Oncology

Front 1

Neoplasia/neoplasm

Back 1

"new cell growth"
-physical evidence of pathologic new cell growth
-solid mass lesion/tumor or a diffuse process like leukemia

Front 2

Tumor

Back 2

-solid mass (subcategory of a tumor)

Front 3

Cancer

Back 3

-reserved for MALIGNANT tumors only

Front 4

Clinical presentation of tumors (general)

Back 4

-often present as occult disease (hidden) with systemic symptoms or metabolic alterations
-mass lesion present
-fever
-anemia
-anorexia, cachexia
-ectopic hormone production
-pathologic bone fracture

**must exclude tumor as an explanation for odd physical or lab results

Front 5

Diagnosing/treating tumors

Back 5

-may be able to treat surgically
-in hollow organs, lesions can cause pain, bleeding, and obstruction; dx with biopsy
-radiographs can find symptomatic or asymptomatic mass lesions (ex: density in lung fields in a smoker is suspicious for lung cancer, but if its in a patient who doesnt smoke but had prior cancer, indicates metastasis to lungs)

Front 6

Most important factor in determining the treatment and prognosis of a tumor

Back 6

-histologic diagnosis!
-made by a surgical pathologist
-benign or malignant

Front 7

Benign (and 4 characteristics)
1) differentiation/anaplasia
2) rate of growth
3) local invasion
4) metastasis

Back 7

-tumor does not metastasize
1) well differentiated tissue, usually typical of the tissue of origin
2) progressive, slow growth; may stop or regress..**rare, normal mitotic figures
3) well demarcated, cohesive, expansile masses that DO NOT invade surrounding tissue
4) NO METASTASIS)

Front 8

Malignant (and 4 characteristics)
1) differentiation/anaplasia
2) rate of growth
3) local invasion
4) metastasis

Back 8

-tumor is capable of metastasis
1) often lacks some differentiation = anaplasia; tissue may be atypical of origin tissue
2) erratic growth, slow or rapid...*numerous, abnormal mitotic figures
3) invades local surrounding tissue, although it may appear cohesive or expansile
4) metastasis is frequently present, depends on how large and undifferentiated the primary tumor is!!

Front 9

Uterine leiomyomas

Back 9

-fibroids
-most common benign tumors in women
-can be large or multiple or symptomatic; can cause discomfort, morbidity and even death, but does not metastasize
-like benign tumors, can recur if not completely metastasized

Front 10

Malignant melanoma

Back 10

-primary skin tumor that can metastasize; it is malignant
-even if primary is very small, can give rise to large, multiple, distant metastases

Front 11

Carcinoma

Back 11

-malignant EPITHELIAL tumor

Front 12

Epithelial tumors: Papilloma

Back 12

-benign
-origin: squamous epithelium
-forms masses (Benign proliferation)

Front 13

Epithelial tumors: Squamous cell carcinoma

Back 13

-malignant
-origin: squamous epithelium
-forms masses

ex: in cervix

Front 14

Epithelial tumors: Adenoma

Back 14

-benign
-origin: glandular epithelium

ex: colonic adenomas (detected by colonoscopy .. important in prevention of adenocarcinoma)

-grow as exophytic polyps, can be biopsied to look for early malignant changes

Front 15

Epithelial tumors: Adenocarcinoma

Back 15

-malignant
-origin: glandular epithelium

-can result from untreated adenomas of the colon
-grow in ulcerated pattern
*malignant glands have INVADED wall of colon, can now metastasize

Front 16

Sarcoma

Back 16

-malignant mesenchymal (connective tissue) tumor
-uncommon, associated with specific inherited cancer syndromes or increased susceptibility

Front 17

Mesenchymal tumors: Lipoma

Back 17

-benign
-common in adults
-origin: adipose tissue

-differentiated from liposarcomas by histology and by location: usually benign if superficial or in subQ of adipose tissue

Front 18

Mesenchymal tumors: Liposarcoma

Back 18

-malignant
-origin: adipose tissue

-usually malignant if deep in the adipose tissue of the extremities or retroperitoneum
-many are indolent

Front 19

Mesenchymal tumors: Leiomyoma

Back 19

-benign
-origin: smooth muscle

Front 20

Mesenchymal tumors: Leiomyosarcoma

Back 20

-malignant
-origin: smooth muscle

Front 21

Mesenchymal tumors: Rhabdomyoma

Back 21

-benign
-origin: skeletal muscle

Front 22

Mesenchymal tumors: Rhabdomyosarcoma

Back 22

-malignant
-origin: skeletal muscle

Front 23

Mesenchymal tumors: Angioma

Back 23

-benign
-origin: blood vessels

Front 24

Mesenchymal tumors: Angiosarcoma

Back 24

-malignant
-origin: blood vessels

Front 25

Mesenchymal tumors: Osteoma

Back 25

-benign
-origin: bone

Front 26

Mesenchymal tumors: Osteosarcoma

Back 26

-malignant
-origin: bone

-usually associated with bony skeleton but can be extraskeletal

Front 27

Teratoma

Back 27

**rarely malignant
-have mature tissues from more than one germ layer, and often all 3: ectoderm, endoderm, mesoderm

*most common location: ovary

Front 28

Mature cystic teratoma (dermoid cyst)

Back 28

-in ovary of young adult women
-most common type of teratoma

-hair, skin, teeth, brain, fat are common components, but occasionally some are monodermal (ex: thyroid tissue)

Front 29

Hamartoma

Back 29

-mass of normal but disorganized tissues indigenous to the site of origin

*most common location: lung (incidental finding on x-ray)

Front 30

Heterotopia

Back 30

-ectopic rest of normal tissue

Front 31

Classification: CNS tumors, leukemias, lymphomas

Back 31

-own nomenclature system DIFFERENT from the solid tumors listed above

Front 32

Cancer incidence rate: reasons for increase

Back 32

-can be reflective of prevalence, but is influenced by screening tests with increased sensitivity for the tumor (more diagnoses picked up on, but not truly new cases)

Also: increased life span (also related to more potential exposures to carcinogens and weakening immunity)

Can be a true increased prevalence for certain cancer due to exposure to a known carcinogen

Note: family history and lifestyle choices also influence risk, but not necessarily influence

Front 33

Cancer survival

Back 33

-proportion of patients alive at some point after cancer diagnosis

Front 34

More breast and prostate cancer?

Back 34

Not true increase in incidence
-reflection of effective screening programs for PSA and mammography

Front 35

More lung cancer?

Back 35

-may be a true increase in incidence due to the introduction of cigarettes

ex: more women began dying of lung cancer in the 60s b/c they started smoking = true increase in prevalence

**some cancers can have a long latency period b4 cancers begin to show up

Front 36

Pediatric tumors

Back 36

-cancer incidence is not distributed evenly, specific types depend on age
-carcinomas present in middle/older age
-children get leukemias and neural, mesenchymal origin tissue tumors
*for kids, strong component of inherited susceptibility, because haven't lived long enough to get enough carcinogen exposure

Front 37

Hereditary Neoplasia

Back 37

-hereditary tumors have a more evenly distributed incidence, present evenly throughout all ages, versus sporadic ones that are uncommon before middle age

-inherited traits make ppl more susceptible to cancer at earlier ages, get multiple tumors that are often bilateral in paired organs; some even have mendelian inheritence

BUT the same genes involved in hereditary tumors are also involved in the sporadic versions

Note: development of cancer at a younger age = strong association with inherited factors; if at old age, less of an association exists

Front 38

Genetic damage role in causing cancer

Back 38

-occurs as non-lethal damage in tumor cells **meaning it can be transmitted to future generations of cancer cells
-acquired from environment or inherited in the germ line

Front 39

Genetic instability

Back 39

-exhibited by most tumors
-leads to accumulation and propagation of more genetic mutations
-leads to tumor progression

*carcinogenesis is a multistep processes in both genotypic and phenotypic levels = tumor progression

Front 40

Gatekeeper genes

Back 40

-regulate entry of cells into tumorigenic pathway

ex: tumor suppressor genes (inhibit growth)

**if germ line mutation of these, much higher risk of cancer, even MORE risk than if mutation inherited in caretaker gene

Front 41

Caretaker genes

Back 41

-do not directly control tumor growth
-BUT affect genomic instability

ex: DNA mismatch repair genes, other repair genes
-loss leads to increased mutation in all genes that INCLUDES GATEKEEPER genes
**if germ line mutation of these, higher risk of cancer but LESS risk than if mutation inherited in gatekeeper gene

Front 42

Tumor suppressor genes

Back 42

-their protein products inhibit cell proliferation
-loss of function leads to uninhibited cell growth and is a key event if many tumors

*physiologic goal is to regulate cell growth, NOT prevent tumor formation

Front 43

Knudson hypothesis

Back 43

"two hit" hypothesis
-to have loss of function of the TSGs, must have deletion or silencing of BOTH ALLELES at a TSG locus - this results in the tumor phenotype

*presence of one normal allele is enough to preserve normal cell function
-however, if inherit one normal allele and one altered to begin with, increases susceptibility to particular cancers because it only takes one more mutation instead of two

Front 44

Retinoblastoma genetics

Back 44

-BOTH normal alleles of the RB locus must be inactivated (two hits) in order for Retinoblastoma to develop

Front 45

Leukocoria

Back 45

-sign of retinoblastoma
-pupil reflects incident light due to the tumor in the vitreous chamber
-pupil is not black as it should be

Front 46

Hereditary (familial) Retinoblastoma

Back 46

-one normal copy and one defective copy of RB are inherited

-if other copy mutates during lifetime by somatic mutation, retinal cell has lost both copies and gives rise to cancer

*these patients also at increased risk for osteosarcoma and soft tissue sarcomas

Front 47

Sporadic Retinoblastoma

Back 47

-two normal RB alleles are inherited, but both RB alleles are lost by somatic mutation during lifetime

-as with the familial type, once both normal copies have been lost in the retinal cell, gives rise to cancer

**note: these patients do not have same risk factors for other cancers as do the familial RB patients

Front 48

Loss of heterozygosity

Back 48

-cancer occurs when a cell becomes homozygous for a mutant allele, aka it loses its heterozygosity for the normal RB gene

*this occurs in individuals who inherit one mutant TSG allele (ex: one mutant RB allele)
Note: in these individuals, all of their somatic cells are normal, except that they are at an increased risk of cancer (if any cells lose heterozygosity for the normal allele)

Front 49

Oncogenes

Back 49

-genes that promote autonomous cell growth in cancer cells, even in the absence of normal mitotic signals
*mutated forms of their normal cellular counterparts, protooncogenes

Front 50

Protooncogenes

Back 50

-NORMAL cell components
-regulate cell proliferation and differentiation (promote growth)
-if mutated, turn into oncogenes

Front 51

Oncoproteins

Back 51

-similar to the normal protein products of protooncogenes, but lacking regulatory elements so they become CONSTITUTIVELY expressed

**gain of function mutation

Front 52

Gain of function mutation

Back 52

-associated w/ oncogenes (like loss of heterozygosity for TSGs)

**only ONE allele needs to be mutated to create a phenotypic effect - an abnormal protein that becomes dominant, promotes its own cell growth (autonomous)

Front 53

How are oncogenes activated? 2 ways

Back 53

-reduplication and amplification of their DNA sequences
-leads to overexpression

ex: HER2/neu amplification in 25% of breast cancers

---------------------------------------------
**Also may occur by chromosomal translocations (expecially if involving TKs)
-Philadelphia chromosome translocation creates the Bcr-Abl oncoprotein

Front 54

Genetic alterations of solid tumors

Back 54

-much more complex, hard to isolate targets for drugs in order to treat
-in comparison to sarcomas and hematopoietic cancers, which are due to translocations, etc. as discussed before

Front 55

Mismatch repair

Back 55

-normally caretaker genes
-damage to pathways lead to inability to correct errors in replication
-allow development of somatic mutations

*defects in this system can be inherited or can be somatic

-not themselves oncogenic, but allow mutations in protooncogenes..

*if inherited, usually autosomal recessive (xeroderma pigmentosum, ataxia-telangectasia, Bloom syndrome)

Front 56

Hereditary Nonpolyposis Colon Cancer

Back 56

-autosomal dominant
-caused by inactivation of a DNA mismatch repair gene

***most common cancer predisposition syndrome

Front 57

Methylation

Back 57

-methylate promotor sequences (CpG islands)
-normal epigenetic regulation process that silences genes but not loss of genes

*if hypermethylate TSGs, will silence them even though the gene itself is not mutated

Front 58

Steps in carcinogenesis: initiation

Back 58

-permanent, nonlethal DNA damage that is IRREVERSIBLE, can be transmitted to the cell's progeny
-mutated DNA template is replicated and becomes heritable

Front 59

Steps in carcinogenesis: promotion

Back 59

-REVERSIBLE biologic processes that can favor neoplasm development (stimulate proliferation of initated cells)
-do NOT cause genetic damage

Front 60

Steps in carcinogenesis: latency

Back 60

-time from exposure to appearance of neoplasm
-due to interplay between initiation and promotion after exposure to carcinogen

Front 61

Carcinogen

Back 61

-agent that increases incidence of neoplasm

Front 62

Neoplastic Cell growth vs. Normal growth

Back 62

-normal growth is at a steady state between loss and creation of cells
-tumors have autonomy of cell division = continued growth

Front 63

Benign vs. Malignant neoplastic cell growth

Back 63

-benign = limited by adjacent normal tissue, rate of enlargement is slow

-malignant = nonstop growth, but limited by cell loss due to degenerative changes in the tumor??

Front 64

Tumor growth fraction

Back 64

-fraction of tumor cells in the replicative pool
-determines rate of growth
**major effect on susceptibility to chemo (ex: aggressive tumors have a larger fraction, very responsive to chemo)

Front 65

Tumor doubling time

Back 65

-growth fraction cells are dividing, but not necessarily finishing cell cycle faster than normal cells; may be longer

*if larger growth fraction, FASTER doubling time

**most carcinomas double in 2-3 months

Front 66

How many doublings before the tumor is clinically detectable?

Back 66

-30 doublings, or 10^9 cells
=1 gram

*Note: only 10 more doublings needed before it becomes 10^12 cells and 1kg aka maximal size compatible with life!!
-therefore, by the time the cancer is detected, tumor has already completed most of its life cycle with very heterogenous mix of cells (result of many independent mutations from genetic instability ... each cell type has different growth rate, metastatic abilities, etc) ..remember that tumor progression is acquired incrementally!

