Mechanism of Disease: Neoplasia PDF

Mechanism of Disease Neoplasia Dr Safinaz Abubakir Mohammed 1  Introduction Cancer is the second leading cause of death in the United States; only cardiovascular diseases exact a higher toll. Even more agonizing than...

Mechanism of Disease Neoplasia Dr Safinaz Abubakir Mohammed 1  Introduction Cancer is the second leading cause of death in the United States; only cardiovascular diseases exact a higher toll. Even more agonizing than the associated mortality is the emotional and physical suffering inflicted by neoplasms. the fundamental and shared characteristics of cancers: Cancer is a genetic disorder caused by DNA mutations. Most pathogenic mutations are either induced by exposure to mutagens or occur spontaneously as part of aging. In addition, cancers frequently show epigenetic changes, such as focal increases in DNA methylation and alterations in histone modifications. These genetic and epigenetic changes alter the expression or function of key genes that regulate fundamental cellular processes, such as growth, survival, and senescence. Cells bearing mutations that provide a growth or survival advantage outcompete their neighbors and thus come to dominate the population. At the time of tumor initiation, these selective advantages are conferred on a single cell, and as a result all tumors are clonal (i.e., the progeny of one cell). 2. In general, neoplasms are irreversible, and their growth is, for the most part, autonomous. Several observations are important: Neoplasms are derived from cells that normally maintain a proliferative capacity. Thus, mature neurons and cardiac myocytes do not give rise to tumors. A tumor may express varying degrees of differentiation, from relatively mature structures that mimic normal tissues to a collection of cells so primitive that the cell of origin cannot be identified. The stimuli responsible for the uncontrolled proliferation may not be identifiable. Neoplasia arises from mutations in genes that regulate cell growth, death or DNA repair. 3  NOMENCLATURE Neoplasia literally means “new growth. Neoplasms therefore enjoy a degree of autonomy and tend to increase in size regardless of their local environment. All neoplasms depend on the host for their nutrition and blood supply. In common medical usage, a neoplasm often is referred to as a tumor, and the study of tumors is called oncology (from oncos, “tumor,” and logos, “study of”). Among tumors, the division of neoplasms into benign and malignant categories is based on a judgment of a tumor’s potential clinical behavior. 4 A tumor is said to be benign when its microscopic and gross characteristics are considered to be relatively innocent, implying that it will remain localized and is amenable to local surgical removal. Affected patients generally survive. Of note, however, benign tumors can produce more than localized lumps, and sometimes they produce significant morbidity or are even lethal. Malignant, as applied to a neoplasm, implies that the lesion can invade and destroy adjacent structures and spread to distant sites (metastasize) to cause death. Malignant tumors are collectively referred to as cancers, derived from the Latin word for “crab”—that is, they adhere to any part that they seize in an obstinate manner, similar to a crab’s behavior. 5  All tumors, benign and malignant, have two basic components: (1) the parenchyma, made up of transformed or neoplastic cells, and (2) the supporting, host-derived, non-neoplastic stroma, made up of connective tissue, blood vessels, and host-derived inflammatory cells. The parenchyma of the neoplasm largely determines its biologic behavior, and it is this component from which the tumor derives its name. The stroma is crucial to the growth of the neoplasm, since it carries the blood supply and provides support for the growth of parenchymal cells. 6  Benign Tumors In general, benign tumors are designated by attaching the suffix -oma to the cell type from which the tumor arises. For example, a benign tumor arising in fibrous tissue is a fibroma; a benign cartilaginous tumor is a chondroma. The term adenoma is generally applied not only to benign epithelial neoplasms that produce glandlike structures, but also to benign epithelial neoplasms that are derived from glands but lack a glandular growth pattern. Thus, a benign epithelial neoplasm arising from renal tubule cells and growing in a glandlike pattern is termed an adenoma, as is a mass of benign epithelial cells that produces no glandular patterns but has its origin in the adrenal cortex. 