Neoplasia & Malignant Neoplasia PDF

Neoplasia: Malignant neoplasia: Uncontrolled & irreversible proliferation of cells, even though the Tumor cells are poorly differentiated, meaning they only slightly or not irritant factor is already absent, which is caused by...

Neoplasia: Malignant neoplasia: Uncontrolled & irreversible proliferation of cells, even though the Tumor cells are poorly differentiated, meaning they only slightly or not irritant factor is already absent, which is caused by the failure of the at all resemble the tissue of origin. regulation mechanism & resulting in benign or malignant neoplasm. Features: A neoplasm consist of 2 components:  Fast growth & more aggressive, due to higher rate differentiation. Parenchyma of neoplastic cells & Supporting Stroma.  Poorly demarcated margins from surrounding tissue. Diagnosed by physical examination, radiography & a biopsy or autopsy.  Destructive local infiltration. Risks of developing neoplasia are sporadic:  Usually non-encapsulated.  Statistical risk: depends on country, race, sex, age, environment etc.  Ability for metastasizing, spreading through lymph, blood & cavities.  Familial risk: if there are more than 3 cases of the same cancer type Local Malignant neoplasia: in a family, not associated with one specific gene. Neoplasia that is non-metastasizing, but is destructive to local tissue.  Genetic risk (most severe): associated with mutation in specific genes. E.G Basal cell carcinoma, which is the most common malignancy of skin. High risk for malignancy- BRCA1/BRCA2 & suppressor genes, like P53. Metastasis: Causes of death: The spreading of malignant cells to distant organs or tissues.  Cachexia: weight loss, weakness & anemia - the end stage of disease. Most common metastatic is in liver & lungs due to their filtration action  Secondary infection: Usually pneumonia. so they get blood from all over the body & also brain & skeleton.  Obliteration of vital organs: by the tumor. Some tumors have the tendency to metastasis to unusual places: Benign neoplasia:  Clear cell carcinoma of kidney - tongue, breast & mandibula. Tumor cells are well differentiated, meaning they resemble origin tissue.  Melanoma malignum – hearth muscles & tongue. Features: Spreading Routs:  Slow growth & not aggressive, due to low rate of cell division.  Lymphatic Spread: The most common, Favored by carcinomas.  Well demarcated, with defined margins from the surrounding tissue.  Hematogenous Spread: Favored by sarcomas, which usually ignore  Commonly encapsulated, but the capsule isn't a critical criterion. lymphatic & spread to blood vessels relatively quickly.  Non-metastasizing (no spreading).  CSF Space: Less common, e.g medulla blastoma. Benign neoplasm can show clinical malignancy:  Contact Spreading: From lip to lip / eyelid to eyelid.  Compression of surrounding tissues: Can destroy important structures.  Cavities Spreading: e.g ovarian serosal carcinoma spreads within the E.G meningioma in skull, eventually increasing intra cranial pressure. peritoneal cavity & is easily fragmented.  Endocrine functions: Secrete active substances. E.G insulinoma which is  Nerve Sheath infiltration: e.g pancreatic adenocarcinoma. a benign adenoma secreting insulin & causing hypoglycemia. Characterized by persistent back pain & bad survival rate. Dysplasia: Epidemiology of cancer: A disturbed architecture of epithelium, due to chronic stress stimuli. Common malignancies depending on Sex: Dysplasia is reversible if the stress is removed, but if the stress persists, In women: Brest carcinoma, Lung carcinoma, Colon adenocarcinoma. the dysplasia will progresses into irreversible neoplasia. In men: Prostate carcinoma, Lung carcinoma, Colon adenocarcinoma. Dysplasia is caused by proliferation of pre-cancer cells, after prolonged Age: pathological stimuli causing hyperplasia or metaplasia. The frequency of cancer increases with age, mostly between 55-75yr. Morphology: Lethal in children: Leukemia, CNS tumors, lymphomas & sarcomas.  Pleomorphism, with cells in different shapes & sizes. Race / Behavior:  Failure of epithelial cells to mature & Loss of tissue orientation. Japan: Increased gastric carcinoma due to smoked seafood.  Increased nuclear-cytoplasmic ratio & clumped chromatin Less prostatic carcinoma due to soya sauce in diet.  Abnormal variations in nuclear size & hyperchromatism. Africa: Hepatocellular carcinoma due to aflatoxin aspergillus in nuts.  