Dra bartolome's neoplasia review
- 1. NEOPLASIA REVIEW Fe A. Bartolome, MD, FPASMAP Department of Pathology Our Lady of Fatima University
- 2. Nomenclature Benign tumors Suffix “oma” generally indicates a benign tumor Benign tumors of epithelial origin Arise from ectoderm or endoderm Example – tubular adenoma arising from glands in the colon Benign tumors of connective tissue origin arise from mesoderm Example – lipoma from adipose
- 3. Nomenclature Benign tumors Tumors that are usually benign Mixed tumors Neoplastic cells have two different morphologic patterns but derive from the same germ cell layer Example – pleiomorphic adenoma of parotid gland
- 4. Nomenclature Benign tumors Tumors that are usually benign Teratomas Tumors that derive from more than one germ cell layer – contain tissue derived from ectoderm, endoderm, and mesoderm Sites: ovaries, testes, anterior mediastinum, and pineal gland
- 5. Nomenclature Malignant tumors (cancers) Carcinomas Derive from epithelial tissue – squamous, glandular, transitional Sites of squamous cell carcinoma Oropharynx, larynx, upper/middle esophagus, lung, cervix, skin Sites of adenocarcinoma Lung, distal esophagus to rectum, pancreas, liver, breast, endometrium, ovaries, kidneys, prostate
- 6. Nomenclature Malignant tumors (cancers) Sarcomas Derive from connective tissue Example – osteogenic sarcoma in bone
- 7. Nomenclature Tumor-like Conditions Hamartoma Non-neoplastic overgrowth of disorganized tissue indigenous to a particular site Examples – bronchial hamartoma, Peutz-Jeghers polyp Choristoma (heterotopic rest) Non-neoplastic normal tissue in a foreign location Examples – pancreatic tissue in stomach wall; gastric mucosa in Meckel diverticulum
- 8. Properties Components of benign & malignant tumors Parenchyma Neoplastic component that determines the tumor’s biologic behavior Stroma Non-neoplastic supportive tissue Most infiltrating carcinomas induce production of a dense, fibrous stroma
- 9. Properties Differentiation Benign tumors Usually well-differentiated – resemble parent tissue Malignant tumors Well-differentiated or low grade Poorly-differentiated, high grade, or anaplastic Intermediate grade – features between low- and high-grade cancers
- 10. Properties Nuclear Features Benign tumors Nuclear:cytoplasmic ratio close to normal Mitoses with normal mitotic spindles Malignant tumors Nuclear:cytoplasmic ratio increased with prominent nucleoli Mitoses have normal and atypical mitotic spindles
- 11. Properties Growth Rate Benign tumors Usually with slow growth rate Malignant tumors Variable growth rate – correlates with degree of differentiation Anaplastic cancers with increased growth rate 30 doubling times required for a tumor to be clinically evident equivalent to 10 9 cells, 1 gram of tissue, volume of 1 ml
- 12. Properties Monoclonality Benign and malignant tumors derive from a single precursor cell Non-neoplastic proliferations derive from multiple cells (polyclonal)
- 13. Properties Telomerase Activity Telomerase function Preserves length of telomeres (sequences of non-translated DNA at the ends of chromosomes) Prevents gene loss after multiple cell division Benign tumors with normal telomerase activity Malignant tumors with increased telomerase activity do not lose genetic material after multiple cell division
- 14. Properties Local Invasion Second most important criterion for malignancy Benign tumors do not invade usually enclosed in a fibrous capsule (except uterine leiomyoma) Malignant tumors invade tissue Basal cell CA of the skin invade tissue but do not metastasize Some tissues resist invasion – mature cartilate, elastic tissue in arteries
- 15. Properties Local Invasion Sequence of invasion by malignant tumors: Loss of intercellular adherence E-cadherin not produced Cell invasion occurs Cell receptors attach to laminin (glycoprotein in the basement membrane) Cells release type IV collagenase dissolve BM Cell receptors attach to fibronectin in the ECM Cells produce cytokines (stimulate locomotion) and proteases (dissolve connective tissue) Cells produce factors that stimulate angiogenesis (EGF, bFGF)
