Neoplasia.docx

L. Kaur

NEOPLASIA Introduction  A neoplasm is a NEW growth** that is an overgrowth of cells that serves no useful purpose - Uncontrolled cellular proliferation & Benign or malignant - Tumor = Neoplasm = Not cancerous! (tumor isn’t cancerous either, just means new growth, can be benign)  Appears not to be subject to the control mechanisms that normally regulates cells  Cancer is the term used for malignant new growths or malignant tumors BENIGN Tumors MALIGNANT Tumors Slow Rapid Growth rate Infiltration/invasion Character of growth Expansion = get larger Remains localized Metastasis by invasion, bloodstream & lymphatics Tumor spread Well differentiated Poorly differentiated Cell differentiation = No difference, = huge difference, looks like cell of origin doesn’t look like cell of origin Invasion/infiltration = going next door (kidney, go thru basement membrane). Metastasis = going far away Cancer Definitions* = EQ  Defined as a malignant growth with: Abnormal cell division, Invasion & Metastasis  Malignant: the ability of the neoplasm to invade & metastasize  Invasion: the ability of the neoplasm to penetrate the basement membrane and infiltrate adjacent structures  Metastasize: the ability to establish tumor growth at a new location, removed from the primary tumor 

Benign Tumors: - *Adenoma: from glandular epithelium - Angioma: from blood vessels - Chondroma: from cartilage - Polyps or papillomas: refers to benign tumor on a stalk arising from an epithelial surface

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Other prefixes used for tumor names: - Fibro: fibrous tissue - Hemangio: blood vessels - Lymphangio: from lymph vessels

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Lipo: fat Myo: muscle Neuro: nerve Osteo: bone

Malignant Tumors:*  Carcinomas: arising from the surface, glandular, or parenchymal epithelium - (parenchymal = functional cell from that tissue/organ) - Further designated by the type of epithelium it came from o Adenocarcinoma = epithelium in nature (parenchymal is solid)  Sarcomas: arising from any primary tissue other than surface, glandular, or parenchymal epithelium (or mesenchyme) - Exact type is specified by prefixing the cell of origin  Osteosarcoma, chondrosarcoma - FYI = mesenchyme is derived from the embryonic mesoderm and includes bone, cartilage, blood cells, endothelial cells, smooth muscle cells, the heart and circulatory system, and the lymphatic system  Leukemias: neoplasm of the blood cells (typically talk about RBCs) - Arise from precursors of WBCs, - Usually do not form solid tumors - Proliferate diffusely within the bone marrow where they overgrow and crowd out the normal forming cells - The neoplastic cells spill over into the bloodstream &  # of abnormal cells circulate in the peripheral blood  Blastomas: - Arise from persistent groups of primitive cells - Common to arise in children (Example: retinoblastoma = primitive cells, its devastating)  Lymphomas: neoplasms of lymphoid tissue - Usually malignant, with rare exceptions = Two major classifications o Hodgkin lymphoma (Hodgkin disease)  Reed-Sternberg cells* (image, owl eyes) o Non-Hodgkin lymphoma

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L. Kaur

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Cancer  Cancer incidence means occurrence.  Cancer deaths mean mortality (incidence does not mean mortality!)  Example: Basal Cell Carcinoma (BCC) = MC occurring cancer, very curable!  incidence  mortality  MC cancers after BCC: (top 3 cancers) - Lung cancer #1 in women & men. - Breast cancer in women. - Prostate cancer in men Epidemiology of Cancer  Mortality from cancer has surpassed heart disease in both men & women! - CDC Stats released in 10/12 for 2011 shows that heart disease outranks CA by a slight margin  Leading cause of death in children 3 - 14 years  Some sources state that up to 90% of all cancers can be attributed to lifestyle or environment - Places cancer in the realm of public health! Bc environment = 2nd hand smoking, particles in air, etc.  CDC reports smoking responsible for 90% of lung cancer in men, and 80% in women (2010 report for 2007) CDC - Top 15 deaths in 2007  Released from CDC 10/2010– Vital Statistics Report  1. Heart disease  9. Nephritis, nephrotic syndrome, & nephrosis  2. Cancer  10. Septicemia  3. CVA = cerebral vascular accident  11. Suicide  4. Chronic lower respiratory diseases  12. Chronic liver disease and cirrhosis  5. Accidents (unintentional injuries)  13. Essential HTN & hypertensive renal disease  6. Alzheimer disease  14. Parkinson disease  7. Diabetes mellitus  15. Assault (homicide)  8. Influenza and pneumonia CDC - Top 15 deaths in 2010  Released from CDC 10/2012– Vital Statistics Report (don’t see homicide here)  1. Heart disease (diseases of the heart)  9. Nephritis, nephrotic syndrome, & nephrosis  2. Cancer (malignant neoplasms)  10. Suicide (more suicides)  3. Chronic lower respiratory diseases  11. Septicemia  4. CVA  12. Chronic liver disease and cirrhosis  5. Accidents (unintentional injuries)  13. Essential HTN & hypertensive renal disease  6. Alzheimer disease  14. Parkinson disease  7. Diabetes mellitus  15. Pneumonitis due to solids & liquids – nursing home,  8. Influenza and pneumonia hospital, they aspirate something and die! Cancer Incidence vs. Cancer Death  Men  Since 1930, males have seen a sharp  in deaths d/t lung cancer  Correlates directly w/ cigarette smoking  Since 1930, males have seen a sharp  in deaths from stomach cancer  d/t a sharp  in use of nitrates in the diet  Prostate, colon, pancreas, liver, and leukemia death rates in men have remained relatively constant Cancer Incidence vs. Cancer Death  Women  Since 1930, women have seen a gradual  in death rates for stomach, uterine, & colon cancer  Since 1930, women have seen a sharp  in death rates for lung cancer  Correlates w/  in female cigarette use  Death rates for breast, pancreas, and ovarian cancers have remained constant - Discouraging since so much attention and research has focused on breast cancer and rates are stable, not improving

