Neoplasm Recorded Lecture PDF

Neoplasms  1st some definitions… Definitions Neoplasia Process that produces a neoplasm Abnormal mass of tissue Growth is greater than and uncoordinated with surrounding tissue Persists even after the stimuli which caused the change has gone “Heritably altere...

Neoplasms  1st some definitions… Definitions Neoplasia Process that produces a neoplasm Abnormal mass of tissue Growth is greater than and uncoordinated with surrounding tissue Persists even after the stimuli which caused the change has gone “Heritably altered, relatively autonomous, new growth of cells” Neoplasm – ‘tumor’ - increase in cell numbers - uncontrolled Must r/o hyperplasia or hypertrophy – both of which are well controlled Benign neoplasms Generally localized, discrete masses of cells that remain confined to their site of origin Malignant neoplasms Have potential to spread beyond site of origin Also called malignancies or cancer Invasion Direct extension of neoplastic cells into surrounding tissue without regard to tissue boundaries Metastasis Transplantation of cells to entirely new site  What is Cancer?  Malignant neoplasm  Group of more than 200 diseases  Characterized by uncontrolled and unregulated growth of cells  Occurs in people of all ages and ethnicities  In Canada, it was estimated in 2019 that  220 400 new cancer cases would be diagnosed  82 100 people would die from cancer  Cancer  Cancer incidence and death rates increase from west to east across the country.  In 2017, cancer was the leading cause of death in Canada, accounting for 30% of all deaths, with cardiovascular diseases (heart and cerebrovascular diseases) in second place.  Overall mortality has declined.  Cancer  Includes large variety of malignant neoplasms  Behavior, treatment, and causes vary  Important variables:  Site of development  Gender  Age  Prevention can reduce incidence of various forms of cancer  Screening allows for early detection and treatment  Cancer generally more common in older persons  Risk Factors  Environmental agents, genetic changes, or behaviors that predispose a person to the development of cancer  Sex, age, and race are strong risk factors for many cancers  Some risk factors involves modifiable behaviors  Modifiable Risk Factors  Known risk factors include tobacco use, excessive body weight, lack of physical activity, unhealthy eating habits, alcohol consumption, and excessive exposure to the sun.  If these lifestyle factors were modified, the rates of cancers and other chronic diseases would be reduced.  Defect in Cellular Proliferation  Most human tissues contain predetermined, undifferentiated stem cells.  Predetermined stem cells give rise to mature cells of the type of tissue where they reside.  All cells are controlled by an intracellular mechanism that determines proliferation.  Cancer cells grown in culture are characterized by loss of contact inhibition.  They grow on top of one another and on top of or between normal cells.  Defect in Cellular Proliferation  Cancer cells respond differently from normal cells to intracellular signals regulating equilibrium.  Divide indiscriminately  Normal Cellular Differentiation  Is normally an orderly process progressing from a state of immaturity to a state of maturity  Stable and will not dedifferentiate  Exact mechanism of normal cellular differentiation and proliferation is not completely understood Normal Cellular Differentiation  Defect in Cellular Proliferation  Stem cell theory  Loss of intracellular control of proliferation results from mutation of stem cells.  DNA is substituted or permanently rearranged.  Once mutated  Cells can die from damage or by initiating programmed cellular suicide (apoptosis).  Can recognize damage and repair itself  Can survive and pass on damage to their daughter cells  Surviving mutated cells have the potential to become malignant.  Defect in Cellular Differentiation  Two types of genes that can be affected by mutation are 1. Proto-oncogenes Regulate normal cellular processes such as promoting growth  Genetic locks that keep cells functioning normally  Mutations that alter their expression can activate them to function as oncogenes. 