratoma or teratocarsanoma. In discussing the nomenclature of neoplasms, it must be pointed out that there are important exceptions. There are, for example, several malignant neoplasms whose traditional names end in oma. Melanoma is a malignant neoplasm of melanocytic origin. Sometimes these malignant melanocytes contain abundant pigment, as in the cell indicated by the arrow. This tumor, which was on the skin, was nearly black. Since it is a malignant neoplasm of epithelial origin, the preferred term is melanocarsanoma. Melanoma is a malignant neoplasm of hepatocellular origin. The hepatocellular features, along with those of anaplasia, are seen in this slide. The preferred term is hepatocellular carcinoma. Lymphomas are malignant neoplasms arising from cells of the lymphoid series. The preferred term is lymphocarcoma. The terms melanoma, hepatoma, and lymphoma are deceptive, but they remain firmly ensconced in the medical literature. In leukemia, there is a malignant proliferation of white blood cells. Large numbers of white blood cells are most evident in the blood, as in this smear. Leukemic cells may be myeloid or lymphoid in origin. Leukemic cells may also be present in solid tissues. They tend to diffusely infiltrate these tissues, rather than form the solid masses typical of other cancers. Another exception to the rules of tumor nomenclature is provided by those neoplasms with eponymic designations. Wilm's tumor was previously mentioned as synonymous with nephroblastoma. Kaposi's sarcoma is an otherwise rare form of cancer, which is relatively common in AIDS patients. Leukemic Kaposi's sarcoma contains prominent vascular and stromal components. Hodgkin's disease is a form of lymphoma. Finally, the hammertoma. Actually, this lesion is generally considered to be non-neoplastic. Hammertomas of the lung are typically discovered in asymptomatic adults who have a chest renconogram. It appears as a solitary, well-demarcated mass. A hammertoma consists of architecturally disorganized, but generally well-differentiated tissues indigenous to the organ in which it occurs. The typical pulmonary hammertoma consists of well-differentiated bronchial components, respiratory epithelium, smooth muscle, and hyaline cartilage, but without recognizable bronchus formation. This lesson has considered the definitive features of neoplasia. It has compared and contrasted benign and malignant neoplasms and outlined and illustrated the classification and nomenclature of neoplasms. Although each program in the series is designed to stand alone, it is recommended that you study Neoplasia I, nomenclature, benign, and malignant states before using this program. Of all the criteria used to describe neoplastic cells, the malignant state is probably best defined by the ability of cells to invade and or metastasize. Although we tend to treat this as a simple concept in which neoplastic cells come to reside in inappropriate sites, it is actually represented by a highly complex sequence of events. During this process, cells from a primary neoplasm become autonomous and undergo a physical separation from the primary tumor. This is referred to as invasion. Next, they enter a compartment or fluid space and are thereby transported to a distant site. Finally, they arrest at a new site and establish themselves in a different environment to produce a metastasis. Although some of the mechanisms related to these steps have been elucidated, the regulatory factors which orchestrate the sequence remain mostly unknown. It is assumed that many neoplasms originate in a manner similar to that scene in this photomicrograph of in situ squamous cell carcinoma of the uterine cervix. Here, the cytologic changes in the epithelial cells are clearly those associated with neoplasia, such as nuclear atypia and loss of maturation. It should be noted, however, that neoplastic cells reside only within the epithelium and that the basement membrane which separates them from their underlying stroma is intact. Once the integrity of the basement membrane has been violated, we use the designation microinvasive. Here, the neoplastic cells can be seen invading across the basement membrane into spaces which are believed to represent both capillaries and lymphatic channels. Further invasion of tumors into their surrounding connective tissue and supporting stromal elements requires that the cells have the ability to modify their microenvironment. Specifically, they must break down a resistive barrier to allow their transit. This process destroys portions of the extracellular milieu and produces the homogenized appearance of the stroma as seen around these prostatic carcinoma cells. This represents loss of macromolecules and entry of edema fluid. The extracellular matrix is in great part composed of collagen fibers suspended in a matrix of glycosaminoglycans. It is not surprising, therefore, that the enzymes believed to be responsible for matrix dissolution include collagenases and glycosidases. In addition, chain reactions can occur that amplify the tumor cell's inherent capabilities. One such mechanism is the activation of latent interstitial collagenase by tumor cell proteases. Although such a process may at first seem foreign or grossly abnormal, it is important to recognize that similar processes are required during embryonic organogenesis. For example, organs, such as the salivary glands, breast and prostate, are formed by a progressive invasion of epithelial buds into beds of mesenchymal cells. Here we see prostatic epithelium growing into a bed of splanknic mesoderm. Branches occur due to differences in rates of cell division, cell death, and matrix breakdown. This process produces complex glands composed of multiple asenar secretory units, linked to each other by a ductal network. As mentioned earlier, in the cascade of metastasis, invasion into tissue is the precursor to establishment of metastatic foci. Certain tumors show a remarkable ability for invading via the vascular system. Here, at the arrow, we see an example of a carcinoid tumor destroying the elastica of a blood vessel as it emigrates out into the surrounding tissue. However, such gross invasion of tumors via large bore blood vessels is rarely witnessed. Instead, we see examples of micrometastasis. Here we see an example of an adenocarcinoma of the prostate metastasizing via the microvascular. Following emigration from the blood vessel wall, metastatic co...