Neoplasia Notes PDF

Learning Outcomes Define dysplasia. Describe the features of dysplasia. Define neoplasm. Classify tumors. Describe the characteristics of benign and malignant neoplasms. Identify carcinogenic agents. Explain the effects of tumors on the host. Describe the grading and staging of cance...

Learning Outcomes Define dysplasia. Describe the features of dysplasia. Define neoplasm. Classify tumors. Describe the characteristics of benign and malignant neoplasms. Identify carcinogenic agents. Explain the effects of tumors on the host. Describe the grading and staging of cancer. Explain the laboratory diagnosis of cancer.  Dysplasia Dysplasia. Disorderly proliferation. Dysplastic epithelium shows loss of cell uniformity (pleomorphism) and architectural orientation. Dysplastic cells exhibit abnormally large, hyperchromatic nuclei. Mitotic figures are more abundant than usual and appear in the superficial epithelium, an abnormal location. Precancerous condition. Pathological hyperplasia and epithelial metaplasia can progress to dysplasia.  Dysplasia Cont. Mild to moderate dysplasia sometimes regresses completely if inciting causes are removed. Carcinoma in situ Severe dysplasia involves the entire thickness of the epithelium. Dysplastic cells do not penetrate basement membrane. Invasive cancer. Cancer cells penetrate basement membrane. ✓ Human papilloma virus type 16 - Cervical dysplasia ✓ Ultraviolet light. Squamous cell dysplasia in skin  Neoplasm Neoplasm. An abnormal mass of tissue the growth of which exceeds and is uncoordinated with that of normal tissues and persists in the same excessive manner after cessation of the stimuli which evoked the change. British oncologist R.A. Willis  Neoplasia Cont. All tumors have two basic components: Parenchyma, made up of transformed or neoplastic cells. Stroma, the supporting host-derived, nonneoplastic connective tissue, inflammatory cells, and blood vessels. The stroma is crucial to the growth of the neoplasm, since it provides the blood supply.  Nomenclature of Tumours Benign Tumour. Suffix: ‘-oma’ Malignant Tumours arise from: ¬ Epithelial cells derived from all three germ cell layers: Carcinoma ¬ Mesenchymal tissue: Sarcoma ¬ Cells of the blood : Leukemias or Lymphomas ¬ Suffix: ‘-oma’ (exceptions include lymphoma, mesothelioma, melanoma, and seminoma) Nomenclature of Tumors Characteristics of Benign and Malignant Neoplasms Differentiation Local invasion Distant metastasis  Differentiation Differentiation. The extent to which neoplasms resemble their cells of origin. Benign neoplasms are composed of well-differentiated cells, closely resemble the tissue of origin. Mitoses are usually rare and are of normal configuration. Malignant neoplasms exhibit a wide range of parenchymal cell differentiation, from well-differentiated cells to poorly differentiated or undifferentiated cells (anaplastic cells). Anaplasia. Lack of (structural or functional) differentiation. A hallmark of malignant tumors. Features of Anaplastic Cells Cellular and nuclear pleomorphism ¬ Large hyperchromatic nuclei Atypical Mitoses ¬ (Increased nuclear-to-cytoplasmic ratio is 1:1). ¬ Prominent single or multiple nucleoli. Numerous atypical mitoses – Triopolar or quadripolar mitotic spindles Tumour giant cells Loss of polarity (normal orientation). Tumour giant cells  Local Invasion Benign tumors grow and expand slowly as cohesive, expansile masses. They are well-circumscribed and remain localized. Benign tumours compress surrounding normal tissue → Pressure atrophy ¬ Fibrous capsule – makes the tumour discrete, moveable (nonfixed), readily excisable by surgical enucleation. ¬ No capsule – leiomyoma, haemangioma Malignant tumors often (but not always) grow rapidly. They are poorly circumscribed and progressively infiltrate, invade, and destroy the surrounding normal tissues. Invasiveness is the feature that most reliably distinguishes cancers from benign tumors.  