Neoplasia and Cancer Handout PDF

Intro to Clinical Medicine Lecture (6) Neoplasia & Cancer Thomas G. Forsthuber, M.D. Dr. Med. Professor of Immunology, Adjunct Professor of Microbiology & Immunology (UT Health) Office: BSE 3.250B E-mail: [email protected] Office Hours: Monday 4:30 –...

Intro to Clinical Medicine Lecture (6) Neoplasia & Cancer Thomas G. Forsthuber, M.D. Dr. Med. Professor of Immunology, Adjunct Professor of Microbiology & Immunology (UT Health) Office: BSE 3.250B E-mail: [email protected] Office Hours: Monday 4:30 – 5:30 pm General characteristics of neoplasia Neoplasia = “new growth” (Greek) Neoplasm = neoplastic growth Neoplasia means uncontrolled, disorderly proliferation of cells resulting in a benign or malignant tumor Note: Neoplasm can be benign or malignant! Cancer = malignant tumors (cancer is Latin word for crab = crab-like growth = cancer takes hold of a tissue like a “crab”) 2023 over 20 million new cases of cancer worldwide and 10 million death from cancer In 2023, over 1.9 million new cancers per year in U.S., approximately 610,000 cancer deaths  Neoplasia Tumors have two basic components: proliferating tumor cells and supporting stroma with connective tissue and vessels. Neoplasms are classified into benign or malignant based on their biologic behavior – Benign neoplasms: Relatively closely resemble original tissue, grow slowly, do not metastasize, are often encapsulated, do not invade and destroy tissues around them – Malignant neoplasms: Undifferentiated, uncontrolled growth invasion of tissue around them, metastasis, The difference between incidence and mortality Cancer Incidence Cancer Mortality  Environment plays an important role! Characteristics of benign tumors: Naming: Benign tumors are designated by the suffix “-oma” – “Lipoma”, “fibroma”, “adenoma” – Note: some cancers also end with “-oma” = lymphoma, sarcoma Biological behavior: slow growth, encapsulated, do not metastasize, not destructive Papilloma: benign neoplasm arising from surface epithelium (e.g. skin, mouth, gut, bladder) = “finger-like projections”. Various causes. Adenoma: benign neoplasm of glandular epithelium Benign neoplasms of mesenchymal origin (e.g muscle, connective tissue, fat, bone, cartilage): – Fibroma (fibroblasts), lipoma (fatty tissue), leiomyoma (smooth muscle tumor, for example uterus), rhabdomyoma (striated muscle cells, skeletal muscle), chondroma (cartilage cells)  Papilloma caused by HPV Warts (Verruca) Papillomatous growth =finger- like projections Typically from squamous cells Adenoma (colonic polyp) Derived from glandular epithelium  Adenomas (polyp) Note: Polyp is abnormal growth of tissue projecting from a mucosal surface. But if they are adenomas higher risk for cancer Polyps often appear as flat bumps, whereas adenomas are protruding, round-shaped to mushroom-like bumps Adenoma of the thyroid E. Klatt, FSU  Adenoma of the liver Most common benign tumor: Nevus (pigmented mole) Nevus: proliferation of melanocytes  Hemangiomas Hemangiomas are benign tumors of the vascular endothelium Infantile hemangioma Congenital hemangioma Most frequent type (4-5% newborns) Less frequent Appears at 4 – 6 weeks of age Present at birth Grow quickly for short time and then May remain or may shrink disappear CMTC-OVM is a worldwide non-profit patient organization that aims to improve Wikipedia the quality of life of people suffering from vascular abnormalities (blood vessel abnormalities), such Cavernous hemangioma Cherry angioma = senile angioma (most often congenital)  Stork bite – NOT A HEMANGIOMA Birthmark Harmless, nevus simplex Present at birth Harmless Dilated/stretched capillaries NOT a neoplasm Typically fade away with time Hamartomas are “tumors” but NOT neoplasms Hamartoma (tumor-like) It is a disorganized overgrowth of different cells and tissues normally found in an organ. Is not a neoplastic proliferation of one cell type. Grows at same speed as normal tissues. Occurs usually in: – Lungs (most frequent location): Consist of Fat, cartilage, connective tissue; – Kidney, Spleen: nodule with increased red pulp, blood vessels Usually discovered by chance (routine chest X-ray, CT) Often has an underlying genetic abnormality  Spleen Hamartoma Benign overgrowth of malformed blood vessels. Tendency to rupture and bleed. Malignant tumors (cancer) Form metastasis = most tell-tale feature of a malignant tumor!!! Invasive growth, no capsule Undifferentiated = may barely resemble tissue of origin (if at all) Important cellular features: – Anaplasia (poorly differentiated) – Pleomorphism (wide variation in the shape and appearance of the tumor cells) – Hyperchromatic nucleus (dark