Front 67

Tumor progression in colon cancer

Back 67

-like certain cancers, has a more predictable pattern with specific alterations from the incremental accumulation of mutations
(but still, heterogeneity occurs far before morphologic changes are clinically evident)

Front 68

Steps in tumor invasion for malignant neoplasms

Back 68

- tumor cells adhere to ECM components; must break through basement membrane of epithelial cells to get to the stroma
-BM sends positive and negative growth signals to the tumor cells, regulates angiogenesis

Front 69

Angiogenesis

Back 69

-blood vessel growth stimulated by tumors
-essential for supplying nutrients to tumor
-without vascularization, can't enlarge beyond 1-2mm in diameter (max distance that nutrients/O2 can diffuse across tissue)

**angiogenesis also required for metastasis

MOA: recruit endothelial cell precursors via existing capillaries
-tumor blood vessels are more tortuous and leaky due to increased production of VEG-F
-tumor cells produce angiogenic factors like VEGF and bFGF

Front 70

Anti-angiogenic therapy

Back 70

new field aimed primarily at blocking VEGF-A/VEGFR2 signaling in order to treat cancers

Front 71

Metastasis

Back 71

-tumor lesions discontinuous with the primary tumor
*primary tumors have preferential locations for metastasis, but not exact
-lets cancers penetrate, vessels, lymph, body cavities

*risk factors: more aggressive, more rapidly growing, larger the primary neoplasm

Front 72

"Seed and Soil" idea of metastasis

Back 72

-solid tumors need interaction between malignant cells as well as the stromal cells it has invaded at both the primary and metastatic sites

Front 73

Pathways of Metastasis (3)

Back 73

1) Direct seeding of body cavities/surfaces
2) Lymphatic spread
3) Hematogenous spread

Front 74

Pathways of Metastasis: Direct seeding of body cavities/surfaces

Back 74

-extension beyond organ of origin directly into adjacent structures
ex: cervical carcinoma
-penetrates wall of bladder and rectum
-makes surgery difficult, not curative (probably has metastasized elsewhere)

**seeding of body cavities occurs with certain carcinomas and melanomas

Front 75

Pathways of Metastasis: Lymphatic spread

Back 75

**most common pathway for initial metastasis of CARCINOMAS

-ex: breast carcinoma in upper outer quadrant disseminate to axillary LNs

Front 76

Pathways of Metastasis: Hematogenous spread

Back 76

**most common pathway for SARCOMAS
-venous invasion, cells travel via vein draining the site of the neoplasm

**peripheral sarcomas tend to metastasize to the lungs

Front 77

Liver metastasis

Back 77

-common site for tumors of the abdominal organs (like colon)
-also occurs via hematogenous metastasis

Front 78

Bony Metastases

Back 78

**most commonly from Prostate, Thyroid, Breast, Lung, Kidney

Front 79

Peritoneal Seeding

Back 79

-natural open space; other body cavities (pleural, pericardial, joint space, etc) can also be affected

*ovarian carcinoma, appendix carcinoma, melanoma (direct seeding)

Front 80

Metaplasia

Back 80

-reversible substitution of one adult cell type for another adult cell type
-may be an adaptation to stressors (cell types better able to withstand the environment due to inflammation, vit deficiency, etc)
*not preneoplastic and is reversible, but malignant transformation can arise if

Front 81

Most common epithelial metaplasia

Back 81

-columnar to squamous
-ex: in the Uterine cervix
-also in respiratory tracts of smokers (ciliated columnar replaced by stratified squamous in trachea and bronchi - **lose mucus secretion function!!)

Front 82

Anaplasia

Back 82

-lack of differentiation
-may exhibit pleomorphism (abnormal nuclei, size and shape), abnormal nuclear morphology, atypical mitotic figures

Front 83

Dysplasia

Back 83

*preneoplastic condition but does not imply it
**in GI, GU, respiratory epithelia
-may revert back to normal if irritant removed if low grade (CIN 1)
**HPV causes cervical, uterine, endocervix dysplasia

-disordered growth and pathological hyperplasia, esp in epithelium

-architectural abnormalities, loss in uniformity of individual cells, abnormal nuclear changes - increased mitotic figures, abnormal basement membrane, nuclear hyperchromasia

Front 84

Atypical hyperplasia

Back 84

*preneoplastic condition like dysplasia
**in breast and endometrium


-increased pathological cell proliferation
-disordered growth, esp in epithelium
-architectural abnormalities, loss in uniformity of individual cells, abnormal nuclear changes

Front 85

Carcinoma in situ (grade CIN 3)

Back 85

-dysplastic changes envolving entire thickness of the epithelium (ex: severe cervical dysplasia)
**confined to epithelium, NO basement membrane penetration
-high risk for progressing to invasive cancer

Front 86

Invasive squamous cell carcinoma of the cervix

Back 86

-from carcinoma in situ
-tumor penetrated epithelial basement membrane
-tumor cells have invaded subepithelial soft tissue
-tumor now has access to lymphatic channels, can metastasize

Front 87

Ductal carcinoma in situ (DCIS)

Back 87

-results from breast preneoplasia (atypical hyperplasia)
-duct filled with atypical cells that remain in the basement membrane

Front 88

Invasive ductal carcinoma

Back 88

-tumor cells have penetrated and stimulate formation of abundant collagenous tumor stroma = desmoplasia
-makes the tumor hard (scirrhous)

Front 89

Grading Malignang Neoplasms

Back 89

-based on degree of differentiation and # of mitosis
-indicates aggressiveness
-Grades I - IV .. relate to increasing anaplasia, although criteria vary
*allows for prognosis and treatment efficacy

ex: squamous cell carcinoma - low grade is well differentiated (intracellular bridges; stratified, flattened cells, cytologically okay) versus moderately differentiated (more cellular, less organized, less flattened, loss of stratification)
-ex: adenocarcinoma, low grade has recognizable glandss and moderate nuclear pleomorphism, whereas high grade (moderately differentiated) has poorly formed glands, pleomorphism and abnormal mitotic figures

Front 90

Immunohistochemistry

Back 90

-ancillary technique to categorize undifferentiated malignant tumors
-helps determine site of origin of a hidden primary tumor
-used to classify leukemia, lymphoma
*prognostic and therapeutic molecules that can be target

*uses monoclonal antibodies
-formalin fixed, paraffin embedded tissue
-localizes specific proteins in the tissue

Front 91

Cancer of unknown origin

Back 91

-metastasis with no obvious primary site, which is important to identify for therapy and prognosis
-can do immunohistochemistry!
-helps subclassify carcinomas, lymphomas and sarcomas and leukemias that may otherwise look similar

Front 92

Review p. 261

Back 92

-markers

Front 93

Breast Cancer and Immunohistochemistry

Back 93

-detects receptors in the nucleus
-if ER or PR or HER2/neu positive, can be offered hormonal therapy, better prognosis than women (anti-estrogens if ER+, trastuzumab if HER2/neu positive)

Front 94

Sentinel Lymph node

Back 94

-first node in a regional lymphatic basin that receives lymph flow from the primary tumor

*determining involvement of axillary LNs is important in staging

Front 95

Fluorescent in situ Hybridization

Back 95

-evaluates gene copy number in certain tumors
-detects translocations, etc. in leukemias, lymphomas
*can assess status of a single gene
-diagnostic, prognostic uses

**used to detect HER2/neu on chrom 17q21 (normal cell has 2 copies of gene; tumor cells with amplification have over 20)

Front 96

Tumor markers

Back 96

-cell surface antigens, cytoplasmic proteins, enzymes, hormones
**NOT diagnostic of cancer!! can be elevated in reactive or inflammatory conditions (ex: PSA)

*indicators of the recurrence of a tumor, or support diagnosis of cancer; can be used to monitor response to therapy (PSA for prostate, CEA for colonic adenocarcinoma, AFP for hepatocellular carcinoma and germ cell tumors, or CA-125 for ovarian carcinoma)

-can be detected in plasma or body fluids

Front 97

Staging: TNM system

Back 97

-T = primary tumor size
-N = regional lymph node involvement
-M = metastatic

*Stage IV reserved for distant metastasis (once this is present, cure unlikely, but long term remission and palliation are possible, esp. if tumor is hormone responsive)

Front 98

AJCC Breast Cancer Stages

Back 98

-I = tumor <2cm, confined to breast, no nodes involved
-II = tumor > 2 cm, metastasis in axillary nodes but not distant metastasis
-III = tumor of any size, extends into chest wall or skin, no distant metastasis
-IV = tumor of any size, with or w/o chest wall involvement or nodal metastases, but distant metastasis present

Front 99

Most important prognostic factor for breast cancer

Back 99

**Axillary lymph node status!!
-most important prognostic factor for invasive carcinoma in absence of distant metastasis

Front 100

2nd most important prognostic factor

Back 100

*tumor size
-independent of lymph node status (although risk of axillary LN status increases with size of carcinoma)

Front 101

Gompertzian curve

Back 101

-mathematical model describing tumor cell growth
-tumor cells grow exponentially in the early stage
*tumor takes constant amount of time to double
-Growth fraction is high
**as tumor grows, doubling time and growth fraction slowed due to lack of nutrients, etc.

Front 102

Best time to attack cancer cells

Back 102

-early growth phase
-more susceptible to chemo when doubling time is short

Front 103

Immunotherapy

Back 103

-used when tumor burden is below 10^5 cells
-use of biologic agents

Front 104

Log-kill hypothesis

Back 104

-fraction of cells killed with each cycle of chemo is constant, regardless of tumor burden (assumes homogenous sensitivity to chemo)

Front 105

How many logs are killed by one round of chemo?

Back 105

-3 logs
ex: 10^10 --> 10^7

**regrowth occurs between cycles!

Front 106

Goldie-Coldman Hypothesis

Back 106

-best strategy for treatment is initiate early
-combine drugs with non-overlapping toxicities

**Goal: prevent tumor resistance!!

Front 107

Types of treatment (6)

Back 107

-single agent
-combo chemo (many agents)
-combo chemo/radiation together
-sequential therapy (combination of chemo followed by another single or combo of chemo)
ex: AC--> Docetaxel
-immunotherapy
-hormonal therapy
-other combinations (radiation and surgery)

Front 108

Treatment of liquid tumors (3)

Back 108

-induction
-consolidation/adjuvant
-maintenance

Front 109

Treatment of solid tumors (3)

Back 109

-adjuvant therapy
-neoadjuvant therapy
-palliation

Front 110

Complete response

Back 110

**REMISSION
-disappearance of all evidence of tumor

Front 111

Partial response

Back 111

-reduction of at least 50% of the diameter of all lesions

Front 112

Stable disease

Back 112

-decrease of less than 50% or increase of less than 25% in diameter of lesion

Front 113

Progressive disease

Back 113

-increase of more than 25% in diameter of any lesion

Front 114

Induction

Back 114

-initial treatment to get patient into COMPLETE REMISSION

Front 115

Consolidation/Adjuvants

Back 115

-used to eradicate micrometastatic disease

Front 116

Maintenance

Back 116

-prolonged therapy

**Used especially for ALL

Front 117

Neoadjuvant

Back 117

-used to reduce tumor burden before surgery

Front 118

Chemo cycles

Back 118

-3 days chemo, 18 days rest, then repeat (21 days total - lets WBCs replete)

Front 119

Tumor burden and chemo response

Back 119

-high initial burden lowers responsiveness of tumor to chemo

(Note: if tumor is heterogeneous, more likely to have chemo resistance)

Front 120

General toxicity: Nausea and vomiting

Back 120

-causes electrolyte imbalances, decreased nutrition, dehydration

*N/V receives input from GI tract (vagal, sympathetic afferents from stomach, serotonin from small intestine), cerebral cortex, vestibular apparatus, chemoreceptor trigger zone and is coordinated by the vomiting center in the meulla, sends efferents to salivary/respiratory and GI tracts
-many NTs involved: sub P, GABA, Ach, serotonin, dopamine, histamine, endorphins

Front 121

Acute chemo-induced N/V

Back 121

-in first 24 hours after chemo, peaks at 3-4 hours later
-treat with serotonin and nk-1 antagonists, corticosteroids

Front 122

Delayed chemo-induced N/V

Back 122

-3-5 days after chemo
-tx. with dopamine antagonists, corticosterois, nk-1 antagonists

*associated with cisplatin, cyclophosphamide and doxorubicin

Front 123

Anticipatory chemo-induced N/V

Back 123

-before chemo
-treat with benzodiazepenes

Front 124

N/V Drugs: Serotonin antagonists

Back 124

-bind serotonin receptors in small intestine and in the CTZ of brain
-odansetron, granisetron, dolasetron .. given IV or oral

**treat acute CINV, not delayed

Side effects: headache, hiccups, QT prolongation, constipation

Front 125

Palonosetron

Back 125

-newest 5-HT3 antagonoist
-one dose per cycle of chemo (long half life, can be dosed every 5-7 days, whereas others only last a few hours)

Front 126

Aprepitant

Back 126

-substance P action (via neurokinin-1 receptor aka nk-1); NK1 antagonist
-for both acute and delayed

Side effects: *multiple drug interactions (CYP34A - if use with dexamethasone, reduce dexa dose), hiccups, fatigue

Front 127

N/V Drugs: Dopamine antagonists

Back 127

-bind dopamine D1 and 2 in CTZ
-prochloperazine, metoclopramide, perphenazine
-for acute and delayed N/V

Side effects: **extrapyramidal side effects (if mild treat with benadryl), sedation

(Prokinetic agents are like these drugs but cause diarrhea also as a side effect)

Front 128

Dexamethasone

Back 128

--corticosteroid
-mechanism unknown for antiemetic

Side effects: glucose intolerance, insomnia, nervousness

Front 129

Olanzapine

Back 129

-atypical antipsychotic
-in trials
-great for acute, less so for delayed

*for refractory cases; antagonist of multiple dopamine, serotonin, histamine receptors...etc. can cause sedation and weakness

Front 130

Erythropoietin (Epo)

Back 130

30-50% of patients respond

*treats anemia from chemo ONLY IF THERE ARE ALREADY ADEQUATE IRON STORES (ex: cisplatin effects on kidney reduce erythropoietin production)
-do iron studies before tx, if iron low, replete iron first

*Side effects: HT, rash, arthralgia

**At 12 Hgb, stop treatment until Hgb drops below 12 again (above 12 can cause death)

-Procrit (short acting, every 1-2 weeks, but works faster to increase HgB) or Darbepoetin (long acting, every 2-3 weeks)
-reassess every 4-6 weeks (should have >1Hgb increase)

Note: **this is ONLY used for chemo patients, not all cancer patients w/ anemia

Front 131

Neutropenia

Back 131

-absolute neutrophil count <500 (some say <1000)

-when ANC <1000, at high risk for infection, which is also related to the length of the neutropenia

Front 132

Myeloid growth factors

Back 132

-enhance prolif/differentiation of myeloid cell lines, aka neutrophils
**to treat neutropenia in chemo patients

-Filgrastim = GCSF, short acting, Pegfilgrastim, long acting GCSF, Sargramostim = GMCSF, short acting)
**interchangeable
**can be used as primary prophylaxis - before chemo for neutropenia (with drugs having a high incidence of it); secondary prophylaxis, which is right after chemo for curative intent; or for established neutropenia

***treat until ANC >1000 (will drop by half after you discontinue it)

Front 133

Pegfilgrastim

Back 133

-polyethylene glycol attached, higher MW, which decreases clearance
-longer half life, but clearance increases as neutrophils recover (self regulating)

**only given once after chemo!
Side effects: fever, bone pain, increases in uric acid, LDH, alkaline phosphatase, rash

Downside: EXTREMELY EXPENSIVE

Front 134

Origin of all cells in the blood, immune system in an adult

Back 134

-BONE MARROW

Front 135

Leukemia versus Lymphoma

Back 135

Leukemia: malignant cells circulate in blood
**can be seen on a blood smear

Lymphoma: malignant cells found mainly within lymphoid organs

Front 136

B cell lymphomas mimic what cell types?

