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patho > neoplasia > Flashcards

neoplasia Flashcards

1
Q

neoplasia (tumors)

A

-new growth

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2
Q

tumor

A

swelling

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3
Q

neoplasm

A

-collection of cells and stroma composing new growth
-“genetic disorder of cell growth triggered by acquired or less commonly inherited mutations affecting a single cell and its progeny”

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4
Q

benign tumors

A

-oma = benign neoplasm
-Mesenchymal tumors
-chrondroma: cartilaginous tumor
-fibroma: fibrous tumor
-osteoma: bone tumor
-leiomyoma – smooth muscle tumor

-Epithelial tumor
-adenoma: tumor forming glands (e.g. colon, stomach)
-squamous cell carcinoma: tumor from squamous epithelium
-papilloma: tumor with finger like projections
-papillary cystadenoma: papillary and cystic tumor forming glands
-ex. lipoma

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5
Q

malignant tumors

A

-Carcinomas: epithelial tumors
-adenocarcinoma: gland forming tumor
-squamous cell carcinoma: squamous differentiation
-undifferentiated carcinoma: no differentiation

-Sarcomas: mesenchymal tumor
-chrondrosarcoma: cartilaginous tumor
-fibrosarcoma: fibrous tumor
-osteosarcoma: bone tumor
-ex. liposarcoma

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6
Q

exceptions to -oma

A

-Sarcomas tend to metastasize via blood; carcinomas more likely spread via lymphatics
-Note nomenclature of these malignancies: Mesothelioma, seminoma, lymphoma/leukemia, melanoma, hepatocellular carcinoma (hepatoma) – all malignant
-Teratoma – all 3 cell lineages: ectoderm, endoderm, mesoderm mature or immature

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7
Q

A 60 year old woman has a benign tumor which arises from the bladder wall. What type of tumor is this most likely to be?

A

A transitional cell carcinoma- malignant
B adenocarcinoma- malignant
C leiomyosarcoma- malignant
D leiomyoma!!!!
E rhabdomyoma- benign skeletal muscle tumor

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8
Q

benign vs malignant

A

-Benign –
-Remains localized to site of origin, usually amenable to surgical removal
-slow growing, little or no mitotic activity
-usually rim of compressed fibrous tissue (capsule) which separates tumor – well-circumscribed
-Capsule and basement membrane intact
-ROUND

-Malignant –
-!Invasion and destruction of adjacent structures and spread to distant sites (metastasize)
-INVASION – BREACHING THE BASEMENT MEMBRANE
-METASTASIS – TUMOR AWAY (DISCONTINOUS) FROM PRIMARY SITE
-Metastasis via direct seeding of body cavities/surfaces (esp. ovarian), lymphatic spread (most common for initial spread of carcinoma), hematogenous spread
-irregular and ugly

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9
Q

differentiation!!!!!!!!!!!!!!!!!!!!!

A

-Helps determine GRADE of tumor – extent that the neoplastic cells resemble corresponding normal cells, morphologically and functionally
-Well (similar to mother cell) to moderately to poorly differentiated (irregular)

-Malignant – ability to metastasize
-Pleomorphism – variation in size and shape of cells
-Abnormal nuclear morphology
-Hyperchromasia
-Increased nuclear/cytoplasm ratio – may approach 1:1 ratio
-Increased mitotic rate (proliferative activity); bizarre mitotic figures more reliable

-Anaplasia – lack of differentiation, “to form backward”
-Loss of polarity – tumor cells grow in disorganized fashion
-Necrosis – outgrowth of blood supply, especially in large tumors

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10
Q

how do we grade

A

-microscopically
-HOW WELL do the tumor cells look like the NORMAL cells from which they arose?
-Micro comparison of normal colonic mucosa (left) and an adenomatous polyp (tubular adenoma) on (right).

-The neoplastic glands are more irregular with darker (hyperchromatic) and more crowded nuclei.