staining nucleus) – High nuclear to cytoplasm ratio – Prominent nucleoli Rapid growth Frequently necrosis (not enough blood supply)  Cancers are named according to tissue origin Carcinoma: malignant tumor of epithelial cell origin – Squamous cell carcinoma – skin, mouth, esophagus – Adenocarcinoma – from glandular tissue, GI mucosa, endometrium – Transitional cell carcinoma – urinary tract Sarcoma: Cancer of muscle, bone, connective tissue, fat tissue, – Leimyosarcoma (smooth muscle, uterus), rhabdomyosarcoma (skeletal muscle), osteosarcoma (bone), chondrosarcoma (cartilage), liposarcoma (fatty tissue) Some cancers have specific names Burkitt’s lymphoma Hodgkin’s disease Wilms’ tumor  Teratoma: Germ cell layer derived tumor (ovary, testis). Can have bone, teeth and so forth Teratomas rarely form outside ovary/testis but it can happen (develop from stem cells) Teratomas are often benign but some can be malignant Immature Teratoma: malignant, usually males in the testicles Mature Teratoma: benign, usually females Biological behavior of cancers Invasion and metastasis Benign lesions have a capsule and grow by pushing other tissues around them aside Malignant tumors don’t care about borders and grow right into other tissues Metastasis: – Tumor grows and becomes vascularized – Tumor can grow into the vessels – Tumor cells become loose and are swept with the blood or lymphatic stream into other tissues where they get stuck and may form islands of new tumor growth – Tumors have frequently particular routs of metastasis Carcinomas metastasize frequently via lymphatics Sarcomas metastasize via the blood – Metastasis targets frequently the liver, lungs, brain, lymph nodes, bone marrow  Clinical manifestations of malignancies Symptoms caused by the tumor and metastasis due to location – Painless swellings, “tumors”, obstruction, easy bleeding, change in color, change in consistency, edema, change in body function Symptoms caused by features of the tumor – Wasting (cachexia): weight loss, weakness, loss of appetite, – Anemia – Infection – Tumors may produce hormones = hormone abnormalities (growth hormone – gigantism) – Paraneoplastic syndromes: Hypercalcemia (cancer makes parathyroid hormone-like protein) Hormone like effects (hypoglycemia produced by insulin like substance made by some tumors, Cushing syndrome by ACTH- like substance by lung cancer) Neurologic abnormalities (antibodies associated with lung cancer) Skin changes (acanthosis nigricans = hyperpigmentation of skin of the neck, groin, axilla)  Why do people die of cancer? Cancer may directly interfere with body function (obstruction, destruction of vital tissue, space occupying lesions Cancer may lead to bleeding Cancer treatment may result in death Cancer may produce substances that alter function of tissues (for example hormones) Cancer-induced cachexia and anorexia found in up to 50% of patients loss of muscle and adipose tissue (other tissues not affected) Good reading on cancer cachexia: Tisdale, M.J., Physiol. Rev 2009 not fully understood why prognostically very important death is imminent with 30 – 35% weight loss Highest weight loss seen in pancreatic and gastric cancer Lowest weight loss in lymphomas, breast cancer, sarcomas Cachexia and cancer death Cancer cachexia: selective loss of fatty tissue and muscle mass – other tissues NOT affected Cancer cells can affect lipid and protein metabolism Cancer can produce substances such as lipolysis and proteolysis inducing factors, and cytokines such as TNF and IL-6 that affect lipid and protein metabolism Loss of muscle mass results in respiratory failure of patients (hypostatic pneumonia due to immobility) Cancer patients eat less (anorexia = loss of appetite) Increased nutrition cannot overcome cancer cachexia Comparison of body composition of cachectic cancer patients with normal controls (Data from Fearon, Proc Nutr Soc 1992) Parameter Normal, kg Cachectic, kg Total body weight 65.6 44.9 Total fat 17.3 3.1 Muscle protein 2.8 0.7 Nonmuscle protein 8.3 8.1 Intracellular water 19.1 12.9 Extracellular water 15.1 17.5 Minerals 3.0 2.6  Diagnosis of cancer Clinical signs: visible tumor, bleeding, weight loss, etc. Diagnostic tests: X-ray, CT, MRI, biopsy, etc. Lab tests: CBC abnormalities, PSA, CEA, etc. Diagnosis and identification of cancer can be difficult because they may resemble other conditions (infections, benign conditions, etc.) Grading and staging Cancers are classified clinically based on their histological appearance, tumor size, and tumor metastasis This helps with prognosis and therapy decisions Grading: histopathologic evaluation based on the degree of cellular differentiation