7. Papillomas are benign epithelial neoplasms , growing on any surface, that produce microscopic or macroscopic fingerlike fronds. A polyp is a mass that projects above a mucosal surface, as in the gut, to form a macroscopically visible structure Although this term commonly is used for benign tumors, some malignant tumors also may grow as polyps, whereas other polyps (such as nasal polyps) are not neoplastic but inflammatory in origin. Cystadenomas are hollow cystic masses that typically arise in the ovary. 8  Malignant Tumors The nomenclature of malignant tumors essentially follows that of benign tumors, with certain additions and exceptions. Malignant neoplasms arising in “solid” mesenchymal tissues or its derivatives are called sarcomas, whereas those arising from the mesenchymal cells of the blood are called leukemias or lymphomas. Sarcomas are designated based on their cell-type composition, which presumably reflects their cell of origin. Thus, a malignant neoplasm comprised of fat-like cells is a liposarcoma, and a malignant neoplasm composed of chondrocyte-like cells is a chondrosarcoma. 9. Epithelia of the body are derived from all three germ cell layers, malignant neoplasms of epithelial cells are called carcinomas regardless of the tissue of origin. Thus, malignant neoplasms arising in the renal tubular epithelium (mesoderm), the skin (ectoderm), and lining epithelium of the gut (endoderm) are all considered carcinomas. 10 The transformed cells in a neoplasm, whether benign or malignant, usually resemble each other, consistent with their origin from a single transformed progenitor cell.In some unusual instances, however, the tumor cells undergo divergent differentiation, creating so-called “mixed tumors”. Mixed tumors are still of monoclonal origin, but the progenitor cell in such tumors has the capacity to differentiate down more than one lineage. The best example is mixed tumor of salivary gland. These tumors have obvious epithelial components dispersed throughout a fibromyxoid stroma, sometimes harboring islands of cartilage or bone (Fig. 6.2). All of these diverse elements are thought to derive from a single transformed epithelial progenitor cell, and the preferred designation for these neoplasms is pleomorphic adenoma. 11. Fibroadenoma of the female breast is another common mixed tumor. This benign tumor contains a mixture of proliferating ductal elements (adenoma) embedded in loose fibrous tissue (fibroma). Unlike pleomorphic adenoma, only the fibrous component is neoplastic, but the term fibroadenoma remains in common usage. Teratoma is a special type of mixed tumor that contains recognizable mature or immature cells or tissues derived from more than one germ cell layer, and sometimes all three. Teratomas originate from totipotential germ cells such as those that normally reside in the ovary and testis. Germ cells have the capacity to differentiate into any of the cell types found in the adult body; not surprisingly, therefore, they may give rise to neoplasms that contain elements resembling bone, epithelium, muscle, fat, nerve, and other tissues, all thrown together in a helter-skelter fashion. 12. Hamartoma is a mass of disorganized tissue indigenous to the particular site, such as the lung or the liver. While traditionally considered developmental malformations, many hamartomas have clonal chromosomal aberrations that are acquired through somatic mutations and on this basis are now considered to be neoplastic. Choristoma is a congenital anomaly consisting of a heterotopic nest of cells. For example, a small nodule of well-developed and normally organized pancreatic tissue may be found in the submucosa of the stomach, duodenum, or small intestine. 13. Although the neoplastic cells largely determine a tumor's behavior and pathologic consequences, their growth and evolution is critically dependent on their stroma. An adequate stromal blood supply is requisite for the tumor cells to live and divide, and the stromal connective tissue provides the structural framework essential for the growing cells. In addition, there is cross-talk between tumor cells and stromal cells that directly influences the growth of tumors. In some tumors, the stromal support is scant and so the neoplasm is soft and fleshy. In other cases the parenchymal cells stimulate the formation of an abundant collagenous stroma, referred to as desmoplasia. 