Neoplasm Lecture Oct 8 Flashcards
What does neoplasmia mean?
It means “new growth”
an abnormal mass ot tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after cessation of the stimuli which invoked the change.
What is a hamartoma?
It’s a non-neoplastic disorganized aggregate of mature tissues which is indigenous to the site of origin
(some can be neoplasms, but not all!)
What is a choristoma?
A heterotopic rest of mature cells
so mature cells that should be in one spot are in the wrong spot - sometimes you get pancreatic tissue in the submucosa of the stomach- it’s a developmental thing.
How do benign and malignant neoplasms differ?
THe key difference is that benign neoplasia cannot spread to other tissues, while malignant neoplasms have the capability of spreading (they don’t necessarily have to)
Which tend to be more locally invasive? benign or malignant neoplasms?
malignant - they ten to destroy adjacent structures
What are neoplasms made up of?
a clonal neoplastic population of parenchymal cells along with varying amounts of stroma
What does the differentiation of a neoplasm refer to?
the extent to which the neoplastic parenchymal cells resemble the normal parenchymal cells (morphologically and functionally)
What are the 6 classes of neoplasms based on cell/tissue of origin
- epithelial orgigin
- mesenchymal origin
- hematopoietic or lymphoid origin
- melanocytic origin
- CNS
- Germ Cell origin
What are malignant epithelial neoplasms called?
carcinomas
For mesenchymal tumors, what are the malignant ones called?
sarcomas
FOr melanocytic tumors, what are benign neoplasms called? What are malignant ones called?
benign = nevi
malignant = melanomas
If a benign epithelial neoplasm shows glandular differentiation, what are they called?
If they are cystic, what are they called?
If they form papillary structures what are they called?
glandular = adenomas
cystic = cystadenomas
papillary = papillomas
Malignant epithelial neoplasms that show squamous differentiation are called what?
Malignant epithelial neoplasms showing glandular differentiation?
squamous = squamous cell carcinomas
glandular = adenocarcinomas
If a tumor shows more than one type of differentiation, showing both epithelial and mesenchymal differentaion, what are they called?
pleomorphic
Germ cell tumors are called what?
teratoma - they have differentiation in all three germ cell layers
Which are more differentiated, benign or malignant neoplasms?
benign
Which has a higher mitotic rate, benign or malignant neoplasms?
malignant neoplasms
When is the term “anaplastic’ used to describe a tumor?
When it’s very undifferentiated
As malignant tumors become less differentiated, growth rate _____.
growth rate increases
What is the growth fration of a tumor?
the proportion of cells within the tumor population that is in the proliferative pool
Which are more likely to be affected by usual chemotherapeutic agents, tumors low high growth rates, or tumors with low growth rates?
tumors with high growth rates are more likely to be affected.
Low growth rate tumors can be regractory to these therapies
What is a desmoplasia?
Most invasive tumors like carcinomas can elicit a fibrous stromal response called desmoplasia - its the host tissue reaction to the tumor
What does it mean for a carcinoma to be in the “in situ” stage?
This is the stage where a malignant epithelial neoplasm hasn’t penetrated the basement membrane yet
What does “dysplasia” refer to?
The disordered growth and cytologic changes seen in epithelium
this is NOT a carcinoma yet, but can progress to one
these often arise in metaplstic epithelium
The big example is dysplasia of the cervix in response to HPV infection before the carcinoma develops
Metastatic spread can occur through which three pathways?
- Direct seeding of a body cavity or surface
- Lymphatic spread (often for carcinomas)
Note that a LN could just be enlarged because of a reaction to the tumor - not metastatic spread - do a biopsy - Hematogenous spread - sarcomas do this (through the blood)
Note that it could seed the next capillary bed down or go to an organ is preferentially seeds
Which cancers have the highest incidence in men?
Highest incidence in women?
Men: prostate, lung, colon
Women: breast, lung, colon
What cancer causes the most deaths in both men and women?
lung
Which are more significant in sporadic cancers: genetic factors or environmental factors?
environmental factors
THe genetic predispositions to cancer fall into these three categories:
- autosomal dominant inherited cancer syndromes
- Defective DNA-repair
- Familial cancers - exact mutations and mode of inheritance unclear
What are wome nonhereditary predisosing conditions for cancer?
Chronic inflammation
(as in ulcerative colitis, H pylori gastritis, and viral hepatitis)
viral infection
exposure to carcinogens
What is the key initiating event in all examples of carcinogenesis?
You need nonlethal genetic damage (a mutation)
then the tumor must be formed by clonal expansion of a single precursor cells that has incurred genetic damage
Which four classes of normal regulatory genes are the principal targets in genetic damage?