Increased number of mitotic figures. Carcinoma In Situ [CIS]: Classification: Irreversible & severe dysplastic changes, which involves the entire Mild / Moderate / Severe (WHO): thickness of epithelium, but doesn't penetrate the basement membrane, Mild/Moderate: Don't involve the entire epithelium & usually reversible. meaning that the carcinoma is still confined to the epithelium. Severe: Involves the entire thickness of epithelium & usually irreversible. It is an early stage of neoplasia, called pre-invasive neoplasm. High Grade / Low Grade: It is always malignant, but has no potential for metastasis. Low Grade: Exhibit many changes, but still resembles the original tissue. 4 Synonyms High Grade: Exhibit more severe cytological & architectural changes. 1. High grade dysplasia. 2. Pre-invasive carcinoma. Cervical Intraepithelial neoplasia (CIN): 3. Intraepithelial carcinoma. 4. Zero grade carcinoma. Associated with HPV infections & Detected by a Pap smear. Morphology: It may progress into invasive squamous cell carcinoma if left untreated.  Loss of organized epithelial architecture. CIN-1: low-grade, CIN-2: reversible high-grade  Still intact basement membrane. CIN-3: Irreversible high-grade = carcinoma in situ.  Irregular nuclei & mitotic figures can be found. Atypia: Treatment: A structural irregular abnormality in a single cell. Local restriction with healthy margins means complete recovery. It may also be present in inflammatory processes, as reactive atypia. Examples: Features: Nuclear pleomorphism, enlargement & hyperchromatism.  Cervical Intraepithelial neoplasia type 3. Pathological mitotic figures, characteristic for malignant process.  Bronchioloalveolar carcinoma- the only form of that can kill directly.  Tumor nomenclature Malignant Tumors = Cancer: Benign tumors: Malignant epithelial tumors = Carcinomas: Benign epithelial tumors: First spread by lymph nodes & later by hematogenous. Papilloma: Neoplasm of surface epithelia (e.g squamous cell papilloma). Squamous cell carcinoma, Papillary Carcinoma. Adenoma: Neoplasm of glandular epithelium (e.g Thyroid adenoma). Adenocarcinoma: arise from glandular epithelium (e.g lung, gastric). Benign mesenchymal tumors: Clear cell carcinoma of kidney is the exception: Named by the tissue of origin +” -oma”. It prefers hematogenous spread & not lymphatic spread. Osteoma (bone) Malignant mesenchymal tumors = Sarcomas: Lipoma (adipose tissue) Spread by blood vessels relatively quickly (hematogenous spread). Fibroma (connective tissue) Osteosarcoma (bone) Leiomyoma (smooth muscle) liposarcoma (adipose tissue), Benign Neuroectodermal tumors: Rhabdomyosarcoma (skeletal m.) Nevus: Neoplasia & hyperplasia of melanocytes. Fibrosarcoma (connective tissue) Glioma: derived from the glial cells of the brain or the spine Leiomyosarcoma (smooth muscle) Benign neuroendocrine tumors: Malignant Neuroectodermal tumors: Secrete polypeptide hormones or active amines Melanoma: derived from melanocytes in skin. Insulinoma: Derived from β-cells of pancreas & secrete insulin. Astrocytoma: derived from astrocytes in the brain / spinal-cord. It causes hypoglycemia & can kill the patient before proper diagnosis. Glioblastoma: derived from glial cells in the brain / spinal-cord. Germinal tumors: Malignant neuroendocrine cells tumors: Teratoma: Secrete polypeptide hormones or active amines. Usually Benign neoplasm, derived from all 3 germ layers. Small cell lung carcinoma: Secrete ectopic ACTH & ADH. Typically form in the ovary, testicle, or coccyx. Malignant Hematopoietic cells tumors: Can transform into Malignant Teratoma. Lymphoma: Derived from lymphocytes in lymphoid tissue. Leukemia: Derived from bone marrow cells. Multiple Myeloma: Derived from plasma cells of bone marrow. Characterized by leaving empty spaces in the skeleton. Gastric Neoplasms: Ovarian Neoplasms: Malignant Epithelial gastric tumors: Epithelial ovarian tumors:  Gastric Adenocarcinoma (95%): All of them can be benign, borderline & carcinomas May be local / diffused.  Serous: Most common, may contain papillary projection. MALT lymphoma:  Mucocinous: Rare. Linked to helicobacter pylori.  Endometrioid Malignant mesenchymal gastric tumors:  From transitional epithelium, like Brenner tumors  GI stromal tumor Stroma Ovarian tumor:  Gastric Sarcoma  Malignant: Granulosa cell tumor. Malignant neuroendocrine gastric tumors:  Benign: Ovarian fibroma.  