Transcript Slackers Guide to Cancer - U

Slackers Guide to Hematologic
Cancers
Mike Ori
Disclaimer
• These represent my understanding of the subject
and have not been vetted or reviewed by faculty.
Use at your own peril.
• I can’t type so below are common missing letters
you may need to supply
• erl
• I didn’t use greek letters because they are a pain
to cut and paste in.
• What are the six hallmarks of cancer
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Evasion of apoptosis
Insensitivity to anti-growth signals
Self sufficiency of growth signals
Limitless replication potential
Sustained Angiogenesis
Tissue invasion and metastasis
• What is the Warburg effect
• It is the observation that cancer cells rely
more heavily on glycolysis than on oxidative
phosphorylation even in the presence of
adequate oxygen supplies. Thus it is believed
that the glycolysis is better suited to meet the
metabolic demands of cancer cells.
• What is epigenetics
• List a few epigenetic mechanisms in the cell
• Epigenetics refers to reversible but inheritable
changes in gene expression that occur without
mutations. Examples include
– Methylation
– Histone acetylation
• Both examples limit the access of promoter
regions to their respective promoters.
• What is the function of micro RNA
• miRNA are small (~22bp) RNA strands that
function at the post transcriptional level to
silence specific genes. Each miRNA may
interact with multiple genes and thus can
serve as an off switch post transcriptionally.
• Some oncogenes control the expression of
miRNA.
• What is mismatch repair?
• DNA replications “spell checker”. It makes
sure A-T and G-C go together.
• What is Nucleotide excision repair
• Removal of pyrimidine dimers caused by UV
radiation
• What is the function of p53
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P53 is a tumor suppressor gene.
It activates DNA repair genes
It can arrest the cell cycle at G1/S checkpoint
It can initiate apoptosis
• What is the function of ATM
• ATM is a tumor suppressor protein
• What is the function of Her2/neu/erb-b2
• An epithelial growth factor receptor whose
gene is amplified in 25% of breast cancers.
• Self-sufficiency in growth signals
• What drug targets her2 and what is its
mechanism
• Trastuzumab is a monoclonal antibody
directed against her2/neu/Erb b2.
• It functions by binding to and disrupting erb
b2
• What is BCR-ABL and how does it result in
cancer
• BCR-ABL is a unique protein that from t(9:22)
translocation that results in the fusion of the
BCR promoter to the ABL tyrosine kinase in
such a way that the kinase no longer requires
a ligand for activation.
• ABL is a proliferative kinase that is active in
hematopoietic cells
• Describe the role of B-catenin and APC in
cancer
• B-catenin is a cell proliferation enzyme that is
sequestered by APC.
• The deletion of one APC allele causes familial
adenomatous polyposis, an autosomal
dominant condition that predisposes to colon
cancer in early adulthood
• Mutations in APC can lead to attenuated colon
cancer forms
• What are the three benign types of
lymphadenopathy
• Follicular
– Expansion of B cells
• Paracortical
– Expansion of T cells
• Sinus histiocytes
– Surgical drainage
• What is the common gene involved with
lymphoma translocation
• The heavy chain gene on CR14
• Why are immune cells susceptible to
translocations?
• DNA cleavage is an important part of
maturation of immune cells. This presents
opportunity for abnormal joining.
• What is the etiologic classifications of
lymphoma
• Translocations
• Inherited
– Downs, neurofibromatosis
• Viruses
– HTLV, EBV, HHV-8
• Environmental agents
• Iatrogenic
– Radiation
• Describe the relationship of lymphoma and
leukemia
• Lymphocytic leukemias evolve to lymphomas
late. Similarly, lymphomas may transform into
lymphocytic leukemias.