- growth-promoting proto=oncogenes
- growth-inhibitin tumor suppressor genes
- genes that regulate programmed apopotisis
- genes involved in DNA repair
how do tumors become increasingly aggressive over time?
they develop as multiple mutations accumulate independently in different cells - leading to subclones with varying abilities to grow, invade and metastasize nad resist treatment
Are tumors homogenous or heterogeneous?
for the most part, by the time they become clinically evident, they are extremely heterogeneous
this makes treatment tricky
it also means you can’t assume you know everything about a tumor just based on a needle biopsy
What are the 8 fundamental changes in cell physiology that together determine the malignant phenotype?
- self suffiency in growth signals
- insensitive to growth-inhibition
- evasion of apopotisis
- limitless replicative potential
- sustained angiogenesis
- ability to invade and metastasize
- defects in DNA repair
- Escape from immune attack
What causes the bast majority of cancer deaths?
metastases
What allows for a tumor fo be self sufficient in growth signasl?
the oncogenes make all the proteins necessary for proliferation
How many alleles need to become mutant in order to turn on an oncogene and cause a tumor?
only one
it’s a gain of function mutation
what mutation is associated with chronic myelogenous leukemia?
what treatment was developed once we figured this out?
THe BCR-ABL translocation from chr 9 to chr 22
it increases tryosine kinase activity
treatment is now a tyrosine kinase inhibitor - imitinib mesylate (gleevac)
Which proto oncogene is mutated in breast cancer?
HER (ERBB2)
If Her2/neu is present, it’s an overexpression of the epidermal growth factor receptor.
It can be treated with herceptin (trastuzumab)
What is the protooncogene mutation in KRAS responsible for?
persistent activation of the RAS signal, resulting in colon cancer
What is mutated if a tumor is insensitivt to growth inhibition or escapes sensecence?
how many alleles need to be locked out?
a tumor suppressor gene
both alleles need to be knocked out in a cell because it’s a loss of fucntion mutation
What will the expression of an oncogene in an otherwise normal cell lead to?
quiescence - permament cell cycle arrest
the tumor suppressor genes are still working, so they stop the shit
What tumor suppressor gene is mutated in familial polyposos (CRC)?
APC
it’s responsible for degrading the transcription factor beta-catenin
if it’s working, you don’t get proliferation
Which tumor supressor gene is mutated in breast cancer?
BRCA
it regulates DNA repair
What tumor suppressor gene is mutated in retinoblastoma?
Rb
Which tumor suppressor gene is the “molecular policement” that prevents the propagation of genetically damaged cells?
p53
How do B cell lymphomas evade apopotisis?
They are produced by a translocation that results in the overexpression of Blc2, which inhibits the release of cytochorme c from the mitochondria
Do tumors that just evade apoptosis show a higher or lower growth rate?
lower - they don’t proliferate rapidly to form the tumor, they just don’t die
How can a tumor cell game limitless replicative potential?
Most normal cells ahve a capacity for doublings which is determined by the progressive shortneing of the telomeres
Many neoplasms up-regulate the expression of telomerase, which promotes the maintenance of telomere length regardless of the number of divisions
Why does the up regulation of telomerase result in a cacner cell having a clomplex karyotype?
With telomerase, the checkpoints that would usually stahl growth don’t work
withou checkpoints, the DNA repair pathway is inappropriatley activated and you get the formation of dicentric chromosomes
then at mitosis, the dicentric chromosomes are pulled apart and you get lots of double stranded breaks
these breaks then activate DNA repair pathways which leads to the random association of double stranded ends and the formation of more dicentric hromosomes
they just keep doing this over and over again and generate massive chromosomal instability and numerous mutations
How do tumor cells promote angiogenesis for their own growth?
they upregulate angiogenic factors like VEGF
How does angiogenesis help the tumor metastasize?
the new blood vessels are often abnormal and leaky, so they have easy access to circulation
What two major steps are involved in the production of metastases?
- invasion of the ECM (degrading the basement menebrane and penetratind the ECM - is requires attachment of the tumor cells to ECM proteins)
- Intravasation into blood vessels and vascular dissemination, homing and then colonization
What are some examples of a cancer caused by a mismatch reapri defects?
hereditary nonpolyposis colon cancer syndrome
What is the dominant mode of immunity when it comes to anti-tumor mechanisms?
Cell mediated!
THe body doesn’t really make antibodies against tumor antigens (although we can make them as treatments)
What are some ways a tumor cell can avoid the cell mediated immune attack?
use antigen negative variants
reduce expression of NHC
Lack the costimulatory molecules needed to activate the T cells
immunosuppression
mask your antigens
kill the cytotoxic t cells
What are the ways chromosomes can change in cancer?
translocations (gene overexpression by swaping regulatory elements or having two unrelated sequences on dif chromosomes recombina nd form a hybrid fusion gene - as in CML)
deletions
reduplication and amplification of proto oncogene DNA sequences - leads to activation and overexpression
What are the two steps required for chemical carcinogenesis?