Back 136

-mimic stages of B cell differentiation that take place in the LYMPH NODES
(follicular dendritic cells, mantle zone cells, marginal zone cells, germinal center cells, etc, ...)

Front 137

B-lymphoid acute leukemias mimic what cell types?

Back 137

-immature B-lymphoid stages that take place in the BONE MARROW

Front 138

Biopsy site for leukemia

Back 138

-bone marrow (even though the tumor cells are circulating)

Front 139

Biopsy site for lymphoma

Back 139

-enlarged lymph node or extranodal mass

Front 140

Myeloperoxidase

Back 140

-histochemistry can differentiate similar leukemias if morphology isnt good enough

**ALL is myeloperoxidase NEGATIVE whereas AML is POSITIVE; even though they appear similar

Front 141

Which antigens are expressed in AML? (2)

Back 141

CD 13 and CD 33

Front 142

Which antigens are expressed in ALL? (2)

Back 142

CD 10 and CD 20

Front 143

How do you detect cell surface antigens (CDs)?

Back 143

Flow cytometry

Front 144

What is the chromosomal abnormality in Burkitt's lymphoma?

Back 144

-translocation of long arms of 8 and 14

t(8;14)

**example of cytogenetics

Front 145

Explain how this translocation causes Burkitt's lymphoma.

Back 145

-t(8;14) brings the c-MYC gene (normally tightly regulated) on 8 next to an Ig heavy chain gene promotor on 14 (highly active in B cells
-overexpression of c-MYC can be deteted by immunohistochemical staining
-MYC is a transciption factor, binds DNA, activates cellular proliferation that leads to this disease
(No net loss or gain of genetic info!!)
-

Front 146

Microarrays

Back 146

-future technique for diagnosing cancers
-analyzing gene expression
-sequence person's genome, add RNA and see if it is highly expressed (red) or low expressed (green) or not (black)

Front 147

acute vs. chronic leukemia

Back 147

-chronic: overproduction of mature myeloid or lymphoid cell types; they are either post-mitotic (granulocytes, erythrocytes) or quiescent, rarely dividing ( mature B and T lymphocytes)

-acute: malignant cells are immature, not usually seen outside the bone marrow

*both have an excess of WBCs

Front 148

How do you tell the difference between CML and infection?

Back 148

-both cause leukocytosis and neutrophilia
-normally differentiated myeloid cells (just too many of them)

**CLONALITY - in CML, all malignant cells are descended from single progenitor that acquired the Philadelphia chrom translocation

Front 149

How do you test for clonality?

Back 149

-look at X inactivation patterns in women with X-linked polymorphisms
-only one active X in each somatic cell
-if you can distinguish paternal from maternal X chromosomes, and active from inactive X, can assess clonality

ex: philadelphia chromosome has clonality (same mutation) in all offspring

Front 150

What are the 4 major features that blood cancers must acquire?

Back 150

-autonomous proliferation
-insensitivity to negative regulatory signals
-increased survival
-limitless replicative potential

(for cancer in general, the other two features are angiogenesis and tissue invasion, but this is less important for blood cancer)

Front 151

How does a tyrosine kinase mutation affect cells?

Back 151

-gain a mutation in tyrosine kinase (ex: the JAK kinases are receptors with associated TKs) that causes increased or unregulated kinase activity in the absence of the growth factor stimulus

*provides autonomous proliferation and increased survival (normally cells are stimulated only by hematopoietic growth factors)

-ex: BCR-ABL --> CML
Mutation causes overproduction of maturing myeloid cells

Front 152

What is the pathogenesis of acute leukemia?

Back 152

-block the normal differentiation pattern of progenitors

*mutations in transcription factors that regulate genes involved in myeloid differentiation

==overgrowth of immature cells

Front 153

What is the pathogenesis/how can you treat certain types of acute promyelocytic leukemia?

Back 153

-subtype of AML
-t(15:17) causes a gene (often PML) to bind the retinoic acid receptor alpha (RARa) gene on 17

-normally RARa is a nuclear hormone receptor, binds retinoids **required for normal myeloid differentiation

*when fusion of the genes occurs, the fused gene binds the target genes and BLOCKS their transcription (instead of activating them)

*Treatment: Give high concentrations of all-trans retinoic acid (ATRA - vitamin A, an RARa ligand); the fusion protein binds the ligand instead of DNA, so the normal RARa protein can induce transcruption .. this allows leukemic blasts to continue differentiating, cause remission!

Front 154

Can leukemia cells self renew?

Back 154

-Yes .. this is a fundamental property that leukemic cells need (must be able to sustain proliferation indefinitely) BUT not ALL of them have this capability (heterogeneity)

Front 155

What markers/properties do leukemia stem cells have?

Back 155

-ex: in AML, only small subpopulation of leukemic cells are self renewing, or "leukemia-initiating"
-more quiescent and resistant to chemo, so may be responsible for RELAPSE following a remission

*CD34+ CD38-

Note: these also exist in solid tumors like breast cancer; probably only 10% of the population

(SCID leukemia initiating cell)

Front 156

Remission

Back 156

-no leukemic cells are detectable by pathology or cytogenetics
NOT the same as "cured"

Front 157

Three properties of the acute leukemic cell

Back 157

1) survival and proliferation
2) impaired differentiation
3) self-renewal (possibly via the Wnt signalling pathway)

Front 158

Discussion review p. 276

Back 158

leukemia/lymphoma symptoms

Front 159

How does a tyrosine kinase mutation affect cells?

Back 159

-gain a mutation in tyrosine kinase (ex: the JAK kinases are receptors with associated TKs) that causes increased or unregulated kinase activity in the absence of the growth factor stimulus

*provides autonomous proliferation and increased survival (normally cells are stimulated only by hematopoietic growth factors)

-ex: BCR-ABL --> CML
Mutation causes overproduction of maturing myeloid cells

Front 160

What is the pathogenesis of acute leukemia?

Back 160

-block the normal differentiation pattern of progenitors

*mutations in transcription factors that regulate genes involved in myeloid differentiation

==overgrowth of immature cells

Front 161

What is the pathogenesis/how can you treat certain types of acute promyelocytic leukemia?

Back 161

-subtype of AML
-t(15:17) causes a gene (often PML) to bind the retinoic acid receptor alpha (RARa) gene on 17

-normally RARa is a nuclear hormone receptor, binds retinoids **required for normal myeloid differentiation

*when fusion of the genes occurs, the fused gene binds the target genes and BLOCKS their transcription (instead of activating them)

*Treatment: Give high concentrations of all-trans retinoic acid (ATRA - vitamin A, an RARa ligand); the fusion protein binds the ligand instead of DNA, so the normal RARa protein can induce transcruption .. this allows leukemic blasts to continue differentiating, cause remission!

Front 162

Can leukemia cells self renew?

Back 162

-Yes .. this is a fundamental property that leukemic cells need (must be able to sustain proliferation indefinitely) BUT not ALL of them have this capability (heterogeneity)

Front 163

What markers/properties do leukemia stem cells have?

Back 163

-ex: in AML, only small subpopulation of leukemic cells are self renewing, or "leukemia-initiating"
-more quiescent and resistant to chemo, so may be responsible for RELAPSE following a remission

*CD34+ CD38-

Note: these also exist in solid tumors like breast cancer; probably only 10% of the population

(SCID leukemia initiating cell)

Front 164

Remission

Back 164

-no leukemic cells are detectable by pathology or cytogenetics
NOT the same as "cured"

Front 165

Three properties of the acute leukemic cell

Back 165

1) survival and proliferation
2) impaired differentiation
3) self-renewal (possibly via the Wnt signalling pathway)

Front 166

Discussion review p. 276

Back 166

leukemia/lymphoma symptoms

Front 167

What is the most common cause of hematological cancer?

Back 167

Non-hodgkin's lymphoma
-5th leading cause of cancer overall
-2nd fastest growing cancer
80% of lymphomas in US

Front 168

Cell origin in NHL?

Back 168

-85% B cells (remainder T cell ... very few NK cell)

Front 169

What age group is affected most by NHL?

Back 169

-elderly patients (older than 60)

Front 170

Symptoms of NHL

Back 170

-fevers, night sweats, weight loss, fatigue (constitutional systemic sx)
-swollen lymph nodes
-pain due to compression/infiltration of LNs (pressing on a nerve, etc)
-organ failure/compromise due to obstruction

**only with aggressive lymphomas (with indolent versions of NHL, often asymptomatic, tumor found incidentally)

Front 171

What chromosomal abnormalities are involved in NHL?

Back 171

proto-oncogenes translocated onto Ig heavy-chain locus at 14q32
-bcl-1 (MCL) - 11:14
-bcl-2 (FCL) - 14:18
-c-MYc (Burkitt's lymphoma) - 8:14

Front 172

Median survival of NHL?

Back 172

-ranges from 2.5 yrs (MCL) to 8 years (FCL)

Front 173

Which cancer expresses CD-5 and cyclin D1?

Back 173

-Mantle cell lymphoma (subtype of NHL)
-particularly poor prognosis
(morphologically, looks just like SLL)

Front 174

Which cancer expresses CD-5 and CD-23?

Back 174

Small lymphocytic lymphoma

Front 175

Which cancer lacks CD10 (and CD5)?

Back 175

Marginal zone lymphoma

Front 176

Low Grade NHL

Back 176

-Small lymphocytic
-Follicular, small
-Follicular mixed, small and large

*indolent

Front 177

Intermediate Grade NHL

Back 177

-Follicular large
-Diffuse small
-Diffuse mixed, small and large

*aggressive

Front 178

High Grade NHL

Back 178

-diffuse large, immunoblastic
-lymphoblastic
-small non-cleaved (Burkitt's)

**highly aggressive

Front 179

Indolent types of NHL (4)

Back 179

*1/2 of NHL tumors
-slow progression, median survival of up to 10 yrs

-follicular lymphoma
-marginal zone B cell lymphoma
-SLL
-lymphoplasmacytic lymphoma

Front 180

Aggressive types of NHL (8)

Back 180

**1/2 of NHL tumors (slightly more common)
-diffuse large B cell lymphoma
-mantle cell lymphoma
-peripheral T cell lymphoma
-primary mediastinal large B cell lymphoma
-anaplastic large cell lymphoma
-Lymphoblastic lymphoma
-Burkitt like lymphoma
-Burkitt's lymphoma

Front 181

Composite lymphoma

Back 181

-more than one subtype of lymphoma in a tumor
-often due to evolution of tumor from indolent to aggressive

Front 182

NHL Diagnosis: Biopsy

Back 182

-from lymph node, extramedullary mass, bone marrow

**fine needle aspiration NOT sufficient (although this is the case for most other malignancies) - use the open excision core needle biopsy which cuts out more tissue

Front 183

NHL diagnosis: Histology

Back 183

-some types are organized in groups similar to germinal lymph nodes b/c retained innate programming (architecture is nodular - MORE LIKELY TO BE INDOLENT)
-others are growing in sheets, diffuse - MORE LIKELY to be AGGRESSIVE

*can't see this architecture with a fine needle aspiration

-Also, look at cell size (small = indolent, less replication/transcription going on vs. large cells means more mitotic, etc = aggressive, less mature phenotype)

Front 184

NHL diagnosis: Immunohistochemistry of T cells vs. B cells

Back 184

-T cells have CD2,3,4,8,5

-B cells have 19,20,22,79a, Ig

-can also look for BCL2, BCL6 (regulate apoptosis) or Cyclin D (cycle checkpoint protein)

Front 185

NHL Staging, I-IV and e

Back 185

-I = single LN group
-II = two LN groups on same side of diaphragm (I and II further classified as bulky, if >10cm or 1/3 thoracic diameter; worse prognosis b/c blood supply doesn't reach center, can't bring drugs to kill it)
*stage I and II pts have limited disease, may just need radiation
-III = two+ LN groups on both sides of diaphragm
-IV - extramedullary disease (includes BM)
*these stages III and IV not amenable to radiation, mainstay is chemo

-"e" is added to any stage if there is just 1 isolated extramedullary node involved

Front 186

NHL Staging, A or B

Back 186

-A = patient is asymptomatic
-B = one or more of the following: fever > 38 without source, night sweats, or >10% weight loss
-B has worse prognosis
-classify in addition to I - IV

Front 187

What is the imaging study of choice for NHL?

Back 187

-CT scan of chest, abdomen and pelvis

Front 188

When would you do a bone marrow biopsy for NHL?

Back 188

-to check for stage IV extramedullary disease during diagnosis phase

Front 189

International Prognostic Index

Back 189

-predicts outcome, high and low risk for death

-Age>60
-Performance status of 2 or worse (pt. can't get through day without napping)
-LDH elevated
-2+ extranodal sites (bone marrow counts too)
-Stage (I,II vs. III,IV)

**DOES A BETTER JOB WITH HIGH RISK PATIENTS

Front 190

Revision: Follicular Lymphoma IPI

Back 190

-determined that Hgb of <12 and number of total nodal sites >5 were more important factors than performance status and extranodal sites

**DOES A BETTER JOB WITH VERY LOW RISK PATIENTS

Front 191

What is the goal of treatment for an indolent NHL?

Back 191

-palliative; grows slowly but cannot be cured!!
-symptom control and Q of life
"WATCH AND WAIT" - only treat if SHOWING symptoms, can only make it worse by treating a patient who has no sx
-eventually all patients die over about 10 years

Front 192

What is the goal of treatment for an aggressive NHL?

Back 192

-cure!
-however, get sick very quickly, high burden of disease
*those who survive the first couple of years are likely to be cured, rarely die of lymphoma (attributed to complications from aggressive therapy, and the aggressive tumor itself)
**Begin treatment promptly!!

Front 193

What is the role of surgery in treating NHL?

Back 193

-rarely used, no significant role b/c usually tumor has already dispersed, surgery will only delay time until medical treatment

-respond much more quickly to chemo and radiation

**DO use surgical tx to relieve obstruction and other complications by the tumor!!

Front 194

What is the role of radiation in treating NHL?

Back 194

-very effective and maybe curative in patients with limited disease
-can be treated without exposing too much normal tissue
**good for discrete problems like a bone lesion or airway compromise (that way you dont need to affect whole body by giving chemo)

Front 195

What is the role of chemo in treating NHL?

Back 195

**mainstay of NHL treatment
-alkylators, anthracyclines, and high doses of steroids
-single doses
-combinations shown to be very effectives
*cure can be achieved by high dose combination therapy + stem cell transplant

Front 196

Rituximab and other new treatments

Back 196

-monoclonal Ab against lymphoma antigens

(2 others that are also linked to radioactive isotopes to kill lymphoma)

-Ontak (IL2 agonist bound to diptheria toxin) and bortezemib (proteosome inhibitor) are other MoAbs

*attempting to use anti-idiotype, dendritic cells as vaccines to teach patient cells to destroy their own lymphoma

Front 197

How do you treat indolent NHL lymphoma that has disseminated?