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LINKS to Cancer  Tobacco = #1  Linked to lung, bladder, and pancreatic cancer (or work at airport)  Alcohol  Linked to primary liver cancer (hepatocellular carcinoma)  Sexual behaviors  Linked to cervical cancer. Human papilloma virus (HPV)* (#1 transmitted)  Occupational exposures  Asbestos = 100% link to lung Ca, silica, plastics (PVC), cadmium, nickel, chromium  Pharmaceutical agents  DES (diethylstilbestrol = synthetic estrogen), estrogen supplements (HRT)  Radiation  Ionizing as well as ultraviolet (coming from ground, bombs)  Endogenous hormones  Breast, ovary, uterus, prostate (we create them bc we create  hormones)  Geography - In comparison to the U.S., breast cancer in Japan is rare, stomach cancer more common (use more nitrates) - Asians who move to the U.S. assume a higher risk than relatives in Asia  Infectious agents (virus and bacteria) - RNA viruses = linked to rare leukemias in Japan & Caribbean (hepatitis) - DNA viruses: o EBV – Burkitt’s lymphoma (ebstein barr) o HBV – hepatocellular carcinoma (hep B) o HCV – hepatocellular carcinoma (hep C) o HPV – cervical cancer (human papilloma) o H. pylori – gastric cancer & MALT lymphoma (bacteria, NOT a virus!!) o HHV8 – Kaposi sarcoma (human herpes virus 8)  Age - Most incidence and mortality occurs between 55 - 75 years of age. Incidence  w/ age until 75 y then ’s! - MC cancers in this age group: Colon, breast, prostate, lung, pancreatic, uterine, cervical, brain, & ovarian Ca - May be d/t accumulated genetic damage = as we age, more damage!  Genetics  Clearly plays a role in inheritance in some cancers, but the role is not a simple issue! - genetics = 5-10%, 95% is sporadic! Pathophysiology  Malignant Neoplasms/Tumors  Malignant tumor starts from 1 cell that has sustained damage to its genome that causes it to proliferate abnormally - Leukemias = monoclonal = all cells have same defect and they proliferate all the same & clone is the same! - First forming clone of identical cells which later mutate! Clone mutates  Key! - Then forming a distinct tumor if left unchecked! (different segments bc dif mutations doing dif things)  Malignant tumor cells exhibit different behaviors than normal cells  DON’T respond to normal growth regulatory signals from other cells & some cells secrete own growth factors! - Don’t listen to chemical messengers & cells proliferate unnecessarily.  

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As they grow, tumor cells acquire properties that allow them to flourish  at expense of normal cells in the area. They secrete enzymes that break down normal cell and tissue barriers (basement membrane), allowing them to infiltrate into adjacent tissues, lymphatic channels, blood vessels, and eventually to spread throughout the body - Invade and metastasize! (via methods above, if fail its bc they don’t have right machinery to do it) Proliferating tumor cells DO NOT “wear out” and die after a specific number of cell divisions as normal cells do! - They don’t loose telomerase, the telomeres normally shorten then cell die but not in this case! They become immortal and proliferate indefinitely

The Genetics of Cancer  There are four large groups of genes that play an important role in regulating cell functions  Derangement of these are associated with the formation of tumors: (multistep insults that are numerous) - Proto-oncogenes - Tumor-suppressor genes - DNA repair genes - Genes that regulate apoptosis o May be dominant (need only to lose 1 allele)

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Proto-oncogenes (The Genetics of Cancer) = NORMAL growth genes in human chromosome  Proto-oncogenes = Promote some aspects of cell growth, differentiation, or mitotic activity  If a proto-oncogene undergoes a mutation or is translocated to another chromosome, it becomes an oncogene - Usually requires mutation of only 1 allele  Oncogene = an abnormally functioning gene that will stimulate XS cell growth, leading to unrestricted cell proliferation Tumor-Suppressor Genes (The Genetics of Cancer)  Tumor-suppressor genes function to suppress cell proliferation (allow to grow or make them undergo apoptosis) - Growth inhibiting genes - “Brakes” on cellular proliferation - Loss of their function by mutation leads to unrestrained cell growth  They exist in pairs at corresponding gene loci on homologous chromosomes, (both on same # chromosome).  On the gene = there are alleles = need to loose both! For tumor suppresser gene to malfunction. - and BOTH suppressor alleles must cease to function BEFORE the cell malfunctions. - Tumor suppressor genes lives in pairs. One can be kille doff or not be born with one (one each from mom & dad)  Common genes: P53 gene & Retinoblastoma gene (RB) P53 GENE (Tumor Suppressor Genes) = The “guardian of the genome”  Senses DNA damage  Stops the cell cycle for repair (quiescence = takes a nap) (mech not understood)  Determines adequacy of DNA repair - If appropriate, cell continues in the cell cycle - If repair is inadequate, the cell will undergo permanent arrest o  Senescense = permanent cell cycle arrest (Not completely understood). Sense DNA damage & stop cycle - Apoptosis – directed by specific genes  Ultimate protective mechanism against neoplastic transformation   