Staging: how large is the cancer, does it invade neighboring tissues, did it metastasize – TNM system T = size and extent of the tumor N = lymph node involvement M = metastasis – Specialized versions of tumor grading and staging geared towards special tumors: Dukes classification (replaced by TNM) = colon cancer Ann Arbor system = Hodgkin disease and non-Hodgkin lymphomas Note: not applicable to leukemias and tumors of CNS  Grading of Malignant Neoplasms Grade Definition I Well differentiated II Moderately differentiated III Poorly differentiated IV Nearly anaplastic E. Klatt, FSU Staging of Malignant Neoplasms Stage Definition Tis In situ, non-invasive (confined to epithelium) T1 Small, minimally invasive within primary organ site T2 Larger, more invasive within the primary organ site T3 Larger and/or invasive beyond margins of primary organ site T4 Very large and/or very invasive, spread to adjacent organs N0 No lymph node involvement N1 Regional lymph node involvement N2 Extensive regional lymph node involvement N3 More distant lymph node involvement M0 No distant metastases M1 Distant metastases present E. Klatt, FSU  Carcinogenesis (how cancers form) Ultimately, cancer is caused by changes to the genome of a cell New genes are introduced that promote cancer – Example: viral oncogenes Genes are damaged/mutated so that they cause cancer Chromosomal translocations bring genes together that cause uncontrolled growth. – Example: [t(8;14)] in Burkitt’s lymphoma = proto- oncogene c-myc is translocated to the Immunoglobulin heavy chain locus on chromosome 14 and becomes overactive Repair mechanisms are defective so that “damaged” genes that could cause cancer cannot be repaired – “Tumor suppressor” genes are damaged (inactivated) Typically “a series of unfortunate events” (several genetic changes) needs to take place before cancer develops (example: colon cancer) Burkitt Lymphoma T(8;14) Chronic myelogenous Wiki leukemia T(9;22) BCR-ABL “Philadelphia chromosome” CML!!! Robbins Pathology Sounders/Elsevier BCR: break point cluster region, Abl: Abelson tyrosin kinase  Cancers can be induced by chemicals or other environmental factors: Chemical carcinogenesis: Two events: “Initiation” = primes for cancers; “promotion” stimulates cell proliferation and promotes the cancers The process of carcinogenesis: Often: stem cells are mutated! 1.Initiation Tumor initiators = mutagens 2.Promotion (more proliferation, less death, more cells with mutations) Tumor promotors = drive proliferation 3.Benign tumors 4.Malignant tumors = cells that acquired additional mutations  Important carcinogens that can lead to cancer: – Chemical carcinogenesis Asbestos = lung, mesotheliomas of the lung, Arsenic = skin cancer, hemangiosarcoma Benzene = leukemia Vinyl chloride = angiosarcoma, liver cancer Benzopyrene = scrotal cancers (chimney sweeps developed squamous cell carcinoma of scrotal skin in 18th century England, “Pott’s cancer”), bladder cancer, lung cancer (smoking) Tobacco smoke: acrolein, formaldehyde, acrylonitrile, 1,3 butadiene, cadmium, acetaldehyde, ethylene oxide, – Radiation carcinogenesis UV light = skin cancer Ionizing radiation = leukemias, lung cancer (uranium miners), osteosarcoma in radium watch-dial workers Thyroid irradiation = thyroid cancers – Viral carcinogenesis = viruses introduce DNA into host cells cause cancer: Human papilloma virus (HPV) = cervical cancer Epstein-Barr virus (EBV) = Burkitt lymphoma, nasopharyngeal CA - Natural products: Aflatoxin B1 (Aspergillus flavus) = hepatocellular carcinoma The discovery of the link of certain chemicals with cancer  Percivall Pott, Cancer Scroti, The Chirurgical Works of Percival Pott. 1775 “there is a disease as peculiar to a certain set of people, which has not, at least to my knowledge, been publicly noticed; I mean the chimney-sweepers' cancer.” How sad it this? Pott published “Cancer Scroti” in 1775!!! Still, in 1819, during a debate in the House of Lords over the use of mechanical chimney cleaning, Lord Lauderdale stated in opposition: “The better way, in judgment, would be to leave reforms of this kind entirely to the moral feeling of, perhaps, the most moral people, on the whole face of the earth”. In the UK it took until 1864 when Lord Shaftesbury brought in the “Act for the Regulation of Chimney Sweepers” which established a penalty of £10.00 for offenders. In the US it took even longer (around 1875) for chimney sweeps to be regulated. In 1933 it was experimentally proven that Benzopyrene causes skin cancer. Cook JW, Hewett CL, Hieger I. The isolation of a cancer-producing hydrocarbon from coal tar. Parts I, II, and III. J Chem Soc 1933;24:395–405.