- exposure of cells to a sufficient dose of a carcinogenic agent causing permament DNA damage/mutation
- Additional exposure to a promoter to enhance the proliferation of the damaged cells
What is the difference between a direct acting carcinogen and an indirect acting carcinogen?
a direct actin requires no metabolic conversion to become carcinogenic
indirect acting agents need metabolic conversion of a procarcinogen to become active
Although any gene can be the target of ac hemical carcinogen, what are the key targets usually?
oncogenes and suppressor genes
RAS and p53 are examples
What are some forms of radiation carcinogenesis?
- ionizing electromagnetic radiation - x rays, gamma rays, particular radiation
- UV rays (Especially UVB) is increased risk of skin cancer through formation of pyrimidine dimers in DNA
What is the warburg effect?
Cancer cells shift their glucose metabolism to aerobic glycolysis and use a lot of glucose
this can be used to visualize tumors on PET when patient sare injected eith fluorodeosyglucose which is a non-metabolizing derivative of glucose that will be taken up into tumor cells and then fluoresce to be visualized
What is the basis for the “multistep carcinogenesis” idea?
cancer results from the accumulatino of multipl mutations in steps.
sometimes the steps need to happen in specific orders too
Both benign and malignant tumors can cause clinical problems including….
Location and impingement on adjacent structures.
Functional activity such as hormone synthesis or the development of paraneoplastic syndromes.
Bleeding and infections when the tumor ulcerates through adjacent surfaces.
Symptoms that result from rupture or infarction.
Cachexia or wasting (seen in cancer).
What is cachexia and what causes it?
It is a hypermetabolic state which presents as progressive loss of body fat and lean muscle mass along with weakness and anorexia
this is likely due to the action of soluble factors –cytokines - that result in a catabolic state along with a supressed appetitie
it’s not that the tumor is using up all thier nutrients
what are paraneoplastic syndromes?
symptoms that cannot be explains by the local or distant spread of the tumor OR by hormones that are indigenous to the tissue from which the tumor arose
What are some major paraneoplastic syndromes?
venous thrombosis
hypercalcemia
hypoglycemia
What does the grading of a cancer take into account?
Grading is based on the degree of differentiation of the tumor cells (and sometimes the # of mitoses seen by light microscopy)
grades can be numerical (with 4 being the least differentiated)
or they can be graded describptively (well differentiated, moderately differentiated, poorly differentiated)
What does staging of cancers take into account?
it’s based on the size/degree of invations, extent of spread to LNs, and the presence of abscence of distinct blood born metastases
it’s a T, N, M classification
What is the first step in pathological diagnosis of a neoplasm?
obtaining a sample containing the tumor
What are some of the different ways you can sample a tissue?
- incisional or excisional biopsy or lesions
- needle or punch biopsy with a hollow core needle
- musocal biopsy through endoscopy or colonoscopy
- Ctystoloy smear - cells are aspirated with a fine needle and syringe
For blood or body fluid…
- Blood smear
- Bone marrow aspiration smear
- Bone marrow core needle biopsy
- Cytology slide (aspirate fluid)
- cell block (aspirate fulid and hen centrifuge down to a pellet and process as tissue)
HOw is immunohistochemistry used for in the laboratory diagnosis of cancer?
It uses pre-formed antibodies to allow for the detection of cell products or surface markers on the tissue being examined
it’s useful to categorize undifferentiated tumors
also useflu to determining the site of origin of a tumor
by detectin molecules that have prognostic of therapeutic significance, it can guide treatment (as in Her2/neu expression being treated with hercepfin)
What is flow cytometry used for in the diagnosis of cancer?
It’s a technique that allows for the quanitfication of cells in a stream of fluid by passing them by an electronic detection devide
different cells are laveles with different lfuorescent antibodies
as the cells are detected and counted, so are the fluoescent signals so you can count different cells within a whole population
this is useful mainly for the luekmeias and lymphomas becase the blood cells all have different marker antigens that can be tagged
What are some reasons to use molecular diagnosis of cancer?
- diagnose malignant neoplasms that are defined by their specific genetic abnormality - like CML
- Test the progrnosis of malignant neolasms because some tumors with certain genetic markers are known to respond to therapy and others aren/t
- Detect the minimal residual disease - sometimes you won’t be able to tsee any more cancer cells by other methods, but testing the bone marrow for genetic markers of the cancer cells will
- Diagnosies of a hereditary predisposition to cacner - like BRCA testing
What does the OncotypeDX do for breast cancer patients?
It looks at 21 genes and determines a recurrence score which can be sued to determine the liklihood of a breast cancer recurrence - such considerations are important in developing a treatment plan
What is the concept behind a tumor marker?
a tumor marker is a protine that a malinant cell will secrete into the blood or body fluid that can be measured to revel the presence of a tumor
they’re helpful for monitoring the effectiveness of treatment and looking for relapse
What is the main issue with tumor markers?
they are often secreted in both malignant and non-malignant conditions (like PSA)
Increasing the prevalence increases the utility of a test because it increases the positive predictive value. How can one change the prevalence in a population though?
You can’t in the population as a whole obviously, but you CAN increase the prevalence in the population being screened by only screening patients who have a liklihood of actually having the disease