Back 197

WATCH AND WAIT is preferred if no symptoms

-if sx, can do single agent chemo or XRT; can do a chemo combo with anthracycline
-transplantation
-antibody-based therapy

Front 198

What is the MOA for rituximab?

Back 198

-attacks CD20 via ADCC, complement-dependent cytotoxicity, and apoptosis
-Fab binds to CD20
-Fc portion recruits immune effector functions that trigger B cell lysis

Front 199

What is the effect of rituximab on survival/response?

Back 199

-dramatic improvement IF COMBINED WITH CHEMOTHERAPY
-high rate of complete response, doubles time to relapse
*if continued after chemo, prolongs time to recurrence even if it is discontinued 2 years after

**NOT USEFUL FOR INDOLENT LYMPHOMA

Front 200

What is the MOA for radioimmunotherapy (MoAbs linked to radionuclides)?

Back 200

-crossfire effect!!

-Radiolabeled MoAbs deliver low dose, site specific radiation to lymphoma cells
-lymphoma cells w/ low Ab binding are killed by radiation from the labeled MoAbs bound to ADJACENT (crossfire) tumor cells

**great for indolent lymphoma, but expensive (similar results to chemo+rituximab)

Front 201

How do you treat indolent NHL lymphoma that has is localized?

Back 201

WATCH AND WAIT if no sx
-use just XRT
-or 3-4 cycles chemo + XRT
-or 6-8 cycles chemo
-immunotherapy

**Note: this type of disease is rare; by the time it presents, it has usually disseminated

Front 202

How do you treat aggressive NHL lymphoma that has is localized?

Back 202

-determined by who can tolerate tx

-3-4 cycles chemo+XRT
-or 6-8 cycles chemotherapy (if tolerated, sufficient if not over-treatment of disease)

-or XRT (rare)

Front 203

Which is better for NHL, chemo or chemo+radiation?

Back 203

-about comparable
-depends on risks of each for particular patient

Front 204

How do you treat aggressive, disseminated NHL lymphoma ?

Back 204

-stage III and IV

-6 months of chemo, systemic

-if young with higher risk of relapse, try high dose chemo and stem cell transplant

*older patients who can't tolerate chemo can receive radiation aimed at relieving symptoms (localized palliation)

Front 205

What is CHOP?

Back 205

-cyclophosphamide
-doxorubicin
-vincristine
-prednisone

*most successful, least toxic chemo regimen for NHL!!

Front 206

Review cases

Back 206

p.293

Front 207

What is SVC syndrome and what causes it?

Back 207

-tumor presses on SVC and blocks outflow
-pt gets face and neck swelling
-tumors of mediastinum = Terrible T's (teratoma, thymoma, testicular/germ cell tumor, thyroid tumor, terrible lymphoma)

Front 208

What are the symptoms of Hodgkin's Lymphoma?

Back 208

VERY similar to NHL, although B symptoms are more prominent in HL
-Progressive lymphadenopathy (usually in neck or mediastinum
-night sweats, fevers, weight loss, Pel-Ebstein fevers
-pruritis
**occasionally, pain at the site of tumor with ingestion of alcohol

Front 209

How does HL spread, and how fast?

Back 209

-slow, orderly growth
-sequential fashion from one lymph node group to the next

Front 210

How does this differ from NHL?

Back 210

-NHL can spread to and from any LN at any time

Front 211

How common is HL?

Back 211

-6% of new hematologic malignancies
-far less common than HL

Front 212

What ages does HL strike?

Back 212

-BIMODAL
-early 20s
-late 60s

Front 213

Name 3 of the epidemiologic risk factors for HL

Back 213

-high socio-economic status (sheltered kids not exposed to germs enough, overprimed immune system)
-immunosuppression (HIV, transplant) - can't recognize cells with viral antigens/chronic infection
-genetics

Front 214

What virus is associated with HL and why?

Back 214

-Epstein Barr
-2 proteins coded by EBV genome mimic B cell surface proteins
-when expressed on the cell surface, provide activation (viral LMP1 protein) and survival signals (viral LMP2 protein)
-activation keeps a B cell alive and causes a nonproductive Ig rearrangement; once the Ig is expressed, the survival signal keeps the Ig expressed (normally, B cells that don't make a productive Ig are apoptosed)

**3-4 fold increased risk of getting HL for 2 years after EBV infection

Front 215

How do you diagnose HL histologically?

Back 215

-Reed Sternberg cells

Front 216

What is a Reed Sternberg cell?

Back 216

-CD30+, CD15+, eosinophil
(smiley face cell!)
*CD20- ... this differentiates HD from NHL which is CD20+!!

-Malignant B lymphocyte with an IgH rearrangement
-multinucleated giant cells that make up a small proportion of the total cells (rest of the B lymphocytes are normal, active)
-much larger than normal lymphocytes

Front 217

What type of biopsy would you do for HL?

Back 217

open biopsy
-need a large piece of tissue because RS cells are uncommon
-FNA is not sufficient ever

Front 218

Which stage of B cell is overproduced in classical HL?

Back 218

-Mature B cells from the germinal center that have undergone IgH rearrangement

Front 219

What are the 4 types of Classical HL?

Back 219

-Nodular sclerosis (most common)
-Lymphocyte rich (this has overlap with NHL, but unlike NHL the lymphocytes are polyclonal and reactive)
-Mixed Cellularity
-Lymphocyte depleted (rare, aggressive)

**treatment is the SAME for all types

Front 220

What is the most common presentation of nodular sclerosis, and what is it?

Back 220

-younger patients, especially women with mediastinal mass
-has the RS cells
-fibrosis surrounding the nodular lymphoid structure

Front 221

What does mixed cellularity type look like?

Back 221

-2nd most common type
-RS cells + inflammatory cells (B and T cells, plasma cells, eosinophils)
*older, male patients

Front 222

What is the 1 subtype of Non-classical HL?

Back 222

-Nodular lymphocyte predominance
-young men, neck or groin

*expresses CD20, NOT CD30 or CD15!
-BUT these are still RS cells
-responds to therapy, but recurs, exactly like indolent forms of NHL

Front 223

How do you stage HL?

Back 223

-Ann Arbor system
-same criteria as NHL
-A/B indicates whether the B symptoms are present
-M = bulky (worse prognosis)
-E = extranodal involvement (infiltration of another organ) ..all of these are also used to describe NHL

ex: IIIB, IAE, IVAE

Front 224

Why do you image with PET or Gallium for NHL and HL?

Back 224

-to see if there is occult disease on the other side of the diaphragm

(in addition to phys. exam, CT scan and BM biopsy)

Front 225

What is the goal of tx for classical HL?

Back 225

-aggressive
*Goal: cure (unless they cannot tolerate therapy, then aim for palliation)

Front 226

How do you treat limited stage (I,II), non bulky HL?

Back 226

-radiation alone or short course chemo (3-4 cycles) + reduced dose radiation, or chemo alone

Front 227

How do you treat extensive stage (III,IV) HL?

Back 227

-chemo .. not really amenable to XRT if mass is >5cm

Front 228

Types of Radiation: Mantle

Back 228

-the part a belly shirt would cover on your body
-targets the involved lymph nodes and the next set of contiguous nodes (anticipates pattern of spread)

Front 229

Types of Radiation: Extended Mantle

Back 229

-adds in the para-aortic nodes and the spleen
(covers the rest of the stomach)

Front 230

Types of Radiation: Sub-total nodal

Back 230

-adds in the part shorts would cover, kills in all lymph nodes but very toxic

Front 231

What is the Chemotherapy regimen for HL? (4)

Back 231

ABVD
-adriamycin = cardiotoxic
-bleomycin = pulmonary toxic
-vinblastine = BM toxicity
-dacarbizine = BM toxicity

*better than the old MOPP regimen (nitrogen mustard, risk of leukemia and infertility)

Front 232

What if treatment doesn't bring about a cure by 15 years?

Back 232

-more likely for pts to die from therapy than from disease, or from 2ndary effects of the therapy (leukemia, **breast cancer in young women with HL, etc)
-must balance efficacy vs. toxicity

Front 233

What are the long term complications of radiation and chemo?

Back 233

-Radiation: secondary malignancies, esp. breast and lung; cardiac disease; pulmonary fibrosis

-Chemo: secondary leukemia and infertility

Front 234

What are 5 factors that predict for treatment failure with local XRT therapy?

Back 234

-presence of B symptoms
-extranodal disease
-bulky disease
-3+ sites of nodal involvement
-SED rate >50

*if any one of these factors is present, and pt failed XRT therapy, use chemo as primary therapy

Front 235

Treatment for early stage, favorable disease for HL?

Back 235

-I and IIA
-most are cured
-extended field radiation or 2-4 cycles chemo plus involved field XRT (improves relapse and survival)
-for younger patients, XRT has long term risks, better to do chemo alone
-in elderly, XRT alone may work and only requires 1 month treatment

Front 236

Treatment for early stage, unfavorable disease for HL?

Back 236

-I and IIB
-same cure rate
-4 cycles chemo + involved field XRT, or 4-6 cycles chemo

Front 237

International Prognostic Score for HL

Back 237

-stages III and IV only!!
-age>45
-WBC>15000
-Albumin < normal
-Lymphocyte count <8%
-Hgb <10.5
-male
-stage IV

*0-2 = low risk, 3+ = high risk, but survival still good (still 55% vs. NHL high risk where survival is only 20%)

Front 238

How do you treat advanced stage, favorable disease?

Back 238

-Stages III and IVA
-75% cure
-6-8 cycles chemo
-or 6-8 cycles + involved field XRT to bulky disease

Front 239

How do you treat advanced stage, unfavorable disease?

Back 239

-III and IV B
-50-65% cure
-6-8 cycles of ABVD, or clinical trial

Front 240

Review cases

Back 240

p.309

Front 241

What is acute leukemia and what is the the typical presentation?

Back 241

-malignant accumulation of transformed hematopoietic progenitor cells
-clonal expansion of leukemic blasts that are self-renewing but unable to differentiate
-when it infiltrates the bone marrow, impairs normal hematopoiesis leading to BM failure

**Patients usually present with symptoms of cytopenias (anemia, bleeding, infection, etc)

Front 242

What are the epidemiologic differences between AML and ALL?

Back 242

-AML: incidence increases with age, median age 65, only 20% in kids
-ALL: slightly less common, but incidence DECREASES with age, median age 3-5 yrs; 75% occurs under age 15; genetics plays a role

**Note: both are slightly more likely in men, and risk is increased in ppl having chromosomal abnormalities (Down's, Klinefelter's) or other hematologic disorders like MDS or CML

Front 243

What is the most common childhood cancer?

Back 243

ALL

Front 244

What are some causes of acute leukemia? (3)

Back 244

-ionizing radiation, AML 5-7 yrs later, or ALL with prenatal exposure
-benzene/chemicals (also cause MDS and aplastic anemia) .. smoking, petroleum, paints, embalming fluids, herbicides, pesticides increase risk of AML
-anti-cancer drugs = therapy related AML (alkylating agents cause defects in chrom. 5 and 7; topo II inhibitors cause defect in 11); radiation+chemo increases risk further

**Note: most patients have no known exposure or predisposing condition

Front 245

What are the symptoms of acute leukemia?

Back 245

-non specific constitutional sx
-bone marrow failure
-present for weeks to months (fatigue, weakness from either anemia or hypermetabolic statet, anorexia, weight loss, fever with no obvious infection; infections may occur, or bleeding/bruising)
-if bone marrow is infiltrated, may have bone pain

Front 246

What is leukostasis?

Back 246

-while some patients present with leukopenia and have few blasts in peripheral blood, patients can also present with leukocytosis resulting in stasis of blood flow in pulmonary and cerebral circulation
-blast count above 50,000

cerebral leukostasis = headache, visual disturbance, confusion, progresses to coma/stroke

pulmonary leukostasis = dyspnea, tachypnea, crackles on physical exam, infiltrates

**Much more common in AML b/c blasts are larger and have adhesion molecules

Front 247

How does DIC relate to acute leukemia?

Back 247

-can be caused by chemotherapy
-more common in AML, especially in APL (acute promyelocytic leukemia)
-can cause intracranial or GI hemorrhage) .. elevated PT, PTT, low fibrinogen

Front 248

What are manifestations of extramedullary leukemia in ALL?

Back 248

-lymphadenopathy
-splenomegaly
*infiltration of lymphoid organs

-in T cell ALL, can present with large mediastinal mass

-can also have leukemic meningitis in relapse (or testicular involvement)

Front 249

What are manifestations of extramedullary leukemia in AML?

Back 249

-leukemia cutis (skin infiltration)
-gingival hypertrophy

-rarely develop solid tumors w/ no infolvement of bone marrow or blood = chloromas (blast tumors, respond well to radiation and chemo combo)

Front 250

What is tumor lysis syndrome?

Back 250

-before or during treatment, especially in ALL due to cell death
-hyperuricemia leads to nephropathy
-hyperphosphatemia

..cause renal failure and hyperkalemia

Front 251

What are the metabolic abnormalities of AML? other general metabolic problems of the two?

Back 251

-hypokalemia due to renal tubular injury by the lysozyme released from myeloid blasts

-in ALL especially, LDH elevaeed
-both types may have hepatic enzymes elevated, or artificial hypoglycemia after phlebotomy draw

Front 252

What is the French-American British criteria for diagnosing leukemia? vs. WHO's criteria?

Back 252

>30% blasts in bone marrow

WHO says only 20% needed

Front 253

AML/M0

Back 253

Myeloblastic leukemia without differentiation

-CD13 and 33+
-peroxidase negative
-mostly cytoplasm, nongranular

Front 254

AML/ML

Back 254

Myeloblastic leukemia without maturation

-Auer rods
-1+ nucleoli
-mostly cytoplasm, nongranular

Front 255

What are Auer rods?

Back 255

-linear aggregates of primary granules in MYELOBLASTS only

Front 256

AML/M2

Back 256

Myeloblastic leukemia with maturation

*all stages of granulocytes present; granular blasts

*t(8,21)

Front 257

**AML/M3

Back 257

Promyelocytic leukemia
**MOST IMPORTANT TO RECOGNIZE because it has UNIQUE TX

*bilobed nucleus
-abnormal promyelocytes
-Auer rods in BUNDLES
-large granules
-can cause DIC

*t(15,17)

Front 258

AML/M4

Back 258

-Myelomonocytic leukemia
-mostly promonocytes

*inv16

Front 259

AML/M5

Back 259

Monocytic leukemia

-poorly differentiated vs. differentiated
-large blasts, rare granules
*extra hematopoietic manifestations

Front 260

AML/M6

Back 260

-Erythroleukemia

>50% erythroblasts in bone marrow

Front 261

AML/M7

Back 261

Megakaryocytic leukemia

Front 262

ALL/L1

Back 262

-small, homogeneous cells

-round nuclei, fine chromatin, no nucleoli
-little cytoplasm

Front 263

ALL/L2

Back 263

-large, heterogeneous cells

-folded nucleus
-coarse chromatin
-1+ nucleoli
-moderate cytoplasm

*same tx as ALL/L1

Front 264

*ALL/L3

Back 264

**BURKITT's LYMPHOMA .. dif tx than ALL 1 and 2

-large, homogeneous cells
-oval or round nuclei
-dense chromatin
-abundant cytoplasm

Front 265

What are the histochemical characteristics of AML?

