Cancer Pathophysiology 2018-2019 PDF

Isra University Faculty of Pharmacy Amman – Jordan 2018-2019 Pathophysiology Prof. Dr. Raad Al-Ani MB.ch.B., Msc, PhD. Pathology Consultant Hematopathologist chapter two Cancer Patho...

Isra University Faculty of Pharmacy Amman – Jordan 2018-2019 Pathophysiology Prof. Dr. Raad Al-Ani MB.ch.B., Msc, PhD. Pathology Consultant Hematopathologist chapter two Cancer Pathophysiology 2017-2018 Faculty of Pharmacy.Isra University Prof. Dr. Raad Al-Ani MB.ch.B., Msc, PhD. Pathology Consultant Hematopathologist Cancer  The incidence of cancer increases markedly with advancing age and is strongly affected by gender, lifestyle, ethnicity, infection, and genetics. We now understand that cancer is a collection of many different diseases, caused by an accumulation of genetic and epigenetic alterations. Environment, heredity, and behavior interact to modify the risk of developing cancer and the response to treatment. Improvements in treatment strategies and supportive care, coupled with new, often individualized therapies based on advances in our fundamental understanding of the basic Pathophysiology of malignancy, have contributed to an increasing number of effective options for these diverse, often lethal, disorders collectively called cancer. Cancer is a disease that results from abnormal growth and differentiation of tissues. (more than 100 different diseases that are characterized by uncontrolled cellular growth, local tissue invasion, and distant metastases.) The most common sites for cancer development are the prostate, breast, lung and.colon Although cancer can arise at any age, the incidence of cancer increases proportionally.with increasing age  Cancer terminology The word tumor originally referred to any swelling that was caused by inflammation, but is now generally reserved for describing a new growth, or neoplasm. Tumoror Tumor neoplasm:IsIsaamass orneoplasm: massof oftissue tissueininwhich whichthe the growth growthrate rateisisexcessive excessiveand anduncoordinated uncoordinatedwhenwhen compared comparedwith withnormal normaltissues tissues Benign neoplasm::Tumor Benignneoplasm Tumorcells cellsthat thattend tendtotobe beclustered clustered.in.inaasingle singlemass massand andare arenot notmalignant malignant Benign tumorsusually Benigntumors usually will will not not cause cause death death unless unless they they.interfere.interferewith withvital vitalfunction function Malignant neoplasms:are Malignantneoplasms: aretumors tumorsthat thathave havethe the ability abilityto metastasizeor tometastasize orbreak breakloose looseand andspread spreadtoto other otherareas areasof ofthe thebody. body.IfIfuntreated, untreated,such suchtumors tumors.can.cancause causegreat greatsuffering sufferingand anddeath death  In general, cancers are named according to the cell type from which they originate. Carcinoma Carcinoma ::Malignant Malignanttumor tumorofofepithelial epithelialcell cellorigin, origin,(if(ifthey theyarise arise from or form ductal or glandular structures are named adenocarcinomas). from or form ductal or glandular structures are named adenocarcinomas)..Sarcoma.Sarcoma::Malignant Malignanttumor tumorofofskeletal skeletalor orconnective connectivetissue tissueorigin origin.Lymphoma.Lymphoma: Malignant : Malignanttumor tumorofoflymphatic lymphatic tissue tissue Glioma Glioma: Malignant : Malignanttumor tumorofofthe theglial glialsupport cellsininthe supportcells thecentral central.nervous.nervoussystem system.Leukemias:.:Leukemiasare arecancers cancersofofblood-forming blood-formingcells cells However, many cancers, such as Hodgkin disease and Ewing sarcoma, are named for historical reasons that do not follow this naming convention.  Classification of Tumors: Classical Histology and Modern Genetics Carcinoma in situ (often abbreviated CIS) refers to preinvasive epithelial malignant tumors of glandular or squamous cell origin. These early stage cancers are localized to the epithelium and have not broken through the local basement membrane or invaded the surrounding stroma. Carcinoma in situ is recognized in a number of sites, including the cervix, skin, oral cavity, esophagus, and bronchus. In glandular epithelium, in situ lesions occur in the stomach, endometrium, breast, and large bowel. In the breast, ductal carcinoma in situ (DCIS) fills the mammary ducts but has not progressed to local tissue invasion. Progression from normal to neoplasm. A sequence of cellular and tissue changes progressing from dysplasia to carcinoma in situ and then to invasive cancer is seen often in the development of cancer. The presence of anaplastic cells and loss of normal tissue architecture signify the development of cancer. This sequence of changes is most easily seen in the squamous epithelium of the uterine cervix, the epidermis of sun-exposed skin, and colonic and gastric mucosa after long- standing inflammation. (Modified from Stevens A, Lowe J: Pathology, ed 2, London, 2000, Mosby.)  