-This neoplasm is benign and well-differentiated = still closely resembles the normal colonic structure

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11
Q

anaplasia

A

-no differentiation into squamous or glandular epithelium
-variation in cellular and nuclear variation in size and shape

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12
Q

A 79 year old man has lower abdominal pain, increasing weakness, and fatigue. He lost 16 pounds in the past few months. His serum PSA is elevated. Rectal exam reveals an enlarged, indurated, nodular prostate. A needle biopsy of the prostate discloses invasive prostatic adenocarcinoma. Histological grading of this patient’s carcinoma is based primarily on which of the following criteria?

A

A. capsular involvement by carcinoma- stage
B. extent of regional lymph nodes involvement- stage
C. presence of pulmonary metastases- stage
D. resemblance to normal tissue of origin!!!!!!!!!!!!!!!!!
E. volume of prostate involved by tumor

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13
Q

dysplasia

A

-Disordered growth”, pre-malignant especially if high-grade
-Often occurs in metaplastic epithelium
-Loss of uniformity of individual cells and loss in architectural orientation
-Cells may be pleomorphic, higher N/C ratio, exhibit architectural disarray
-If dysplastic changes involve entire thickness of epithelium but do NOT go through the basement membrane -> CARCINOMA-IN-SITU
-carcinoma-in-situ is curable once resected
-Once dysplastic cells breach basement membrane: INVASIVE CARCINOMA
-Though dysplasia may be a precursor to malignancy, it does not always progress to malignancy -> always take it out

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14
Q

undifferentiated

A

-once you describe something as undifferentiated its malignant

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15
Q

stage

A

-based on extent of spread of cancer, size, local invasion, lymph node, involvement, metastasis
-once you hit lymph -> you go up a stage
-lymph invovlement = chemo
-stage 4- metastases

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16
Q

significance of nodal (lymph node) mets

A

-Prognostic
-Number of involved nodes is an important component of TNM staging system

-Therapeutic
-Overall risk of recurrence
-Extent of nodal involvement
-Histologic grade and other considerations
-“Adjuvant” chemotherapy!

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17
Q

grading vs staging

A

-Grade:
-Based on cellular appearance and mitotic activity microscopically
-Based on degree of differentiation
-idea that biological behaviour and differentiation are related,
-i.e., poorly differentiated tumors behave more aggressively
-Correlation not perfect

-Stage:
-Degree of localization/spread based on size, local and regional lymph node spread, and distant metastases
-determined clinically by surgery and/or radiology; more clinically relevant
-TNM Tumor, Nodes, Metastases
- T0 = in situ

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18
Q

STAGE TNM

A

-Tumor size or spread
-N- lymph node involved
-M- presence of metastases

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19
Q

grade: histology

A

-well differentiated
-moderately differentiated
-poorly differentiated
-undifferentiated, no resemblance to tissue of origin

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20
Q

predisposing factors for cancer

A

-Age – older (exception of childhood leukemia, brain and bone tumors)
-Genetics – familial cancer syndromes (early age onset, two or more primary relatives with the cancer)

-Nonhereditary conditions
-Chronic inflammatory conditions – cell injury, proliferation of cells to repair damage, activated immune cells produce ROS that may damage DNA and mediators that promote cell survival
-Precursor lesions – localized morphological changes in cells with increased risk for malignant transformation – hyperplasia, metaplasia, dysplasia
-Immunodeficiency

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21
Q

environment and cancer/epidemiology

A

-Infectious agents (e.g. HPV and cervical cancer)
-Smoking
-Alcohol
-Diet
-Obesity
-Reproductive history
-Environmental carcinogens – chemicals/radiation/viruses, etc.
-Sun exposure

-In US most common cancers:
-Males – Prostate, lung, colon
-Females – Breast, lung, colon

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22
Q

geographic and environmental

A

-Sun exposure- Melanomas 6x incidence New Zealand vs Iceland
-Smoking and alcohol abuse
-Body mass- Overweight = 50% increase in cancer
-Environmental vs racial factors