Malignant Tumour Cont. Malignant tumours  Stimulate fibroblast to produce collagen  Convert into dense fibrous tissue  Fix the malignant tumour to surrounding structures Cancers may induce stromal responses.  Malignant Tumour Cont. Metastasis Metastasis. The spread of a tumor to sites physically discontinuous with the primary tumor. A hallmark of malignant tumors. All cancers can metastasize except basal cell carcinoma Pathways of Metastasis 1. Blood spread 2. Lymphatic spread 3. Seeding within body cavities 4. Iatrogenic spread: Spread of tumour cells on surgical instruments  Malignant Tumour Cont. Blood Spread More typical of sarcoma. Thin-walled veins > Thick-walled arteries Common sites: Liver, lungs, brain, bone, and adrenals Rarely sites of secondary deposits: Skeletal muscle and spleen. Liver. Jaundice, hepatomegaly  Malignant Tumour Cont. Lung: Cough, dyspnoea, and haemoptysis  Malignant Tumour Cont. Brain Increased intracranial pressure Headache Convulsion  Malignant Tumour Cont. Bone: Pain, fracture Vertebral column - Cancer (Thyroid and prostate)  Malignant Tumour Cont. Lymphatic Spread More typical of carcinoma. Enlarged lymph node is due to: ✓ Spread and growth of cancer cells. ✓ Reactive hyperplasia (Tumor-specific immune response).  Malignant Tumour Cont. Tumour emboli  Afferent lymphatic vessel  Sinuses of the regional lymph nodes  Invade the parenchymal tissue of the lymph node  Efferent lymphatics vessel  Thoracic duct  Systemic circulation  Malignant Tumour Cont. Breast cancer  Axillary lymph node  Lymph node enlargement  Malignant Tumour Cont. Seeding within Body Cavities Cancer cells exfoliate from the surface of an organ  Muscle Spread across the body cavity: wasting pleura, pericardial, peritoneal, subarachnoid, and joint spaces  Seed on the surface of body cavities Ascites and organs  Malignant Tumour Cont. Carcinoma of the ovary or appendix → Spread to peritoneum → Ascites  Carcinogenic Agents 1) Chemicals Carcinogenic agents 2) Radiation  Genetic damage 3) Microbes  Carcinogenesis Oncogenes: Her2/neu, RAS Tumour suppressor genes: p53, BRCA1 and 2 Genes that regulate apoptosis Genes that regulate interactions between tumour cells and host cells  1) Chemical Carcinogens Direct-Acting Agents Weak carcinogens. Do not require metabolic conversion to be carcinogenic. E.g., Cancer chemotherapeutic drugs (e.g., alkylating agents) Indirect-Acting Agents (Procarcinogens) Require metabolic conversion become active carcinogens. The carcinogenic products are called ultimate carcinogens. E.g., Polycyclic hydrocarbons, β-naphthylamine, benzo[a]pyrene, aflatoxinB1, nitrates, vinyl chloride, arsenic, nickel, chromium, insecticides, fungicides, and polychlorinated biphenyls  Carcinogens and associated cancers Chemical Cancer Alkylating agent Acute myeloid leukaemia AflatoxinB1 Hepatocellular carcinoma Arsenic Lung and skin cancer Asbestos Lung, oesophagus, stomach, and colon cancer; mesothelioma Benzene Acute myeloid leukaemia Cadmium Prostate cancer Chromium Lung cancer Nickel Lung and oropharyngeal cancer Nitrosamine Oesophagus and stomach cancer Radon Lung cancer Vinyl chloride Hepatic angiosarcoma Occupational exposure The initiation-promotion sequence of chemical carcinogenesis. Initiators or mutagenic chemicals have highly reactive electrophile groups that damage DNA. Promoters (e.g., phorbol esters, hormones, phenols, certain drugs) are not mutagenic. They stimulate the proliferation of initiated (mutated) cells.  