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>70% of cancers have a defect in this gene! (oncogene issue & P53 gene issue). Proto-oncogene becomes mutated = oncogene w/ uncontrolled cell proliferation + p53 gene get losts from both mom & dad => damage unrepaired! With homozygous loss of p53: - DNA damage goes unrepaired & Mutations become fixed in dividing cells  Cells become malignant cells P53 is activated by different mechanisms: - Cell stress d/t anoxia (lack of O2), inappropriate oncogene signaling (wild proliferation), & DNA damage o Proto-oncogene = normal cell signaling but oncogene = inappropriate cell signaling. Other common tumor suppressor genes: - RB, APC, RB1, BRCA-1, BRCA-2 o RB = retinoblastoma. If second allele lost as an adult = loose guardian of genome o APC = Adenomatous polyposis coli = genetic disaster gene, its dominant! Just need 1  colon w/ polyps o BRCA = both TS genes. BUT Mutated BRCA1/2 genes = cancer (we all have BRCA but its mutated)

DNA Repair Genes (The Genetics of Cancer)  Any change in the normal arrangement of DNA nucleotides on the DNA chain constitutes a DNA mutation  DNA repair genes regulate the processes that monitor and repair any error in DNA duplication - During cell division OR, caused by DNA damage from radiation, chemicals, or other environmental agents  Failure of DNA repair genes to function  likelihood of DNA mutations within the cell  Mutations get passed along The Genetics of Cancer  Cancers result from multiple genetic insults to genome, not from mutations of a single gene (rare for 1 gene = Ca)  Typically insults are characterized by: Activation of oncogenes AND Loss of function of tumor suppressor genes  Once a cell has been deregulated and has formed a tumor, -  additional random genetic changes take place in tumor cells  Indicative of instability of the tumor cell genome Failure of Immune Defenses (The Genetics of Cancer)  Mutations leading to neoplastic transformation of cells are relatively common (everyone has neoplastic cells)  A mutant cell often produces different cell proteins not present in a normal cell  Different cell proteins  recognized as abnormal by immune system  The body recognizes the mutation & attempts to destroy abnormal cells w/ cell-mediated & humoral mechanisms - Cell mediated (Cytotoxic T-lymphocytes, natural killer cells, macrophages) – dominant mechanism - Humoral mediated (anti-tumor antibodies) = B cells (plasma cells)  A tumor may partially be considered a failure of the body’s immune defenses

L. Kaur

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Heredity and Tumors* (EQ) (The Genetics of Cancer)  MC malignant tumors have NO strong hereditary predisposition.  Hereditary factors do play a role in some common tumors  *Predisposition is the result of: -  Multifactorial inheritance patterns o Results in an inherited set of genes that influences hormonal or enzyme regulated biochemical process within the body that slightly increases the susceptibility to a specific cancer o (murky, familial inheritance that can be hormonal (more estrogen) OR produce set of enzymes that function differently  leave group to be more susceptible to spp Ca than general population) hard to detect -

 Autosomal Dominant patterns o Result in a greatly elevated risk of cancer (you have a bad gene, no denying it)

HEREDITARY Cancers* know this slide!  The following hereditary cancers account for no more than 5 – 10% of all human cancers  Hereditary forms of cancer can be divided into 3 categories: - 1) Inherited cancer syndromes o AD inheritance = directly inherited from mom or dad (ex: Retinoblastoma, familial adenomatous polyposis) -

2) Familial cancers o Common cancers that occur sporadically, also occur in families (colon, breast, ovary, brain)  Across the family tree, not necessarily from mom or dad (breast Ca with male uncle = BRCA = familial) o Transmission mechanism is not always clear = AD? Multifactorial mutations? (familial vs sporadic)

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3) Defects in DNA repair genes o Autosomal recessive syndromes of defective DNA repair genes

INHERITED cancer syndromes  Inheritance of a single mutant gene greatly increases the risk of a person developing a malignancy-genetic defect related to a mutated tumor suppressor gene 

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Example: Retinoblastoma (RB gene) - Type of cancer that develops in the retinal cell(s) of a child’s eye(s) -

Approximately 40% inherited - runs in families (MC Dx in 4 months old or less) o Inherited one mutant allele from parent, then develops a sporadic mutation in the other allele during fetal development = so now have 2 bad copies (inherited + sporadic mutation  all daughter cells r bad copies)   Causes “wild” proliferation & affects ALL retinal cells from that line of developing retinal cells o 90% will develop retinoblastoma = the actual tumor o Tumors develop earlier, usually multiple tumors, bilaterally (can also have later in life! If mutated later) o This type associated with sarcomas, breast, bladder, & lung CA (chromosome 13 & RB gene)

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60% sporadic (MC Dx by 2 yo) o TWO spontaneously mutated alleles during development in a single retinal cell (not all retinal cells) o Child develops one tumor in one eye, does not pass on mutation! (bc its sporadic)

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BOTH types present with LEUKOCORIA – loss of red reflex!

