Basics of Neoplasia PDF

Basics of Neoplasia DSPR 139: Neoplasia and Genetics Daria Vasilyeva, DDS  Course Information Final exam: 50 MCQs, 100% of final grade  1. Definitions 2. Basic features 3. Nomenclature At a glance 4. Cancer epidemiology...

Basics of Neoplasia DSPR 139: Neoplasia and Genetics Daria Vasilyeva, DDS  Course Information Final exam: 50 MCQs, 100% of final grade  1. Definitions 2. Basic features 3. Nomenclature At a glance 4. Cancer epidemiology 5. Basics of carcinogenesis: mutations, predisposing factors, genetics  Neoplasia vs. Tumor Neoplasia/neoplasm ○ Literally, new growth Tumor ○ Literally, swelling ○ Non-specific term but is used near-synonymously with neoplasm Is all new growth neoplastic? Not all new growth is neoplastic - Wound repair and healing: granulation tissue Not all new growth is neoplastic - Hyperplasia: - increase in number of cells in an organ/tissue - Occurs in response to stimulus - can be physiologic or pathologic - Ends when stimulus removed - e.g. thickness of endometrium during menstrual cycle - Hypertrophy: - increase in cell size - no cell division -- no change in number of cells - increased production of proteins inside the cell - can be physiologic or pathologic - e.g., muscle hypertrophy  Right ventricular hypertrophy in Left ventricular hypertrophy in setting of pulmonary hypertension setting of systemic hypertension  Hypertrophy and Hyperplasia - Hypertrophy and hyperplasia both result in increase in size of organ - Hypertrophy and hyperplasia frequently occur together  Not all new growth is neoplastic Metaplasia: - Reversible change: one differentiated cell type is replaced by another - Nearly always found in association with tissue damage/repair/regeneration - Typically replacing cell type better suited to alterations in local environment - Underlying stem cells reprogrammed to differentiate along new pathway Stem cells: - self-renewing cells Normal columnar cells of trachea/bronchi - in adults, present in all tissues that continue to replaced by stratified squamous epithelium divide: bone marrow, skin, GI tract lining etc. (more rugged) in smokers - generate differentiated cells Not all new growth is neoplastic Questions?  What is neoplasia? Disorder of cell growth triggered by series of genomic alterations - Excessive proliferation is independent of and uncontrolled by physiologic growth signals - Alterations give neoplastic cells survival and growth advantage - Alterations affect a single cell and its clonal progeny - Neoplasms are clonal:neoplastic cells derive from a single mother cell Neoplasia is new tissue growth that is unregulated, irreversible, and clonal; these features distinguish it from hyperplasia and repair. e.g. multiple myeloma: neoplasm of plasma cells Plasma cells are normally polyclonal: kappa and lambda light chains Multiple myeloma is clonal: plasma cells only express one chain (here -- lambda)  Neoplasms: Benign and Malignant Benign neoplasms: - stay localized -- do not spread/metastasize to other sites - usually well-circumscribed and non-infiltrative - possible to remove surgically Malignant neoplasms = cancer Chondroma - invasive growth” destroy adjacent tissues - can spread to distant sites (metastasize) - approximately 30% of tumors first present as metastatic disease - treatment is complicated, especially in advanced disease - prognosis may be questionable Metastatic lung adenocarcinoma Osteosarcoma Ameloblastoma Caveat #1: Benign neoplasms may behave aggressively, cause significant morbidity, or be fatal Caveat #2: Cancers may occasionally be quite small and require high level of clinical skill to suspect and identify  Caveat #3: Some cancers, like basal cell carcinoma, have low metastatic potential and can be treated quite simply/conservatively  General (but not 100% reliable) features Benign Malignant Slow growth (months/years) Rapid growth (days/weeks) Expansile (pushing) growth Invasive, destructive growth Not metastasizing Metastasizing Symmetrical, well-circumscribed Asymmetrical Nodular, pedunculated Exophytic Yellow, pink, blue Black, brown, red Benign: Less specific: Less specific neurofibroma ○ Movable or fixed ○ Fixed ○ Firm or soft ○ Can be ulcerated with no hx of trauma ○ Can be ulcerated if traumatized ○ +/- pain ○ +/- pain Malignant: Kaposi sarcoma  Lipoma (left): circumscribed, uniform in appearance, easily removed Liposarcoma (right): infiltrative/poorly circumscribed, heterogenous appearance with hemorrhage/necrosis, must remove surrounding normal tissue to achieve adequate surgical margin Benign or malignant? Benign or malignant? Benign or malignant?  