2) Radiation Source. UV rays of sunlight, radiographs, nuclear fission, radionuclides Thyroid, breast, colon, and lung cancer; leukaemia UV rays - Skin cancers (squamous cell carcinoma, basal cell carcinoma, melanoma) Invasive squamous cell Basal cell carcinoma Melanoma carcinoma  3) Microbes Microbes Cancer Epstein-Barr virus Burkitt lymphoma, nasopharyngeal carcinoma Hepatitis B virus Hepatocellular carcinoma Hepatitis C virus Hepatocellular carcinoma Human papillomavirus Squamous cell carcinoma of the cervix, anogenital region, and oropharynx Human T-cell leukemia virus type 1 Adult T-cell leukemia/lymphoma Kaposi sarcoma herpesvirus Kaposi sarcoma (human herpesvirus-8) Merkel cell virus Merkel cell carcinoma Helicobacter pylori Gastric adenocarcinoma and gastric lymphoma Schistosoma haematobium Bladder cancer Liver flukes Cholangiocarcinoma  Acquired predisposing conditions to cancer Chronic inflammation Precancerous conditions - Pathological hyperplasia, epithelial metaplasia, dysplasia Immunodeficiency state: T-cell immunodeficiency Incidence of cancer increases with age due to Accumulation of somatic mutation in cells. Decreased host immune response. Interactions between environmental factors and genetic factors may be important determinants of cancer risk. Chronic Inflammatory States and Cancer Inherited Predisposition to Cancer  Clinical Aspects of Neoplasia Effects of tumor on the host. Grading and staging of cancer. Laboratory diagnosis of neoplasms.  Effects of Tumor on the Host Location Benign tumours compress the surrounding normal tissue. E.g., Small pituitary adenoma can compress the surrounding normal tissue → Hypopituitarism Malignant tumours invade and destroy the surrounding normal tissue. E.g., A small cancer within the common bile duct → Biliary tract obstruction Tumour arise in endocrine gland. Functioning tumour → Increased hormone production E.g., Adenoma and carcinoma of  cells of the pancreatic islets of Langerhans → Hyperinsulinism Adenoma and carcinoma of the adrenal cortex → Cushing syndrome Non-functioning tumour → Decreased hormone production Leiomyoma of uterus compress Uterine cavity - Infertility, abortion Adjacent organs - Urinary frequency Malignant and benign tumors may cause injury through ulceration of surfaces → Bleeding and infection Breast cancer → Invasion to skin → Ulcer → Infection  Malignant Tumour Cont. Growth pattern of GIT cancer Polypoid and infiltrative growth - Obstruction - vomiting, abdominal distension, visible peristalsis, constipation Ulcerative - Bleeding (haemetemesis, melena), infection  Malignant Tumour Cont. Cancer Cachexia A common complication of advanced cancer. Progressive loss of body fat and lean body mass with profound weakness, muscle wasting, anorexia, and anemia. Tumour necrosis factor (TNF) and cytokines produced by macrophages or by the tumor cells.  Malignant Tumour Cont. Paraneoplastic Syndrome Defined by the presence of symptoms that are not explained by tumor spread or by release of hormones appropriate to the tissue. Appear in 10% to 15% of patients with cancer. The earliest manifestation of occult neoplasm. May produce significant clinical illness or even be lethal. May mimic metastatic disease and confound treatment. Cushing syndrome Adrenocorticotropic hormone Lung and pancreas cancer Hypercalcaemia Parathyroid hormone-related protein Breast and lung cancer Venous thrombosis Hypercoagulability Cancer Nonbacterial thrombotic endocarditis Clubbing of the fingers Unknown Lung cancer Hypertrophic osteoarthropathy  Comparisons Between Benign and Malignant Tumors Characteristics Benign Tumors Malignant Tumors Differentiation Well differentiated Lack of differentiation (anaplasia) Rate of growth Usually slow Usually rapid Rare and normal mitosis Numerous and abnormal mitosis Boundaries Circumscribed or well-demarcated margin, Irregular or ill-defined margin and non- often encapsulated encapsulated Relationship to Compresses normal tissue. Invades and destroys normal tissues. surrounding Do not invade or infiltrate surrounding tissues normal tissues. Spread (the most Remains localised Spread via lymphatics, blood vessels, direct important feature) seeding of body cavities and surfaces (metastases) Effects Produced Destroys structures, causes bleeding, forms by pressure on vessels, nerves, tubes, organs strictures by excess production of substances, e.g. hormones.  