14  Tissue of Origin Benign Malignant Connective tissue and Fibroma Fibrosarcoma derivatives Lipoma Liposarcoma Chondroma Chondrosarcoma Osteoma Osteogenic sarcoma Endothelial and Related Tissues Blood vessels Hemangioma Angiosarcoma Lymph vessels Lymphangioma Lymphangiosarcoma Synovium Synovial sarcoma Mesothelium Mesothelioma Brain coverings Meningioma Invasive meningioma 15 Blood Cells and Related Cells Benign Malignant Hematopoietic cells Leukemias Lymphoid tissue Lymphomas Muscle Smooth Leiomyoma Leiomyosarcoma Striated Rhabdomyoma Rhabdomyosarcoma Tumors of Epithelial Origin Stratified squamous Squamous cell papilloma Squamous cell carcinoma Basal cells of skin or adnexa Basal cell carcinoma Epithelial lining of glands or Adenoma Adenocarcinoma ducts Papilloma Papillary carcinomas Cystadenoma Cystadenocarcinoma Cystadenoma 16 Respiratory passages Bronchial adenoma Bronchogenic carcinoma Renal epithelium Renal tubular adenoma Renal cell carcinoma Liver cells Liver cell adenoma Hepatocellular carcinoma Urinary tract epithelium Transitional-cell papilloma Transitional-cell carcinoma (transitional) Placental epithelium Hydatidiform mole Choriocarcinoma Testicular epithelium (germ Seminoma cells) Tumors of Melanocytes Nevus Malignant melanoma MORE THAN ONE NEOPLASTIC CELL TYPE—MIXED TUMORS, USUALLY DERIVED FROM ONE GERM CELL LAYER Salivary glands Pleomorphic adenoma Malignant mixed tumor of (mixed tumor of salivary salivary gland origin origin) Renal anlage Wilms tumor 17 MORE THAN ONE NEOPLASTIC CELL TYPE DERIVED FROM MORE THAN ONE GERM CELL LAYER—TERATOGENOUS Totipotential cells in gonads Mature teratoma, dermoid Immature teratoma, or in embryonic rests cyst teratocarcinoma 18. Papilloma of the colon with finger-like projections into the lumen. 19 Gross appearance of several colonic polyps. 20 Gross appearance of an opened cystic teratoma of the ovary. Note the presence of hair, sebaceous material, and tooth. 21 A microscopic view of a similar tumor shows skin, sebaceous glands, fat cells, and a tract of neural tissue 22 Leiomyoma 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.. 23 Benign chondroma. A. Normal cartilage. B. A benign chondroma closely resembles normal cartilage. 24 Hamartoma of the lung. The tumor contains islands of hyaline cartilage and clefts lined by cuboidal epithelium embedded in a fibromuscular stroma. 25  Benign tumor (adenoma) of the thyroid. Note the normal-looking (well-differentiated), colloid-filled thyroid follicles 26 Malignant tumor (adenocarcinoma) of the colon. Note that compared with the well-formed and normal-looking glands characteristic of a benign tumor 27 Anaplastic tumor of the skeletal muscle (rhabdomyosarcoma). Note the marked cellular and nuclear pleomorphism, hyperchromatic nuclei, and tumor giant cells 28  The cells of this anaplastic carcinoma are highly pleomorphic (i.e., they vary in size and shape). The nuclei are hyperchromatic and are large relative to the cytoplasm. Multinucleated tumor giant cells are present (arrows).. 29 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 pearls (arrow). 30 Adenocarcinoma of the stomach. Irregular neoplastic glands infiltrate the gastric wall. 31  CHARACTERISTICS OF BENIGN AND MALIGNANT NEOPLASMS There are three fundamental features by which most benign and malignant tumors can be distinguished: differentiation and anaplasia, local invasion, and metastasis. 32  DIFFERENTIATION AND ANAPLASIA Differentiation refers to the extent to which neoplastic parenchymal cells resemble the corresponding normal parenchymal cells, both morphologically and functionally; lack of differentiation is called anaplasia. In general, benign tumors are well differentiated cells. that closely resemble their normal counterparts. In well-differentiated benign tumors, mitoses are usually rare and are are of normal configuration. 33. Malignant neoplasms are characterized by a wide range of parenchymal cell differentiation, from surprisingly well differentiated to completely undifferentiated..The morphologic diagnosis of malignancy in well-differentiated tumors may sometimes be quite difficult. Malignant neoplasms that are composed of poorly differentiated cells are said to be anaplastic. Lack of differentiation, or anaplasia, is considered a hallmark and reliable indicator of malignancy. the term anaplasia implying de differentiation or loss of the structural and functional differentiation of normal cells. 34  Anaplastic cells often display the following morphologic features: Pleomorphism (i.e., variation in size and shape) Nuclear abnormalities, consisting of extreme hyperchromatism (dark-staining), variation in nuclear size and shape, or unusually prominent single or multiple nucleoli. Enlargement of nuclei may result in an increased nuclear-to-cytoplasmic ratio that approaches 1 : 1 instead of the normal 1 : 4 or 1 : 6. Nucleoli sizes, sometimes approaching the diameter of normal lymphocytes. 