Neoplasia PDF

HISTOPATH LEC 6 NEOPLASIA Neoplasia “new growth,” and a new growth is called a neoplasm Oncology (Greek “oncos” = tumor) is the study of tumors or neoplasms. NEOPLASM British oncologist Willis : “A neoplasm is an abnormal mass of tissue, the gro...

HISTOPATH LEC 6 NEOPLASIA Neoplasia “new growth,” and a new growth is called a neoplasm Oncology (Greek “oncos” = tumor) is the study of tumors or neoplasms. NEOPLASM British oncologist Willis : “A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after cessation of the stimuli which evoked the change” disorder of cell growth that is triggered by a series of acquired mutations affecting a single cell and its clonal progeny 2 Basic Components of Tumors 1) Parenchyma The classification of tumors and their biologic behavior are based primarily on the parenchymal component 2) Reactive Stroma connective tissue, blood vessels, and variable numbers of cells of the adaptive and innate immune system. growth and spread are critically dependent on their stroma Mixed Tumors Pleomorphic adenoma These tumors contain epithelial components scattered within a myxoid stroma that may contain islands of cartilage or bone Teratoma Tumor which contains recognizable mature or immature cells or tissues belonging to more than one germ cell layer originates from totipotential germ cells that are normally present in the ovary and testis and sometimes also found in abnormal midline embryonic rests. Hamartomas Disorganized but benign masses composed of cells indigenous to the involved site Cells belong to the site but just grew too much! Choristoma Heterotopic rest of cells Small nodule of well-developed and normally organized pancreatic tissue may be found in the submucosa of the stomach, duodenum, or small intestine Cells don’t belong to the site (got lost!)  HISTOPATH LEC 6 Characteristics of Benign and Dysplasia Malignant Neoplasms Dysplasia is a term that literally means “disordered growth ” It is encountered principally in epithelia and is characterized by a constellation of changes that include a loss in the uniformity of the individual cells as well as a loss in their architectural orientation. The growth of cancers is accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Nearly all benign tumors grow as cohesive expansile masses that remain localized to their site of origin and lack the capacity to infiltrate, invade, or metastasize to distant sites. Benign tumors usually develop a rim of compressed fibrous tissue - capsule Malignant tumors are usually poorly demarcated. Next to the development of metastases, invasiveness is the most reliable feature that differentiates cancers from benign Differentiation tumors. refers to the extent to which neoplastic parenchyma cells resemble the corresponding normal parenchymal cells, both Metastasis morphologically and functionally Spread of a tumor to sites that are physically discontinuous Anaplasia with the primary tumor, and unequivocally marks a tumor as lack of differentiation malignant Benign tumors are well differentiated Pathways of Spread Malignant neoplasms exhibit a wide range of parenchymal cell differentiation, most exhibit morphologic alterations that Dissemination of cancers may occur through one of three betray their malignant nature pathways: Malignant neoplasms that are composed of poorly (1) direct seeding of body cavities or surfaces differentiated cells are said to be anaplastic. (2) lymphatic spread (3) hematogenous spread Morphologic changes associated with ❖ Iatrogenic spread of tumor cells on surgical instruments anaplasia may occur—it is the reason, for example, why biopsies of 1. Pleomorphism testicular masses are never done—it is generally rare 2. Abnormal nuclear morphology hyperchromatism SEEDING OF BODY CAVITIES AND SURFACES irregularly clumped chromatin May occur whenever a malignant neoplasm penetrates into prominent nucleoli a natural “open field” lacking physical barriers increased N: C ratios Most often involved: peritoneal cavity 3. Mitoses – abundant or atypical mitoses LYMPHATIC SPREAD 4. Loss of polarity - the orientation of anaplastic cells is markedly disturbed. Transport through lymphatics is the most common pathway for the initial dissemination of CARCINOMAS. Pleomorphism Sarcomas may also use this route. SENTINEL LYMPH NODE “the first node in a regional lymphatic basin that receives lymph flow from the primary tumor” HEMATOGENOUS SPREAD Hematogenous spread is typical of SARCOMAS but also seen in carcinomas Veins > Arteries The liver and the 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. The Global Impact of Cancer 2008 2030 12.7 million new cancer 21.4 million new cancer  HISTOPATH LEC 6 cases worldwide cases worldwide 7.6 million deaths 13.2 million deaths (21,000 deaths per day) Environmental Factors Although both genetic and environmental factors contribute to the development of cancer, environmental influences appear to be the dominant risk factors for most cancers. Best established environmental factors affecting cancer risk: Infectious agents Smoking Alcohol consumption Molecular basis of cancer: Role of genetic and epigenetic Diet alterations Obesity 4 Fundamental principles Reproductive history 1. Non Lethal genetic damage lies at the heart of Environmental carcinogens carcinogenesis. ENVIRONMENTAL, INHERITED, “BAD LUCK” 2. A tumor is formed by the clonal expansion of a single precursor cell that has incurred genetic damage 3. Four classes of normal regulatory genes are the principal targets of cancer-causing mutations a. proto-oncogenes b. tumor suppressor genes c. apoptosis-regulating genes d. DNA repair genes 4. Carcinogenesis results from the accumulation of complementary mutations in a stepwise fashion over time. Age Age has an important influence on the likelihood of being afflicted with cancer. Most carcinomas occur in the later years of life (>55 years). Acquired Predisposing Conditions chronic inflammations precursor lesions immunodeficiency state  