AUTONOMOUS GROWTH Consequence of germline or somatic mutations. Common in tissues with rapid turnover 1. Tissues exposed to environmental agents Epidermal or lining epithelial tissues which is why the majority of malignancies encountered are termed CARCINOMA (malignancy of epithelial tissue)2. Tissues whose proliferation is hormone dependent i.e. breast and prostate are under hormonal control of estrogen and testosterone respectively. The growth of cancer is expressed in terms of doubling time.o Time it takes for the tumor to double its size o This can determine the rate of progression and the aggressiveness of the tumor The shorter the doubling time, the more aggressive the tumor tends to be The longer the doubling time, the less aggressive the tumor

GOMPERTZIAN TUMOR GROWTH

Tumor cell growth is Gompertzian (s-shaped) with 3 phases:

Growth curve 1. Lag phase – Slow growth potential Tumor cells are small in number Small amount of growth factors Low nutrient supply (due to underdeveloped blood supply)

2. Log phase – Rapid proliferation phase Once hypoxia (stimulus for blood vessel proliferation) sets in, blood vessels develop and growth becomes logarithmic Phase targeted by agents that are cytotoxic in nature. DNA is a robust molecule and its double helix structure protects it. DNA is only vulnerable when it is open and unwound which only happens during the process of replication.

3. Plateau phase – Terminal growth phase Cells become big enough that they start to outstrip their blood supply. Apoptosis sets in to conserve resources.

Net rate of growth is flat or zero. Number of cells growing = number of cells dying or sent to resting phase Relative insensitivity to chemotherapy because of slow replication.Need to combine modalities to debulk the tumor. Must be allowed to go back to the log phase before you institute chemotherapyJunction between lag and log phases – cells slowly grow and proliferate - earliest time for cancer to be clinically detected

CONSEQUENCES OF AUTONOMY

Results in formation of a mass Anaplasia - unregulated growth results in architectural disorganization; main histologic presentation in most cancer patients. Several histological abnormalities – leads to impairment of normal differentiation and organ function MICROSCOPIC APPEARANCE OF CELLS Malignant cells Irregular shape cells and their nuclei are very large. They have variations in cell size and they lose their specialized features.

CARCINOGENESISA state of mutation as an effect of the external environment; process by which you create malignancy from an environmental cause.

Two Phases of Carcinogenesis1. Initiation Rapid, genotoxic, irreversible effect Results in mutation in DNA or an initiated cell Requires at least one round of cell division Normal cells are exposed to a carcinogen o Direct-acting carcinogens o Indirect-acting carcinogens or procarcinogensProcarcinogen → Cytochrome p450 →Ultimate carcinogen

May not progress to cancer (because it can still be destroyed by the body’s immune system; only a few number of cells involved)

2. PromotionChronic (must have a long exposure)Epigenetic (damage is above the DNA and has affected the set of proteins in transduction cascade which can activate your oncogenes)Potentially reversible Initiated cells are exposed to promoters o Properties of promoters -Reversible -Dose-dependent -Time-dependent

NINE WARNING SIGNS OF CANCER CAUTION US!C – hange in bowel/bladder habits Alternating onset of pain and diarrhea, hematuria A – sore that does not heal Particularly body parts that are exposed to the sun that may cause squamous cell carcinoma U – nusual bleeding/discharge Hemoptysis, hematuria, postmenopausal bleeding. Hemoptysis is usually misdiagnosed and mistreated for as TB. T – hickening of a lump in breast or elsewhere Any mass in an adult should be managed as potentially malignant, observe 2-3 months, unless proven otherwise. I – ndigestion or difficulty in swallowing O – bvious change in warts/moles Pay attention to size and color, areas exposed to sun and sites commonly associated with trauma(soles of feet and sclera), may cause malignant melanoma.N – agging cough/hoarseness Tumor of the lungs, lung CA, laryngeal CA particularly with smokers U – nexplained anemia If cause cannot be explained then consider malignancy as differential diagnosis S – udden Unexplained weight loss Weight loss of 10% in a month is alarming.

CLINICAL SEQUELAE OF CANCER

MASS EFFECTSAblation by crowding or invasion Obstruction of vessels, tubes and ducts Rupture of blood vessel It is usually the symptoms that patients will complain Depends on the site of growth o Near blood vessels- bleeding, superior vena caval syndrome o Brain- increased ICP, headaches, altered sensorium o Lungs- hemoptysis o GIT- hematochezia

o GUT- hematuria (bladder cancer) o Colon cancer- late manifestations, poor prognosis o Neurologic cancer- early manifestation of symptoms, spinal cord compression

REMOTE EFFECTS (PARANEOPLASTIC EFFECTS)Very rare occurrence (less than 1%) Can be as simple as fever or as complicated as hypocalcemia Ectopic hormone production (e.g. small cell carcinoma of the lungs, Cushing like symptoms with oat cell carcinoma). Neuropathies and CNS abnormality Dermatologic abnormalities (e.g. Ichthyosis nigricans or rashes in axilla and neck is the hallmark of gastric cancer) Metabolic disorders (e.g. hypercalcemia causes delirium, dementia, etc. and must be recognized early in diagnosis of squamous cell carcinoma; parathyroid-like symptoms, poor sensorium, lymphoma can present fever every 3-4 days; tumors express substances to promote cachexia leading to weight loss) Hematologic disorder like anemia (most common) Immunosuppression wherein patients become more prone to infections Collagen vascular disorders (e.g. rheumatoid arthritis, SLE-like symptoms seen in hematologic malignancies)