Carcinoid Tumor: Germ-cells ovarian tumor: Commonly located in GIT & secrete serotonin. Benign / malignant Teratoma tumor. Skin Neoplasms: Lung Neoplasms: Malignant skin tumors: Malignant Epithelial lung tumors:  Basal cell carcinoma:  Lung squamous cell carcinoma  Melanoma:  Small cell lung carcinoma Benign skin tumors:  Mesothelioma  Squamous cell papilloma:  Lung Adenocarcinoma  Nevus: Malignant Primary lung lymphoma: Linked to oncogenic Epstein-Barr virus (EBV). Prophylaxis of cancer: Therapy of cancer: Prevention (primary): The purpose of treatment can be to Cure / to Control / Palliative care. By modifying life style factors: Surgery: Normal weight, exercise, no smoking, minimal UV exposure, Resecting the tumor with healthy margin is ideal in early stages. Moderate alcohol consume, protective vaccination against HPV & Radiotherapy: internal / external. Prophylaxis mastectomy in case of BRCA gene. Chemotherapy: usually in more advanced stages. Early detection (Secondary): Immunotherapy / Hormonal therapy / Biological therapy. By screening test, PAP smear, mammography breast & colonoscopy. Grading: Staging: Histopathology assessment of differentiation & architectural changes, Indicates how clinically advanced a tumor is, therefore allowing us to meaning how much the cells resembles the tissue of origin. predict the malignancy prognosis & to administer adequate treatment. Important for determining malignancy prognosis: well-differentiated This indicator allows assessment of size & spread of the malignancy & cancers have better prognosis than poorly differentiated. Helps to calculate 5-year survival rate. Grading:  Early stage, means good prognosis & usually treated by surgery.  G1:  Advanced stage, means bad prognosis & require aggressive treatment Well Differentiated, resembles the origin tissue & slow growing. like hormonal / chemo therapy, but no surgery. More resistant to chemo, so it is usually treated by surgery. Staging (TNM):  G2: T = Indicates the tumor size or depth of invasion (depending on tissue): Moderately Differentiated. For example, in breast carcinoma T indicates the size of tumor.  G3: In the GI, T indicated depth of invasion (because it consist of layers). Poorly differentiated, less resemblance, fast growing & more solid.  T0: denote in-situ lesion. More vulnerable to chemotherapy, because the cells are young & blastic,  T1-T4: denote larger size or more infiltration into nearby tissues. so they are more responsive to toxins. N = Indicates involvement of Lymph Nodes metastases:  G4:  N0: denote no involvement of lymph nodes. Anaplastic, with loss of differentiation & often more aggressive.  N1-N3: denote increasing number & range of lymph nodes involved. It is impossible to identify the origin of the cells.  N1: denote involvement of local nodes metastasis. Indicators of poor differentiation:  N2: denote involvement of distant nodes metastasis.  Increased pleomorphism: size & shape variations of tumor cells, which M = Indicates Metastases to distant organs: increases with failure of differentiation.  M0: denote no metastasis.  Increased mitotic index: meaning increased cellular proliferation, of  M1-M2: denote the presence & estimated number of metastases. cells undergoing mitosis & containing mitotic figures.  MX: denote more metastases  Enlarged & Hyperchromatic nucleus. Pre-neoplastic Diseases: Non-neoplastic diseases are known to increase the risk of later development of neoplasia if left untreated, like cysts in ovary, thyroid or breast. For example: Squamous metaplasia & dysplasia of the bronchial mucosa, seen in smokers poses a risk factor for lung carcinoma. Another example: Endometrial hyperplasia & dysplasia, due to estrogen stimulation, poses a risk factor for endometrial carcinoma. More examples: Celiac disease which poses a risk for gut lymphoma & Autoimmune thyroiditis which poses a risk for thyroid lymphoma. 5-year survival rate: Paraneoplastic Syndromes: The survival rate for estimating the prognosis of disease during Tumor-associated syndromes, with clinical symptoms that are not diagnosis. It is the percentage of patient with a malignant disease, who directly related to the spread of the tumor (not due to metastasis), survived for 5 years after their initial diagnosis. But are usually connected to a substance that the tumor secrete. It can be used to compare the effectiveness of treatments. They appear in 10% to 15% of patients with cancer. There are 2 ways to estimate the 5-year survival rate: They usually present much earlier than the malignancy diagnosis.  