Benign vs. Malignant: microscopic features Well-differentiated (resembling normal tissue) vs. poorly-differentiated (not resembling normal tissue) ○ Typical tissue organization vs. Atypical tissue structure ○ Rare, normal mitoses vs. Frequent, abnormal mitoses Histologic features of malignancy: ○ Pleomorphism: variable size and shape of cells/nuclei ○ High nuclear/cytoplasmic ratio of cells ○ Loss of identifiable differentiation  Lipoma (left): resembles normal adipose tissue Dedifferentiated liposarcoma (right): does not resemble normal adipose tissue Questions?  Neoplasm Nomenclature Beginning of the name: identifies tissue of origin Myo- muscle ○ Leiomyo- smooth muscle ○ Rhabdomyo- skeletal muscle Neuro/schwanno- neural tissue Lipo- adipose tissue (= fat) Fibro- fibrous connective tissue Angio- vessel ○ Hemangio - blood vessel ○ Lymphangio - lymph vessel Exceptions: Ending of the name: Fibroma: not a neoplasm -oma = tumor ○ usually means neoplasm Lymphoma: ~solid~ malignancy of lymphocytes Leukemia: malignancy of peripheral blood ○ usually benign Melanoma: malignancy of melanocytes Certainly malignant: Mesothelioma: malignancy of mesothelium ○ -carcinoma (epithelial malignancy) -adenocarcinoma - glandular features ○ -sarcoma (mesenchymal malignancy)  Dysplasia Intraepithelial neoplasia - Genetically altered cells stay within epithelium - Basement membrane acts as barrier between epithelium and connective tissue - Dysplasia cannot grow aggressively or metastasize (yet) - The patient can be cured by surgical excision Dysplasia is a precursor to carcinoma - once dysplasia invades through basement membrane into connective tissue, it becomes carcinoma Carcinoma in situ: dysplasia involving full thickness of epithelium but still confined by basement membrane; patient can still be cured by complete surgical excision Teratoma: benign tumor containing cells/tissues from more than one tissue type and more than one germ layer - (Germ layers: endoderm, mesoderm, ectoderm) - Nearly all other neoplasms consist of cells of one tissue type - Originates from germ cells - Totipotential stem cells normally present in testes and ovaries Hamartoma: benign proliferation of cells/ tissues native to involved site - Considered a benign, highly differentiated neoplasm Choristoma: benign proliferation of cells/ tissues in non-native site -- shouldn’t be there! - Considered a benign, highly differentiated neoplasm Compound odontoma Odontoma Cartilaginous choristoma Questions?  Cancer Epidemiology - Cancer is the 2nd leading cause of death in both adults and children. - The leading causes of death in adults are (1) cardiovascular disease, (2) cancer, and (3) chronic respiratory disease. - The leading causes of death in children are (1) accidents, (2) cancer, and (3) congenital defects. - The most common cancers by incidence in adults are (1) breast/prostate, (2) lung, and (3) colorectal cancer. - The most common causes of cancer mortality in adults are (1) lung, (2) breast/prostate, and (3) colorectal.  Cancer Epidemiology Cardiovascular disease is the leading cause of death in US and worldwide Cancer is the second leading cause of death in US and worldwide ~$100 billion in US healthcare costs Lifetime cancer risk: Males - Risk of developing: 40% - Risk of death: 21% Females - Risk of developing: 39% - Risk of death: 18% Approximately 50% of US cancer diagnoses/ deaths are accounted for by the ‘big 4’: Lung Breast Prostate Colorectal Some cancers are more aggressive than others  Basal cell carcinoma and squamous cell carcinoma of skin Most common human cancers by far - BCC: 3-4 million cases per year in US - SCC: 2-3 million cases per year in US Not included in cancer registries or epidemiology statistics - So much more common than other cancers that their inclusion would markedly skew statistics - A lot more indolent and treatable In the last 20-25 years, overall cancer death rates have decreased: - changes in risk factors (e.g. smoking) - increased screening (e.g. pap smears, mammograms, colonoscopies) - better therapy (immunotherapy, biologics, targeted therapy) https://doi.org/10.1002/cncr.34479 Incidence trends reflect changes in risk factors and screening test use  Cancer Screening Screening seeks to catch dysplasia (precancerous change) before it becomes carcinoma; or carcinoma before clinical symptoms arise. Purpose of screening is to decrease cancer-specific mortality. - Cancers that do not produce symptoms until late in disease will have undergone additional divisions and, hence, additional mutations. - Cancers that are detected late tend to have a poor prognosis. Common screening methods: - Pap smear - detects cervical dysplasia (CIN) before it becomes carcinoma - Mammography - detects in situ breast cancer (e.g., DCIS) before it invades or invasive carcinoma before it becomes clinically palpable - Prostate specific antigen (PSA) and digital rectal exam - detects prostate carcinoma before it spreads - Hemoccult test (for occult blood in stool) and colonoscopy - detect colonic adenoma before it becomes colonic carcinoma or carcinoma before it spreads  Cancer and Age Most cancers occur over 55 years of age Men aged 60-79: main cause of death Women aged 40-79: main cause of death Explained by: Accumulation of pathogenic genomic alterations in (stem) cells over lifetime Decline in immune system competence Cancer accounts for 10% of all childhood deaths 80% of childhood cancers are cured Most common pediatric cancers are leukemia/lymphoma and brain/CNS tumors Questions?  