• Describe follicular lymphoma
• Common indolent lyphoma
• Back to back follicles
• T(14:18) BCL-2
– Anti-apoptotic
• May transform into diffuse large cell
lymphoma
• Describe diffuse large cell lymphoma
• Large round lymphocytes
• Alterations in BCL-6
– Germinal center formation disrupted
• Describe Burkitts Lymphoma
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Rapidly aggressive lymphoma
T(8:14) c-myc oncogene
Association with EBV
Starry sky pattern due to histiocytes
• Describe marginal zone lymphomas
• Associated with MALT in gut
• Chronically inflamed tissue
– H. pylori
• Indolent but may transform to diffuse B-cell
• Describe hodgkins lymphoma
• Common cancer of young adults
• Orderly progression from local nodes to
spleen to liver to bone marrow
• Reed-sternberg cells
• Describe Mycosis Fungoides
• T cell lymphoma
– CD4+
– Band like infiltrates in dermis
• Flat erythematous rash -> plaques -> tumor
nodules
• TX with local control early
• Sezary syndrome
– Widespread rash
– Blood and lymph node involvement
– Poor prognosis
• List the myeloid cells
• Granulocytes
– Neutrophils
– Eosinophils
– Basophils
• Monocytes
• Erythrocytes
• Megakaryocytes
• Differentiate myeloproliferative neoplasms,
myelodysplastic syndromes, and myelogenous
leukemias
• MPN
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Clonal proliferation of a myeloid precursor
Retains ability to mature
Effective hematopoiesis
Expansion of one or more related cell lines
Normal blast levels
• MDS
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Clonal proliferation of myeloid precursors
Retains ability to mature
Ineffective hematopoiesis
Peripheral cytopenia
Elevated blasts account for < 20% of marrow
• Leukemia
– Malignant neoplasms of the hematopoietic precursors
– Blasts account for more than 20% of the marrow
– Classified as acute or chronic depending on maturity of cells
• Describe the blood counts of leukemic
patients
• In some instances there may be elevated
counts and in some instances cytopenia may
result.
• If a sample shows clonal origin, what does this
imply?
• This strongly implies a dysplastic/neoplastic
process. Excess growth hormones would
affect all members of a lineage sensitive to the
hormone.
• Why is BCR-ABL a favorable indicator in CML
but not in AML
• The fusion products are similar but are not the
same.
• Are auer rods present in ALL
• No. Auer rods are an AML finding.
• What are the two categories of acute
lymphoblastic leukemia
• B cell
• T cell
• What are the classic populations for ALL
• B cell – children
• T cell – adolescent males as lymphoma
• What are the prognostic indicators for ALL
Favorable
Unfavorable
Hyperdiploidy
hypodiploidy
1-10 yo
<1 or > 10 yo
WBC < 50x109 /L
WBC > 50x109 /L
TEL-AML1
MLL, BCR-ABL, E2A-PBX1
Trisomy 4,10, or 17
Induction failure
CNS disease
• Describe the treatment terms for leukemia
• Induction
– Therapy intended to reduce cancer cells to below
cytologic detection levels
• Consolidation
– Therapy intended to further reduce tumor cells
• Continuation
– Maintenance therapy intended to insure
continued remission
• When would a stem cell transplant be
considered in ALL
• 1st remission if poor prognostic factors
• 2nd remission if < 1 year
• What is the cell of origin for chronic
lymphocytic leukemia?
• 95% are B-cell
• 5% are T cell
• What is the initial treatment for CLL
• Watchful waiting
• 10% yearly transform to diffuse B-cell
• When would it be prudent to institute TX in
CLL?
• Conversion to prolymphocytic or diffuse B cell
lymphoma
• Worsening B symptoms
• Progressive adenopathy or hepatosplenomegaly
• Peripheral blood cytopenias
• Recurring infections
• Immune mediated complications such as
hemolytic anemia
• Short doubling time of peripheral lymphocyte
count
• List the myeloproliferative disorders
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Chronic Myelogenous Leukemia
Polycythemia Rubra Vera
Essential thrombocytosis
Primary myelofibrosis
• List several attractions of CML’s favorite city
• Philadelphia
– Cheese steaks
– Liberty bell
– Independence hall
– Eagles
– http://www.phillyfunguide.com for more…who
knew ( I just realized knew is a funny word)
• What are the common clinical and lab findings
in CML?