5-year absolute survival rates: The neoplasms most often associated with these syndromes are: The percentage of alive patients, 5-years after their diagnosis. Lung cancers, breast cancers, leukemia & lymphoma.  5-year relative survival rates (more common): The most common paraneoplastic syndromes are: The percentage of patients with a disease alive five years after the  Hypertension: disease is diagnosed, divided by the percentage of the general population Due to clear cell carcinoma of kidney/thyroid & adrenal gland tumor. of corresponding sex and age alive after five years.  Hypercalcemia: 5-year survival rate depends on: Due to PTHrP secretion, by tumors like lung squamous cell carcinoma.  The stage of malignancy, when it is first diagnosed  Cushing's Syndrome & Hyponatremia:  The possible treatments that are available Due to small cell lung carcinoma (oat cell) secreting ACTH & ADH.  The grading & staging - low grade means higher survival rate. ACTH causes increased cortisol secretion from the adrenal cortex & For example, prostatic carcinoma stage-1 has 95% 5-year survival rate, ADH causes increased water reabsorption & hyponatremia. while prostatic carcinoma stage-4 has only 20%.  Migratory thrombophlebitis & Trousseau's Syndrome: Examples: Due to pancreatic adenocarcinoma, causing hypercoagulability & clots.  Lung Carcinoma: 10%, meaning 1 out of 10 patients will survive the These blood clots are causing inflammation of veins. 5-years, while 9 will die during that 5-year period.  Polycythemia:  Pancreatic adenocarcinoma: 1.8% Due to erythropoietin secretion, by tumors like renal cell carcinoma  Hodgkin lymphoma: 90%  Hypoglycemia:  Non-Hodgkin lymphoma: 70% Due to Insulin secretion, by insulinoma tumors.  Osteosarcoma: 60%  Pheochromocytoma:  Leiomyosarcoma: 40% Due to Catecholamine secretion from various tumors. Gallbladder carcinoma & glioblastoma multiform: These types of tumors do not get estimated by the 5-year survival rate because their survival rate is usually between 12 weeks to 6 months. Carcinogens: Oncogenic viruses (biological carcinogens): Agents that cause genetic damage & induce neoplastic transformation. Viruses which are linked to development of malignancy. Indirect-acting carcinogens: RNA Oncogenic viruses: Pro-carcinogens which require metabolic conversion to become active.  Human T-cell leukemia virus (HTLV-1): Direct-acting carcinogens: Causes adult T-cell leukemia/lymphoma. Already active & mostly weak carcinogens, which directly modify DNA. DNA Oncogenic viruses; Chemical carcinogens:  Epstein-Barr virus (EBV):  Alkylating agents: used in chemotherapy & cause leukemia/lymphoma. Causes Burkitt lymphoma, Hodgkin Lymphoma, Nasopharyngeal &  Cigarette’s: the most common carcinogen worldwide. gastric carcinomas & Primary CNS lymphoma in immunocompromised. Causes carcinoma of esophagus, lung, kidney, bladder & oropharynx.  Hepatitis B + C virus (HBV+HCV)::  Asbestos: causes lung carcinoma & mesothelioma. Causes Hepatocellular carcinoma that starts from liver cirrhosis.  Alcohol: causes pancreatic carcinoma & hepatocellular carcinoma.  Human papilloma virus (HPV)  Aflatoxin: derived from aspergillus & causes hepatocellular carcinoma. Causes benign squamous papilloma (warts) & squamous cell carcinomas  Aromatic amines: in rubber & dye industry, causes bladder carcinoma. mainly in the cervix, but also in vulva, vagina, penis, anus & oral cavity.  Seafood: causes gastric carcinoma.  Herpes virus (HHV8): Physical Radiation Carcinogens: Causes Kaposi sarcoma.  UV ray: the most carcinogenic, particularly in light-skinned people. Bacterial Carcinogens: Increase the risk of basal cell carcinoma & melanoma of the skin.  Helicobacter pylori:  Ionizing Radiation (X-ray): mostly effect cells in G2 phase & Cause Causes gastric adenocarcinoma & gastric lymphomas (MALT). skin carcinoma, chronic myelogenous & acute Myeloid Leukemias.  Radioactive iodine: Cause thyroid carcinoma. Genetic Oncogenes: Are created by mutations in proto-oncogenes, which are involved in regulating protein production for cell growth & cell differentiation. When they are mutated, it leads to overexpression of signaling proteins & growth factors, thus causing uncontrolled cellular proliferation. Oncogenes can be divided to: Growth factors, Growth factor receptors & Signal transduction proteins Examples:  BRAF: Melanoma, Non-Hodgkin's lymphoma & papillary thyroid carcinoma.  