35. Tumor giant cells may be formed. These are considerably larger than neighboring cells and may possess either one enormous nucleus or several nuclei. Atypical mitoses, which may be numerous. Anarchic multiple spindles may produce tripolar or quadripolar mitotic figures. Loss of polarity, such that anaplastic cells lack recognizable patterns of orientation to one another. Such cells may grow in sheets, with total loss of communal structures, such as glands or stratified squamous architecture. Anaplastic tumor cells are much less likely to have specialized functional activities than well differentiated tumor cells. 36 37  Dysplasia Dysplasia is a term that literally means disordered growth. Dysplastic epithelium is recognized by a loss in the uniformity of individual cells and in their architectural orientation. Dysplasia often occurs in metaplastic epithelium, but not all metaplastic epithelium is also dysplastic. Dysplastic cells exhibit considerable pleomorphism and often contain large hyperchromatic nuclei with a high nuclear to-cytoplasmic ratio. The architecture of the tissue may be disorderly. Mitotic figures are more abundant than usual, and frequently appear in abnormal locations within the epithelium. 38 When dysplastic changes are marked and involve the entire thickness of the epithelium but the lesion remains confined by the basement membrane, it is considered a preinvasive neoplasm and is referred to as carcinoma in situ. Once the tumor cells breach the basement membrane, the tumor is said to be invasive. Dysplastic changes are often found adjacent to foci of invasive carcinoma, and in some situations, such as in long-term cigarette smokers and persons with Barrett esophagus, severe epithelial dysplasia frequently antedates the appearance of cancer. However, dysplasia does not necessarily progress to cancer. Mild to moderate changes that do not involve the entire thickness of epithelium may be reversible, and with removal of the inciting causes the epithelium may revert to normal. Even carcinoma in situ may take years to become invasive. 39 40. As you might presume, the better the differentiation of the transformed cell, the more completely it retains the functional capabilities found in its normal counterparts. Despite exceptions, the more rapidly growing and the more anaplastic a tumor, the less likely it will have specialized functional activity. The cells in benign tumors are almost always well differentiated and resemble their normal cells of origin; the cells in cancer are more or less differentiated, but some derangement of differentiation is always present. 41  LOCAL INVASION Nearly all benign tumors grow as cohesive expansile masses that remain localized to their site of origin and do not have the capacity to infiltrate, invade, or metastasize to distant sites, as do malignant tumors. Because they grow and expand slowly, they usually develop a rim of compressed connective tissue, sometimes called a fibrous capsule, which separates them from the host tissue. Although a well-defined cleavage plane exists around most benign tumors, in some it is lacking. 42  Fibroadenoma of the breast. The tan-colored, encapsulated small tumor is sharply demarcated from the whiter breast tissue. 43 Microscopic view of fibroadenoma of the breast. The fibrous capsule (right) delimits the tumor from the surrounding tissue. 44  Cut 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 45 Colon carcinoma invading pericolonic adipose tissue 46. The growth of cancers is accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. In general, malignant tumors are poorly demarcated from the surrounding normal tissue, and a well-defined cleavage plane is lacking. Slowly expanding malignant tumors, however, may develop an apparently enclosing fibrous capsule and may push along a broad front into adjacent normal structures. Histologic examination of such pseudo-encapsulated masses almost always shows rows of cells penetrating the margin and infiltrating the adjacent structures, a crablike pattern of growth that constitutes the popular image of cancer. 47. Most malignant tumors are obviously invasive and can be expected to penetrate the wall of the colon or uterus, for example, or fungate through the surface of the skin. They recognize no normal anatomic boundaries. Such invasiveness makes their surgical resection difficult or impossible, and even if the tumor appears well circumscribed it is necessary to remove a considerable margin of apparently normal tissues adjacent to the infiltrative neoplasm. Next to the development of metastases, invasiveness is the most reliable feature that differentiates malignant from benign tumors. 