• WBC
– count > 50k/ul
– All forms increases
• RBC
– Decreased
• Thrombocytosis
• Splenomegaly
• What is the common genetic pathway altered
in other myeloproliferative disorders
• JAK2
• Describe polycythemia vera
• Absolute increase in RBC’s but other lines may
also be affected
• Platelets often 500,000/ul
• Issues related to blood viscosity
• What is the most likely outcome of increased
blood viscosity
• Thrombosis
• What is the treatment course for PV
• Watchful waiting
• Blood letting
– phlebotomy
– Leeches
– Cage matches
• 16 references were cited on the Blood Letting wikipedia
page vs 93 references on the Professional Wrestling
Match types page so I guess cage matches have more
evidence. No chochrane reviews though.
• Describe essential thrombocytosis
• ET is an increase in thrombocytes that cannot
be explained by any other cause
• Megakaryocytes have decreased need to
growth factors and thus are increased in the
marrow
• Platelet function may be poor.
• What is the primary risk with ET
• Abduction and probing
• Really, if you didn’t know it was thrombotic
events, you are a slacker.
• Describe myelofibrosis
• Fibrous marrow
• Primary
– If no other reason established
• Secondary
– Arises due to “burned out” marrow from CML or
PV
• Extramedullary hematopoieis
– Massive splenomegaly
• What drug is useful in decreasing WBC count
in CML
• Hydroxyurea
• What is the most common pediatric leukemia
and what is its survival rate
• ALL
• 80% survival
• List the genetic changes in lymphoma
ALL
TEL-AML1
T(12;21)
AML converts from a transcription activator
to a repressor. Only good indicator.
ALL
BCR-ABL
T(9;22)
Constitutively active tyrosine kinase
ALL
MLL
ALL
E2A-PBX1
T(1;19)
HOX gene regulator
Burkits
Myc
T(8;14)
Myc oncogene
HOX gene promoter
• What is the typical age of presentation for
hodgkins vs non-hodgkins lymphoma
• Hodgkins = late 20’s
• NHL = 60’s
• List the major risk factors for lymphoma
• Immunodeficiency
– Acquired
• HIV, organ transplant
– Inherited
• Autoimmune disease
– RA, SLE, Sjogrens, Celiac
• Infection
– Viruses
• HIV, EBV, HTLV, HEP C, HHV 8
– Bacteria
• H pylori
• What are the B symptoms
• Drenching night sweats
• FUO
• Unexplained weight loss > 10%
• Describe the biopsy technique for suspected
lymphoma
• Preferable is excisional biopsy of the
suspected node. Otherwise need a core
needle biopsy. Fine needle is insufficient
• List the Ann Arbor criteria for staging
lymphomas
Stage
I
Single lymph node region
II
Multiple lymph node regions on same side of diaphragm
III
Multiple lymph node regions across diaphragm
IV
Extralymphatic non-contiguous involvement
Suffix
B
B sx present
A
No B sx
E
Extralymphatic
X
Bulky
S
Splenic
• What are the prognostic factors for lymphoma
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APLES
Age > 60
Performance status > 1
LDH > normal
Extra nodal sites > 1
Stage III/IV
• What are the risk factors for Non-hodkgins
lymphoma
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WALSHAM
WBC > 15K
Albumin < 4 g/dl
Lymphocyte count < 600/ul
Stage IV
Hemoglobin < 10.5 g/dl
Age > 45
Male
• List the indolent, aggressive, and highly
aggressive lymphomas
• Indolent
– Follicular
– Small lymphocytic
– Marginal zone
• Aggressive
– Diffuse large B-cell
– Mantle cell
• Highly aggressive
– Burkitts
– Precursor B/T cell
• What is the treatment for indolent lymphoma
• Watchful waiting until
– cytopenia
– Leukemia
– Marked splenomegaly, pelural effusion,
compressive symptoms
– Single large node > 7cm
– 3 nodes > 3cm
• What is the treatment for aggressive
lymphoma
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R-CHOP
Rituximab
Cyclophosphamide