Example: Familial adenomatous polyposis of the colon (FAP) - FAP results in numerous polyps in the colon at birth or shortly after = Up to 2500 polyps! - Autosomal dominant inheritance pattern o Only ONE “bad” gene necessary to cause disease. Loss of the APC tumor suppressor gene (AD!) - 100% chance of developing colon cancer by age 50, most develop CA by age 39 yo - Treatment: prophylactic colectomy by age 25 yo (take out colon, have outpouching). Can have dif inherited/genetic. If inherited = APC (AD) will have colon Ca!

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FAMILIAL Cancers:  Type of cancer that runs in families and are characterized by: - An earlier age of onset than sporadic cancers. Tumors in 2 or more close relatives. Multiple / bilateral tumors  Genetic transmission pattern is unclear  May be AD gene or multifactorial = Unknown - AD pattern thought to affect a tumor suppressor gene - AR pattern thought to affect DNA repair genes  Examples: breast, colon, ovary, and brain  One genetic linkage that is known is the inheritance of mutated BRCA 1 & BRCA 2 genes - Leading to familial breast & familial ovarian cancer. Also leads to Prostate cancer  BRCA 1 and BRCA 2 are tumor suppressor genes, and when mutated, allows malignant growth to occur  Tumor markers: can test for these mutated genes  Expensive, and insurance may not cover it  Some women are screened at an early age for mutations - They will opt for prophylactic mastectomy and hysterectomy with oophrectomy Defective DNA Repair  Represents small group of autosomal recessive dz characterized by DNA instability or chromosomal instability  DNA loses ability to repair itself  Example: Xeroderma pigmentosum = DNA cannot repair itself after UV light exposure (best studied example) - Abnormal pigmentation and dryness on sun-exposed areas o Freckles at an early age - Extreme skin sensitivity to sunlight o Severe sunburn after brief exposure, lasting for weeks o Eyes are extremely sensitive to light - Patients have increased risk of developing skin cancers. 8 yo, commonly  risk of metastatic skin cancer o ( = squamous cell carcinoma, basil CC, sebaceous CC, malignant melanoma, fibrosarcoma) - 20% that get defective DNA repair  will also have neural aspect as well! o microcephaly, spasticity, hyporeflexia, ataxia, chorea, deafness, mental retardation, hypogonadism, dwarfism. - Treatment: AVOID SUN EXPOSURE, dermatologist Benign Neoplasms  Usually an encapsulated mass or tumor. Exhibits expansile growth = compress surrounding normal tissue!  Usually designated with the suffix “-oma” - Leiomyoma, meningioma, fibroma, chondroma, teratoma => derived from a germ cell - Exceptions to this rule = lymphoma, sarcoma (these aren’t benign)  Usually not too concerned about the growths  May be life threatening depending on location (trachea or nerve)  Growth pattern is important Benign Neoplasms - Review  If the benign epithelial growth resembles a gland in structure we give the term adenoma  Benign growths that project above the surface on a stalk are referred to as polyps  Papilloma, or papillary growth = benign epithelial neoplasms growing on a surface - produce microscopic finger-like projections  Cystadenomas - hollow cystic masses typically seen in the ovary  Fibroma - benign mass growing in connective tissue  Chondroma - benign mass growing in cartilage  Osteoma – benign mass growing in bone  Is there a risk that a benign growth may transform into a malignancy? Depends  Adenomas of the colon  40% of sessile villous adenomas more than 4 cm in diameter transform to malignancy! - sessile =stalkless. villous = small projection from colon  Leiomyomas of the uterus  Extremely rare transformation to a leiomyosarcoma Characteristics of Benign Growths Similarity to cell of origin in appearance & growth pattern  Growth is uniform across the lesion. Grows with compression of surrounding tissue  Growth pattern is smooth without ulceration or necrosis  KEY feature  Rate of growth is generally SLOW. Vascularity = adequate. Recurrence = rate low  NO systemic effects unless caused by compression 