Back 265

-myeloperoxidase (in primary granules of granulocytic precursors)
-lysozyme

-non specific esterase in the monocytic subtype (M5)

Front 266

What is a histochemical characteristic of ALL?

Back 266

-terminal deoxynucelotidyl transferase (TdT) positive

-expressed in nucleus of lymphoblasts

**Note: lymphoblast subtypes also have more nucleus than cytoplasm, nucleoli not as prominent

Front 267

What are the flow cytometry (immunophenotyping) results for AML? ALL?

Back 267

-AML - CD13, CD33, CD117

-ALL - most are B precursor cell type = CD10, CD19, CD22; those of precursor T type have 1a,2,3,4,5,7,8

**BUT 5% of ALL has myeloid markers CD13 and CD33

Front 268

What is the WHO classification system?

Back 268

-4 subtypes of AML based on cytogenetics

AML with genetic abnormalities (see p. 323)
AML with multilineage dysplasia
AML, therapy related
AML, not otherwise categorized

-ALL uses immunophenotyping
Precursor B cell ALL
Precursor T cell ALL

(Burkitt's is classified as a lymphoma, not with this system for the WHO)

Front 269

Can you treat acute leukemia with blood transfusions?

Back 269

-yes - required for effective treatment
-for RBC transfusion, depends on patient's status (younger patients tolerate a lower Hgb level)

-for platelets, transfuse if fewer than 10,000/uL platelets (prophylactically for bleeding)

*make sure you give leukodepleted blood products to prevent CMV transmission, decrease risk of alloimmunization (Abs against transfused platelets); irradiate blood products to prevent GvHD especially in BMT

Front 270

How do you treat leukostasis?

Back 270

medical emergency!
-IV hydration and leukapheresis to reduce blast count
-hydroxyurea
-steroids if ALL
-diagnose acute leukemia, then start chemo

**avoid RBC transfusion in any leukocytotic patient because it will raise blood viscosity, can start leukostasis

Front 271

What is hydroxyurea?

Back 271

ribonucleotide reductase inhibitor
-can treat leukostasis by reducing blast burden

Front 272

How do you manage DIC?

Back 272

-replace clotting factors with FFP
-replace fibrinogen with cryoprecipitate
-platelet transfusion

Front 273

How do you manage tumor lysis syndrome?

Back 273

-IV hydration for diuresis
-urine alkalinization - adding bicarbonate to hydration
-allopurinol

*renal failure may still develop - give hemodialysis if this occurs

Front 274

Bicarbonate role?

Back 274

increases solubility of uric acid, prevents urate nephropathy in tumor lysis syndrome

Front 275

Allopurinol role?

Back 275

-prevents accumulation of uric acid in tumor lysis syndrome

Front 276

How do you manage infection in pts with acute leukemia?

Back 276

-prophylax with antibiotics, anti-fungal, anti-viral meds
-all acute leukemia patients are at risk
-sepsis, sinusitis, bronchitis, pneumonia, UTI

*be sure to look for infection any time patient presents with a fever (though it could be due to the leukemia itself)

Front 277

What are some prognostic factors in AML?

Back 277

-advanced age (over 60) is negative
-some cytogenetic abnormalities have favorable prognosis, or can be unfavorable; those with no abnormalities are at intermediate phenotype
-patients with an MDS or MPS or aplastic anemia disorder that develop AML (secondary leukemia) have poor prognosis
-therapy related AML from alkylating agents or topo II inhibitors have unfavorable prognosis

Front 278

Which cytogenetic abnormalities have a favorable prognosis?

Back 278

-genes affecting Core Binding Factor transcription
ex: t(8;21), an AML1-ETO gene fusion inAML/M2
also inv16, an AML1 smooth muscle myosin heavy chain fusion .. AML/M4

these patients have CBF AML and have a 90% prob of achieving remission

**the t(15,17) in APL M3 subtype is from a fusion of the PML gene with RARa gene on 17 .. can be treted, 85% remission

Front 279

Which cytogenetic abnormalities have an unfavorable prognosis?

Back 279

-del5, del7 or monosomy5 or 7 (associated with alkylating agents)
-deletions or translocations in 11q23 (associated with use of topoII inhibitors) .. what subtypes??
-inv(3)

OR multiple abnormalities

Front 280

How do you treat AML?

Back 280

-induction chemo to get <5% blasts in the bone marrow, no blasts in periphery, and restoration of normal hematopoiesis (remission); use 3+7 regimen

-next, do consolidation therapy to prevent relapse; eradicate residual cells; induction lowers blasts 1 log from original 10^12
-2-4 monthly cycles of 2+5, or high dose cytarabine alone; can go into long term remission; can also do an intensified version

**Failure to achieve remission, or a relapse after remission = poor prognosis

-40-70% in long term remission = Cure!

Front 281

3+7 regimen

Back 281

-3 days anthracycline plus cytarabine for 7 days
-standard induction therapy

(but high %age of death from toxicity - WATCH FOR INFECTION, myelosuppression lasts 21-28 days)

Front 282

2+5 regimen

Back 282

-anthracycline 2 days
-cytarabine 5 days

Front 283

What is the intensified post remission therapy?

Back 283

-in place of regular consolidation therapy
-cures more patients
-either high dose cytarabine, HSCT (autologous) or HSCT (allogeneic - therapy of choice with unfavorable disease)

**Note: HSCT (allogeneic) can salvage some patients who failed other regimens

Front 284

How do you treat APL?

Back 284

-acute promyelocytic leukemia often present with leukopenia and DIC
-median age is 30-40 years
-blasts have primary granules and Auer rods
**t(15,17) cytogenetic abnormality (PML-RARa fusion)

*treat with ATRA!! induces complete remission in 85% w/o blast lysis or marrow aplasia seen in chemo .. simply induces differentiation

Front 285

Complication of ATRA?

Back 285

Capillary leak syndrome/APL differentiation syndrome
- weight gain, edema, fever, hypoxia, pulmonary infiltrates
-few days to weeks of ATRA initiation
-due to a rapidly rising WBC count

**TREAT WITH STEROIDS or else rapidly fatal
-incidence is decreased by giving ATRA with anthracycline

Front 286

Arsenic Trioxide

Back 286

-can also be used to treat AP
-ATO causes apoptosis in APL cells with 85% remission

*QT prolongation, AV block and toursade de pointes; can also cause APL differentiation syndrome

**use anthracycline+ATRA as induction, maintain with ATRA and an oral anti-metabolite; if relapse, THEN use ATO

Front 287

What are the prognostic factors in ALL?

Back 287

-excellent prognosis in kids, poor if >60
*infants also have a poor prognosis
-if philadelphia chromosome present, poor prognosis (more common in adults)
-if MLL gene of 11q23 involved, high rate of relapse (seen in infants and adults, poor prognosis)
-t(12,21) from fusion of TEL and AML1 genes has excellent prognosis, usually seen in kids

*precursor B cell ALL has better prognosis than precursor T cell

-if high WBC count, failure to achieve copmlete remission in 1 month, high LDH are all poor prognostic factors

Front 288

Treatment for ALL?

Back 288

-kids usually cured with standard chemo; adults have less response
-anti-metabolites, vincristine, cytarabine, cyclophosphamide, L-asparaginease, etoposide, glucocorticoids

-2-3 years

Front 289

Stages of ALL treatment

Back 289

-induction therapy with 4-5 drugs (anthracycline, vincristine, glucocorticoids)

-intensification: need to target CNS, which is a great place for leukemic blasts to live .. likely site of relapse! Prophylax with intrathecal administration of cytarabine and methotrexate with or without cranial irradiation

-Maintenance - extends disease free survival esp in kids, high relapse in adults: give daily oral plus weekly chemo for 2 yrs

Front 290

What about patients with high risk for relapse?

Back 290

-cytogenetic abnormalities, failure to achieve remission

-allogeneic HSCT! especially if a sibling matches as a donor

Front 291

What is the most common leukemia in the western world?

Back 291

CLL
-long median survival, so there is a high prevalence

Front 292

What is the median age of diagnosis for CLL?

Back 292

-60

Front 293

What is CLL?

Back 293

-too many mature B cells (naive B lymphocytes, low density Ig)
-smudge cells

Front 294

What are smudge cells?

Back 294

-seen in CLL
-cells have fragile membranes, often rupture during slide preparations
-rupture during flow through cell counting machine, difficult to get a count

Front 295

How do you diagnose CLL?

Back 295

-lymphocytosis >5000 / uL
-30% lymphocytes in BM
-<50% immature lymphocytes in peripheral blood (> would instead lead to dx of prolymphocytic leukemia diagnosis)
-clonal expansion of abnormal B cells

*Note: some ppl have CLL cells under 5000 count (analogous to MGUS) but never get CLL

Front 296

What is expressed on CLL cells?

Back 296

-CD19,20,24

**CD5 is the ONLY T cell marker expressed on the CLL B cells
-B cell is monoclonal, either kappa or lambda light chains
-low density Ig (IgD?)

Front 297

How does CLL progress?

Back 297

-asymptomatic at diagnosis
-indolent
-incidental diagnosis
-may have enlarged nodes or anemia
-progresses to involve BM, HSM, increased infections/anemia/thrombocytopenia, hypogammaglobulinemia, autoimmune complications (hemolytic anemia, TTP due to impairment in regulator T cell function influenced by CLL)

*in least aggressive form, patients die of other causes first, finish normal length of life

*in the long term, can evolve to a more aggressive disease, similar to diffuse large B-cell lymphoma

Front 298

What are CLL patients most likely to die from (CLL-related)?

Back 298

INFECTION

(CLL suppresses normal antibody production leading to infection especially with encapsulated organisms)

Front 299

SLL

Back 299

-small lymphocytic leukemia
-just like CLL but the disease is in the LN instead of the blood
-become the same disease as CLL in the long term, outcome is the same

Front 300

What are the autoimmune complications of CLL?

Back 300

-AIHA (coombs positive)
-pure red cell aplasia (Coombs negative, less common, deficiency of red blood cell precursors)
-immune thrombocytopenic purpura
-neutropenia
**Note: other autoimmune diseases are uncommon

Front 301

Where would you find normal CD5+ B cells?

Back 301

-edge of germinal centers in the mantle zone of lymphoid follicles

-produce polyreactive, low affinity autoantibodies
(this is involved in autoimmune Abs because they interact with malignant cells and T cells to produce polyclonal Abs not made by malignant clone)

Front 302

Long term complications of CLL

Back 302

-severe systemic infections
-bleeding
-Richter's transformation
-prolymphocytoid transformation
-second malignancies
-AML (usually due to treatment, not CLL itself)

Front 303

What is Richter's transformation?

Back 303

-most common complication of CLL
-CLL evolves into diffuse large cell immunoblastic lymphoma
-poor survival

Front 304

What is prolymphocytoid transformation?

Back 304

-CLL complication .. changes to larger cells with nucleoli, less dense chromatin

*refractory to typical chemo

Front 305

How do you treat CLL?

Back 305

-Watchful waiting
-palliation
-oral chemo
-cingle agent, combo
-high dose chemo and autoSCT
-allogeneic HSCT

*depends on aggressiveness and patient age b/c CLL is an indolent disease

Front 306

What is the Rai and Binet classifications?

Back 306

-staging systems for CLL
-correlate with patient survival
-Rai: stage 0 is at low risk (only in blood, bone marrow), I/II intermediate (lymphoid organ enlargement), III/IV high (hematopoietic compromise)

-since most patients are asymptomatic at diagnosis, this system is less useful b/c puts most pt at low risk

Front 307

2 Versions that cause CLL (2)

Back 307

-1) naive B cell (has not yet recognized antigen but has rearranged Ig) has oncogenic event and transforms to a CLL cell, has not undergone SHM so it is "unmutated" because it is the same as the original germ cell line

2) naive B-cell encounters antigen in the lymph node, activates, undergoes HSM and THEN gets an oncogeneic hit, becomes CLL cell; significant changes from germ cell line, therefore it is "mutated"

Front 308

Which is better, mutated or unmutated CLL?

Back 308

-mutated is better!!
-only 9 year survival if unmutated

Front 309

Are CD38+ cells good or bad in CLL?

Back 309

-patients with >30% CD38+ cells do poorly, similarly to the unmutated group

**note: even if poor risk groups, still live a long time, only limiting on life if the patient is young

Front 310

What is the role of Zap 70?

Back 310

-zeta assoc protein
-normally expressed in NK and T cells, associated with the CD3 zeta chain of TCR complex
-tyrosine kinase

**if expressed in CLL, worse prognosis!

Front 311

Which abnormalities are associated with CLL? (seen by FISH)

Back 311

-del 17p or 11q have an aggressive phenotype, poor prognosis

-del 13q has a better prognosis and longer survival

*no cytogenetic abnormality has intermediate prognosis

Front 312

How should you treat CLL?

Back 312

-so indolent that often treatment is not needed early on .. watch and wait until they are symptomatic

**treat with chlorambucil, an alkylator
*fludarabine is newer, more effective .. BOTH can be used as single agent treatment

*Rituximab works great but ONLY in combination with chemo!! doesn't significantly change toxicity .. MUST be given at same time as chemo for synergy <<THIS IS THE BEST TREATMENT

Front 313

Alemtuzumab

Back 313

-MoAb against CD52 (on all lymphoid cells)

*used for relapse in CLL

-has "compartmentalization" - doesn't work for all parts of body! great for blood and bone marrow, but not for lymph node disease

-not well tolerated, chills and sweats, fevers, myelosuppression
-affects both B and T cells makes pts especially immunosuppressed; can cause reactivation of CMV, other infections

-may be good for del17p patients

Front 314

When to give high dose chemo, autologous HSCT?

Back 314

-refractory or relapsed CLL patients

Front 315

CLL vs. CML

Back 315

CLL - proliferation of mature lymphocytes, multiple cytogenetic abnormalities involved, long survival with rare leukemic transformation, no available targeted therapy yet

CML - proliferation of maturing myeloid cells; only caused by the t(9,22) abnormality; has a 25% PER YEAR risk of AML transformation, but DOES have a targeted therapy (imatinib and TKIs against BCR-Abl fusion)

Front 316

Review case

Back 316

-p.350

Front 317

What are plasma cell dyscrasias?

Back 317

-clonal proliferation of abnormal mature plasma cells
-usually produce Ig
-blue cytoplasm, clock face eccentric nucleus

-Monoclonal Gammopathy of Undetermined Significance (MGUS)
-Multiple Myeloma
-Plasma Cell Leukemia
-Waldenstroms Macroglobulinemia
-Heavy Chain Disease
-Cryoglobulinemia

Front 318

Immunoglobulin Structure

Back 318

-2 light chains identical, 2 heavy chains identical, disulfide bonds
-each from recombination of v,d,j families; go through splicing to make variable regions of Ig for antigen specificity

Front 319

What is the purpose of the Fc region? What are the different classes of Ig?

