Slackers Guide to Hematologic Cancers Mike Ori. Disclaimer These represent my understanding of the...
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Transcript of Slackers Guide to Hematologic Cancers Mike Ori. Disclaimer These represent my understanding of the...
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
• e r l• I didn’t use greek letters because they are a
pain to cut and paste in.
• Evasion of apoptosis• Insensitivity to anti-growth signals• Self sufficiency of growth signals• Limitless replication potential• Sustained Angiogenesis• Tissue invasion and metastasis
• 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.
• 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.
• 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.
• 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
• An epithelial growth factor receptor whose gene is amplified in 25% of breast cancers.
• Self-sufficiency in growth signals
• Trastuzumab is a monoclonal antibody directed against her2/neu/Erb b2.
• It functions by binding to and disrupting erb b2
• 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
• 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
• Follicular– Expansion of B cells
• Paracortical– Expansion of T cells
• Sinus histiocytes– Surgical drainage
• DNA cleavage is an important part of maturation of immune cells. This presents opportunity for abnormal joining.
• Translocations• Inherited– Downs, neurofibromatosis
• Viruses– HTLV, EBV, HHV-8
• Environmental agents• Iatrogenic– Radiation
• Lymphocytic leukemias evolve to lymphomas late. Similarly, lymphomas may transform into lymphocytic leukemias.
• Common indolent lyphoma• Back to back follicles• T(14:18) BCL-2– Anti-apoptotic
• May transform into diffuse large cell lymphoma
• Rapidly aggressive lymphoma• T(8:14) c-myc oncogene• Association with EBV• Starry sky pattern due to histiocytes
• Associated with MALT in gut• Chronically inflamed tissue– H. pylori
• Indolent but may transform to diffuse B-cell
• Common cancer of young adults• Orderly progression from local nodes to
spleen to liver to bone marrow• Reed-sternberg cells
• 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
• MPN– Clonal proliferation of a myeloid precursor – Retains ability to mature– Effective hematopoiesis– Expansion of one or more related cell lines– Normal blast levels
• MDS– 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
• This strongly implies a dysplastic/neoplastic process. Excess growth hormones would affect all members of a lineage sensitive to the hormone.
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
• 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
• 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
• Chronic Myelogenous Leukemia• Polycythemia Rubra Vera• Essential thrombocytosis• Primary myelofibrosis
• Philadelphia– Cheese steaks– Liberty bell– Independence hall– Eagles– http://www.phillyfunguide.com for more…who
knew ( I just realized knew is a funny word)
• Absolute increase in RBC’s but other lines may also be affected
• Platelets often 500,000/ul• Issues related to blood viscosity
• 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.
• 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.
• Fibrous marrow • Primary– If no other reason established
• Secondary– Arises due to “burned out” marrow from CML or
PV• Extramedullary hematopoieis – Massive splenomegaly
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 HOX gene promoter
ALL E2A-PBX1 T(1;19) HOX gene regulator
Burkits Myc T(8;14) Myc oncogene
• Immunodeficiency– Acquired
• HIV, organ transplant
– Inherited• Autoimmune disease– RA, SLE, Sjogrens, Celiac
• Infection– Viruses
• HIV, EBV, HTLV, HEP C, HHV 8
– Bacteria• H pylori
• Preferable is excisional biopsy of the suspected node. Otherwise need a core needle biopsy. Fine needle is insufficient
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
SuffixB B sx present
A No B sx
E Extralymphatic
X Bulky
S Splenic
• WALSHAM• WBC > 15K• Albumin < 4 g/dl• Lymphocyte count < 600/ul• Stage IV• Hemoglobin < 10.5 g/dl• Age > 45• Male
• Indolent– Follicular– Small lymphocytic– Marginal zone
• Aggressive– Diffuse large B-cell– Mantle cell
• Highly aggressive– Burkitts– Precursor B/T cell
• Watchful waiting until– cytopenia– Leukemia– Marked splenomegaly, pelural effusion,
compressive symptoms– Single large node > 7cm– 3 nodes > 3cm
• Autologous– From self– Risk of recurrence due to contamination or
continued gene defects– No graft v leukemia reaction– No graft v host reaction
• Syngenic– From an identical twin– No contamination with disease cells– Genetic defects remain– No graft v leukemia reaction– No graft v host reaction
• 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
• Bone marrow aspirate• Cord blood• Peripheral blood– G-CSF– AMD3100 – allows stem cells to leave marrow
ALL
AML Allogenic 1st remission high risk, 2nd otherwise
CLL Allogenic or autologous
CML Allogenic After imatinib failure
NHL
Hodgkins Autologous
Myelodysplastic Syndroms
Allogenic If < 40yo and high risk
Multiple myeloma
Autotransplant
Most common reason for autotransplant
• T1 – incidental finding• T2 – confined to prostate• T3 – outside of prostate capsule• T4 – Invading other pelvic structures
Low riskT1-T2a
Radiation or radical prostatectomy
Medium riskT2b/c, PSA 10-20
Radiation if expected survival > 10 yearsHormone therapy
High riskT3, PSA > 20
RadiationHormone therapy
• Acquisition of additional mutations in an initiated/promoted cell that confer more advanced neoplastic phenotype
• Cells are initiated by uv or other environmental insults. Over time promotion and progression occur until a frank tumor arises.
• 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%)
• 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 (?)
• 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.
• A germline mutation in genes involved in nucleotide excision repair.
• Associated with increased levels of BCC and 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
• 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.
• A tribute band to AC/DC– http://www.abcdband.com/
• Melanoma mnemonic – Asymmetry - asymmetrical– Borders - irregular– Color - uneven– Diameter - 6mm+
• 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
• Melanoma cells eventually gain self sufficiency in growth signals by producing their own fibroblast growth factor, a substance normally generated by keratinocytes.
• 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
• A critical locus on CR9 in that codes for INK4a and p14ARF. Both genes act as negative regulators of cell growth pathways.
• UVA– Mildly carcinogenic– Photoaging
• Solar elastosis?
• UVB– Carcinogenic– Causes burns
• UVC– Highly carcinogenic– Blocked by ozone
• 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.
• Early detection combined with excision.• Non-surgical interventions have poor
performance
• Proper prior planning prevents painfully poor performance.
• Perfectly posed purple plumed piccolo players piped prodigiously
• Pink penguins played peek-a-boo
• 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