Clinical Cancer 2 Flashcards
3 many ways to classify tumors
1) organ or tissue of origin
2) cell type (nomenclature)
3) degree of differentiation (resemblance to normal counterpart)
Grading
- level of differentiation
- is pathological
Staging
- shows extent of the spread
- is mostly clinical
- most important tumor classification
why need grading and staging?
1) quantify probable clinical aggressiveness
2) determine extent & spread
3) make accurate prognosis
4) compare end results of treatment protocol, will guide treatment
How describe grading of a tumor based on differentiation?
- provide it grade 1-4 based on differentiation of the tumor cells
- although now prefer to use low grade vs high grade because hard to distinguish between the grades
Well differentiated
- Grade 1 (best one to have)
- tumor cells and their arrangement closely resemble their normal tissue counterpart
Poorly differentiated
- (Grade 3)
tumors cells lose their normal staining characteristics, organization and functions
Intermediately Differentiated
- (Grade 2)
- in between grade 1 and 3
Anaplastic
- (Grade 4) the worst
- tumor cells have no resemblance to normal tissue counterpart
how provide grading via microscopic evaluation?
1) degree of differentiation of tumor cells
2) number performing mitosis
3) architectural features (types of cell/tissue)
4) necrosis
tumors and their necrosis?
- tumors eventually over grow vasculature & die due to lack of resources
- tumors that grow fast= less necrosis
- tumors that grow slow= more necrosis
When do you use staging? what does it tell you?
- where is all the cancer at time of diagnosis
- tells you extent of:
1) local invasion (primary tumor size)
2) regional spread (extent of spread to regional lymph nodes)
3) distant spread (presence/absence of blood borne metastases)
4) tumor grade (occasionally)
Why is Staging Important?
1) Determines prognosis (estimate)
2) Guides treatment strategy
3) Every cancer has a distinct set of rules; so hard to know how to stage each type, or accurately predict prognosis
3 types of staging?
1) TNM Staging
2) Summary Stage
3) clinical staging
TNM staging
T – tumor size and extent of local invasion (0-4)
N – involvement of regional lymph nodes (0-3)
M – spread to distant sites and organs (0 or 1)
Summary Stage
- Combines T & N & M scores
- gives out put as I II III IV
Clinical Staging
- non-invasive testing (physical exam, labs, radiologic studies)
- pathologic staging: information gained from definitive surgery, retrieve piece of tumor to ID it
T in the TNM (x-4)
-T= tumor size and extent of local invasion
Tx-Primary tumor can’t be assessed
Tis-Primary tumor not invasive
T0-No evidence of primary tumor
T1-Small minimally invasive tumors
T2-Larger invasive tumors
T3-Very large or deeply invasive or critically located
T4-Invading adjacent distinct tissues (i.e. bone, muscle)
N staging
N =Involvement of regional lymph nodes
Based on number, size and location of cancer- containing regional lymph nodes
Nx = Cannot (or did not) assess
N0 – No regional lymph node involvement
N1 – Minimal regional lymph node involvement
N2 – Moderate regional lymph node involvement
N3 – Extensive regional lymph node involvement
M staging
M= Spread to distant sites and organs
M0-No evidence of distant spread (metastasis)
M1- Clear evidence of distant spread
what does each stage 1-4 mean?
I - Locally confined; surgically resectable for cure
II - Locally extensive, still curable & benefits from adjuvant therapy
III - Locally advanced, requires more than surgery; sometimes inoperable
IV – Metastatic (widespread)
most often not curable
adjuvant therapy
-continued radiation/chemo treatment after surgery
do all cancers use this staging system?
-no;
1) hematologic malignancies have their own system (leukemias/lymphomas)
2) alternative (very old) systems for prostate, colon melanoma
3) brain cancer lacks staging
TNM always preferred!!!!
what does the primary tumor characteristic in breast cancer tell us?
- some tumor characteristics predict chance of distant spread & prognosis
1) tumor size
2) tumor grade
3) number of lymph nodes (more= worse prognosis)
4) positive for cancer
8 ways to diagnose type of cancer & TNM?
1) Clinical information
2) Histologic methods
3) Cytologic methods
4) Immunohistochemistry (IHC)
5) Flow cytometry
6) Tumor markers
7) Molecular & cytogenetic diagnostics
8) Circulating tumor cells
Histological cancer diagnosis?
1) Biopsies
2) Frozen section: rapid evaluation
what do biopsy’s need to be/have?
- must be
1) adequate in size
2) representative (take from actual tumor)
3) properly preserved in formalyn so doesn’t dry out
what do histological frozen sections tell us?
histology= study of tissues
1) nature of the lesion
2) it’s margins
3) adequate material
4) decide additional studies, as needed
what is cytology and it’s two types?