Nomenclature of Epithelial Neoplasms Epithelial tissues Benign Malignant neoplasms neoplasms Skin & Mucus Papilloma Papillary carcinoma Glandular Adenoma AdenoCarcinoma Epithelium Placental Hydatidiform Mole Chorion epithelium Carcinoma 11  Nomenclature of Connective Tissue Neoplasms Connective tissues Benign neoplasms Malignant neoplasms Fibroma Fibrous tissue Fibrosarcoma Lipoma Fatty tissue Liposarcoma Osteoma Osteosarcoma Osteoid tissue 12  Characteristics of Neoplasia (Benign versus Malignant Tumors) Benign Tumors Malignant Tumors Grow slowly Grow rapidly Have a well-defined capsule (Encapsulated) Are not encapsulated )Non-encapsulated( Are not invasive Invade local structures and tissues )Loss of contact inhibition( Well differentiated; looks like the tissue from Poorly differentiated; may not be able to tell which it arises from what tissue it arose Have a low mitotic index; dividing cells are rare High mitotic index; many dividing cells Do not metastasize Can spread distantly, often through blood vessels and lymphatics Express foreign antigens, Abnormal gene expression Loss of cellular and tissue differentiation during the development of cancer. The cells of a benign neoplasm (B) resemble those of the normal colonic epithelium (A), in that they are columnar and have an orderly arrangement. Loss of some degree of differentiation is evident in that the neoplastic cells do not show much mucin vacuolization. Cells of the well- differentiated malignant neoplasm (C) of the colon have a haphazard arrangement and although gland lumina are formed, they are architecturally abnormal and irregular. Nuclei vary in shape and size, especially when compared with A. Cells in the poorly differentiated malignant neoplasm (D) have an even more haphazard arrangement, with very poor formation of gland lumina. Nuclei show greater variation in shape and size compared with the well-differentiated malignant neoplasm in C. Cells in anaplastic malignant neoplasms (E) bear no relation to the normal epithelium, with no recognizable gland formation. Tremendous variation is found in the size of cells and their nuclei, with very intense staining (hyperchromatic nuclei). Not knowing the site of origin would make it impossible to tell what sort of tumor this is by microscopic appearance alone. Well-differentiated tumors often resemble their cell of origin, as shown in the example of a benign tumor of smooth muscles (F). (From Stevens A, Lowe J: Pathology, ed 2, London, 2000, Mosby.)  Metastasis:isisthe Metastasis: theability abilityof oftumor tumorcells cellsto tospread spread to toother otherparts partsof ofthe thebody bodyand andestablish establishsecondary secondary.tumors.tumors Malignant tumor cells can break off and utilize blood vessels or lymphatic vessels to spread to other areas of the body. Tumor Tumorcells cellsenhance enhancetheir theirpotential potentialfor formetastatic metastaticspread spread by byreleasing proteaseenzymes releasingprotease enzymesthat thatdigest digestthe the extracellular extracellularmatrix matrixsurrounding surroundingadjacent adjacentcells. cells. Malignant Malignanttumor tumorcells cellsmay mayalso alsoproduce producegrowth growthfactors factors that thatstimulate stimulatethe theformation formationof ofnew newblood bloodvessels vessels ((angiogenesis angiogenesis),),which whichininturn turnsupport supportthe therapid rapidgrowth growth of oftumor tumorcells. cells. Certain organs such as the lungs are prime locations for the formation of metastases because of the large amount of blood flow they receive from the body. The liver is also a common site of metastasis for tumors originating in the GIT because blood draining the intestines must first pass through the liver via the hepatic portal system. Common Sites of Metastasis for Selected Cancers Breast cancer: Bones, lymph nodes (axillary), brain Lung cancer : Many organs (liver, brain, bone….ect) Prostate cancer : Bones, lungs, liver, endocrine glands Colon cancer : Liver Testicular cancer : Lungs, liver Ovarian cancer : Peritoneum, liver, lungs, diaphragm  Theories of oncogenesis Oncogenesis