Doxorubacin
Vincristine
Prednisone
• What is the treatment regemin for nonhodgkin’s lymphoma
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ABVD
Doxorubicin
Bleomycin
Vinblastine
dacarbazine
• What is the signature side effect for
doxorubicin
• CHF/cardiac toxicity
• AML
• What is the principle side effect of vincristine
• Peripheral neuropathy
• Constipation
• What is the principle side effect of bleomycin
• Pulmonary fibrosis
• Describe autologous stem cell transplant
• Autologous
– From self
– Risk of recurrence due to contamination or
continued gene defects
– No graft v leukemia reaction
– No graft v host reaction
• Describe syngenic stem cell transplant
• Syngenic
– From an identical twin
– No contamination with disease cells
– Genetic defects remain
– No graft v leukemia reaction
– No graft v host reaction
• Describe allogenic stem cell transplant
• Allogenic
– From another member of the species that is not
identical
– No contamination with disease cells
– Should not have similar genetic defects
– Graft v leukemia reaction
– Graft v host reaction
• What are the sources for stem cells
• Bone marrow aspirate
• Cord blood
• Peripheral blood
– G-CSF
– AMD3100 – allows stem cells to leave marrow
• When should SCT be considered
ALL
AML
Allogenic
CLL
Allogenic or
autologous
CML
Allogenic
1st remission high risk, 2nd otherwise
After imatinib failure
NHL
Hodgkins
Autologous
Myelodyspl Allogenic
astic
Syndroms
Multiple
myeloma
If < 40yo and high risk
Autotransplan Most common reason for autotransplant
t
• What are the risk factors for prostate
adenocarcinoma
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Age
Race
Family history
Diet
Cadmium exposure
Vasectomy (controversial)
• What are the screening tools for prostate
cancer
• Digital rectal exam
• PSA
• What is the staging for prostate cancer
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T1 – incidental finding
T2 – confined to prostate
T3 – outside of prostate capsule
T4 – Invading other pelvic structures
• Which patients should receive radiation
therapy
Low risk
T1-T2a
Radiation or radical prostatectomy
Medium risk
T2b/c, PSA 1020
Radiation if expected survival > 10 years
Hormone therapy
High risk
T3, PSA > 20
Radiation
Hormone therapy
• Define initiation
• A mutation defect resulting in a
phenotypically normal but altered cell.
• Define promotion
• The proliferation of a cell as a result of genetic
changes occurring in initiation
• Define progression
• Acquisition of additional mutations in an
initiated/promoted cell that confer more
advanced neoplastic phenotype
• Describe tumorgenesis in skin cancer
• Cells are initiated by uv or other
environmental insults. Over time promotion
and progression occur until a frank tumor
arises.
• What is the prevalence of basal cell
carcinoma, squamous cell carcinoma, and
malignant melanoma.
• BCC
– #1 epithelial skin cancer
– Low death rates
• Squamous cell carcinoma
– #2 epithelial skin cancer
– Low death rates
• Malignant melanoma
– #3 skin cancer (?)
– #1 in deaths (75%)
• Describe basal cell carcinoma
• Slow growing epithelial skin cancer with no
known precursor lesion that is locally invasive
and only rarely metastatic.
• Often translucent when stretched due to
mucin (?)
• Where do BCC’s arise
• Keratinocytes associated with hair follicles
• What is the role of ptch1 in bcc
• Patch -----| smo ------> n-myc
• N-myc is a proliferative gene
• Describe grolin’s syndrome
• An inheritable defect in ptch1 that
predisposes carriers to BCC
• What is the precursor lesion of squamous cell
carcinoma
• Actinic keratosis
• Describe AK
• A rough, dry, scaly, red/brown patch on the
skin.
