Lecture 2. [Pathophysiology]

Transcription

1 II. Rate of Growth Most benign tumors grow slowly, and most cancers (malignant tumors) grow much faster. However, there are some exceptions to this generalization e.g., the rate of growth of leiomyomas (benign tumor of smooth muscle) of the uterus may increase rapidly during pregnancy under the influence of estrogen hormone. In general, the rate of growth of cancers correlates inversely with their level of differentiation, i.e., undifferentiated malignant tumors grow faster than differentiated malignant tumors. Note Rapidly growing cancers often contain central areas of ischemic necrosis because the tumor blood supply fails to provide the oxygen needs for the expanding mass of cells. III. Local Invasion Benign tumors remain localized at their sites of origin. They have no capacity to infiltrate, invade, destroy or penetrate the surrounding tissue. In addition, most benign tumors are enclosed by fibrous capsule that separate them from the surrounding tissue. On the other hand, the malignant tumors are capable to grow by progressive infiltration, invasion, destruction and penetration of the surrounding tissue. They do not develop capsules. Note 1. The lack of capsule does not necessarily indicate that the tumor is malignant.. The infiltrative growth mode in malignant tumors makes it necessary to remove a wide margin of surrounding normal tissue when surgical removal of such tumors is attempted. 3. Local invasiveness is considered the second most reliable feature that distinguishes malignant from benign tumors. 1

2 IV. Metastasis Metastasis means the development of secondary implants (metastatic tumor) discontinuous with the primary tumor, possibly in remote tissues. Note 1. Approximately 30% of the newly diagnosed patients with cancers present with clinically evident metastases.. In general, the more anaplastic and the large the primary tumor, the greater the possibility of metastatic spread, however, many exceptions are found. 3. Metastasis is the first most reliable features that distinguish malignant from benign tumors. 4. Not all malignant tumors have equivalent ability to metastasize. E.g.: a. At one extreme, there are the basal cell carcinomas of the skin and most primary cancers of the CNS that rarely metastasize. b. At the other extreme, there are the bone sarcomas, which usually have metastasized to the lungs at the time of initial discovery. 5. Benign tumors never metastasize. Pathways (Routes) of Metastasis Malignant tumors metastasize via one of 3 pathways: 1. Seeding within body cavities, e.g., carcinoma of the colon may penetrate the wall of the gut and re-implant at distant sites in the peritoneal cavity.. Lymphatic spread which is more typical for carcinomas, e.g., the lung carcinomas that arise in the lung and metastasize to the regional bronchial lymph nodes and tracheobronchial lymph node. 3. Hematogenous spread which is the most feared consequence of the cancers. It is the favored pathway for sarcomas, but carcinomas may use it as well. 1. The liver and lung are the most frequently involved secondary sites in hematogenous spread because all portal blood flows to the liver, and all atrial (venous) blood flows to the lung.

3 . The natural pathways of venous drainage do not completely explain the hematogenous spread of the secondary cancer implants, e.g.: a. Prostatic carcinomas preferentially spread to bone. b. Bronchogenic carcinomas tend to involve the adrenals and the brain. c. Conversely, skeletal muscles are rarely the site of secondary cancer implants. Differentiation between benign and malignant tumors The characteristics mentioned in the following table are dependable for the discrimination between benign and malignant tumors. Benign tumors vs malignant tumors Characteristics Benign tumors Malignant tumors 1. Differentiation Well differentiated. Structure similar to original tissue. Some lack of differentiation. Structure often atypical. Variable degree of anaplasia.. Rate of Growth 3. Local invasion Slow, progressive expansion. Rare mitotic figures. Normal appearing mitotic figures. No invasion. Cohesive and expensile growth. Capsule often present. Slow or rapid growth. Mitotic figures often numerous. Mitotic figures sometimes abnormal. Local invasion. Infiltrative growth. Usually no capsule is present. 4. Metastasis Never metastasize. May or may not metastasize. Tumor epidemiology: There are some epidemiological factors (related to the patient and environment) that influence the predisposition of tumor: 3

4 I. Geographic and environmental factors It has been indicated that the proportion of tumor risk from geographic and environmental factors is about 65%, whereas heritable factors contribute only 6-4% of the tumor risk. These proportions are supported by geographical differences, e.g.: 1. Human death rates from breast cancer are about 4 5 times higher in the USA and Europe compared to Japan.. Human death rates from stomach carcinoma in men and women are about 7 times higher in Japan than in the USA. 3. Liver cell carcinoma is relatively infrequent in the USA but is the most lethal cancer among African native populations. Nearly all evidences indicate that these geographical differences are related to environmental rather than heritable factors, e.g.: 1. Type of food. Personal practices (such as cigarette smoking and chronic alcohol consumption). 3. Occupation. 4. Type of setting (urban or rural setting). II. Age: In general, the frequency of tumor increases with age. In humans, most tumor mortality occurs between ages 55 and 75 years. This may be explained by: 1. The accumulation of somatic mutations.. The decline in immune competence that accompanies aging. Tumors cause slightly more than 10% of all deaths among children younger than 15 years. III. Heredity: The evidences now indicate that many types of tumors are predisposed not only by environmental factors but also by hereditary factors, e.g., the hereditary predisposition to lung cancers in cigarette smokers. 4