is the process by which normal cells are transformed.into cancer cells Abnormalities of tumor suppressor/inducer Several proteins produced genes within cells such as the p53 protein are known to limit cellular division by regulating certain parts of.the normal cell cycle The genes that code for these proteins are referred Failure to as anti-oncogenes since Failure of these anti-oncogenes may lead of these anti-oncogenes may lead.to they to thesuppress cell growth the unregulated unregulated cellular cellular division division that that is is.characteristic.characteristic of of cancer cancer cells cells In contrast, other groups of genes present in all cells are classified as proto-oncogenes since they produce proteins and substances that enhance cellular growth.and proliferation Excessive activity of these genes (or a lack of their regulation) may likewise cause excessive cellular.division and growth Mutation of DNA Numerous chemical, physical and biologic agents have been shown to be carcinogenic and can damage cellular DNA, either directly or through the production of toxic.intermediates such as free radicals Certain viruses are also oncogenic in that they may induce mutations in host cell DNA.or alter rates of cellular transcription Mutations of cellular DNA can lead to the formation of cells with abnormal growth and.differentiation patterns Possible Cancer-Causing Agents Chemicals — Many such as benzene, vinyl chloride, cigarette smoke, aromatic hydrocarbons Radiation, radon gas, radioactive materials, ultraviolet radiation Occupational exposure — Asbestos, coal dust, uranium, solvents Oncogenic viruses Dietary factors — High-fat diet, excessive alcohol intake, nitrosamine preservatives, grilled or charred Oncogenic Viruses in Humans A number of DNA and RNA viruses have been shown to be “oncogenic,” meaning they can.cause cancers in the hosts they infect Human Papillomavirus — Cervical carcinoma Hepatitis B Virus — Liver cancer Epstein–Barr Virus — Burkitt’s lymphoma, nasopharyngeal cancer HIV Virus — Kaposi’s sarcoma Hereditary A genetic predisposition has been observed for a number of cancers including colon cancer, breast cancer, retinoblastoma and certain forms of leukemia and lymphoma. A great deal of recent research has focused on identifying certain genetic markers in individuals that might pinpoint them as at risk for the development of certain types of  Manifestations of cancer Local effects of cancer.1 Compression of blood vessels Ischemia Pain Bleeding Infection Altered tissue function Systemic effects of cancer.2 Fatigue - Cachexia - Bleeding and hemorrhage - Anemia due to chronic bleeding or bone - marrow destruction; this anemia may be exacerbated by may be exacerbated by chemotherapy Altered organ function - Abnormal hormone production from an - affected gland or directly from certain types of hormone-producing tumors Cachexia A complex syndrome characterized by anorexia, weight loss and lean body (muscle) wasting seen in a significant percent of patients with cancer and AIDS. A number of metabolic abnormalities have been demonstrated in patients with cachexia that lead to poor utilization of nutrients and.overall malnutrition A key factor in cachexia appears to be the production of cytokines such as tumor necrosis factor and interleukins in response to.the presence of cancer  Tumor Tumors arestaging classified or “staged” based upon the “TNM” system that includes a description of tumor size (T), involvement of lymph nodes (N) and.metastasis (M) T — Primary tumor (Is there a tumor and if so how big is it?) TX — Primary tumor cannot be assessed TO — No evidence of primary tumor Tis — Carcinoma in situ T1–T4 — Increasing size of tumor N — Involvement of lymph nodes (Has the tumor spread to the lymph nodes?) NX — Regional lymph nodes cannot be assessed NO — No evidence that the tumor has metastasized to lymph nodes in the region of the primary tumor N1–N3 — Progressive involvement of regional lymph nodes M — Distant metastasis (Has the tumor spread to distant sites in the body?) Mx — Distant metastasis cannot be assessed MO — No evidence of distant metastasis  Cancer detection Tumor cell markers Substances produced by or found on the -.surface of tumor cells Tumor cell markers may be used clinically - to screen for the presence of tumor cells in.the body Drawbacks to the use of tumor markers in cancer diagnosis include that they may not be specific for a certain type of cancer and that by the time tumor cell markers are detected, the particular cancer may be