Carcinogenesis Carcinogenesis results from accumulation of complementary genomic alterations - These alterations must be accumulated in a stem cell (or a cell that acquires stem-like properties) Genomic (genetic and epigenetic) alterations come from three sources: - DNA replication errors during (stem) cell division - Approximately 65-70% of mutations in human cancers - ~ 3 mutations and an unknown number of epigenetic alterations occur every time a normal human stem cell divides - Environmental factors - Inherited/hereditary genetic mutations - 5-10% of cancers have a hereditary component  Stem cells in different adult tissue types undergo different numbers of cell divisions There is a strong correlation (0.8) between average number of stem cell divisions per tissue and rate/risk of cancer in that tissue DNA replication errors during cell division  Environmental Factors Remarkable geographic variation in cancer incidence Evidence of role of environmental carcinogens Environmental influences appear to be dominant risk factors for many cancers Approximately 20-40% of cancers (maybe more?) may be preventable Cancer incidence in males Tobacco: - world’s single greatest preventable cause of death - single most important factor contributing to premature death in US - Implicated in 80% of 140,000 annual lung cancer deaths - 4000-7000 due to secondhand smoke Also implicated in cancers of: Oral cavity, pharynx, larynx Esophagus Pancreas Colon Bladder Obesity: - Strongly associated with cancer risk - 10% of cancer deaths attributed to obesity Linked with > 10 cancers Colon Rectum Postmenopausal breast Ca Prostate Today, more than two-thirds of Americans are overweight/obese 20% of children/adolescents obese Alcohol: - Contributes to 5% of cancer deaths - Increased risk of cancers of: Oral cavity, pharynx, larynx Esophagus Liver Colon Breast Alcohol and tobacco synergistically increase risk of cancers in upper aerodigestive tract 15% of cancers worldwide are caused by infectious agents 30-45% of cancers in the developing world e.g., many individuals infected with hepatitis C virus (HCV) may develop hepatocellular (liver) carcinoma _________________ Human papillomavirus (HPV) - Cause of cervical carcinoma - Cause of increasing fraction of head and neck cancers - Oropharynx, in particular - Incidence of HPV-positive oropharyngeal cancer has now surpassed incidence of cervical carcinoma  Reproductive history: Cumulative exposure to estrogen stimulation increases risk of breast and endometrial cancer ½ the risk of breast cancer if age at first full-term pregnancy < 20 years compared to > 35 years Postmenopausal hormone replacement therapy: Worldwide incidence of breast cancer increases risk of breast cancer Other environmental carcinogens: In environment: UV rays, smog In workplace: asbestos Diet: grilled meat, fat, alcohol  Acquired predisposing conditions Gastric reflux: Chronic inflammation increased risk of (infectious or non-infectious) esophageal Increased cell proliferation to repair damage → carcinoma increased opportunity for genetic mutations Presence of activated immune cells in inflamed tissue produced reactive oxygen species are directly Alcoholism → pancreatitis: genotoxic increased risk of pancreatic carcinoma Inflammatory bowel disease: increased risk of colorectal carcinoma Autoimmune diseases, e.g. Sjögren syndrome: increased risk of MALT lymphoma  Acquired predisposing conditions Immunodeficiency: Intact immune system, in particular intact T-cell immunity, is critical for normal cell surveillance Deficits in immune function associated with increased cancer risk HIV/AIDS Chronic pharmacologic immunosuppression Kaposi sarcoma: seen in HIV/AIDS  Acquired predisposing conditions Precursor lesions Metaplasia e.g. Barrett’s esophagus Hyperplasia Dysplasia Benign neoplasia  Acquired predisposing conditions Precursor lesions Metaplasia Hyperplasia e.g. endometrial hyperplasia Dysplasia Benign neoplasia  Acquired predisposing conditions Precursor lesions Metaplasia Hyperplasia Dysplasia Benign neoplasia  Acquired predisposing conditions Metaplasia Hyperplasia Dysplasia Benign neoplasia e.g. colorectal adenoma  Genetics and Cancer to be continued nevoid basal cell carcinoma syndrome (NBCCS)