48  METASTASIS Metastases are tumor implants discontinuous with the primary tumor. Metastasis unequivocally marks a tumor as malignant because benign neoplasms do not metastasize. The invasiveness of cancers permits them to penetrate into blood vessels, lymphatics, and body cavities, providing the opportunity for spread. With few exceptions, all malignant tumors can metastasize. The major exceptions are most malignant neoplasms of the glial cells in the central nervous system, called gliomas, and basal cell carcinomas of the skin. Both are locally invasive forms of cancer, but they rarely metastasize. It is evident then that the properties of invasion and metastasis are separable. In general, the more aggressive, the more rapidly growing, and the larger the primary neoplasm, the greater the likelihood that it will metastasize or already has metastasized. 49  Pathways of Spread Dissemination of cancers may occur through one of three pathways: (1) direct seeding of body cavities or surfaces, (2) lymphatic spread, and (3) hematogenous spread. Although direct transplantation of tumor cells, as for example on surgical instruments, may theoretically occur, it is rare and we do not discuss this artificial mode of dissemination further. 50 Seeding of Body Cavities and Surfaces. Seeding of body cavities and surfaces may occur whenever a malignant neoplasm penetrates into a natural “open field.” Most often involved is the peritoneal cavity ( Fig. 7-16 ), but any other cavity—pleural, pericardial, subarachnoid, and joint space—may be affected. 51  Lymphatic Spread. Transport through lymphatics is the most common pathway for the initial dissemination of carcinomas, and sarcomas may also use this route. The pattern of lymph node involvement follows the natural routes of lymphatic drainage. Local lymph nodes, however, may be bypassed—so-called “skip metastasis”—because of venous-lymphatic anastomoses or because inflammation or radiation has obliterated lymphatic channels. 52. biopsy of sentinel nodes is often used to assess the presence or absence of metastatic lesions in the lymph nodes. A sentinel lymph node is defined as “the first node in a regional lymphatic basin that receives lymph flow from the primary tumor In many cases the regional nodes serve as effective barriers to further dissemination of the tumor, at least for a while. Conceivably the cells, after arrest within the node, may be destroyed by a tumor-specific immune response. Drainage of tumor cell debris or tumor antigens, or both, also induces reactive changes within nodes. Thus, enlargement of nodes may be caused by (1) the spread and growth of cancer cells or (2) reactive hyperplasia. 53  Axillary 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 54  Hematogenous Spread. Hematogenous spread is typical of sarcomas but is also seen with carcinomas. Arteries, with their thicker walls, are less readily penetrated than are veins. With venous invasion the blood-borne cells follow the venous flow draining the site of the neoplasm, and the tumor cells often come to rest in the first capillary bed they encounter. Understandably the liver and lungs are most frequently involved in such hematogenous dissemination, because all portal area drainage flows to the liver and all caval blood flows to the lungs. Cancers arising in close proximity to the vertebral column often embolize through the paravertebral plexus, and this pathway is involved in the frequent vertebral metastases of carcinomas of the thyroid and prostate. 55  liver studded with metastatic cancer. 56  Microscopic view of liver metastasis. A pancreatic adenocarcinoma has formed a metastatic nodule in the liver.. 57  Comparisons between Benign and Malignant Tumors Characteristics Benign Malignant Differentiation/anaplasia Well differentiated; Some lack of differentiation structure sometimes typical with anaplasia; structure of tissue of origin often atypical Rate of growth Usually progressive and Erratic and may be slow to slow; may come to a rapid; mitotic figures may be standstill or regress; mitotic numerous and abnormal figures rare and normal Local invasion Usually cohesive expansile Locally invasive, infiltrating well-demarcated masses surrounding tissue; that do not invade or sometimes may be infiltrate surrounding normal seemingly cohesive and tissues expansile Metastasis Absent Frequently present; the larger and more undifferentiated the primary, the more likely are 58 metastases Comparison between a benign tumor of the myometrium (leiomyoma) and a malignant tumor of similar origin (leiomyosarcoma). 59