- the study of cells
1) cytologic smears (exfoliative cytology)- screen for carcinomas in cervix
- any sites that shed cells
2) Fine-needle aspiration (FNA)
Immunohistochemistry (IHC) tells us what about the cancer?
- uses immunologic principles (antigen-antibody complexes)
1) categorization of undifferentiated malignant tumors
2) determination of site of origin of metastatic tumors
3) detection of molecules that have prognostic or therapeutic significance
-help us define treatment
IHC & categorization of undifferentiated malignant tumors?
- undifferentiated tumor cells look nothing like original tissue and can be distant from initial tissue
- use antibodies to ID specific tissue antigens within the tumor to determine where it initially came from
what do we use flow cytometry for?
- Identify cell antigens expressed by “liquid” tumors (leukemia/lymphoma)
- Multiple antigens can be assessed simultaneously
How else can you obtain liquid tumor to do flow cytometry?
-can take any solid tumor make suspension of cells and run this, ID on DNA content
flow cytometry & CBC lab tests?
- When get complete CBC blood count from patient they run blood through flow cytometry
- light scattered by cells will tell size of cell, size of nucleus irregularities of nucleus, size of cytoplasm
what can tumor markers be used for?
- can’t be used for definitive diagnosis of cancer, but:
1) help w/ detection of cancer
2) determine effectiveness of therapy
3) determine appearance of recurrence - hcG, PSA, AFRP etc
Circulating Tumor Cells
- if tumor invasive, assume it is circulating in blood/lymph
- doesnt meant it will metastasize in other tissue, just more likely to
- this testing allows us to do assays of circulating tumor & see if DNA is being shed into bodily fluids
What does molecular & cytogenetic diagnostics help us with?
1) diagnosis & prognosis of malignant neoplasms
2) detection of minimal residual disease
3) diagnosis of hereditary predisposition to cancer
4) guiding therapy with oncoprotein-directed drugs
* this is personalized med*
How determine molecular profiles of tumors?
1) DNA microarrays
2) Next gen sequencing
gene expression in malignant cells?
1) malignant diff from healthy cells in the ratio of normal to mutated genes expressed
2) cancer cells phenotype & genotype based on pattern of genes expressed in malignant tissue
3) similar cancers can vary widely in their prognosis & treatment response
what is the hypothesis about understanding pattern of gene expression in cancer cells?
- detailed analysis of pattern of gene expression of a patient’s cancer would enable accurate prediction of rates of response to therapy, risk of relapse, & may suggest novel therapeutic targets
- this is personalized medicine
How is detailed analysis of gene expression accomplished?
- gene expression array analysis
- this is personalized medicine
how does gene expression array work?
1) compare the level of all expressed genes in a cancer cell with the level of expression of all expressed genes in a same tissue non cancer cell
2) compare variations in patterns of expressed genes in a cancer cell from the same cancer in diff patients
which version of the gene expression array is most useful?
- comparing variations in patterns of expressed genes in cancer cells from the same cancer in diff patients
- can help explain why patients respond differently
how can gene expression array help determine treatment & prognosis?
- if know higher expression of gene A= worst prognosis, and patient has elevated gene A expression then need to give more aggressive treatment & know that prognosis is poor
what does gene expression array help determine?
1) prognosis (chance of death/recurrence)
2) treatment options
3) personalized medicine if possible for patient
Next Generation DNA sequencing
- rapid, inexpensive DNA sequencing
- sequence human genome in 1 day for ~ $1000
- sanger had to do one base at a time, next gen does it all at once so goes faster
three things can do with next gen?
1) Whole genome sequencing
2) exon sequencing (just expressed genes)
3) transcriptome sequencing; just trxned genes (is RNA sequencing)
Whole genome sequencing in cancer can tells us?
-structural changes (translocations, deletions) -gene copy number changes -point mutations -gene expression level changes
Exome sequencing in cancer can tells us?
- copy number changes
- point mutations
Transcriptome sequencing in cancer can tell us?
- structural variations like fusion proteins
- translocations
- siRNA variation
What is goal w/ next gen sequencing and cancer treatment?
- want to do sequencing on many patients w/ same cancer, and compare
- realize that tumors are genetically heterogenous
- assign personalized treatment to every patient, so treat that persons type of cancer, not cancer generally
3 types of Cancer Treatments?
1) surgery: resect visible tumor with margins
2) Radiation: lethally irradiate all detectable tumor & include a rim of normal tissue
3) Systemic Therapy: treatment reaches malignant cells throughout body
four types of systematic therapy?
1) Chemotherapy
2) Hormonal therapy
3) Immunotherapy
4) Targeted Therapy
Chemotherapy
- drugs that act through chemical rxt to disrupt normal cell functions & lead to apoptosis
- attack cells in cell cycle
- first line of cancer defense
Hormonal Therapy:
-Drugs that bind to intracellular hormone receptors to block or overstimulate normal gene expression and lead to apoptosis
Immunotherapy
- drugs which target or stimulate components of normal immunity to destroy malignant cells
- enhance immune system
- antigen specific cancer cell, but also kill healthy cells w/ same antigen
targeted therapy
drugs that act by interfering w/ specific cell processes unique to the cancer cell
–typically less toxic, more specific than cytotoxic chemo
most common chemo targets?