-Viral exposure
-Human papilloma virus (HPV) and cervical cancer
-Hepatitis B virus (HBV) and liver cancer (Africa, Asia)
-Epstein-Barr Virus (EBV) and lymphoma

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23
Q

hallmarks of malignant tumors

A

-Proliferate without external stimuli (growth signals), usually because of oncogene activation – self-sufficiency
-Insensitive to growth-inhibitory signals
-Undergo metabolic switch to aerobic glycolysis (Warburg effect) which enables synthesis of macromolecules needed for fast cell growth (dont need to know second part)
-Evade apoptosis (p53 inactivation or activation of anti-apoptotic genes)- tumors are resistant to programmed cell death
-Have limitless proliferative capacity = immortality (telomerase!)
-Sustained angiogenesis (new vessel growth)
-Ability to invade and metastasize
-Evade host immune response

24
Q

molecular basis of cancer

A

-NON-lethal genetic damage
-A tumor is formed by the clonal expansion of a single precursor cell (monoclonal)

-4 classes of normal regulatory genes (dont know details except p53)
-PROTO-oncogenes - normal genes that can becomeoncogenesdue to mutations or increasedexpression; code forproteinsthat help regulatecell growthanddifferentiation; Oncogenes -> Oncoproteins; Involved in normal cell growth and repair (Abl, HER, MYC, Ras) – growth promoting
-TUMOR SUPPRESSOR GENES - protect against unregulated cell growth (p53, APC, BRCA) – growth inhibiting
-DNA repair genes
-Anti-Apoptosis genes - overexpression prevents apoptosis (Bcl-2); apoptosis genes mutations prevent programmed cell death, i.e promotes proliferation

-Carcinogenesis is a multistep process

25
Q

oncogenes (dont need to know)

A

-Promote autonomous cell growth in cancer cells
Include
-growth factors
-growth factor receptors – receptor tyrosine kinases most important
-signal transduction proteins (RAS)
-nuclear regulatory proteins
-cell cycle regulators

-Created by mutations in proto-oncogenes (their unmutated cellular counterparts)
-Products are oncoproteins - promote cell growth in absence of normal growth promoting signals
-Mode of activation may be overexpression, amplification, point mutation, translocation

26
Q

ex: MYC oncogene- nuclear regulator

A

-Activation linked to proliferation; activates expression of many genes involved in cell growth
-Many ways MYC can be deregulated in cancer cells
-Translocation of the gene causes dysregulation of Myc expression in Burkitt lymphoma
-Amplified in breast, colon, lung and other cancers which results in overexpression

27
Q

RAS oncogene, example- signal transducer

A

-Most common type of abnormality involving proto-oncogenes in humans
-HRAS, KRAS, NRAS
-Point mutation of RAS genes - single most common abnormality of proto-oncogenes in human tumors
-15-20% of all human cancers express mutated RAS
-Usually carcinomas, esp. colon and pancreas, are associated with KRAS, bladder tumors with HRAS, and hematopoietic tumors with NRAS
-Mutated RAS protein is permanently activated (stimulates downstream regulators of proliferation), causing continuous stimulation of cells without external trigger

28
Q

tumor suppressor genes

A

-Stop cell proliferation – mutations in these genes cause failure of growth inhibition
-“Two-hit” hypothesis of oncogenesis (Knudson’s hypothesis) – two mutations (hits) which involve both alleles of gene required
-In familial cases one defective copy is inherited (first hit)
-In sporadic cases both normal alleles become mutated

29
Q

P53- tumor suppressor gene

A

-Tumor suppressor gene mutated in majority of cancers
-Normally regulates cell cycle progression, DNA repair, senescence, and apoptosis

-Normally prevents neoplastic transformation via
-Temporary cell cycle arrest (quiescence)
-Induction of permanent cell cycle arrest (senescence)
-Triggering programmed cell death (apoptosis)

-Acts mainly via cell cycle inhibitor p21 to cause cell cycle arrest
-Causes apoptosis by inducing transcription of genes such as BAX
-Required for G1/S checkpoint, main component of G2/M checkpoint
-“molecular policeman”: prevents propogation of genetically damaged cells

