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Flashcards in Pathology: neoplasia Deck (40):

Cancer results from...

-Abnormal growth, can be caused by a defect in 3 possible areas
-Can be abnormally high activity of proto-oncogenes (which would therefore be oncogenes)
-Can be abnormally low activity of tumor suppressor genes
-Can be a abnormally low activity of apoptosis genes
-Usually a number of these factors leads to cancer


Atrophy, hypertrophy, hyperplasia

-Atrophy: decrease in size of cells or number of cells (reversible)
-Hypertrophy: increased size of cells, cell number remains content (reversible)
-Hyperplasia: increased number of cells, size stays constant (reversible)
-Both hyperplasia and hypertrophy can be physiologic (increased demand) or pathologic (in the absence of increased demand)



-Abnormality in cellular differentiation. A cell type exist where it should not be (glandular epithelia becoming squamous epithelia)
-Squamous metaplasia most common (cell type changes to squamous epithelia)
-Carries no increased risk of cancer (reversible), but can be accompanied by or lead to dysplasia
-Almost always due to chronic inflammation



-Abnormality in differentiation and maturation
-Contain nuclear abnormalities (large nucleus, hyperchromatism), cytoplasmic abnormalities (failure to differentiate normally), and increased rate of multiplication
-Can be mild, moderate, or severe
-Dysplasia is theoretically reversible, but at severe state is close to cancer


Significance of dysplasia

-These are premalignant lesions. Carcinoma in situ = severe dysplasia (no invasion)
-Risk of developing cancer comes from: grade of dysplasia, duration of dysplasia, and site (premalignant qualities)
-Difference from cancer: no invasion, reversible
-Dx of dysplasia: microscopy of biopsy, must be distinguished from inflammatory, regenerative/degenerative changes (which may show some degree of disorganization or atypia)



-Can be benign or malignant, neoplasia just means new growth (not reversible)
-Is an abnormality of cellular differentiation, maturation, and control of growth
-Classified by cell/tissue of origin and by site, embryologic derivation and gross features
-Benign (-oma): generally grow slowly, encapsulated and does not spread
-Malignant (carcinoma, cancer): generally grows fast, invades (infiltrates surrounding tissue), and spread widely (metastasize)
-Assessment of neoplasia: radiology, microscopy, culturing (cell cycle)
-Benign tumors can become malignant (there is a spectrum)


Ways to classify neoplasms

-Rate of growth: slow for benign, fast for carcinoma
-Degree of differentiation: benign is usually well-differentiated, malignant is usually poorly-differentiated (anapestic- very poorly differentiated, no resemblance to normal tissue)
-Malignant neoplasms have distinct histologic changes: more densely cellular, larger nucleus, variable appearance, abnormal differentiation, necrosis frequent
-Often shows hyper chromatic and aneuploidy, can use molecular markers to identify action of apoptidic, tumor suppressor, and oncogenes
-Invasion of nearby cells, metastases (absolute evidence for malignancy), no capsule


Classification based on differentiation potential

-Totipotent: germ cell tumors (seminoma, embryonal carcinoma, teratoma, choriocarcinoma, yolk sac carcinoma)
-Teratomas: contain all three germ layers (ecto, meso, endoderm) and can be mature (well-differentiated, usually benign) or immature (fetal tissue, malignant)
-Pluripotent: blastomas (fetal cells) of children
-Unipotent (most common): most adult type cells (adult tumors)
-Permanent cells are fully differentiated and don't produce tumors


Pluripotent cancer classification

-From partially differentiated fetal type stem cells
-Give rise tom blastomas: nephroblastoma, neuroblastoma, retinoblastoma, medulloblastoma, embryonal rhabdomyosarcoma
-Resemble early embryonic organs, occur in childhood, are malignant


Unitpotent cancer classification

-Most common, occur only in adults
-Can be epithelial or mesenchymal in origin, can be benign or malignant, can arise from various tissue types
-Epithelial benign: papilloma (outward-projecting "fingers") which can be squamous, glandular, or transitional, and adenomas (duct-forming cell clusters) which are only in glandular epithelia
-Epithelial malignant: squamous carcinoma, adenocarcinoma, transitional carcinoma
-Mesenchymal benign: lipoma (fat), chondroma (cartilage), angioma (endothelia), fibroma (fibroblast), ect
-Mesenchymal malignant: liposarcoma, chrondrosarcoma, angiosarcoma, fibrosarcoma, ect


Exceptions to naming rules

-Lymphoma, plasmacytoma, melanoma, glioma, astrocytoma are all malignant
-Leukemias do not usually produce local tumors, classified by acute vs chronic and cell of origin
-Mixed tumors can be more then one neoplasia cell type
-Tumors named after people