Grading and Staging of Cancer Clinical staging is of greater clinical value than tumour grading. Grading of a cancer Determined by cytologic appearance. Based on the degree of differentiation of the tumor cells. The number of mitoses, extent of tumor necrosis, and the presence of architectural features (e.g., loss of gland formation and replacement by solid sheets of cells). Range from two categories (low grade and high grade) to five categories. Poorly differentiated = Aggressive behavior Clinical Staging Tumor staging (extent of tumor) is determined by surgical exploration or imaging. The staging of solid cancers is based on 1) The size of the primary lesion. 2) The extent of its spread to regional lymph nodes. 3) The presence or absence of metastases.  Laboratory Diagnosis of Neoplasms 1) Morphologic Methods Histology Cytology – Fine-needle aspiration of tumors – Cytologic (Papanicolaou) tests Immunohistochemistry Flow Cytometry 2) Tumour Markers 3) Molecular Diagnosis Clinical and radiologic data are invaluable for optimal pathologic diagnosis.  Histology  Biopsy of the mass or specimen must be adequate, representative, and properly preserved.  No area of haemorrhage and necrosis  Routine - Haematoxylin and Eosin stain  Neoplastic cells and supporting tissue.  Cytology Cancer cells are less cohesive and shed into fluid or secretion. Fine needle aspiration of tumours A minimally invasive approach that can be performed in the clinic setting. Palpable organs, e.g., breast, thyroid gland, lymph nodes, and salivary glands. Deep structures (image guidance), e.g., liver, pancreas, and pelvic lymph nodes. Cytologic (Papanicolaou) tests Most widely to detect neoplasia of the uterine cervix. Natural body secretions, e.g., urine (prostate, bladder), sputum(lung)  Immunhistochemistry Use specific antibody to identify tissue type. 1) Diagnosis of undifferentiated carcinoma rather than lymphoma. Cytokeratin (+) Cytokeratin (-) Carcinoma Lymphoma 2) Determine the site of origin of metastatic tumors. ✓ Prostatic specific antigen (+): Carcinoma of the prostate ✓ Thyroglobulin (+): Carcinoma of the thyroid 3) Prognostic or therapeutic significance ✓ Breast cancer: ‡ Estrogen receptor(+) - Good prognosis & response to hormonal Rx ‡ Her2/neu (+) - Ab block Her2/neu receptor ER (+) Breast cancer  Flow Cytometry Used routinely in the classification of leukemias and lymphomas.  Tumour Markers Biochemical assays for tumor-associated enzymes, hormones, and other tumor markers in the blood. Screening tests. Monitoring the response to therapy. Detecting disease recurrence. Cannot be utilized for definitive diagnosis of cancer. Tumour marker Cancer Prostate specific antigen (PSA) Prostatic carcinoma Carcinoembryonic antigen (CEA) Colon, pancreas, stomach, and breast cancer  fetoprotein (AFP) Hepatocellular carcinomas, yolk sac tumor, and embryonal carcinoma Cancer antigen 125 (CA-125) Fallopian tube, ovary, and colon cancer Cancer antigen 19-9 (CA-19-9) Pancreas, gastrointestinal and hepatobiliary tract, and ovary cancer Cancer antigen 15-3 (CA-15-3) Breast cancer  Molecular Diagnostics and Cytogenetics 1) Diagnosis of cancer: BCR-ABL: chronic myeloid leukaemia 2) Prognosis of cancer: HER-2/NEU: poor prognosis 3) Detection of minimal residual disease 4) Diagnosis of hereditary predisposition to cancer: BRCA-1 and BRCA-2 in breast cancer 5) Therapeutic decision-making. Thank You