HISTOPATH LEC 6 stimulation of nuclear transcription factors that drive Cellular and molecular hallmarks of cancer growth-promoting genes. Include products of the MYC, MYB, JUN, FOS, and REL 1. Self-sufficiency in growth signals proto-oncogenes 2. Insensitivity to growth-inhibitory signals MYC is most commonly involved in human tumors 3. Altered cellular metabolism 4. Evasion of apoptosis MYC ONCOGENE 5. Limitless replicative potential MYC proto-oncogene is expressed in virtually all eukaryotic 6. Sustained angiogenesis cells 7. Ability to invade and metastasize Activates the expression of many genes that are involved in 8. Ability to evade the host immune system cell growth ONCOGENES Considered a master transcriptional regulator of cell growth. PROTO-ONCOGENES: normal cellular genes whose Can reprogram somatic cells into pluripotent stem cells products promote cell growth ONCOGENES: mutated/ overexpressed versions of Cyclins and Cyclin- Dependent Kinases proto-oncogenes that function autonomously. Progression of cells through the cell cycle is orchestrated by Oncogenes are created by mutations in proto-oncogenes cyclin dependent kinases (CDKs) and encode proteins called ONCOPROTEINS that have the Activated by binding to cyclins ability to promote cell growth in the absence of normal growth-promoting signals. Cells expressing oncoproteins are thus freed from the normal checkpoints and controls that limit growth, and as a result proliferate excessively. Insensitivity to Growth Inhibition: Tumor Suppressor Genes RAS MUTATIONS Tumor suppressor genes apply brakes to cell proliferation, Point mutations of RAS family genes constitute the most and abnormalities in these genes lead to failure of growth common type of abnormality involving proto-oncogenes in inhibition, another fundamental hallmark of carcinogenesis. human tumors. Form a network of checkpoints that prevent uncontrolled 3 in humans (HRAS, KRAS, NRAS) growth 15-20% of all human tumors express mutated RAS proteins ALTERATIONS IN NONRECEPTOR TYROSINE KINASES Non membranous tyrosine kinases (cytoplasm or nucleus) May also activate the same signaling pathways as receptor tyrosine kinases ABL tyrosine kinase TRANSCRIPTION FACTORS Regulate the expression of pro-growth genes and cyclins The ultimate consequence of deregulated mitogenic signaling pathways is inappropriate and continuous  HISTOPATH LEC 6 Mutations affecting the type II receptor are seen in cancers of the colon, stomach, and endometrium. PTEN A membrane-associated phosphatase encoded by a gene on chromosome 10q23 Acts as a tumor suppressor Mutated in Cowden syndrome Autosomal dominant disorder Frequent benign growths, such as tumors of the skin appendages Increased incidence of epithelial cancers, particularly of the breast endometrium, and thyroid. RB: Governor of Cell Proliferation First tumor suppressor gene discovered RB, a key negative regulator of the G1 /S cell cycle transition, is directly or indirectly inactivated in most human cancers RB controls cellular differentiation TP53: Guardian of the genome TP53 Tumor suppressor gene that regulates cell cycle NF1 progression, DNA repair, cellular senescence and apoptosis Encodes neurofibromin 1 , a GTPase that acts as a Most frequently mutated gene in human cancers negative regulator of RAS Encodes for the protein p53 Germline mutation cause neurofibromatosis type 1 Autosomal dominant disorder MDM2 High risk of neurofibromas and malignant peripheral nerve Proteins of MDM2 family stimulate the degradation of p53 sheath Overexpressed in malignancies with normal TP53 alleles NF2 MDM2 gene is amplified in 33% of human sarcomas – Encodes neurofibromin 2 (merlin), a cytoskeletal protein functional deficiency of p53. involved in contact inhibition APC Germline mutations in the NF2 gene predispose to the development of neurofibromatosis type 2, autosomal encodes a factor that negatively regulates the WNT pathway dominant disorder associated with high risk of bilateral in colonic epithelium by promoting the formation of a schwannomas complex that degrades β-catenin Mutated in familial adenomatous polyposis E-cadherin (CDH1 gene) Cell adhesion molecule that plays an important role in contact-mediated growth inhibition of epithelial cells → involved in cellular adhesion and polarity maintenance Germline LOSS-OF-FUNCTION mutations in e-cadherin gene (CDH1) is associated with autosomal dominant familial gastric carcinoma, lobular breast carcinoma CDKN2A Complex locus that encodes two tumor suppressive proteins, p16/INK4a, a cyclin-dependent kinase inhibitor that PTCH1 augments RB function and ARF which stabilizes p53 Encodes membrane receptor that a is a negative regulator Loss-of-function mutations are associated with autosomal of the Hedgehog signaling pathway dominant familial melanoma Germline LOSS-OF-FUNCTION mutations cause Gorlin TGF-β pathway syndrome, autosomal dominant disorder associated with Potent inhibitor of proliferation high risk of basal cell carcinoma and medulloblastoma It regulates cellular processes by binding to a serine-threonine kinase complex composed of TGF-β receptors I and II  HISTOPATH LEC 6 VHL Encodes a component of a ubiquitin ligase that is responsible for degradation of hypoxia-induced factors (HIFs), transcription factors that alter gene expression in response to hypoxia Germline LOSS-OF-FUNCTION mutations cause von Hippel- Lindau syndrome, autosomal dominant disorder associated with a high risk of renal cell carcinoma and pheochromocytoma GROWTH PROMOTING METABOLIC ALTERATIONS WARBURG EFFECT Discovered by OTTO WARBURG Also known as aerobic glycolysis Cancer cells demonstrate a distinctive form of cellular metabolism characterized by: ✓ High glucose uptake ✓ Increased conversion of glucose to lactate via glycolytic pathway Aerobic glycolysis provides rapidly dividing tumor cells with metabolic intermediates that are needed for the synthesis of cellular components, whereas mitochondrial oxidative phosphorylation does not.