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Preneoplastic Disorders  = Some benign clinical conditions are well-recognized predispositions to malignant neoplasms  The underlying feature of preneoplastic disorders is unwarranted & persistent cell proliferation, hyperplastic or dysplastic proliferations, and/or inflammatory conditions  What conditions are considered preneoplastic? - Ex: Chronic gastritis, ulcerative colitis, liver cirrhosis, margins of an unhealed skin wound (picking skin) & HPV - Chronic inflammation is a key to all of these!  Essentially promotes the growth of a neoplasm & malignant transformation - Note: most preneoplastic disorders do not turn into cancer, but they have the ability to do so!  Examples:  ALL DUE TO CHRONIC INFLAMMATION! (dysplasia & metaplasia = cells become malignant) - Stomach cancer frequently occurs at the margins of persistent peptic ulcers (also Barretts esophagus) - Chronic hepatitis B & C, & liver cirrhosis are clearly linked w/ the development of hepatocellular carcinoma - Chronic ulcerative colitis has increased risk for colorectal carcinoma with longstanding disease - Villous colon adenomas = high risk (40% go to malignancy) - PTs w/ long standing fibroadenomas and fibrocystic disease of breast that include cellular necrosis and unwanted cellular proliferation are at greater risk for developing breast cancer Characteristics of Malignant Growths = MANY systemic effects  Growth occurs w/ invasion of surrounding normal tissues, is primary at the EDGES & is irregular.  Ulceration & necrosis are common  A hallmark of malignancy  Rate of growth is generally fast. Recurrence rate is high. ( recurrence & growth) Limitless replicative ability  May lose similarity of appearance to cell of origin = Referred to as differentiation of the cells  Vascularity = Usually very good at the growing edge (want to grow outward) & Poor at the center (outgrows blood supply)  Necrosis at center  A hallmark of malignancy  Self sufficiency in growth signals. Insensitivity to growth inhibitory signals. Overexpression of receptors  Evasion of apoptosis. Ability to invade & metastasize. Development of sustained angiogenesis Overexpression of Receptors (big research topic)  Overexpression of growth factor receptors make cells hypersensitive to growth factor levels which would NOT normally generate proliferation (cancer  receptors = can collect more growth factors)  Epidermal growth factor (EGF) receptor family - Overexpressed in: 80% of SCC of lung. >50% of glioblastomas. 80-100% of epithelial tumors of head & neck  A related receptor is the HER2/NEU receptor - Overexpressed in 25-30% of: Breast cancers. Adenocarcinomas of the lung, ovary, & salivary glands - High level of HER2/NEU is associated with poor Px - New research/treatment involves blocking this receptor with anti-HER2/NEU antibody Tumors: Blood Supply & Necrosis  Tumors initially derive their blood supply from the tissues they invade & remain in situ (and remain small)  Later, malignant tumors induce new BV to proliferate in adjacent normal tissues to supply demands of the rapidly growing tumor outward - Neovascularization or vasculogenesis (Neovascularization = NOT normal = tumor isn’t normal) (EQ*) o Vascular genesis = bone marrow to give us the blood supply (vessels out of nothing) - Tumor vasculature is abnormal vasculature o Leaky, dilated, w/ haphazard pattern of connections  Leads to blood loss and anemia  A malignant tumor may outgrow its blood supply, so parts of tumor w/ the poorest blood supply undergo necrosis!  Depending on tumor location, blood supply will be rich or poor.  If tumor is growing w/in lung (surrounded by normal tissue), blood supply is best = periphery & poorest = center!  If tumor is growing outward from epithelial surface (ex: colon), BEST blood supply = base & poorest = surface. - Often, small BV are exposed in ulcerated base of a tumor.  Blood may ooze continuously from the vessels, eventually leading to anemia from chronic blood loss! - Male or child-bearing age female with blood loss & anemia, DDx = cancer - Leaky vessels from neovascularization and vasculogenesis, or ulcerated sections of tumor that expose vessels  Blood within the GI tract may produce a + hemoccult test, depending on the site of the tumor  Possible = ulcerated tumor is source of severe hemorrhage.

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*Mechanism of Spread  Background  Tumor cells must go through a series of steps that are subject to influences that may kill the breakaway tumor cells  To illustrate this point, studies in animals & humans have shown that millions of tumor cells are released into the circulation each day from a primary tumor, yet only a few metastases are produced.Why inefficient? Mechanism of Spread  Overview:*  A carcinoma first must breach the underlying basement membrane (ECM material), then pass thru the interstitial connective tissue (ECM), & then gain access into circulation by penetrating the vascular basement membrane  The cycle repeats when the tumor cell (or tumor emboli) exits the circulation to the distant site of metastasis  Tumor cells must go across the vascular basement membrane again, through the interstitial ECM again, and into the basement membrane ECM of the tissue they are invading  Active process that not all cancer cells can do Picture  Blue cancerous cell (metastatic subclones) chew thru basement membrane & interstitial membrane into vessel. Squeezes thru endothelial cells. 1) Tumor cell can go it alone (not successful) OR 2) tumor cell can collect together = tumor cell emboli (immune system attacks) = more efficient OR 3) become tumor platelet emboli (HIDES from immune system) OR 4) become tumor leukocytes  3&4 is more successful but don’t have the machinery to do this.  Gets out of vasculature tree & into new organ! Grows there. Mechanism of Spread  Within a tumor there exists a metastatic potential  Not all tumor cells possess all of the necessary “machinery” to complete the metastatic process!  The process can be divided into 4 phases: - 1) Detachment of tumor cells from each other - 2) Degradation of the ECM (with enzymes) - 3) Attachment of tumor cells to matrix components - 4) Migration of tumor cells  Homing follows migration Mechanism of Spread  Detachment of Tumor Cells  To detach & spread, tumor cells must first loosen up! (in normal cells, adhesive proteins hold cells together)  These include the family of proteins known as cadherins & integrins - E-cadherins are the “glue” between cells & E-cadherin function is LOST in nearly all epithelial cancers - Integrins have cell-matrix and cell-cell adhesion properties  Both classes of proteins are reduced in most malignant cells making them less likely to stay together - One article states that d/t sub-families of integrins one may help it to loosen from other cells, and another provide good binding to the ECM to metastasize easily. (need both types of integrins to work) Mechanism of Spread  Local Degradation of the Basement Membrane & Interstitial Connective Tissue  Tumor cells must elaborate enzymes that degrade the basement membrane (begin & end) & interstitial connective tissue - They can also induce normal cells (fibroblasts and inflammatory cells) to degrade the basement membrane too  Enzymes include MMPs = matrix metalo-protease (collagenase= protein), cathepsin D, and others. -  Proteases - Benign tumor cells exhibit little of this enzymatic activity  Levels of cathepsin D in the serum may be prognostic in PTs w/ breast cancer  Patients with elevated levels of cathepsin D fare less well than those without elevated levels ( enzyme = bad) - Presumed to be harboring a more invasive tumor d/t ↑ enzyme  Tx = Protease inhibitors