30
Q

p53

A

-Homozygous loss occurs in almost all types of cancer e.g. lung, colon, breast
-Over 50% of tumors have mutations of p53 – biallelic loss-of-function mutations

-Li-Fraumeni syndrome –
-patients inherit only one mutant p53 allele
-25-fold greater chance of developing a malignant tumor by age 50 than general population
-sarcomas, breast cancer, leukemia, brain tumors, adrenal cortex carcinomas

31
Q

tumor (GROWTH) suppressor genes- other (DONT NEED TO KNOW)

A

-APC (Adenomatous polyposis coli)– downregulates growth-promoting signaling pathway; part of WNT signaling pathway; holds beta-catenin activity in check; forms “destruction complex” leading to degradation of beta-catenin; loss-of-function mutations disrupts destruction complex and cells act as if continuously stimulated by WNT – Familial adenomatous polyposis, early onset colon cancer

-E-cadherin – cell surface protein which maintains intercellular adhesiveness – loss-of-function allows disaggregation of cells which can invade and metastasize

-CDKN2A – mutations associated with familial forms of melanoma (germline) and sporadic mutations present in bladder cancer, head and neck tumors, ALL, and cholangiocarcinoma
TGF-beta pathway – normally turns on antiproliferative genes and turns off genes that drive cell growth; loss-of-function mutations common in cancers of colon, stomach, and endometrium
PTEN – normally puts brake on PI3K/AKT signaling pathway
VHL – germline loss-of-function mutations associated with hereditary renal cell carcinoma; somatic mutations occur in some sporadic renal cell carcinoma

32
Q

evasion of apoptosis/cell death

A

-Mutations in genes in tumor cells may result in resistance to apoptotic cell death
-Greater than 85% of follicular B-cell lymphomas show overexpression of the antiapoptotic gene BCL2 because of translocation t(14;18)
-Loss of TP53 function

33
Q

genomic instability enables cancer (DNA repair gene defects)

A

-Inherited mutations involved in DNA repair increase risk for cancer
-Example: Xeroderma pigmentosa – defect in nucleotide excision repair pathway – increased risk of cancers of skin exposed to UV light because of inability to repair pyrimidine dimers

34
Q

chromosome changes in cancer

A

-translocations and inversions- piece of gene went to another gene
-occur in MOST lymphomas/leukemias
-occur in many non-hematologic malignancies also

35
Q

tumor cells are immortal

A

-Tumor/cancer cells:
-Evade senescence
-Evade mitotic crisis – telomeres shorten, if cells in crisis reactivate telomerase, then the cells can restore telomeres and survive – see below
-Capacity for self-renewal – each time a stem cell divides at least one of the two daughter cells remains a stem cell; some cells in cancer must be stem cell-like which may arise by transformation of normal stem cell or acquired genetic mutations that give a stem-like state on more mature cell
-Evade apoptosis

-Telomeres
-sequence of repetitive bases at end of linear chromosomes
-prevent chromosomes from attaching
-determine limited number of cell replications

-Telomerase
-present in 90% of human cancers; most somatic cells do not express telomerase
-changes telomeres so they have unlimited replicative potential

36
Q

cancer: limitless replication potential!!!!!!!!!!! TEST

A

-TELOMERES determine the limited number of duplications a cell will have; sequence of repetitive bases at ends of linear chromosomes that prevent adjacent chromosomes from attaching to each other
-TELOMERASE, present in >90% of human cancers, changes telomeres so they will have UNLIMITED replicative potential

37
Q

carcinogenesis is multistep

A

-NO single oncogene causes cancer
-BOTH several oncogenes AND several tumor suppressor genes must be involved

-Gatekeeper/Caretaker concept
-Gatekeepers: ONCOGENES and TUMOR SUPPRESSOR GENES
-Caretakers: DNA REPAIR GENES