2. Tumour suppressor genes Suppress growth  Transformation  Non-repair of genetic defect before division, resulting in “fixed” genetic alteration  Normal cell is “transformed” into cell with potential to generate neoplastic clone  Mutation  Any type of genetic change  Oncogene Transformation  Oncogene  Mutated proto- oncogene that becomes constitutively activated  Caused by activating mutations  Only one allele needs to be mutated for altered protein function to have phenotypic  Tumor Suppressor Gene Transformation  Tumor suppressor gene  Codes for proteins that normally inhibit growth  Detect and repair defective DNA before cell can transition through cell cycle and undergo mitosis  Can be deactivated by mutations  Most commonly mutated is p53  Transformation  Alterations in function of other proteins affecting growth can also contribute to carcinogenesis  Cancer cells can also acquire immortality Tumours can be classified as benign or malignant neoplasms Benign Malignant  Well-differentiated  Usually undifferentiated  Usually encapsulated  Able to metastasize  Expansive mode of growth  Infiltrative and expansive growth  Metastasis absent  Frequent recurrence  Rarely recur  Moderate to marked vascularity  Rarely encapsulated  Becomes less like parent cell Naming Neoplasms Suffix –oma refers to tumor Carcinoma Malignant neoplasm of epithelial tissues Sarcoma Malignant neoplasm arising from mesenchymal, or connective, tissue  Cancer is a Disease of Genes  Very few mutations lead to cancer  Single alteration does not cause cancer  Must be interplay between environmental and genetic factors for development of malignant growth  Cancer is a Disease of Genes  Neoplasms  Behave like parasitic organism  Respond to growth promoting stimuli  New mutations provide ability to evade host’s growth control mechanisms  Multiple “hits” to genome required for collection of cells to acquire malignant phenotype  First “hit” in familial cancers is inherited  Most sporadic cancers have extremely complex genetic profiles due to accumulation of mutations during development  Causes of Altered Gene Expression  Chemicals  Initiating chemical causes mutation  Additional chemical promotes growth  Neoplasia only develops if genetic mutation is fixed and cells are induced to proliferate  Progression required for malignancy  Causes of Altered Gene Expression  Ionizing radiation  Damages any atom it comes into contact with  Effect is dose-dependent  Can take decades for neoplasms to appear  Radiation known to cause cancer includes x-radiation, γ-radiation, and ultraviolet light  Causes of Altered Gene Expression  Microorganisms  Only Helicobacter pylori has been identified as a carcinogen in humans  Several oncogenic viruses are known  Best understood oncogenic pathway is driven by high-risk HPV  Causes of Altered Gene Expression  Familial predisposition  Location of exact mutation in single gene can vary  Many familial cancers rare in general population  Genes involved in driving familial cancer are not necessarily those that are most important in sporadic counterparts  The Natural History of Cancer  Multiple genetic “hits” develop over years  Earliest “hits” may not result in changed phenotype  Morphologic features of malignancy develop with further accumulation of mutations in the form of cellular atypia  The Natural History of Cancer  Cancer causes uncontrolled growth  Nuclei enlarged because of excess chromosomal material  Multiple, enlarged nucleoli translate genetic codes into proteins at faster rate than normal  Mitotic figures indicate frequent cell division  Dysplasia  Neoplastic clone atypical in appearance, but still localized to tissue of origin  Dysplastic cells do not necessarily become malignant  Can range from low grade to high grade (in situ)  Recognized precursor lesions for carcinomas  Invasion and Metastasis  Malignant cells must:  Destroy basement membrane  Move into new niche and tap into blood supply  Neoplastic cells grow into mass that alters composition and appearance of tissue  Invasion is a local process theoretically cured by surgical incision  Metastasis  Non-contiguous spread of malignant cells to different areas in the body  Occurs fairly late in natural history of malignant neoplasms  Invasion and Metastasis  For metastasis to occur, malignant cells must:  Invade neighboring tissue  Engage in intravasation  Evade host’s immune system  Travel through blood  Engage in extravasation  Establish themselves in new location  Stage: Prognosis and Treatment  Stage describes extent of spread of cancer  Designated by TNM system:  T describes tumor  N describes extent of lymph node metastasis  M describes whether distant metastasis has occurred  Stage: Prognosis and Treatment  Four stages for all cancers:  Stage I represents most local manifestation  Stage IV connotes metastatic spread  How T, N, and M classifications are combined in stages varies by organ  Stage: Prognosis and Treatment  Measurement of 5- or 10- year survival