- 16. Properties Metastasis Benign tumors do not metastasize Malignant tumors metastasize Pathways: Lymphatic spread to lymph nodes – usual for carcinomas Hematogenous Usual for sarcomas Cells entering portal vein liver Cells entering vena cava lungs Seeding – malignant cells exfoliate from surface and implant and invade tissue in a body cavity
- 17. Properties Metastasis Bone metastases Vertebral column Most common metastatic site in bone Due to Batson paravertebral venous plexus Osteoblastic metastases Radiodensities seen on radiograph (eg prostate cancer) Increased serum alk phos reactive bone formation
- 18. Properties Metastasis Bone metastases Osteolytic metastases Radiolucencies on radiographs (eg lung CA) Pathogenesis: Production of substances that activate osteoclasts (e.g. PGE2, IL-1) Production of parathyroid hormone-related protein (e.g. Squamous cell CA in lungs, renal cell CA) Consequences: pathologic fractures, hyper-calcemia
- 19. Properties Metastasis Metastasis often more common than a primary cancer Lymph nodes – metastatic breast and lung CA Lungs – metastatic breast CA Liver – metastatic lung CA Bone – metastatic breast CA Brain – metastatic lung CA
- 20. Acquired neoplastic disorders Autosomal dominant cancer syndrome Retinoblastoma – inactivation of RB suppressor gene Familial adenomatous polyposis - inactivation of APC suppressor gene; colorectal cancer by age 50 Li-Fraumeni syndrome – inactivation of TP53 suppressor gene Hereditary nonpolyposis colon cancer (Lynch syndrome) – DNA mismatch repair genes Breast & ovarian cancer – BRCA1 and BRCA2 genes
- 21. Acquired neoplastic disorders Autosomal recessive syndromes with defects in DNA repair Xeroderma pigmentosum – skin cancer due to UVL (basal cell CA, squamous cell CA) Chromosome instability syndromes – damage by ionizing radiation and drugs Include Fanconi anemia, ataxia telangiectasia, Bloom syndrome
- 22. Acquired neoplastic disorders Familial cancer syndromes No defined pattern of inheritance Cancers (breast, ovary, colon) develop with increased frequency in families Sometimes involves BRCA1 and BRCA2 genes
- 23. Carcinogenesis Types of gene mutation Point mutations – most common type Balanced translocations Other mutations Deletion, gene amplification (multiple copies of a gene), over-expression (increase in baseline gene activity
- 24. Carcinogenesis Genes involved in cancer Proto-oncogenes Involved in normal growth and repair Protein products include: growth factors, growth factor receptors, signal transducers, nuclear transcribers Mutations cause sustained activity of the genes
- 25. Carcinogenesis Genes involved in cancer Suppressor genes (anti-oncogenes) Protect against unregulated cell growth Control G1 to S phase of the cell cycle and nuclear transcription Mutations cause unregulated cell proliferation
- 26. Carcinogenesis Genes involved in cancer Anti-apoptosis genes ( BCL2 family of genes) Protein products prevent cytochrome c from leaving the mitochondria Mutation causes increased gene activity (e.g.overexpression) prevents apoptosis (e.g. B-cell follicular lymphoma) Translocation t(14:18) cause over-expression of BCL2 protein prevent apoptosis of B cells
- 27. Carcinogenesis Genes involved in cancer Apoptosis genes Regulate programmed cell death Example – BAX apoptosis gene Activated by TP53 if DNA damage is excessive Protein product inactivates BCL2 Inactivation of TP53 BAX inoperative no apoptosis
- 28. Carcinogenesis Genes involved in cancer DNA repair genes Examples of DNA repair Mismatch repair genes – correct errors in nucleotide pairing Nucleotide excision repair – excise pyrimidine dimers in UVL-damaged skin Mutation allows cells with non-lethal damage to proliferate increased risk for cancer
- 29. Chemical Carcinogens Polycyclic hydrocarbons in tobacco smoke Most common group of carcinogens in the USA Mechanisms: Direct-acting carcinogens With electron-deficient atoms that react with electron-rich atoms in DNA (e.g. Alkylating agents) Indirect-acting carcinogens Activated by the liver cytochrome P-450 system (e.g. Polycyclic hydrocarbons)