-Tumor “PROGRESSION”
-ANGIOGENESIS
-HETEROGENEITY from original single cell

38
Q

malignancy

A

-Genetic alteration – as discussed

-Angiogenesis
-tumors beyond 1 – 2 mm need blood supply
-Hypoxia triggers angiogenesis by actions of HIFI-alpha on transcription of pro-angiogenic factor VEGF
-Driver mutations favor angiogenesis – p53 stimulates expression of anti-angiogenic thrombospondin-1 and represses VEGF; mutations in p53 favor angiogenesis
-Proteases elaborated by some tumor or stromal cells release bFGF from ECM
-VEGF inhibitors used to treat some cancers

-Invasion
-“loosening” of tumor cell-to-cell interactions (changes in intercellular adhesion molecules)
-degradation of ECM
-attachment to new ECM components
-migration of tumor cells

-Metastasis – tumors develop metastatic genotype

39
Q

invasion

A

-1. Dissociation of cancer cells from one another usually because of changes in intracellular adhesion molecules

-2. Degradation of basement membrane and interstitial connective tissue – tumor cells secrete proteolytic enzymes or induce stroma cells

-3. Changes in attachment of tumor cells to ECM protein

-4. Locomotion – stimulated by cytokines – leads tumor cells through degraded basement membrane and areas of matrix proteolysis

40
Q

metastasis

A

-Vascular dissemination, homing, colonization
-Tumor cells more likely to migrate as multicellular aggregates
-Where tumor cells eventually metastasize to depends on location and vascular drainage of tumor, tropism for specific tissues, escape from tumor dormancy
-Once tumor cells at distant site, extravasation of tumor cells involves transmigration through basement membrane
-needs action of adhesion molecules, proteolytic enzymes, and chemokines, which may come from tumor cells or innate immune cells
-!Tumor cells secrete cytokines, growth factors, and ECM molecules that act on resident stromal cells – makes metastatic site habitable for cancer cells

41
Q

evasion of host response (dont know details)

A

-basically tumor cells can disguise themselves so they are not recognized as foreign and invade immune system
-Immune system recognizes tumor cells and can destroy them via CTLs (cytolytic T lymphocytes) specific for tumor antigens
-Tumor antigens are presented on cell surface by MHC class 1 molecules and are recognized by CD8+ CTLs
-Different classes of tumor antigens (recognized by immune system as foreign antigens) – neoantigens

-Tumor cells can escape/evade immune system by:
-selective outgrowth of antigen-negative variants
-loss or reduced expression of MHC molecules
-engagement of pathways that inhibit T-cell activation
-secretion of immunosuppressive factors (e.g., TGF-beta)
-induction of regulatory T cells (Tregs)

-Antibody therapy exists for patients with advanced cancer; Abs overcome mechanisms of immune evasion

42
Q

carcinogenesis!!

A

-Initiation/Promotion concept:
-BOTH initiators AND promotors are needed
-NEITHER can cause cancer by itself
-INITIATORS (carcinogens) cause MUTATIONS
-PROMOTORS are NOT carcinogenic by themselves, and MUST take effect AFTER initiation
-PROMOTORS enhance the proliferation of initiated cells

43
Q

initiation and promoters

A

Initiation causes permanent,
irreversible DNA damage but
is not sufficient for tumor formation.

All initiating chemical carcinogens
are highly reactive electrophiles
(have electron-deficient atoms) and their targets are DNA, RNA, and proteins

Promoters induce tumors in
initiated cells but are not
tumorigenic themselves; the cellular changes of promoters do not directly affect DNA and are
reversible.

44
Q

chemical carcinogenesis

A

-Chemical Carcinogenesis
-Initiation – exposure of cells to a sufficient dose to cause permanent DNA damage (mutations)
-Promoters – proliferation and clonal expansion of initiated (mutated cells)
-Initiating chemical carcinogens are highly reactive electrophiles (electron-deficient atoms) that may react with nucleophilic (electron-rich) atoms in cell- targets are DNA, RNA, proteins
-Direct acting carcinogens – do not need metabolic conversion to be carcinogenic
-Indirect-acting carcinogens – need metabolic conversion to become active carcinogens

45
Q

chemical carcinogens: initiators (dont need to know)

A

-Vinyl chloride -> angiosarcoma *

-Direct carcinogens initiators cause mutations DIRECTLY.“Pro”-carcinogens initiators are metabolized into substances which are more direct.