5 Although neoplasms themselves are not inherited, the hereditary factors play an important role in determining the susceptibility of an individual to the various carcinogens (etiological agents of tumors), e.g., carriers of the mutant gene which is responsible for developing childhood retinoblastoma, have a 10,000-fold greater risk of developing this tumor than the non-carries. Etiology of Tumor (Carcinogenic Agents or carcinogens): The principle feature for all carcinogens is the induction of mutation in those portions of the cell s genome that control mitotic division and differentiation, i.e., the principle feature for all carcinogens is the induction of genetic damage. Three major classes of carcinogens are capable to interact with the nuclear DNA and induce miscoding of genetic information (i.e., induce genetic damage or mutation) including chemicals, radiant energy, and viruses. I. Chemical carcinogens: Chemical carcinogens are of two types, either natural or synthetic and they are either direct acting chemical agents or indirect acting chemical agents. A. Direct acting chemical agents: Direct-acting agents require no metabolic conversion to become carcinogenic. They are in general weak carcinogens but are important because some of them are cancer chemotherapy drugs (e.g., alkylating agents such as cyclophosphamide, chlorambucil, nitrosoureas, and others) used in regimens that may cure certain types of cancer (e.g., Hodgkin lymphoma), only to evoke a subsequent, second form of cancer, usually leukemia. This situation is even more tragic when the initial use of such agents has been for non-neoplastic disorders, such as rheumatoid arthritis. The risk of induced cancer (leukemia, lymphoma and other cancers) by using of such chemicals is low, but the fact that it exists dictates its practical use. 5

6 B. Indirect acting chemical agents: The indirect acting chemical agents become carcinogenic only after metabolic conversion (activation) in vivo. Such agents are referred to as procarcinogens and their active end products are called ultimate carcinogen. Indeed, most chemical carcinogens are indirect acting agents e.g.: 1. Polycyclic hydrocarbons: Polycyclic hydrocarbons are the most potent indirect carcinogens. They are: a. Present in fossil fuels, such as: Benz[a] anthracene which produces cancer wherever it is applied: When painted on the skin, it induces skin cancers and when injected subcutaneously, it induces fibrosarcomas. b. Produced in combustion of organic substances. For example, benzo[a]pyrene and other carcinogens which are formed in the high-temperature combustion of tobacco in cigarette smoking. These products are implicated in the causation of lung cancer in cigarette smokers. c. Produced from animal fats during the process of boiling meats. d. Present in smoked fish and meats.. Aromatic amines Aromatic amines are used in industries of aniline dye and rubber (e.g., β-naphthylamine which was (in the past) responsible for a 50-fold increased incidence of bladder cancer in heavily exposed workers in the aniline dye and rubber industries. 3. Some of the azo dyes which were developed to color food. 4. Nitroseamines and nitroseamides 5. Aflatoxin B1 Aflatoxin B1 is an indirect acting chemical carcinogen produced by some strains of Aspergillus, a mold that grows on improperly stored grains and nuts. There is strong correlation between the dietary level of this food contaminant and the incidence of hepatocellular carcinoma in some parts of Africa and the Far East. 6. Vinyl chloride, arsenic, nickel, chromium, insecticides, fungicides, and polychlorinated biphenyls which are considered potent carcinogens in the workplace and about the house. 6

7 II. Radiant energy: Radiation whatever its source (ultraviolet rays of sunlight, X-rays, nuclear fission, radioactive nuclides) is regarded as an established carcinogens. Examples of tumors induced by radiation 1. Many of the pioneers in the development of roentgen rays (X rays) developed skin cancers.. High incidences of skin cancers (squamous cell carcinoma, basal cell carcinoma and melanoma) are reported among persons with fair skin. 3. Miners of radioactive elements (radium and uranium) have suffered a 10-fold increased incidence of lung cancer. 4. Bombs dropped on Hiroshima and Nagasaki in Japan has disclosed a markedly increased incidence of leukemia. 5. Therapeutic irradiation has been documented to be carcinogenic, e.g., thyroid cancers have developed in 9% of those exposed during their infancy and childhood periods to head and neck irradiation. III. Oncogenic viruses: A large number of DNA and RNA viruses have proved to be oncogenic (carcinogenic) in animals but only few of them are oncogenic in human. E.g.: A. Oncogenic DNA viruses Hepatitis B virus (hepatocellular carcinoma). Epstein-Barr virus (EBV), which has been implicated in Burkitt lymphoma, B-cell lymphomas in immunosuppressed patients, nasopharyngeal carcinoma. Human papilloma virus (HPV), which causes benign squamous papillomas warts and a variety of carcinomas (cervical, vulvar, vaginal, penile, and anal). Kaposi-sarcoma-associated Herpes virus (HHV8) which causes Kaposi sarcoma. B. Oncogenic RNA viruses: Human T-cell leukemia virus (HTLV-1) causes adult T-cell Leukemia/lymphoma. 7