L. Kaur

Mechanism of Spread  Attachment to Matrix  Next, malignant cells must become more firmly attached to basement membrane & interstitial connective tissue  Accomplished by presence of more receptors for basement membrane proteins - Cancer cells have more receptors for laminin and fibronectin than seen in normal cells - Laminin & fibronectin are components of the normal basement membrane and interstitial connective tissues Mechanism of Spread  Locomotion  Locomotion is the next step in metastasis  Propelling tumor cells through the degraded basement membrane and interstitial matrix (ECM)  Occurs through the areas of matrix degradation  Migration is mediated by tumor cell-derived cytokines which induce motility by binding to a specific receptor - Autocrine motility factors  Next must either “chew through” the neighboring tissue or the vasculature to continue the process Mechanism of Spread  Vascular Dissemination and Homing of Tumor Cells  Once in the general circulation, tumor cells are particularly vulnerable to destruction by immune defenses  First, tumor cells face a daunting task just to continue the process of metastasis & not get recognized - They need to fall out of circulation, drop out & resist blood flow to initiate the process of escaping the vessel  Cytotoxic T-lymphocytes (CTLs), natural killer cells (NK cells) (specific class of lymphocyte), & macrophages are important in controlling hematogenous spread of tumors  Homing is the process & determination of where metastatic cell will ‘land’ once the cell is in the vasculature/BV - Most circulate as single cells OR “clumps” of tumor cells  Particularly vulnerable to immune system! - Some circulate by binding to leukocytes or platelets  Advantageous, bypasses the immune system  Within the circulation, some tumor cells aggregate in clumps => tumor clumps attract platelets (or lymphocytes)  Formation of platelet-tumor aggregates enhance tumor cell survival & implantability  escapes immune system  Arrest and extravasation (getting through the vessel) of tumor emboli at distant sites involves adhesion to the endothelium or exposed basement membrane at sites of endothelial injury  Attachment to the distant site is followed by emergence through the basement membrane using the same mechanisms by which the tumor cells escaped Three Homing Mechanisms: **EQ (Liver, Lung, Adrenal gland = lots of ‘orange’ receptors)  Cancer cells metastasize to organ that represents the 1st capillary bed they encounter after entering circulation  2) Other cell types bind to predictable, specific organs or tissues - Prostate cancer – bone - Lung cancer – adrenals, never skeletal muscle - Process may be related to the adhesion molecules expressed on the tumor cell and the “matching” ligands expressed on the organ  3) Chemotaxis is another homing mechanism - Chemokines direct the movement of cancer cells to a new location - Breast cancer cells express levels of chemokine receptors o  cells grab chemokines & will move them to a new, specific location - Ligands for the receptor/chemokines expressed only on organs where breast cancer metastasizes and attaches Grading of Cancer (grading = microscope, Staging = surgery)  Grading is based on: The microscopic appearance of tumor cells under the microscope  Bx or excision - Also based on the # of mitoses w/in the tumor & appearance of the nuclei  Graded I – IV, w/ increasing abnormality  Generally,  grade = aggression of tumor & poorer outcome for Pt.  Different grading systems – prostate cancer uses the Gleason score, grades I – X (complicated & for prostate Ca)  Description and comparison of cells is termed differentiation  Degree of differentiation is the extent which cancerous cells resemble the comparable normal cells - Morphologically & functionally  Overview: - Well differentiated – abnormal cells looks much like the normal cells of origin - Poorly differentiated – abnormal cells do not look like the normal cells of origin

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Grading of Cancer  4 stages ** (MC is grade 1&2 = pull weeds, freq come back)  Grade 1 – well differentiated = Low grade  Grade 2 – moderately differentiated = Intermediate grade  Grade 3 – poorly differentiated = High grade  Grade 4 – undifferentiated - Anaplasia (Anaplastic) – lack of differentiation - Primitive, embryonic looking cells - Angry, aggressive cells, difficult to treat (familial bladder cancer) Staging of Cancers  Based on: The size of the primary lesion & Extent of spread   Cancer stage =  outcome.  Many different staging systems - MC = TNM system (TMN = Tumor/Nodes/Metastasis). Covers many types of Cancer - Other specific staging systems focus on a particular type of cancer (BQ, not an EQ) o Modified Dukes Criteria  colorectal cancer o Ann Arbor Criteria  lymphomas Staging of Cancers  TNM System  T: size & extent of tumor  N: extent of spread to the lymph nodes  M: the presence of metastasis Staging  Stage 0 and I = Superficial disease, CIS  Stage II = Invasion into muscle  Stage III = Deeper invasion into muscle  Stage IV = Invasion to adjacent structures (local metastasis)  Nodes +/ Metastasis +/-