Hamartomas and Choristomas

-Types of benign growths (not true tumors) that have abnormal development
-Do not show excessive growth
-Hamartoma: composed of tissue normally present in site it arises (growing in a disorganized mass)
-Choristoma contains tissue not normally present in site it arises in (but tissue is normal)



-Cells vary in size and shape, often the nucleus is almost the entire cell


Causes of blastomas

-Nephroblastoma: mutation in Wilms gene, leads to Wilms tumor
-Retinoblastoma: Rb 2 hit
-Neuroblastomas: Myc amplification


Squamous carcinoma

-Can be skin or bronchus in origin
-5 P's: pale, pink, polyclonal (flatten out), prickle, pearls (keratin pearls)


Transitional carcinoma

-Bladder/urethra origin usually
-Multiple layers of similar cells, fewer keratin, rounded nuclei
-Has linear basement membrane btwn the layers


Malignant lymphoma

-Mesenchymal in origin, looks like a lot of lymphocytes



-Origin is usually kidney, breast, stomach, pancreas
-More variable depending on organ and differentiation
-Do not make clear glandular structures
-Irregular piled up cells forming disorganized lumens w/ variable multiple nuclei



-Spindle-type cells w/ variable nuclei (makes up most of the cell)
-Mesenchymal tissue of origin
-Melanomas may appear brown due to production of melanin


Incidence of cancer

-40% chance of getting it in your life
-Most common incidence in males: prostate, then lung, then colorectal, then urinary, then leukemia/lymphoma
-Most common in females: breast, then lung, then colorectal, then uterus, then leukemia/lymphoma
-85% of all adult cancers are carcinomas, 7% are sarcomas, 8% are lymphomas and leukemias


Death rates of cancer

-For male the highest rate of mortality are: lung, prostate, colon, pancreas
-For females the highest mortality rates are: lung, breast, colon, pancreas


Incidence of childhood cancers

-Lymphoma and leukemia: 50%
-Brain: 25%
-Blastomas (wilms, retina, neuro, retino, nephro, osteo)


Cancer risks

-Sex, age, carcinogens, viruses/bacteria, radiation, heredity, occupation, lifestyle, childbearing, age of menarche, breast feeding
-Some disorders that are not neoplastic carry an associated higher risk of developing cancer (pre-neoplastic diseases
-All of these factors can lead to hits on a gene. Need multiple hits to give rise to neoplasm
-Hits give rise to mutated proto-oncogenes and tumor suppressor


Monoclonal neoplasia

-Occur in a single cell, which divides to produce a clone (most cancers are clonal)
-The carcinogen may produce changes in the cells, giving rise to a field of potentially neoplastic cells
-Clones in theory are the same, but are different from each other b/c they diverge from the germ line DNA
-Evidence: B cell lymphomas, K/L light chain restriction


Multifactorial origin of neoplasia

-Initiator (carcinogen) action is followed by prolonged action of one or more promoters
-Many cancers result from multiple hits involving oncogenes and suppressor genes
-Multiple hit theory takes explains the long latent period: takes many years to reach clinical significance, but can become life-threatening very fast
-Evidence: Burkitt lymphoma. First hit is infection of EBV which results in potentially immortal B cells (still required BCGF).
-Second hit is due to promoter effect. Chronic malaria causes translocation of genes. Leads to myc and Ig genes being right next to each other. Dysregulation of myc leads to continually evolving tumors (no longer need BCGF to divide)


Example of multifactorial origins

-First get a mutation in APC (hyperplasia)
-Then get a mutation in KRAS (metaplasia and inflammation)
-Then get a mutation in SMAD4 (dysplasia)
-Finally get a mutation in p53 (malignant)


Other characteristics of cancer stages

-Monomorphic: all same cell type
-Polymorphic: multiple cell types
-Stage 1 & 2 are both non-invasive (benign): 1 is in situ
-Stage 3 & 4 are both invasive (malignant): stage 3 is just crossing the basement membrane, stage 4 is metastasizing
-Polyp: benign, from tissue response to inflammation
-Leiomyeloma: CA on smooth muscle of uterus


Genetic mutation theory mechanisms

-Genetic changes (mutations, epigenetics) can cause inactivation or activation of certain genes, which could lead to cancer. Usually 1 hit is not enough
-Ex of mechanisms: replication errors, excessive growth factors (receptors or genes), decreased suppressor factors (receptors or genes), lack of apoptidic genes, abnormal methylation of DNA silencing genes
-May be inherited or acquired by: indel (frameshift), substitution (non or missense), insertion or deletion of whole gene/chromosome (possibly virus), translocation, amplification (as in neuroblastoma by myc)
-Genes mostly affected: proto-oncogenes, tumor suppressor genes, apoptosis genes, DNA repair genes