-“PRO”CARCINOGENS
Polycyclic and Heterocyclic Aromatic Hydrocarbons
Aromatic Amines, Amides, Azo Dyes

Natural Plant and Microbial Products
Aflatoxin B1-> Hepatomas
Griseofulvin-> Antifungal
Cycasin-> from cycads
Safrole-> from sassafras
Betel nuts-> Oral SCC

46
Q

promoters

A

-hormones, drugs
-“Initiated” cells respond and proliferate FASTER to promotors than normal cells
-Promotors are NOT carcinogenic by themselves, but often are agents of hyperplasia, e.g., steroid hormones.A “promotor” might cause hyperplasia in cells even without the effect of a carcinogen

47
Q

radiation carcinogenesis

A

-Ionizing radiation causes chromosomal breakage, translocations, and sometimes point mutations which lead to genetic damage and carcinogenesis
-UV rays form pyrimidine dimers within DNA; patients with defects in repair of these dimers have xeroderma pigmentosa and are at increased risk for skin cancers

48
Q

oncogenic infectious agents

A

-HTLV-1 (RNA, retrovirus) = Adult T cell leukemia/lymphoma
-!!!!!!HPV (DNA virus) = squamous papilloma, squamous cell carcinoma (cervix, skin); integration into host genome; high risk HPV types express oncogenic proteins that inactivate tumor suppressors, activate cyclins, inhibit apoptosis, and combat cellular senescence
-EBV = Burkitt lymphoma; uses CD21 to attach and infect B cells – indirect acting -acts as polyclonal B-cell antigen which sets stage for acquiring t(8:14) and other mutations
-HBV, HCV = hepatocellular carcinoma
-HHV8 (Human herpes virus 8 aka Kaposi sarcoma herpesvirus)
-Helicobacter pylori
-gastric adenocarcinoma – increased epithelial cell proliferation in background of chronic inflammation
-gastric lymphoma (MALToma)– infection leads to H. pylori infected T cells which stimulate polyclonal B cell proliferation, and unknown mutations occur giving individual cells growth advantage

49
Q

overview

A
50
Q

effects of tumor on the host

A

-Location -> anatomic ENCROACHMENT
-HORMONE production
-Bleeding, Infection
-ACUTE symptoms, e.g., rupture, infarction
-METASTASES

51
Q

cachexia

A

-reduced diet: fat loss > muscle loss
-cachexia: fat loss AND muscle loss
-TNF alpha
-IL-1

52
Q

paraneoplastic syndromes

A

-May represent early manifestation of occult neoplasm
-10% of persons with malignant disease
-May be earliest manifestation of occult neoplasm
-Endocrinopathies
-Nerve and muscle syndromes – e.g., myasthenia gravis
-Dermatological disorders
-Vascular and hematological changes
-Others – bone, joint, soft tissue changes, nephrotic syndrome

53
Q

lab dx

A

-biopsy
-cytology- exfoliative
-cytology- FNA

54
Q

immunohistochemistry

A

-categorization of undifferentiated tumors
-leukemias/lymphomas
-site of origin- special stain
-receptors- ER, PR

55
Q

tumor markers

A

-Many can be produced in non-neoplastic conditions as well (low sensitivity and low specificity); may be good for follow-up (detecting tumor recurrence)
-PSA – prostate
-CEA – colon, pancreas, stomach, breast
-Alpha-fetoprotein – liver, yolk sac tumors
-HCG – trophoblastic tumors, non-seminomatous testicular tumors
-Calcitonin – medullary carcinoma of thyroid
-CA-125 – ovary
-CA-19-9 - pancreas

patho (11 decks)

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