Back 319

-encodes class of Ab (IgA,M,D, E, G)
-IgA most abundant, but usually secreted into GI
-IgM has high avidity, responsible for early immune response
-IgD binds B cell membrane and is an antigen receptor
-IgE activates mast cells and basophils
-IgG is most abundant in blood circulation, mediates mature immune response to infection (binds complement, recognized by effector cells for ADCC)

Front 320

What is an M spike?

Back 320

-M = monoclonal

-an abnormal peak on an electrophoresis created by a plasma cell malignancy (secretes the same Ig)

-different from the classic pattern of distrib into 1 of 5 regions (alpha1,2,beta,gamma,albumin)

Front 321

Immunofixation

Back 321

-staining proteins separated by electropheresis to MoAbs against different Ig classes, and against kappa/lambda light chains

-note: IgG,M,A most common

*can also see an M spike on this analysis and can identify the type of Ig and whether it's kappa or lambda light chain

Front 322

What is MGUS?

Back 322

-monoclonal gammopathy of unknown significance
*most common plasma cell dyscrasia (2% of population over 50!)
-associated with autoimmune disease (immune response not shut off after response to infection, antibody production continues)

*incidental diagnosis
-prognosis is good, 1%/yr progression

Front 323

How do you diagnose MGUS?

Back 323

-routine lab
-total protein exceeds albumin by a lot
-monoclonal Ig is present but not more than 3g/dl and <10% plasma cells in bone marrow
**If exceeds these criteria, = Multiple Myeloma!

Globulin protein = Total protein - albumin (so Total protein = globulin + albumin) therefore, if total protein highly exceeds albumin, the total protein is mostly globulin

Front 324

Treatment for MGUS?

Back 324

-just watch
-repeat the SPEP every 6-12 months

Front 325

Most common emergent hematologic malignancy from MGUS?

Back 325

Multiple myeloma
-can progress to the other PCDs

Front 326

Multiple Myeloma: Epidemiology

Back 326

-relatively uncommon (1% of all cancers, 10% of heme cancer)

-incidence rising slowly; pts living longer
*median age 65
-more common in African Americans and males; less in Asians

Front 327

Causes of Multiple Myeloma

Back 327

-progression from MGUS (not the majority)
-occupational exposure to radiation (uranium mines)
-chemicals used by sheet metal workers
-benzene

*genetics and environment also

Front 328

What is multiple myeloma?

Back 328

-clonal proliferation of terminally differentiated, Ig secreting plasma cells; it is a post-germinal center B-cell that have the ability to mature to plasma cells
-can switch Ig class, because it is not yet committed to a particular class

Front 329

Where does MM live and why?

Back 329

-rarely outsid ethe bone marrow
*out of the heme cancers, relies most on its environment due to its adhesion molecules
-make physical contact with bone marrow stroma; contact induces antiapoptotic signals

Front 330

What is the role of cytokines in MM?

Back 330

-IL-6, etc. are released and play a role in MM survival, provide survival signals
-also activate osteoclast which causes bone resorption after MM cells adhere to the bone marrow

Front 331

What is the role of viruses in MM?

Back 331

viral infections like HHV-8 that secrete an IL-6 like cytokine
-mutations in oncogenes also play a role (RB, p53, Ras, bcl-2, c-Myc)

Front 332

How does the M protein affect the other immunoglobulins?

Back 332

-monoclonal immunoglobulin is often in the serum and can spill out into the urine
-serves as negative feedback on normal plasma cells, causes overall Ig to fall, even the types of MM that don't secrete Abs and have no detectable protein (this type probably has mutation in Ig gene so they can't produce M protein, but still have same sx)

Front 333

Multiple myeloma presentation

Back 333

-bone marrow suppression sx (anemia from cytokine mediated suppression or from crowding out of BM, infection - may need Ig infusion)
-w/ or w/o lytic bone lesions (80%)***hallmark .. may also have bone pain or fractures
-hypercalcemia (causes constipation, lethargy, weakness, confusion .. due to increased osteoclasts)
-renal failure (from hypercalcemia+dehydration, or light chains getting trapped in the kidney causing abnormal accumulation of protein - amyloidosis, or light chains themselves are toxic to collecting tubules and cause irreversible damage)
-hyperviscosity (due to high levels of Ig in serum, slows blood flow and O2, increases risk of arterial thrombosis)
-amyloidosis (accumulation of protein due to tropism of M protein for nervous tissue)
-neurologic (autoimmune destruction of nervous system tissue)

Front 334

What do the MM bone lesions look like?

Back 334

"punched out"
-no reactive changes that indicate repair
-just lytic lesions from osteoclast activation

Front 335

Which 2 tests are acceptable in MM? Which test would you not perform?

Back 335

-plain xrays or MRI are good

**Bone scans show NO abnormality, not a good test!

Front 336

How do you diagnose MM?

Back 336

-imaging
-must meet two major criteria, or certain combinations of major and minor criteria (major have to do with too many plasma cells) .. see p.377

-can also do Serum Protein Electrophoresis (SPEP) or 24hr urine protein electrophoresis (UPEP)
-bone marrow aspirate and biopsy
-quantify Igs
-skeletal survey (plain xrays)

Front 337

Plasmocytoma

Back 337

-major criterion for MM
-can be seen in a biopsy from a pathologic fracture, or from an extramedullary site (most commonly in the nasopharynx)

-collection of malignant plasma cells

Front 338

What is the staging system for MM?

Back 338

-Durie/Salmon

-presence vs. absence of:
anemia
hypercalcemia
lytic bone lesions
amount of M protein
presence or absence of renail failure

*if all absent, stage I; if grossly abnormal, III, in middle is II

*if renal failure, add a B; if absent, add an A

**NO STAGE IV

Note: in D/S, IB is worse than IIIA (unlike with TNM system where IIIA is worse than IIB)

Now use a new ISS prognostic scoring system like the IPI using just two parameters

Front 339

Treatment of MM

Back 339

-always fatal if untreated (<1 yr survival)

-with chemo, survival is about 3 years
-traditional therapy is melphalan and prednisone
-autologous SC rescue with high dose mephalan wipes out patients BM permanently and increases survival to 5 years; only use if <70 yrs old

Front 340

What is the role of a second transplant in MM?

Back 340

-two transplants are better than 1 but works the best in patients who had an INCOMPLETE response to the first transplant

Front 341

What is the role of allogeneic SCT in MM?

Back 341

-very toxic with chemo and radiation .. not currently used

Front 342

New potential drug for MM:

Back 342

-MM has ability for angiogenesis because the tumor lives in the bone marrow, so can treat with thalidomide (anti-angiogenic); however, this is only a small portion of MM's abilities, and there are many thalidomide mechanisms, so doesn't work for all patients

-Best in combination with steroids for treatment naive patients (though it does work in some heavily pre-treated pts)

*significant side effects (sedation, periph neuropathy, DVTs)

Lenalidamide is a analog of thalidomide, but works more like chemo; has more of the immunomodulatory effects of thalidomide on cytokine signalling and immune stimulation
-fewer side effects
-20-30% efficacy with steroids

Front 343

What about chemo+ thalidomide?

Back 343

-very potent for MM, but toxicity is significant
-many subjects died of PE

"MPT" - mephalan, prednisone, thalidomide

Note: if administer anticoagulants, the toxicity is minimized

Front 344

Do proteosome inhibitors work in MM?

Back 344

-bortezemib has activity in MM
-causes apoptosis by preventing cell cycle progression
-MM cells are influenced by NFKb, a promoter of cell growth; it complexes with IKb which is regulated by the ubiquitin pathway

-inhibiting that pathway by stopping the proteosome makes Ikb accumulate which then inactivates NFkb, so MM cells can't grow, apoptose

Front 345

Outpatient therapy for MM

Back 345

-healthy patients under 70 (no comorbidity) ca nget thalidomide and dexamethasone orally for induction, then considered for one round of high dose chemo and autologous SCT (with a 2nd one if they don't respond)

Front 346

What about MM patients over 70 or with comorbid conditions?

Back 346

-not candidates for transplant, but can still give the MPT combo

-lenalidomide and bortezomib are also obtions (just more expensive, and bortezomib is IV whereas thal and lena are oral)

Front 347

What is Plasma Cell leukemia?

Back 347

-unusual subtype of MM
-high $ of malignant plasma cells circulating in blood (same as for MM)
-two forms: primary and secondary
-survival is short in both cases

Front 348

Primary PCL

Back 348

-no preceding diagnosis of MM (5%)
-emerge with ability to travel in bloodstream
-bias towards IgA
-patients present with extensive lytic bone lesions
-same tx as with MM (transplant, etc..leukemia tx don't work)

Front 349

Secondary PCL

Back 349

-end state of heavily treated MM
-can't travel in bloodstream until much later (acquire mutations over time)

Front 350

Waldenstrom's Macroglobulinemia

Back 350

-Plasma cell disorder
-Lymphoplasmacytic lymphoma
-malignancy of plasma cell like cells, can be confused with MM

*low grade lymphoma with a mix of mature B cells, plasma cells and in between cells
*IgM spike, leading to hyperviscosity!! BUT no bone lesions
-does have lymphadenopathy

*subtype of NHL

Front 351

How do you treat Waldenstrom's Macroglobulinemia?

Back 351

-like an NHL
-plasmapheresis for viscosity sx

Front 352

Heavy Chain Disease

Back 352

-VERY VERY RARE
-B cell lymphoproliferative disorder
-secretes a mutated monoclonal Ig that has a shortened piece of the Fc region; light chains and variable portion of heavy chain are missing

-1/3 cases come from CLL, 10% from MM

Front 353

How does HCD present?

Back 353

-constitutional symptoms
-HSM
-lymphadenopathy
-lytic bone lesions
-recurrent infection

-lymphocytes nad plasma cells on histology, vacuoles with abnormal mu protein

Front 354

Treatment of HCD

Back 354

-palliation, relieving tissue infiltration

-chemo is an option but the disease is so rare that experience is limited

Front 355

Cryoglobulinemia

Back 355

-presence of Igs in serum that PRECIPITATE at less than body temperature

-causes systemic inflammation from precipitated immune complexes

-Types I - III

Front 356

Type I Cryoglobulinemia

Back 356

-monoclonal Ig, usually IgM
-associated w/ underlying lymphoproliferative disorder (need abnormal B cell clone)

*does not activate complement, no systemic inflamm
-hyperviscosity, small vessel obstruction, digit gangrene

Front 357

Type II Cryoglobulinemia

Back 357

-mixed cryoglobulinemia
-monoclonal rheumatoid factor that binds Fc part of IgG
-also IgM from lymphoprolif disorders, autoimmune diseases, chronic infections (HepC, EBV, CMV, syphilis)

*immune complexes activate complex
-get arthralgias, myalgias, renal disease, cutaneous vasculitis (erythematous macules and purpuritic papules, ulcerations)
- if immune complexes in kidneys, causes membranoproliferative glomerulitis
-can have neuropathy or pulmonary infiltrates

Front 358

Type III Cryoglobulinemia

Back 358

-polyclonal, from rheumatoid factor IgM's against Fc part of IgG

*same sx as type II

Front 359

Treating Cryoglobulinemia

Back 359

-not needed until end organ damage
-avoid cold
-plasmapheresis

*Type I: treat underlying lymphoproliferative disorder

Types II and III: anti-inflammatories, steroids, immunosuppressants
-look for and treat HCV with IFN-alpha and ribaviron

Front 360

Review cases

Back 360

p.388

Front 361

MPDs (6)

Back 361

-"Pre-leukemic disorders"
CML**
-Chronic Neutrophilic leukemia
-Chronic Eosinophilic Leukemia/HES
-Polycythemia Vera
-Essential Thrombocytosis
-Primary myelofibrosis

Front 362

Four common features of MPDs

Back 362

-clonal disorder arising from a HEMATOPOIETIC stem cell
-overproduction of a specific lineage of myelo-erythroid cells
-tendency to progress to acute leukemia (100% in CML, less than 5% in ET ..10-20 in PV)
-abnormalities of coagulation (increase in thrombohemorrhagic events)

Front 363

How does clonal hematopoiesis occur? (MPDs)

Back 363

-acquired dominant bone marrow disorder

Front 364

What is overexpressed in CML?

Back 364

neutrophils and their precursors

Front 365

What is overexpressed in Chronic eosinophilic leukemia?

Back 365

eosinophils

Front 366

What is overexpressed in PV?

Back 366

mature erythrocytes, increased red cell mass

Front 367

What is overexpressed in ET?

Back 367

platelets and bone marrow megakaryocytes

Front 368

What is overexpressed in primary myelofibrosis?

Back 368

marrow fibroblasts with extramedullary hematopoiesis (must rule out CML and MDS first)

(React to megakaryocyte signals)

Front 369

Thrombohemorrhagic complications of MPD

Back 369

-arterial and venous thromboses
-microcirculatory disorders like erythromelalgia (painful red fingers and toes)
-mild, mucosal bleeding episodes

Front 370

What is often the underlying pathogenesis for MPDs?

Back 370

-dysregulated tyrosine kinases

Front 371

CML epidemiology

Back 371

-low incidence; 20% of adult leukemia
*people live a long time so prevalence is high

Front 372

What is the only documented risk factor for CML?

Back 372

-ionizing radiation (A-bomb survivors, etc)

-possibly post therapy, not proven .. and genetics, etc. are not associated

Front 373

What are the three phases of CML?

Back 373

-Chronic phase
-Accelerated phase
-Blast crisis (progression to AML or ALL)

Front 374

What are lab findings associated with CML?

Back 374

-low leukocyte alkaline phosphatase (LAP) = how you tell infection from CML
-splenomegally
-mild anemia
-WBC > 100,000
-high platelets (>600,000)

Front 375

What are the clinical manifestations of CML?

Back 375

-asymptomatic at dx often
-if sx, fatigue, malaise, weight loss, SWEATING
-abdominal fullness and early satiety (splenomegaly)
-acute gouty arthritis from hyperuricemia
-bleeding episodes from platelet dysfunction

Front 376

Chronic phase

Back 376

- large increase in committed myeloid progenitors with leukocytosis and thrombocytosis, left shift, can see basophils
-neutrophils can cause organ infiltration, HSM ..
*relatively stable phase

Front 377

Accelerated phase

Back 377

-increasing WBC
-increasing splenomegaly, tissue infiltration
-need more intensive myelosuppression therapy
-impairment of neutrophil differentiation
-increasing left shift
-increasing circulating and BM blasts

-still good myeloid cell maturation (unlike AML/ALL)

**percentage of blasts is <20%

Front 378

Blast crisis

Back 378

-resembles acute leukemia
-profound block in differentiation of cells

2/3 of cases are AML, 1/3 ALL
-inevitable progression within 3-5 yrs after dx and 3-18mo after accelerated phase

Front 379

Diagnosis of CML

Back 379

*requires detection of Ph chromosome or if cytogenetics negative, detecting BCR-ABL gene by FISH

Front 380

BCR-ABL mechanism

Back 380

-ABL on 9q moves to BCR on 22q
-creates novel fusion protein that increases levels of tyrosine phosphorylated proteins, constitutive activation of pathways leading to increased proliferation, survival, and resistance to DNA damage

Front 381

What is the purpose of reverse-transcriptase PCR?