-Accelerate cell growth, when abnormally activated become oncogenes
-RNA oncogenic viruses got the oncogenes from human proto-oncogenes
-Many code for growth factors, growth factor receipts, or transduction and transcription factors
-Can be a target for 1 hit
-Examples: SRC and ABL (signal transduction; thyroid sarcoma), BCL2 (cell cycle/apoptosis control; breast, SCA), n-myc (TF; leukemia, breast, colon, neuroblastoma, lung)


Tumor suppressor genes

-Down regulate growth, are lost or inactivated in cancer and lead to uncontrollable growth
-In many instances both copies of the gene must be non-functional (2 hits) and these genes are major sites for hits
-p53 mutation most common mutation in cancer
-Exs: p53 and RB (cell cycle brakes; bladder, lung, ovary, retinoblastoma, bone), BRCA1/2 (DNA repair; hereditary breast CA), APC (colon CA), MSH2 and LH1 (mismatch repair; colon and endometrium CA)


Apoptosis-regulating genes

-Decrease in apoptosis allows cells to avoid death and may accumulate into a neoplasm
-Can be the loss of function of apoptosis inducer (p53)
-Can be the activation of an apoptosis suppressor (BCL2)


DNA repair, aging, and epigenetics

-Absence of DNA repair proteins leaves mutations not corrected and increases chance of CA
-Some repair are: MSH2 and LH1 (MMR) and BRCA (non MMR)
-Aging increases time exposure to carcinogens and chance of hits to accumulate, also failing immune system leads to increased CA risk
-Telomerase extends the telomeres only to a certain extent before the cell eventually dies (part of aging), but some cancers have elevated telomerase levels and are "immortal"
-Changes in methylation (suppression) of a gene or protein phosphorylation can changes the role of a gene/protein (epigenetics). Some changes can be passed down to daughter cells and even children
-Ex: phosphorylation of Rb leads to Rb and E2F dissociating and E2F starting the cell cycle



-May act by altering DNA and/or inducing cell proliferation (by either acting as inhibitors or promoters)
-Most common: polycyclic hydrocarbons (tobacco smoke, chimneys) and accounts for more CA than all other carcinogens combined
-Also: aromatic amines, saccharin/cyclamates, azo dyes, aflatoxin (aspergillus), nitrosamines, asbestos (mesothelioma)
-Others: ionizing radiation, oncogenic viruses


Oncogenic viruses

-RNA viruses use reverse transcriptase to insert a viral oncogene (v-onc) or insert a promoter (LTR) near a proto-oncogene and turn it into an oncogene
-DNA viruses insert their genome into host cells and produce proteins that block suppressor gene function (may persist over many generations
-Also H. Pylori can cause stomach inflammation and eventually CA


Role of inheritance

-Single gene inheritance: if dominant, these mutations produce a molecule that directly causes neoplasia. If recessive, both copied must be inactivated to lead to failure of production of growth control factor
-Exs: retinoblastoma (Rb gene on chrom 13 lost), wilms tumor (WT1 gene on chrom 11)
-Germ line hit affect all cells (one copy lost in all cells), or somatic hits affect only 1 cell (germ line much more rare)
-High risk syndromes often are defects in DNA repair nzs that are inherited (BRCA), but also probably multifactorial


Pre-malignant conditions

-For some reason or another (hyperplasia/inflammation/metaplasia), dysplasia will always precede neoplasia
-Only dysplasia can lead to malignancy (invasion), only malignancy can lead to metastases


Malignant conditions

-Can be well-differentiated, poorly-differentiated, or anaplastic (undifferentiated, the worst)
-Metastases usually go to: lymphatics to sentinel lymph node or blood stream to first capillary bed (i.e. liver from GI or lungs from venous system)
-Body cavity spread is very rare


Stages vs grade

-Grade: histologic evaluation of the degree of differentiation (dysplasia, pre-malignant, malignant)
-Stage: extent of spread of a malignant neoplasm
-Stage 1: primary tissue only
-Stage 2: local (sentinel) nodes
-Stage 3: distant nodes
-Stage 4: liver, bones, brain, ect



-Balance all variables of a history: family, social, occupational, activities, sex/children
-Early detection is key (screening)
-Use cytologic diagnosis (cells in sputum, urine, CSF, bone marrow)
-Histologic Dx is definitive method: tells the type, grade, stage possibilities, prognosis
-Can do rapid (frozen), but is poor histology. H&E gold standard (but slower)
-Use radiologic and serologic markers



-Surgery (usually at benign and stage 1 only), resection of lymph nodes required at stage 2
-Immunotherapy (Abs)