is used for predicting behavior of cancers  What percentage of patients with a particular neoplasm at a particular stage of time will still be alive 5 or 10 years after initial diagnosis  Stage groupings correlate with survival  Stage: Prognosis and Treatment  Cancers of different organ systems spread in predictable ways  Some patterns of spread are idiosyncratic  Cancers may come to clinical detection because of secondary effects of metastatic lesions  Grade of tumor  Assessment of how differentiated tumor appears  Degree of differentiation and grade roughly estimate tumor’s malignant potential  Stage: Prognosis and Treatment  After cancer is diagnosed, additional studies are undertaken to determine the stage  Initial assessment of T, N, and M can be performed clinically or by imaging  Pathologist performs definitive assessment on surgically removed malignancy  Stage: Prognosis and Treatment  Treatment depends on stage of disease  Surgery is basic modality of cancer treatment  Radiation therapy and chemotherapy may also be used to reduce or destroy neoplastic cells  Hormonal therapy is effective in some cancers  Targeted therapies are currently approved for use almost exclusively for end-stage disease  Clinical Detection: Screening and Diagnosis  Neoplasms come to clinical detection in a variety of ways:  Producing symptoms related to local growth  Causing systemic manifestations  Producing produce hormones  Increasingly detected before producing symptoms  Mass  Benign neoplasms  Produce discrete single mass  Form capsule when located within solid organs or connective tissue  Very closely resemble cells of origin  Demonstrate minimal degrees of cellular atypia  Malignant neoplasms  Can grow very large  Not encapsulated  Have irregular borders  May be detected by imaging modalities  Pain  Cancer causes pain by:  Destruction of tissue  Invasion of nerves  Obstructing hollow organs  Causing inflammation  Obstruction  Tumors can obstruct body passageways:  Within their lumens  By external compression  Infection is a complication of obstruction  Hemorrhage  Cancers on mucosal surfaces or skin can ulcerate and bleed  Chemical test during routine examination can detect occult blood  Blood in urine may be an initial sign of bladder cancer  Pathologic Fracture  Primary bone cancer or metastatic cancers can invade and locally destroy bone  Lung, breast, and prostate cancers are likely to metastasize to bone  Multiple myeloma can destroy adjacent bone  Certain tumors can cause osteoporosis  Infection  Interplay of a variety of mechanisms produces infection in patients with cancer:  Erosion or ulceration of epithelial surfaces  Obstruction  Compromised immune system  Inadequate nutrition  Suppressed leukocyte production (chemotherapy)  Anemia  Major mechanisms:  Blood loss caused by hemorrhage  Bone marrow replacement by neoplastic cells  Decreased red blood cell production  Cachexia  Generalized wasting that occurs in terminal cancer patients  Contributing factors:  Anorexia  Nutritional demands of rapidly growing neoplasm  Cytokines produced by inflammatory response  Hormone Production  Some neoplasms secrete hormones that lead to specific clinical manifestations  Benign neoplasms of endocrine glands  Malignant endocrine gland neoplasms  Paraneoplastic syndromes  Manifestations of aberrant and uncontrolled hormone production by malignant neoplasm  Diagnosis  Based on investigation of cause of symptoms or on screening tests  Diagnosis is confirmed by pathologic examination of tissue or fluid removed from lesion  Treatment decisions are based on pathologic diagnosis  Diagnosis  Screening test criteria:  Must be able to detect disease when it is present  Everyone in population must be screened in order for test to provide survival benefit  Test must be affordable  Test must be safe and easy to administer  Must be an effective treatment for the disease  Diagnosis  Screening tests are available for some cancers, but none are ideal  All have a false positive rate, so additional tests are performed for further assessment  Accumulating knowledge about cancer biology offers promise that simple tests may soon be available  Tumor markers (prostate-specific antigen) Cyto-logic studies (Pap smear) Tissue biopsy (fine needle aspiration) Immunohistochemistry (estrogen receptor) Microarray technology (gene chips) Interprofessional Care 18-52  Death  Combination of treatment modalities can delay death from metastatic disease  Mechanisms causing death in cancer patients:  Infection  Cachexia  Metabolic and endocrine effects  Hemorrhage Thank you…