- DNA, RNA, & microtubules
- need rapidly dividing cells to be effective, means if tumor has stopped progressing, then will be less effective
normal vs malignant cell damage w/ chemo?
-normal cell damage does happen but is easily reversible while malignant cells have lost DNA repair mechanisms therefore they die
general trend of tumor growth
- tumors grow w/ gompertzian kinetics
- means they have fast (exponential) initial phase and slow (quasi linear) in late phase
-this happens cuz tumors outgrow nutrients & oxygen supply so mature tumors are experiencing necrosis
chemotherapy and tumor growth issue?
- when tumor is at most rapid point (best for chemo) it is undetectable
- once reach detectable point only have a small window b4 tumor hits plateau, stops dividing, & is immune to chemo and patient dies
how many cancer cells does systematic therapy have to destroy to be effective?
- virtually every cancer cell capable of dividing
- remission induction treatment, then treat throughout remission (immune system increasing here too) to remove all cancer cells or else will come back
how do you optimize systematic treatment?
1) maximize dose intensity
2) optimize treatment duration & schedule
3) combine agents w/ non overlapping toxicities & differing mechanisms of action
3 uses of chemotherapy?
1) primary therapy for chemo-sensitive localized cancers
2) induction therapy for advanced malignancies
3) adjuvent therapy for distant micrometers
chemo toxicity?
- toxic to all dividing cells; so see:
1) hair loss
2) mucosistis in GI tract
3) bone marrow depression
4) gonadal dysfunction (infertility) - nausea & vomiting
targeted systematic therapy
-goal is to block the signaling progression from extracellular receptors to intracellular proliferation signals to prevent growth signals and cell will die
how targeted systematic therapy work?
-inhibting growth factor signaling by using immune system (antibodies) to block either growth factor itself, the receptor for growth factor or intracellular action of the receptor
Targeted Therapy Strategy of attack (4)
1) Target the extracellular signaling molecule
2) Target a cell surface receptor
3) Target a novel oncogene
4) Target intracellular signal transduction components
chromic myelogenous leukemia (CML)
due to translation of chrom 9 & 22. t(9;22)
- creates a chimeric fusion protein (BCR-ABL) completely unique to cancer; not in body normally
- protein involves an intracellular tyrosine kinase
treatment of CML?
- Imatinib mesylate (Glibic)
- STI571 signal transduction inhibitor
- selective & specific inhibitor of tyrosine kinase activity in:
1) BCR-ABL
2) c-kit
3) PDGF-Ra - so does have side effects in some healthy cells
effects of imatinib mesylate (Glibic)?
- inhibits TK activity
- good responses in CML accelerated phase & blast crisis
- effective in low grade GI sarcoma (GIST)- attacks c-kit
- oral drug w/ few side effects
- effective in hypereosinophilic syndrome
STI571 Mechanism of Action
healthy: atp binds BRC-ABL and phoshphorylates substrate on tyrosine kinase, activate downstream stuff
cancer: STI571 binds the ATP binding pocket so can’t phosphorylate substrate and growth halts
Support for Patients with Cancer:
1) medications
2) nutrition support
3) transfusions
4) blood cell growth factor injections (red, white, & platelets)
medications to support cancer patients?
1) pain control
2) stool softeners
3) antidepressants
4) energy stimulants – caffeine, ritalin, provigil
Nutrition supporter cancer patients?
1) calorie & protein rich diet
2) appetite stimulants (due to cahcexia)
3) gastrostomy tube feeding
transfusions done to cancer patients?
1) red cells, platelets
2) rarely white cells
red blood cell growth factor injections?
- erythropoietin
- stimulates erythropoiesis (RBC production)
-mass produced by recombinant DNA method
white blood cell growth factor injections?
- granulocytes – monocytes
- GCSF (granulocyte colony stimulating factor)
- GMCSF (granulocyte/monocyte colony stimulating factor)
-mass produced by recombinant DNA methods
platelet growth factor injections?
not so much
Prevention measures for cancer patients?
1) Intravenous hydration
2) Antibiotics and G-CSF or GM-CSF
3) Anticoagulation (prevent blood clots)
4) Transfusion & Erythropoietin for low RBC (anemia)
Support for Ppatient with cancer?
1) cancer support groups
2) emotional support from cancer specific counselors & oncologist
3) palliative Care
4) hospice
Palliative Care
- specialty care focusing on relieving physical symptoms & emotional stress from cancer during treatment & after effective treatments have been exhausted & the cancer continues to grow and spread
- partners w/ Cancer Treatment Specialists who focus on quality of life