Back 381

-detects minute amounts of BCR-ABL fusion mRNA

*used to monitor response of disease to therapy (more accurate because just restoring hematopoiesis and having negative Ph by cytogenetics/FISH isn't definitive; low sensitivity)

Remember: on FISH, yellow = BCR ABL fusion (normally 2 red and 2 green dots, if Ph chrom has 1 red, 1 green, 2 yellow)

Front 382

How does atypical CML present?

Back 382

-analyze by FISH or RT-PCR detects BCR-ABl fusion

-behave just like classic Ph+ CML

Front 383

How are patients who lack BCR-ABL classified?

Back 383

MDS or other atypical chronic myeloid disorder
-associated with other dysregulated tyrosine kinases, may be treatable with a different TKI

Front 384

How do you treat CML?

Back 384

**gold standard = kinase inhibitor therapy
-hydroxyurea
-busulfan

Front 385

Effects of hydroxyurea and busulfan

Back 385

-hydroxyurea inhibits ribonucleoside reductase which inhibits DNA synth

-both drugs lower leukocyte count and decrease spleen size, but do not prevent progression to blast crisis!!
-also affect normal BM cells equally
**NO SURVIVAL BENEFIT

Front 386

Effect of IFN alpha

Back 386

-survival benefit
-drug is toxic, inconvenient, and does not give a complete response
-get flu like symptoms

Front 387

What chemo drug can you combine with IFNalpha?

Back 387

-cytarabine
-better than IFN alpha alone

Front 388

Imatinib

Back 388

-BCR-ABL inhibitor
-phenylamino pyrimidine core

*suppresses growth of Ph+ myeloid progenitors without affecting normal progenitors!

MUCH better than IFNa because:
-complete hematologic remission (normalizes blood counts)
-major ctogenetic remission (<35% Ph cells)
-major molecular response (>1000 fold drop in BCR-ABL transcript levels)
**

Front 389

TK inhibitor mechansim

Back 389

-competes with ATP for binding to kinase catalytic domain

Front 390

Oncogene addiction

Back 390

-specific killing of Ph+ chrom cells demonstrated by imitinab
-suggests that Ph+ cells have become dependent on the activity of BCR-ABL

Front 391

Problems with Imitinab?

Back 391

-most patients dont go into molecular remission (don't become PCR negative)
*suppresses disease but not curing it
-also, quiescent Ph+ progenitor/stem cells are not killed by imitinab
-many still have progression of their disease on the drug (don't stay in chronic phase)

-toxicity: edema, N/V/D, cramps, myelosuppression

Front 392

How can CML become resistant to Imitinab? (2)

Back 392

-mutations in ABL
-T3151 (point mutation)
-doesn't allow drug to bind, so it becomes resistant

-2nd mechanism: amplification of BCR-ABL causing overproduction, so it is harder to totally inhibit it with the drug

Front 393

What are the two major complications of ET?

Back 393

-hemorrhage

-thrombosis

Front 394

What is the goal of ET treatment and what is used to treat it?

Back 394

-reduce platelet count below 400,000 to reduce risk of thrombosis
-hydroxyurea
-also use low dose aspirin to reduce thrombosis

*if low risk, can be managed to observation alone

Front 395

Anegrelide

Back 395

-lowers platelet counts in ET but doesn't reduce thrombosis risk

Front 396

What is primary myelofibrosis?

Back 396

-MPD with clonal HSC disorder, but has increased bone marrow fibrosis
-BM myeloproliferation, dysplastic Mks, nonclonal BM fibroblast proliferation due to TGFB and PDGF (causes overgrowth of BM space)
-overgrowth causes HSC to circulate in the blood and add areas of new hematopoiesis in spleen, etc...

**some evolve from PV or ET
-extramedullary hematopoiesis

Front 397

What mutation is the cause of PMF?

Back 397

-JAK 2 mutation (30% of cases)
**Note: this also occurs in ET

Front 398

Risk factors for PMF (3)

Back 398

-ionizing radiation
-benzene
-thorium dioxide

Front 399

Presentation of PMF

Back 399

-nonspecific systemic symptoms, fatigue
-marked HSM
-anemia
-high or low platelets and WBC counts

Front 400

Labs for PMF?

Back 400

-normocytic with TEARDROPS (dacrocytes) on smear
-leukoerythroblastic changes
-BM shows fibrosis, fatty change
-massive splenomegaly

*cytopenias

Front 401

Dacrocytes

Back 401

-in peripheral blood
-permanent RBC deformation, caused when immature erythrocyte moves from fibrotic bone marrow

Front 402

What is the critical finding on the BM biopsy for PMF?

Back 402

-increased collagen fibrosis (reticulin stain)

Front 403

Second generation ABL kinase inhibitors for CML

Back 403

-nilotinib (more potent)
-dasatinib (dual ABL/SRC inhibitors)

-work for some BCR-ABL mutants

Front 404

What is the only known curative therapy for CML?

Back 404

-allogeneic HSCT due to strong GvL effect
-best with HLA matched sibling
**give as a last option, due to major difficulties that many patients go through after (GvHD, etc)..try TKIs first

Front 405

Prognostic factors for CML

Back 405

-depends on age (increase in GvHD)
-CP responds better than AP >> BC
-time from Dx
-prior Rx (IFNa, busulfan, Gleevec)

Front 406

What are the disadvantages of matched unrelated donors (MUD)?

Back 406

-increased graft failure and GvHD
-decreased overall and DF survival
-better outcomes in young (<35) patients

Front 407

Chronic Eosinophilic Leukemia

Back 407

-rare clonal chronic MPD like disorder
-dysplastic eosinophils in BM, peripheral blood overproduced
-secondary cause of eosinohpilia must be excluded (infection, allergy, etc)
-exclude eosinophilic variant of CML (PH+) or AML-M4 (inv16)

Front 408

What is the mutation in CEL?

Back 408

-*deletion on chrom 4 that causes fusion of PDGFRalpha (receptor TK) with another protein
**also respond to imatinib!!

Front 409

Polycythemia vera

Back 409

-autonomous overproduction of mature RBCs (Epo-independent)
-increased hematocrit and Hgb, increased total body red cell mass

Front 410

How does PV present

Back 410

-often asymptomatic
-hemolytic anemia
-fatigue, dizziness
*post shower pruritis and erythromelalgia
-A/V thrombosis and gout
-plethora
-HSM

Front 411

What do the labs show in PV?

Back 411

-increased leukocytes
-increased platelets
-erythrocytosis

*cytogenetics normal!!

Front 412

Diagnosing PV

Back 412

-Hct>48% if female, 52% if male
-Hgb>16.5 or 18.5
-increased red cell mass
-normal arterial O2 saturation with no secondary polycythemia
-splenomegaly, cytogenetic abnormalities, platelets >400,000, absolute neutrophils >10,000, low Epo

-1 in 10 patients with polycythemia actually have P.vera, and only 40% of increased Hct have polycythemia
(ex: polycythemia can be caused by COPD, etc due to increased Epo)

Front 413

Secondary Polycythemia

Back 413

-chronic hypoxia-smoking, COPD, CO exposure
-Epo secreting tumors or RCC/hemangioblastoma
-hemoglobinopathy with increased O2 activity
-congenital polycythemia-EpoR mutation (Chauvash polycythemia)

*erythrocytosis caused by increased Epo levels .. NOT PV! may just be at high altitude, etc..

Front 414

What is the mutation in PV?

Back 414

-JAK 2 (nonreceptor tyrosine kinase)
-increase in JAK2 in absence of Epo mimics effects of Epo on erythroid cells
-analogous to BCR-ABL fusion only with V617F mutation
-mutation is in the autoinhibitory domain of JH2, activates the kinase in absence of Epo stimulation

**can be detected molecularly (JAK2 V617F)

Front 415

Treatment for PV

Back 415

-no targeted JAK 2 inhibitors currently available
*goal in treatment is to reduce hematocrit to normal, which reduces risk of fatal MI or stroke

*phlebotomy (reduces hematocrit, but red cells are quickly replaced, inconvenient, exacerbate PV)
-myelosuppressive therapy with hydroxyurea for high risk patients
-can also give low dose aspirin

Front 416

Treatment for refractory patients?

Back 416

-IFNa
-anagrelide if really refractory
-allopurinol to treat hyperuricemia

Front 417

Essential thrombocytopenia

Back 417

-too many platelets
-median age 60 yrs
-clonal disorder with a FEMALE disposition
-same JAK2 V617F mutation
-1/3 asymptomatic, can have vasomotor sx, thrombosis, hemorrhage
-low incidence of AML transformation
-spontaneous abortion in 1st trimester

Front 418

How do you diagnose ET?

Back 418

-its a diagnosis of exclusion
-persistently increased platelets > 600,000
-abundance of platelets with Mk fragments
-bone marrow biopsy shows megakaryocytic hyperplasia
*must be no evidence of BCR-ABL fusion by FISH or PCR, and no evidence of MDS - cytogenetics usually normal

Front 419

How are PV and ET different? (Besides that one is RBCs and one is platelets)

Back 419

-PV has low Epo levels
-ET has variable thrombopoietin levels

Front 420

What are some cytogenetic abnormalities in PMF?

Back 420

-13qdel, 20qdel
**must not have Ph chromosome+

(remember: must exclude causes of secondary fibrosis like infection, malignancy, or other Ph-MPD)

Front 421

PMF prognosis?

Back 421

-very poor, average 2-3 years following diagnosis
-only curative treatment is alloHSCT (works even though BM is fibrosed)
-mostly supportive tx (transfusions and growth factors)
-treat anemia (androgens, danazol, corticosteroids, thalidomide)
-chemo (for organomegaly or constitutional sx with melphalan, busulfan, HU
-splenectomy for pain, transfusion dependent anemia, or thrombocytopenia

Front 422

Significance of the JAK2 mutation?

Back 422

-if positive, means its a myeloproliferative neoplasm rather than a benign condition
-if it is negative in a ptient with polycythemia, probably a benign cause

Front 423

MDS syndromes (6)

Back 423

-Refractory anemia
-Refractory anemia+ringed sideroblasts
-Refractory cytopenia w/ multilineage dysplasia (RCMD
-RCMD + ringed sideroblasts
-Refractory anemia with excess blasts types I (5% blasts) and II (5-19% blasts)
-Deletion(5q)

Front 424

What are myelodysplastic syndromes?

Back 424

-clonal hematopoietic stem cell diseases that can't properly differentiate
-cytopenias with cellular BM (NOT aplastic anemia, just have dysplasia), dysplasia, and ineffective hematopoiesis in 1+ cell lines
-variable progression to acute myeloid leukemia
-may be de novo or after therapy

Front 425

What do the stem cells in MDS look like?

Back 425

-defective self renewal and differentiation
-abnormally increased cell death, apoptosis, in MDS marrow (ineffective hematopoiesis)

Front 426

What does the bone marrow look like in MDS?

Back 426

-increase of myeloblasts, but <20%
-but lack of mature blood cells

Front 427

Who gets MDS?

Back 427

-elderly, median age is 70 yrs
-very increased risk if they've received chemo for another malignancy (alkylating agents, topo inhibitors) ..10-15% of cases

Front 428

What are the causes of de novo MDS?

Back 428

-unknown
-viruses
-benzene and chemicals
-cigarette smoking
-fanconi anemia (congenital BM failure)

Front 429

What causes Therapy related MDS (t-MDS)?

Back 429

-exposure to chemo, esp alkylating agents (and topo II inhibitors)
-radiation therapy
**has a latency period before it develops after treatment
*see complex karyotypes

Front 430

MDS prognosis?

Back 430

-poor, very resistant to most therapies

Front 431

How do patients present with MDS?

Back 431

-many asymptomatic
-previously unrecognized anemia (fatigue, exercise intolerance, etc..)
-neutropenia, thrombocytopenia (infection, bruising)
-fever, weight loss later

Front 432

Does MDS progress to AML?

Back 432

Yes

Front 433

Why do people with MDS get infections?

Back 433

-neutropenia
*major clinical problem in MDS, main cause of death
-esp. if ANC is below 1000, esp below 500
-bacterial infections especially, some fungal
-skin is most common site
(also due to impaired granulocyte function)

Front 434

What are the three ways to diagnose/classify MDS?

Back 434

-peripheral blood cytopenias, which ones?
-BM morphology
-BM cytogenetics

Front 435

Name some possible peripheral blood findings in MDS (8)

Back 435

-anemia w/ low reticulocyte
-normo or macrocytic RBCs (must rule out B12 deficiency)
-ovalomacrocytosis, elliptocytes, teardrops, stomatocytes, acanthocytes
-basophilic stippling, Howell-Jolly bodies, megaloblastoid nucleated RBCs
-leuko or thrombocytopenia
**Pelger-Huet anomaly (Pince nez)
-sometimes monocytosis or large platelets

Front 436

What does the bone marrow look like in MDS?

Back 436

-HYPERcellular (90%..normal is 40-50%..opposite of aplastic anemia )
-erythroid dysplasia
-sometimes "ringed sideroblasts"
-myeloid dysplasia + karyorrhexis (fragmented nuclei)
-micromegakaryocytes (hypolobarity)

Front 437

Types of dysplasia in the erythroid lineage

Back 437

-megaloblastoid change (nuclear:cytoplasm ratio)
-cytoplasmic vacuolization
-binucleation, nuclear budding or irregularities
-ringed sideroblasts

Front 438

What are ringed sideroblasts?

Back 438

-dysplastic erythroid precursors w/ iron laden mitochondria surrounding nucleus

Front 439

Types of dysplasia in the myeloid lineage

Back 439

-pseudo Pelger-Huet nucleus (bilobed)
-nuclear hypersegmentation or abnormal shape
-cytoplasmic hypogranulation or abnormal granulation

Front 440

Types of dysplasia in the Megakaryocyte lineage

Back 440

-small size
-nuclear simplification
-separated nuclear lobes

Front 441

What are the most common cytogenetic abnormalities in MDS? (3)

Back 441

-del5q
-del7q
-11q23

in 40-70% of patients with primary MDS

Front 442

What is the significance of an 11q23 cytogenetic abnormality?

Back 442

-common in t-MDS secondary to topo inhibitor therapy (but can also have primary 11q23 MDS)

Front 443

What is the significance of a del5q or 7q cytogenetic abnormality?

Back 443

-can be primary or secondary MDS
-but if t-MDS, caused by the ALKYLATORS (topo inhibitors cause the 11q23 translocation)

Front 444

Which abnormalities are favorable?

Back 444

-del5q
-normal karyotype
-del20q
-Y

Front 445

Which abnormalities are not favorable?