Important Terms = Dysplasia, Carcinoma in situ, Metaplasia Dysplasia  Characterized by loss of uniformity of individual epithelial cells & loss in their architectural orientation  Dysplasia does not mean cancer  can be Pre-cancerous changes, disordered growth  Frequently reversible = Mild to moderate changes are reversible & Epithelium can revert to normal  However, next step from highly dysplastic tissue is carcinoma in situ so => clear link between dysplasia & cancer - CIS = Marked dysplasia or dysplasia involving the entire thickness of the epithelium Carcinoma In Situ  A special designation  This is considered cancer, yet invasion & metastasis have NOT occurred - Last step prior to invasion & metastasis!!  Key = if left alone and untreated, invasion and metastasis WILL occur Metaplasia  Term used to describe a transformation of one epithelial cell type to another epithelial cell type  Usually done in response to a more hostile environment - Esophageal metaplasia o Squamous to columnar epithelium  Reversible  Carries an elevated risk of malignant transformation

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Terms of Malignancy = Invasion & Metastasis  Invasion - One of the hallmarks of cancer is invasion - Accompanied by progressive infiltration, invasion, and destruction of the surrounding normal tissue o Malignant lesions do not develop well-defined capsules like benign lesions 

Metastasis - Secondary tumor implants discontinuous with the primary tumor in remote tissues - Spread is by penetration into vascular and lymphatic channels o “Seeding” through vasculature and lymph nodes - Spread also occurs by direct extension to body cavities  Local metastasis (invasion) o Kidney to spine - Tumor cells always resemble tumor of origin regardless of location - 30% of newly diagnosed patients have identifiable metastasis - 20% of newly diagnosed patients have occult metastasis o Chemotherapy

Clinical Manifestations of Neoplasms  Local effects  Systemic manifestations  Paraneoplastic syndromes  Cachexia  Tumor markers Local Mass Effects  Early stages – asymptomatic  Later stages – depends on site - Compression of blood supply of involved organ - Bronchial carcinoma may only manifest itself as atelectasis, or pneumonia distal to the site - Tiny tumor within the brain could be fatal if compresses respiratory center - Renal cell carcinoma tumors often become massive before diagnosis - Ovarian cancer also may be massive before diagnosis Systemic Manifestations  Usually seen in more advanced states  Up to 75% of all persons with malignancy experience some systemic effects  Include anorexia, nausea, weight loss, malaise, night sweats, fever, anemia, infection  Paraneoplastic syndromes also cause systemic sx - “Alongside cancer” - Used to denote systemic effects that cannot be attributed either to direct invasion or to distant metastases, or by elaboration of hormones indigenous to the tumor - Malignancy produces a substance that creates symptoms Pathophysiology of Paraneoplastic syndromes = can be caused by a variety of mechanisms:  Tumor secretion of proteins not associated with the normal tissue - Hormones (common) - Cytokines that produce local tissue destruction  Antibodies that are directed against tumor cell antigens that have cross reacted with normal tissue antigens and create neurologic symptoms  Unknown mechanisms - Unidentified tumor products or circulating immune complexes that create specific SXs in specific cancers - Osteoarthropathy is a paraneoplastic syndrome associated with bronchogenic carcinoma

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Systemic Manifestations  Paraneoplastic Syndromes  Occurs in 10-15% of patients  ~Few percent if remove cachexia from the list  Important to recognize because: - May be the earliest manifestation of an underlying malignancy o 2/3 of paraneoplastic syndromes arise before the malignancy is dx - May represent significant clinical problems that may be lethal  Severe electrolyte disturbances - May mimic metastatic dz & make Tx more difficult o When actually a small, treatable tumor is present - If you’re aware of the syndrome, you may find an early tumor! - Fix the tumor, you fix the paraneoplastic syndrome o Exceptions - Cancer recurrence may be preceded by return of the systemic symptoms  Paraneoplastic syndromes are diverse and associated with many different tumors  Clinical findings may resemble primary metabolic, hematologic, dermatologic, neuromuscular, or specific cancer related syndromes 

MC syndromes are: Hypercalcemia, Cushing syndrome & Nonbacterial thrombotic endocarditis

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MC tumors associated with these syndromes are: Lung CA, Breast CA, & Hematologic malignancies

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Hypercalcemia - Presence of hypercalcemia can be multifactorial - MC mechanism is the synthesis of a parathyroid hormone-related protein by the tumor cells - TGF-α produced by the tumor may also activate osteoclasts - Hypercalcemia d/t widespread osteolytic metastatic disease of the bone is NOT a paraneoplastic syndrome o Skeletal metastases w/ a direct cause

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Cushing Syndrome - A paraneoplastic syndrome related to tumor cell production of ACTH or ACTH-like polypeptides o MC in small cell (oat cell) lung CA

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Other effects: - Sometimes one tumor can induce multiple syndromes at the same time - Bronchogenic carcinomas may elaborate ACTH, ADH, PTH, serotonin, human chorionic gonadotropin, others - Paraneoplastic syndromes may manifest as hypercoagulability leading to DVTs and nonbacterial thrombotic endocarditis

Cachexia  Syndrome characterized by loss of body fat and lean body mass  Accompanied by profound weakness, anorexia, and anemia  Not caused by nutritional demands of the tumor  Current thought is a result of cytokines: produced by the tumor or by the host in response to the tumor - TNF-, IL-1, IFN- are examples  Puts this in the realm of paraneoplastic syndrome Paraneoplastic Syndromes Syndrome Cushing syndrome Hypercalcemia Hyponatremia Polycythemia

Mechanism ACTH – like substance Parathyroid – like substance Inappropriate ADH secretino Erythropoietin – like substance