well progressed. In addition, certain noncancerous conditions may also be associated with the appearance of some of these markers in the.blood  Examples of Tumor Cell Markers α-Fetopotein CA 19-9.Secreted by embryonic liver cells Elevated in cancers of the gastrointestinal High levels seen in liver, ovarian and testicular tract and pancreas. May also be elevated in cancer. May also be observed with viral gallbladder disease and pancreatitis hepatitis CA 27-29 Prostate-specific antigen (PSA) Elevated in breast cancer as well as a.Markedly increased in prostatic cancer number of other cancers. May also be elevated in benign breast disease as well as Slightly elevated in benign prostatic disease of the kidney and liver hypertrophy CA 15-3 CA 125 Elevated in ovarian cancer. May be elevated Elevated in breast cancer in pregnancy and with pelvic inflammatory High levels often indicate advanced or disease metastatic breast cancer. May be elevated in benign breast disease or liver disease Human chorionic gonadotrophin Used as a marker for a number of different cancers. Elevated in pregnancy Visualization Radiography, computer tomography - (CT scans), magnetic resonance imaging Endoscopy: may also be utilized to - visually detect tumors in the bronchi and GI tract Identifies the presence of a tumor or - tumors; can also be used to evaluate metastasis Biopsy Removal of a piece of suspect tissue for detailed histologic or.histochemical analysis May be accomplished surgically, by a needle biopsy, by scraping cells from a surface (Pap smear) or by.endoscopic biopsy  Rationale for therapy Surgical Surgicalremoval removalof oftumors, tumors,as aswell wellas as.chemotherapy.chemotherapyand/or and/orradiation radiationtherapy therapy AAnumber numberof ofimmune-based immune-basedtreatments treatmentsareare currently currentlyunder underinvestigation investigationas asalternatives alternatives to totoxic toxicchemotherapy chemotherapyand andradiation radiation therapy. therapy.Treatment Treatmentwithwithspecific specifichormones hormones has hasalso alsobeen beenshown showntotoinhibit inhibitthe thegrowth growthof of certain certaintypes typesof ofcancers cancers Treatment of cancer Surgical removal If accessible, tumors should be surgically removed. Often accompanied by chemotherapy or radiation therapy to kill any cancer cells that are not removed or have.metastasized Chemotherapy Drugs used for chemotherapy of cancer fall into several categories  Chemotherapy Drugs Alkylating agents and nitrosureas (examples: cyclophosphamide, carmustine) Cytotoxic to cancer cells due to alkylation of cancer cell DNA. Major toxicities include nausea and vomiting, and bone marrow suppression. Antimetabolites (examples: methotrexate, fluorouracil) Inhibit synthesis of essential nucleotides and nucleic acids in cancer cells. Major toxicities include myelosuppression, nausea, vomiting, oral and GIT ulceration. Plant alkaloids (examples: vinblastine, vincristine) Disrupt mitosis in cancer cells by interfering with formation of the mitotic spindle. Numerous toxicities including cardiotoxicity, bone marrow depression, neurologic and muscle effects as well as alopecia. Antibiotics (examples: doxorubicin, bleomycin) Bind directly to cancer cell DNA to block the formation of new RNA or DNA. Major toxicities include bone marrow suppression, alopecia. Hormonal therapy Sex hormones are routinely used to inhibit tumor growth in breast, prostate and uterine cancer. The estrogen inhibitor tamoxifen has also been shown to be effective in the treatment of breast cancer and may eventually be used as a prophylactic agent in women who are at a high risk for developing breast cancer. The androgen inhibitor flutamide has also been.approved for treatment of prostate cancer Radiation therapy Radiation therapy utilizes ionizing or particle beam radiation to destroy cancer cells that are highly mitotic and most susceptible to the lethal effects of radiation. Radiation therapy can have a number of localized and systemic side effects including alopecia, diarrhea,.tissue irritation and organ inflammation Immune-based therapies Biologic response modifiers” such as“ interferons, immunomodulators, tumor antigens and lymphokines/cytokines are being investigated as means of enhancing the immune system response of individuals.with cancer Monoclonal antibodies have also been studied as a highly specific means of delivering chemotherapeutic drugs directly to and only.to cancer cells  Next Lecture chapter three Disorders of hemostasis and coagulation