- 30. Chemical Carcinogens Sequence of chemical carcinogenesis Initiation Irreversible mutation Promotion Promoters (e.g. Estrogen) stimulate mutated cells to enter the cell cycle Progression Development of tumor heterogeneity Examples – production of cells that invade or metastasize
- 32. Radiation Ionizing radiation Hydroxyl free radical injury to DNA Examples: AML or CML; papillary thyroid CA; lung, breast or bone cancers Leukemia – most common cancer due to ionizing radiation UV light Formation of pyrimidine dimers distort DNA Examples: basal cell CA (most common), squamous cell CA, malignant melanoma
- 33. Host Defense vs. Cancer Humoral immunity – antibodies and complement Type IV cellular immunity Most efficient mechanism Cytotoxic CD8 T cells – recognize altered class I antigens on neoplastic cells and destroy them Natural killer cells – direct and indirect killing via type II hypersensitivity Macrophages – activated by gamma-interferon
- 34. Cancer Grading Degree of differentiation Low, intermediate, or high grade Nuclear features invasiveness
- 35. Cancer Staging Most important prognostic factor TNM system Progresses from the least to the most important prognostic factor T – tumor size > 2 cm correlates with metastatic ability N – nodal involvement M – extranodal metastases
- 36. Cancer Effects on Host Cachexia (wasting disease) Irreversible catabolic reaction Mechanism: tumor necrosis factor-alpha Secreted from host macrophages and cancer cells Suppresses the appetite center Increases beta-oxidation of fatty acids
- 37. Cancer Effects on Host Anemia Anemia of chronic disease Iron deficiency due to GI blood loss Macrocytic anemia – due to folate deficiency from rapid tumor growth Myelophthisic anemia Anemia related to bone metastasis Immature hematopoietic elements in peripheral blood Teardrop RBCs indicate myelo-fibrosis secondary to bone metastasis
- 38. Cancer Effects on Host Hemostasis abnormalities Increased risk for vessel thrombosis Due to thrombocytosis, increased synthesis of coagulation factors (fibrinogen, factors V and VIII) Release of pro-coagulants from cancer cells (e.g. Pancreatic CA) DIC due to release of tissue thromboplastin from cancer cells
- 39. Cancer Effects on Host Paraneoplastic syndromes Distant effects of a tumor that are unrelated to metastasis – may predate the onset of metastasis Occur in 10-15% of cancer patients Involve multiple organ systems and mimic metastatic disease May involve ectopic secretion of hormone
- 40. Cancer Effects on Host Syndrome Associated cancer Comment Acanthosis nigricans Stomach carcinoma Black verrucoid-appearing lesion Eaton –Lambert synd. Small cell CA of lung Myasthenia gravis-like symptoms Hypertrophic osteoarthropathy Bronchogenic CA Periosteal reaction of distal phalanx Nonbacterial thrombotic endocarditis Mucus-secreting pancreatic and colorectal carcinomas Sterile vegetations on mitral valve Seborrheic keratosis Stomach carcinoma Sudden appearance of numerous pigmented seborrheic keratoses (Leser-Trelat sign) Superficial migratory thrombophlebitis Pancreatic carcinoma Release of pro-coagulants (Trosseau sign)
- 41. Cancer Effects on Host Disorder Associated cancer Ectopic hormone Cushing syndrome Small cell CA of lung, medullary thyroid CA ACTH Gynecomastia Choriocarcinoma (testis) hCG Hypercalcemia Renal cell CA, primary SCCA lung, breast CA PTH-related protein Hypocalcemia Medullary thyroid CA Calcitonin Hypoglycemia Hepatocellular CA Insulin-like factor Hyponatremia Small cell CA of lung ADH Secondary polycythemia Renal cell and hepato-cellular CA erythropoietin
- 42. Tumor Markers Biologic markers Include hormones, enzymes, oncofetal antigens, glycoproteins Identify tumors Estimate tumor burden Detect recurrence
- 43. Tumor Markers Tumor marker Associated cancer AFP Hepatocellular CA, yolk sac tumor (endodermal sinus tumor) of ovary or testis Bence Jones protein Multiple myeloma, Waldenstrom’s macroglobulinemia (represent light chains in urine) CA 15-3 Breast carcinoma CA 19-9 Pancreatic carcinoma CA 125 Surface-derived ovarian cancer (e.g. Serous cystadenocarcinoma) CEA Colorectal and pancreatic carcinomas PSA Prostate carcinoma (also increased in prostate hyperplasia)