Example Small cell (Oat) carcinoma Lung cancer (squamous cell) Small cell (Oat) carcinoma Renal cell carcinoma

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Tumor Markers  Tumor-associated enzymes, hormones, or markers within serum indicating disease, but cannot be used for definitive diagnosis of CA - Substances which should be absent or present in very low quantities normally - Low sensitivity and specificity  Some contribute to finding cases through screening - In some instances helps to determine effectiveness of Tx or recurrence of disease  Prostate specific antigen (PSA), carcinoembryonic antigen (CEA), alpha fetoprotein (AFP), human chorionic gonadotropin (HCG), alkaline phosphatase, CA-125 - Some can be used for screening, others cannot - Some used only for effectiveness of Tx or disease recurrence 

Clinical effectiveness or usefulness of markers is variable - Agents have no physiologic effects in adults - By age 50, all males should have a baseline PSA determined o Values greater than 4 ng/ml may indicate prostate disease (cancer, BPH, prostatitis, ejaculation)  Low specificity - PSA prior to and following radical prostatectomy o Very high prior to surgery, then drops to normal levels after surgery o If after a year, PSA levels increase, what does that mean?

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Sometimes patients with normal PSA values present with prostate cancer - Need to pay attention to changes in PSA levels over time o Eg. Going from 1 to 2 ng/ml in 1 year is usually significant Only about 40% of patients with colon cancer will express CEA - Clinical effectiveness only limited to those patients with elevated CEA levels  Low sensitivity - CEA also elevated in pancreas, stomach, and breast  Low specificity Elevated alkaline phosphatase is suggestive of bone metastasis - Especially for prostate cancer!!

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HCG monitored in cases of testicular and ovarian germ cell tumors to detect recurrence AFP can indicate hepatocellular carcinomas, germ cell cancers, and embryonal cancers Chromosomal abnormalities – Philadelphia chromosome in CML, ALL, and AML is another classic example - Use of fluorescence in situ hybridization (FISH) test to detect chromosomal abnormalities is increasing o Can find small, microdeletions/translocations for many cancers BRCA1, BRCA2 CA-125

Tumor Markers BRCA1&2 Mutations  ~ 5-10% of breast cancers are related to specific inherited mutations  Suspect inherited mutated gene when: - Breast cancer occurs before menopause - Bilateral cancer occurs - Have other associated cancers in the family (ovarian) - Cases of both breast and ovarian cancer in family - Family member with primary cancer at two sites - Significant family hx o Multiple family relatives affected - Belong to certain ethnic groups (Ashkenazi Jewish decent) - Have a male in the family with breast cancer*  ~50% have BRCA1 mutation (chromosome 17)  ~50% have BRCA2 mutation (chromosome 13)

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BRCA1 and BRCA2 Mutations  BRCA1 & BRCA2 are tumor suppressor genes - The gene product is a protein that inhibits growth - Also halts the cell cycle and calls in DNA repair genes - When mutated, the gene product is defective and inhibition of growth is removed - Brakes removed…unchecked cell cycle and DNA 

Women w/ an inherited mutation to BRCA1 have an 80% chance of developing breast or ovarian cancer by age 70 - They inherit one bad copy as a germline mutation and have a sporadic “hit” to the other allele - 7% chance of a woman with normal BRCA1 to develop breast cancer sporadically o Role of BRCA1 & 2 is less clear in sporadic breast Ca bc they are infrequent mutations in sporadic tumors

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Males with a BRCA1 mutation have a slightly higher risk of prostate cancer BRCA2 gene mutation increases the risk of breast CA in both men and women, as well as other cancers: - Ovarian, prostate, pancreas, gallbladder, bile ducts, stomach, lymphoma, and melanocytes in men and women

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BRCA1 & BRCA2 Genes Ovarian Cancer  Majority of hereditary ovarian cancers caused by mutations in the BRCA genes - Increased risk for both ovarian and breast cancers  BRCA1 mutations = increase overall risk for ovarian CA by 30%  BRCA2 mutations = slightly lower risk  8-10% of sporadic ovarian cancers have BRCA1 or BRCA2 mutations too  HER2/NEU is overexpressed in 35% of ovarian cancers  POOR Px!!  K-RAS protein is overexpressed in 30% of (mostly benign) ovarian tumors  P53 is mutated in 50% of all ovarian cancers

Cancer Antigen-125 or CA-125 Ovarian Cancer  Elevations of protein CA-125 have been reported in 75% - 90% of women with epithelial ovarian cancer - Many types of ovarian cancers: stromal, follicle lining granulosa cells, germ cells  Protein is undetectable in as many as 50% of women with cancer limited to the ovary - Not sensitive for early detection  Present in high concentrations in a variety of benign conditions as well as non-ovarian cancers (not specific) - Increased in pregnancy, normal menstruation, endometriosis, uterine fibroids, pancreatitis, PID, liver disease, benign ovarian tumors, breast CA, lung CA, colon CA, fallopian tube CA  Used best in monitoring response to ovarian CA therapy - Small rise or fall is not significant - Halving or doubling is significant

Recent Developments  Number of cancer deaths in the United States has decreased  Due to a number of factors including better and more aggressive surgery, chemotherapy, radiation, and combinations  Fewer adults smoking  Have seen decreases in lung, breast, prostate cancer deaths  Most dramatic – reduction in colon cancer deaths due to widespread use of colonoscopy