HER2: Breast & ovarian carcinomas. KRAS: Colon, lung & pancreatic tumors  C-ABL: Chronic myeloid leukemia & acute lymphoblastic leukemia. BCR-ABL: on Philadelphia chromosome, also causes CML & ALL. Tumor suppressor genes: Genes that normally regulate & inhibit cell proliferation, thus prevent uncontrolled growth. Abnormalities in these genes will lead to failure of growth inhibition, which will lead to Neoplasia. P53: Responsible for cell cycle arrest & apoptosis in response to DNA damage. A mutation will cause a decrease in cell cycle regulation & make it impossible to Initiates apoptosis. P53 mutations are found in almost every type of cancer, including carcinomas of the lung, colon & breast.  Li-Fraumeni syndrome: Results from autosomal hereditary p53 mutations. Characterized by a higher risk of developing malignancies at an early-age, like sarcoma, breast carcinoma & leukemia. RB gene: Responsible for regulation of cell cycle. A mutation will lead to increased E2F transcription factor activity, so the cells can enter the cell cycle without a growth stimulus. RB mutations are found in sporadic cancers, like Retinoblastoma, osteosarcoma & breast carcinoma. BRCA1/2: Responsible for the repair of double-stranded breaks in DNA. BRCA mutations are found in breast carcinomas, posing 25% of familial cases & also found in ovarian carcinomas & prostate cancer. APC gene: Responsible for down-regulation of growth-promoting signals, thus prevent unregulated cell proliferation. A mutation will lead to familial adenomatous polyposis in the colon, with high risk of malignant transformation into colon carcinoma. APC mutations are found in 70% - 80% of sporadic colorectal cancers. BCL2: Anti-apoptotic protein – prevent programmed cell death by limiting the exit of cytochrome c from mitochondria. BCL2 overexpression mutations are found in more than 85% of follicular B-cell lymphomas. Retinoblastoma: Liposarcoma: The most common primary intraocular (eye) malignancy in children. Malignant tumor of mesenchymal origin, arising from adipose tissue. It is caused by a deletion/inactivation mutation in the RB tumor Located in deep soft tissues & distinguished by the presence of lipoblasts. suppressor gene, leading to the loss of function of cell cycle regulation It is the most common sarcoma (25-30%) & occurs mainly in adults. & increased E2F transcription factor activity, triggering more mitosis. Lipoma: Classification: Benign tumor of mesenchymal origin, arising from adipose tissue.  Single / Multifocal: Are soft & painless & they usually occur just under the skin. Meaning one or several tumors within the eye. Typically occur between 40-60yr & more often in males than females.  Unilateral / Bilateral: Generally not associated with a future risk of cancer. Meaning in one eye or in both.  Hereditary / Non-Hereditary: Fibrosarcoma: Non-Hereditary (60%) - Sporadic: Malignant tumor of mesenchymal origin, arising from connective tissue. Usually unilateral due to local mutation & only one sibling is affected. Built from immature proliferating fibroblasts. Hereditary / Congenital (40%): It invades long or flat bones, such as the femur, tibia & mandible. Usually bilateral & with few siblings are affected. Fibroma: At higher risk for developing osteosarcoma & other soft tissue tumors. Benign tumor of mesenchymal origin, arising from connective tissue. Metastases is observed in: It is grey, small, firm & encapsulated. Cervical lymph nodes, CNS, skull & distal bones. It is built from closely packed spindle shape fibroblasts & collagen. Treatment: It mostly arises in ovaries & along nerve trunks. Removal of the eyeball, to prevent infiltration to the optic nerve. Leiomyoma: Myosarcoma / Leiomyosarcoma: Benign tumor of mesenchymal origin, arising from smooth muscles. Malignant tumor of mesenchymal origin, arising from smooth muscles. It's the most common benign tumor in women, arising from the uterus Located in deep soft tissues, almost always arise de novo from the uterus myometrium & is usually pre-menopausal & multiple. myometrium & is usually post-menopausal & solitary (only one). It is white, variable in size, firm & with Well delineated borders. It is yellow, large, soft, invasive & with often nodular borders. Signs: Frequent periods & urination, sudden pelvic pain & infertility. Distinguished by atypia, high mitotic rate & necrosis in the tumor. Metastases can occur in the lungs & the 5-year survival rate is 40%.