Back 445

-del7q
-complex karyotype (>3 abnormalities)
-11q23

Front 446

Refractory anemia

Back 446

-anemia with few or no blasts
(erythroid dysplasia)

Front 447

Refractory anemia with ringed sideroblasts

Back 447

-anemia with no blasts, ringed sideroblasts
(erythroid dysplasia)

Front 448

RCMD

Back 448

-cytopenias involving 2+
-no or few blasts
-ringed sideroblasts if they have RCMD RS

(dysplasia of 2+ lineages)

Front 449

Refractory anemia with excess blasts

Back 449

-cytopenias
-excess blasts (5-9% in type I, 10-19% in type II)

Front 450

5q syndrome

Back 450

-40% of t-MDS
-overrepresented in femalse
-megakaryocytes with hypolobated nuclei
-refractory macrocytic anemia
-normal or increased platelets

**good clinical course

Possible cause: tumor suppressor gene (RPS14) on 5q

Front 451

IPSS in MDS

Back 451

-looks at marrow blast %, marrow karyotype, # and degree of cytopenia, and age

-predicts clinical survival

Front 452

Treatment of MDS: Goals

Back 452

-control symptoms from cytopenias
-improving quality of life, minimizing toxicity of therapy
-decreasing progression to AML

Front 453

How do you treat MDS?

Back 453

-transfusion with iron chelation therapy
-growth factors (G-CSF, Epo)
-low dose chemo (cytarabine) has a little role because dysplastic cells can't be eliminated
-allogeneicHSCT(ONLY CURATIVE TX, but limited to young patients with HLA matches)

Front 454

Revlimid

Back 454

-new treatment
-derivative of thalidomide
-works for 5q syndrome

Front 455

Decitabine, azacytidine

Back 455

-demethylating agents
-suppress MDS by altering gene expression patterns
(immunomodulatory)

Front 456

When do you consider bone marrow transplant?

Back 456

-patients who relapse after chemo and receive salvage chemo, because their long-term survival is basically zero (except for lymphoma)
-consider for transplant as opposed to undergoing more chemo
**esp because risk of 2ndary leukemia increases with more chemo

Front 457

Why get an SCT from sibling or unrelated donor?

Back 457

-immunological graft versus tumor effect (GvT), even cells that high doses of chemo can't kill
-with GvT, controls re-emerging clonal cells via the donor derived immune system (the donor's T cells, NK cells and cytokines)

Front 458

What is the pre-transplant workup?

Back 458

-cardiac function test (MUGA) & pulmonary function test .. these can be affected by high dose chemo/radiation
-check for hepatitis, HIV, CMV, EBV (can reactivate during neutropenia period after transplant)
-dental eval if poor dental health
-radiation-oncology eval
-check vascular access

Front 459

What cells are harvested in SCT?

Back 459

-early hematopoietic stem cell
-quiescent, non-dividing, but can give rise to committed progenitor cells
*CD34+
*need 2x10^6/kg stem cells to repopulate a myeloablated patient

Front 460

What are the three sources of stem cells in body?

Back 460

-marrow from upper iliac crest by aspiration under general anesthesia
-peripheral blood stem cells are mobilized to enter blood and collected by apheresis
-umbilical cord blood donated after the delivery of a baby

Front 461

How do you stimulate stem cells to enter the periphery for a PBSC collection?

Back 461

-five days of G-CSF - Neupogen

Front 462

How do you prepare (condition) a patient for HSCT?

Back 462

-5-7 days of either myeloablative therapy or reduced intensity (if older or comorbidities) myeloablation

Purpose: kill any residual cancer cells in patient's body
-if it's an allogeneic HSCT, induce an immuno-suppressed state that allows it to accept the transplanted graft and not reject it

Front 463

Myeloablative prep

Back 463

-2 days high dose cyclophosphamide
-3 days TBI
total 5 days

Reduced intensity is 6 days, first 2 are photopheresis, then 2 days pentostatin and 2 days TBI

Front 464

How do you prepare for an autologous SCT?

Back 464

-1 day of cyclophosphamide to kill cancer cells and committed progenitor cells
-gets neutropenia for 2 weeks (G-CSF administered to help them recover)
-then stem cell collection from their peripheral blood and freeze it
-patient is admitted and given high doses myeloablative chemo (melphalan) just before the stem cell influsion

Front 465

How do you harvest allogeneic stem cells?

Back 465

-either do leukapheresis (give donor Neupogen for 5 days and then collecting)
-or through a bone marrow harvest (donor placed under anasthesia, take from iliac crest) performed on the same day as the transplant

Front 466

How do you prepare patient for an allogeneic SCT?

Back 466

-for patient: 2 days photopheresis, 2 days pentostatin, 2 days

Note: stem cells for allogeneic are not cryopreserved, more like a blood transfusion

Front 467

Complications of an autologous SCT

Back 467

-rare
-related to cryoprotectant used to freeze the cells
-fluid overload, fever, hypertension, bradycardia, SOB, hypotension, shock, death

Front 468

How do you handle patients after an autologous transplant/post-transplant complications?

Back 468

-very neutropenic for 8-12 days, give prophylactic antibiotics
-may need parental nutrition from mucositis or lack of appetite
-watch out for SOS
-pulmonary hemorrhage is rare, usually in pts with prior lung radiation

Front 469

Sinusoidal Occlusion Syndrome

Back 469

-patients who have been heavily pre-treated can have organ compromise of the liver (can also hvae renal failure)

Front 470

Mortality of an autologous SCT? allogeneic?

Back 470

1-2% for autologous

10-30% for allogeneic

Front 471

What about patient tx after an allogeneic SCT?

Back 471

-same care as autologous + immunosupprsesive meds to prevent rejection of the graft (this is rare in comparison to solid organ transplants) and GvHD

Front 472

What is GvHD?

Back 472

initiated by the donor's T-lymphocytes
-recognize minor antigens on patient tissue
-produce cytokines like TNF that cause tissue damage in 3 organs

Front 473

Which 3 organs are affected by GvHD?

Back 473

-skin (rash is mild or can burn, exfoliate)
-GI system (N/V/D, severe abdominal pain, bleeding, ulceration)
-liver (transaminase, bilirubin elevation)

Front 474

When does GvHD develop?

Back 474

-2-4 weeks after transplant (when donor cells engraft in recipient)

Front 475

What is the frequency of GvHD?

Back 475

-50% of patients even with prophylaxis

Front 476

How do you treat GvHD?

Back 476

-steroids

Front 477

What is chronic GVHD?

Back 477

-after several months of insufficiently treated/non-responsive acute GvHD

-can also occur denovo

-autoimmune diseases:
vitiligo
dyspigmentation
scleroderma-like
contractures
hair and nail abnormalities
dry eyes (keratitis)
immune deficiency
lung
vagina

Front 478

Define "cure"

Back 478

-long term survival without disease recurrence
-more than 10 years

*can be achieved with HSCT (autologous) in MM after induction, NHL and HD after remission, AML

*for allogeneic HSCT, can cure aplastic anemia, AML, ALL, MDS, CML, MM, NHL (peripheral T cell/MCL), CLL, hemoglobinopathies

Front 479

Why give autologous HSCT instead of allogeneic?

Back 479

-less mortality (death with these is more likely due to recurrence of primary disease; with allogeneic, more likely due to a complication of the transplant like infection)
-if patient is elderly or comorbidities

*these only allow you to increase patient's ability to tolerate higher doses of chemo; lacks the GvT effect of an allogeneic transplant

Front 480

How likely is an HLA match between siblings?

Back 480

-25%
-inherit one gene haplotype from each parents
-4 possible different haplotype combinations

-if no sibling donor found, search National Marrow Donor Registry

Front 481

Which ethnic group is most likely to have a match? For which is a match difficult to find?

Back 481

...see slide on TUSK

Front 482

How do you obtain cord blood?

Back 482

-let gravity empty placenta
-80-100 cc of blood
-shipped to blood bank for storage

Front 483

What are the limitations of using cord blood?

Back 483

-only a limited number of stem cells in the umbilical cord blood
-ideal source of transplantation for kids, but not enough for adults

Front 484

Why use marrow/blood as opposed to cord blood and vice versa?

Back 484

-marrow/blood takes 3-4 months with potential for diseaes transmission and GvHD, but has enough stem cells for an adult

-cord blood only takes 13.5 days to find a match, and no donor issues or viral infection risks; less GvHD
-less useful in adults unless there is a disease progressing so fast there is not enough time to find an unrelated donor

Front 485

2 most common uses of autologous HSCT

Back 485

-MM
-lymphoma

Front 486

2 most common uses of allogeneic HSCT

Back 486

-leukemia
-MPD

Front 487

Mini transplants

Back 487

-safer, lower doses of chemo
-only done in patients who are in remission at time of transplant
-still get GvT (more important than in regular allogeneic SCT because you are giving less chemo)

Front 488

High vs. low penetrance genes

Back 488

*intrinsic susceptibility variables HIGH
-low frequency (affect small proportion of patients)
-high risk
-environment plays a minor role in causation

LOW
-affect most people with cancer
-environment has a much larger role in cancer causation

Front 489

How much of breast cancer cases have a family history?

Back 489

-20%

**80% don't have a family history!!

Front 490

Is this type of breast cancer caused by high or low penetrance genes?

Back 490

-undefined low penetrance genetic predispositions (not known germline mutations)
-risk increases with increasing number of affected relatives

Front 491

How much of breast cancer is related to familial cancer syndromes, and what type of genes cause this form of breast cancer?

Back 491

-10%
-2/3 are BRCA1 or BRCA2 genes, which are predisposing, high penetrance genes
-autosomal dominant inheritance
-associated with other cancers like ovarian, prostate, colon, etc.
-secondary breast cancer (BRCA1) or male breast cancer (BRCA2)
-extremely high lifetime risk of breast cancer
**increased in Ashkenazi Jews, populations with restricted gene pool mixing

Front 492

Is BRCA1 hormone receptor positive?

Back 492

usually not

Front 493

Is BRCA2 hormone receptor positive?

Back 493

usually positive!

Front 494

What other types of familial diseases can increase risk of breast cancer?

Back 494

-Li Fraumeni (p53), Cowden syndrome (PTEN), CDH1, ataxia-telangectasia(ATM)
-Klinefelter's syndrome increases risk of male breast cancer 50!! equivalent to female risk!

-if a female patient known to have one of these diseases, can do further testing like MRI screening in addition to mammograms

Front 495

What has the highest incidence of cancer in women?

Back 495

breast cancer
-also a very high prevalence (22% of cancer)

Front 496

Why has the incidence of breast cancer been increasing?

Back 496

-likely not true incidence increase but due to better detection methods; coincides with mammography
-this is further evidenced by the corresponding increase in early stage detection/in situ carcinomas (microcalcifications that are not clinically palpable, still localized to breast)
-similar thing has occurred with prostate cancer and PSA screening

Front 497

Has this corresponded with a decrease in mortality for breast cancer?

Back 497

-yes
-more women are treated at a stage that is more curable

Front 498

What is the defect in Hereditary Non-Polyposis Colon cancer?

Back 498

-microsatellite instability and repetition

Front 499

Hereditary Melanoma/Xeroderma pigmentosum

Back 499

-defects in CDKN2A locus (cell cycle inhibitor); XP genes have defective nucleotide excision repair, UV induced damage causes melanoma

Front 500

Retinoblastoma

Back 500

-most common childhood intraocular tumor is 40% hereditary with a high risk of developing other sarcomas and melanoma

Front 501

Pheochromocytomas

Back 501

-rare catecholamine secreting tumors of adrenal medulla

*15% familial (multiple endocrine neoplasia syndrome - RET tyrosine kinase defect, von Hippel Lindau - VHL tumor suppressor, Neurofibromatosis)

Front 502

Neurofibromatosis

Back 502

-cutaneous disorder, cafe au lait spots, neurofibromas

Type 1 has a defect in NF1 gene, half of cases are familial

-neurofibromin normally inactivates ras

Front 503

Extrinsic vs. Intrinsic exposure (ex: estrogens)

Back 503

-extrinsic factor = exposure to estrogen

-oral contraceptives, HRT
-in Klinefelter's, more endogenous estrogen

-intrinsic factor = # periods (early menarche, late menopause), genes

Front 504

Favorable risk factors in breast cancer

Back 504

-higher # pregnancy = intrinsic
-longer periods breast feeding = intrinsic

Front 505

Other factors that increase breast cancer risk

Back 505

-higher bone density (higher circulating estradiol) =intrinsic
-increased age at first life birth (after age 30) = intrinsic
-prenatal use of diethylstilbestrol = extrinsic (nonsteroidal synthetic estrogen used for post-menopause and prematurity, no longer used) causes bc in the mother; baby girl at risk for vag/cervical cancer but not bc

Front 506

What other cancer is most likely to lead to breast cancer in young women?

Back 506

-Hodgkins lymphoma in early 20s (or NHL) if patients receive ionizing radiation to chest
-10-30% increase in risk

Front 507

What is the "ultimate" extrinsic risk factor?

Back 507

-smoking!!
-increase in incidence in lung cancer and other related cancers

Front 508

Diet

Back 508

-extrinsic factor extremely important in development of colorectal cancer
"Western" diet is bad; African diet is good b/c high in fiber

Front 509

Alcohol

Back 509

-contributes to development of many cancers
-co-carcinogen with smoking! enhances carcinogenicity of tobacco (mouth, larynx, pharynx, esophagus) AND breast cancer

Front 510

Viruses

Back 510

-HBV, HCV = hepatocellular carcinoma
-HPV = cervical cancer
-HHV8 = vascular tumor in AIDS pts
-EBV = NHL, HL, Burkitt's, etc)
-H. pylori

Front 511

Other lifestyle factors in breast cancer

Back 511

-alcohol
-high BMI
-sedentary lifestyle

Front 512

Origins of breast cancer

Back 512

-95% epithelial (most from ductal cells, 10% lobular cells)

Front 513

How do you describe the location of a breast tumor?

Back 513

-upper outer, upper inner, lower outer, lower inner quadrant
OR
-clock face (ex: 1cm mass in UOQ 3 cm from the nipple towards 11:00)

Front 514

Lymphatic drainage of the breast

Back 514

-axillary, then supraclavicular chains (may be palpable if abnormal)
*Note: lower inner quaddrant drains a bit to internal mammary chain

Front 515

How do you stage breast cancer?

Back 515

-TNM system
-T0 = in situ
-T1 = <2cm, T2 = 2-5, T3 = >5, T4 = any size but involves skin or chest wall
-N0 = no nodes, N1 = 1-3, N2 = 4-9, N3 = >10
-M0 = no metastasis, M1 = metastasis

Front 516

Stage 0 breast cancer

Back 516

T0N0M0 ... in situ

Front 517

Stage I breast cancer

Back 517

-T1 N0 M0

Front 518

Stage IIA breast cancer

Back 518

-T0 N1 M0 up to T2 N0 M0

Front 519

Stage IIB breast cancer

Back 519

-T2 N1 M0 up to T3 N0 M0

Front 520

Stage IIIA breast cancer

Back 520

-T0 N2 M0 up to T3 N2 M0

Front 521

Stage IIIB breast cancer

Back 521

-T4 N0 M0 up to T4 N2 Mo

Front 522

Stage IIIc breast cancer

Back 522

any T, but 3 nodes involved, M0

Front 523

Stage IV breast cancer

Back 523

-any T, any N, M1 (metastasis)
*18% 10 yr survival (in contrast to in situ which is stage 0 and 92% survival)