• Describe the role of the immune system in
SCC development
• The immune systems role is not well described
but it plays some role as SCC increases with
immune suppression and stimulation of the
adaptive system is a treatment for both SCC
and BCC.
• What are common genetic defects seen in SCC
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INK4a – a tumor suppressor is inactivated
P53 \/
Map kinase /\
NF-kB /\
• What is xeroderma pigmentosum
• A germline mutation in genes involved in
nucleotide excision repair.
• Associated with increased levels of BCC and
SCC
• Why is XP associated but not causative for
BCC/SCC
• Uv is a major culprit in creating dimers that
must be removed by excision repair.
Therefore, if an XP patient were to limit their
sunlight exposure, they limit their risk of
developing SCC and BCC
• Why is malignant melanoma prone to
metastasis?
• Melanoma arises from melanocytes which are
of neural crest origin. These cells migrate
widely in the developing embryo and its
believed that this trait is re-emerges in cancer.
• What are the ABCD’s
• A tribute band to AC/DC
– http://www.abcdband.com/
• Melanoma mnemonic
– Asymmetry - asymmetrical
– Borders - irregular
– Color - uneven
– Diameter - 6mm+
• What are the two phases of melanoma
development and their prognosis
• Radial phase
– Growth contained to the plane of the epidermis.
– Curable with surgery alone
• Vertical phase
– Growth perpendicular to the plane of the
epidermis resulting in invasion of the dermis and
underlying tissue
• Explain the role of melanoma depth of
invasion as a prognostic indicator
• Depth of invasion is inversely related to
prognosis. In other words, deeper = deadlier.
• What is the role of growth factors in
malanomagenesis
• Melanoma cells eventually gain self sufficiency
in growth signals by producing their own
fibroblast growth factor, a substance normally
generated by keratinocytes.
• Once again, what is INK4
• A gene located on CR9 that is lost in 20-40% of
melanomas. Hereditary melanomas are
associated with loss of INK4A.
• A negative regulation of cell growth through
the RB pathways
• What is the CDKN2A locus
• A critical locus on CR9 in that codes for INK4a
and p14ARF. Both genes act as negative
regulators of cell growth pathways.
• For no reason at all here’s Abu
• List the types of ultraviolet light
• UVA
– Mildly carcinogenic
– Photoaging
• Solar elastosis?
• UVB
– Carcinogenic
– Causes burns
• UVC
– Highly carcinogenic
– Blocked by ozone
• Are sunscreens protective for sundamage
• Sort of. SPF relates the amount of UVB
blocked by a properly applied sunscreen.
There is no current rating for blocking UVA
and many sunscreens do not do so.
• Many people use sunscreens to extend the
time they are in the sun thus effectively
negating their benefit.
• What is the best therapy for malignant
melanoma
• Early detection combined with excision.
• Non-surgical interventions have poor
performance
• Proper prior planning prevents painfully poor
performance.
• Make up your own sentence where every
word begins with P.
• Perfectly posed purple plumed piccolo players
piped prodigiously
• Pink penguins played peek-a-boo
• What are the histological hallmarks of
melanoma
• Lack of maturation with descent
• Single cells predominate over nests
• Pagetoid appearance with migration upward
resulting in buckshot appearance
• Where would you typically expect to see
superficial spreading malignant melanoma
and what phase is it in
• On intermittently sunburned skin
• Radial phase
• Where would you expect to see lentigo
melanoma and what phase is it in
• On chronically sun damaged skin in the elderly
• Radial phase
• What phase is nodular melanoma in
• Vertical
• Can be rapidly fatal
• Where would you expect to find acral
lentiginous melanoma and what phase is it in
• On darker skinned people on the palms, soles,
and nails. Radial phase.
• What are the poor histologic factors for
melanoma
• Thickness
– > 1mm
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Ulceration
Vascular invasion
Microscopic satellites
Increased mitotic rate
Minimal lymphoid response
Partial regression