Myeloproliferative disorders, multiple myeloma, leukemia, lymphoma (Week 8) Flashcards
(208 cards)
1
Q
Acute vs. chronic leukemias in general
A
Acute leukemias involve blasts (immature cells); generally worse prognosis (short and drastic course); blocked differentiation; children or elderly
Chronic leukemias involve more differentiated cells (mature cell); generally better prognosis (longer, less devastating course; midlife age range
2
Q
Myeloproliferative disorders
A
Clonal disorder of hematopoiesis characterized by excessive growth and differentiation of blood cells
Excessive production of mature blood cells, all of which are derived from single hematopoietic progenitor
1) Polycythemia rubra vera
2) Essential thrombocythemia
3) Myelofibrosis (agnogenic myeloid metaplasia with myelofibrosis)
4) Chronic myelogenous leukemia (CML)
3
Q
Philadelphia chromosome
A
Over 90% of patients with CML have Philadelphia chromosome (in all cancer cells!)
Shortened chromosome 22 has bcr (breakpoint cluster region) plus long arm of chromosome 9 with abl oncogene
Fusion product P210 has tyrosine kinase activity (constitutive) and cells with the fusion protein grows out of control (unresponsive to suppressive elements)
Results in constitutive activation of bcr-abl tyrosine kinase which leads to intracellular signaling pathway going to nucleus and activating altered proliferation, adhesion and survival
4
Q
Myelodysplastic syndromes (MDS)
A
Dysplastic and ineffective blood cell production –> decreased WBC, RBC, platelets
NOT a subset of myeloproliferative disorders (duh…this is decreased everything) but usually in the bone marrow have hypercellular hematopoiesis produced by few clones of cells with dysplastic characteristics
Typically have chromosomal abnormalities
Often called “preleukemia” but remember that some subtypes of myelodysplasia rarely evolve into leukemia while others are very close to leukemia
5
Q
Clonal disorders of hematopoiesis
A
Acquired
Expansion of pluripotent hematopoietic stem cell
Abnormal production of mature blood cells
Predisposition to leukemia transformation
6
Q
Myeloproliferative syndromes
A
Includes 4 myeloproliferative disorders plus more
CML
PV
ET
Myelofibrosis
Chronic monocytic leukemia
Chronic neutrophilic leukemia
7
Q
Characteristics of chronic myeloproliferative disorders
A
Hepatosplenomegaly (clones go to embryonic sites of bone marrow production!)
Hypermetabolism
Clonal increase in number of one or more circulating mature blood cell types
Clonal hematopoiesis without dysplasia
Predisposition to evolve to acute leukemia
8
Q
Atypical myeloproliferative diseases
A
Not the main 4!
Chronic neutrophilic leukemia
Chronic eosinophilic leukemia and hypereosinophilic syndrome
Systemic mastocytosis
9
Q
Chronic myelogenous leukemia
A
Defined by Philadelphia chromosome: short chromosome 22; translocation of bcr from chromosome 22 and abl from chromosome 9
Over 90% patients have Philadelphia chromosome in all clonal cells
Usually in people 30-60 but can happen at any age; slightly more common in males; no heredity
Get hyperleukocytosis which causes rheologic (flow) problems which manifests as dyspnea, dizziness, slurred speech, visual blurriness, diplopia, decreased hearing, tinnitus, confusion, retinal hemorrhage, paiplledema, priapism, neuro findings, hepatosplenomegaly
Also get fatigue, anorexia, abdominal discomfort, early satiety, weight loss, diaphoresis, arthritis, leukostasis, urticaria (basophils and mast cells), pallor, sternal tenderness
Clone cell of CML makes all cells: lymphoid, myeloid, erythroid, megakaryocytic cells
Increased basophils seen in CML (especially at terminal stage), hypersegmentation (ran out of folate), anemia
Hypercellular bone marrow, reticulin fibrosis
10
Q
Accelerated phase of CML
A
Transformation to more malignant phenotype
Additional chromosomal abnormalities cause disordered growth, diminished maturation
Clinical features: fever, diaphoresis, weight loss, splenomegaly, adenopathy, extramedullary blast crisis
Treatment: supportive care, chemotherapy, interferons, leukapheresis, splemectomy, radiotherapy, bone marrow transplantation
11
Q
Should you give a healthy-seeming CML patient bone marrow transplant?
A
Hard to do, but yes because 70% cure rate if treated during chronic phase but only 15% cure rate if wait until blast crisis (even after phase)
Unsure about this…
12
Q
Three phases of CML
A
1) Chronic phase
2) Accelerated phase
3) Blast crisis
13
Q
Predictors of adverse outcome after allogenic transplant for CML
A
Advanced age of recipient
Prolonged duration of CML
Advanced stage of CML
T-cell depletion
Persistence of molecular positivity after transplant
Absence of a/c GvHD (?)
14
Q
Imatinib mesylate (Gleevac)
A
Targets and inhibits product of brc-abl gene, P210 tyrosine kinase (the cause of CML)
Fits into ATP binding site of P210 and disrupts tyrosine kinase activity (doesn’t allow P210 to add phosphate to the substrate)
Completely gets rid of cells with Philadelphia chromosome in 68% of people! And reduces Ph+ to <35% in 15%
Response occurs quickly, after only 3 months
15
Q
Therapeutic milestones in management of CML
A
Hematologic remission
Cytogenetic remission
Molecular remission
16
Q
Monitoring during therapeutic management of CML
A
Hematologic monitoring weekly until stable, every 2-4 weeks until complete cytogenetic response achieved, then 4-6 weeks until molecular response, then every 6 weeks
Cytogenetic motoring every 3-6 months until complete cytogenetic response (CCyR = no cells contain Ph chromosome)
Molecular monitoring every 3 months
17
Q
Polycythemia vera
A
Hematopoietic stem cell disorder with sustained erythrocytosis, increased RBC mass, cellular proliferation
Peak onset 50-60; males more than females; less common in Asians, more common in Ashkenazi Jews
Clinical features: headache, dizziness, vertigo, visual disturbances, angina, claudication, early satiety, abdominal pain, pruritus, thrombosis (Budd-Chiari syndrome), hemorrhages, plethora, retinal hemorrhages, hepatosplenomegaly
Lab findings: high B12, hyperuricemia, decreased erythropoietin, acquired mutation in JAK2
Treatment: phlebotomy (to decrease hematocrit), radioactive phosphorus, other myelosuppressive agents, Jakafi (ruxolitinib; Janus kinase inhibitor; doesn’t work as well as Gleevec does for CML), Hydroxyurea, alpha-interferon, anagrelide, treat symptoms (antihistamine, allopurinol, aspirin)
Prognosis: 30% evolve to spent phase (marrow completely scarred); only 1% evolve to leukemia
18
Q
What else other than PV can cause increased erythrocytosis (DDx for PV)
A
Relative (stress) erythrocytosis
Secondary erythrocytosis (anything that causes hypoxemia): cardiopulmonary disease, high-affinity hemoglobin, decreased FiO2, COPD
Malignant neoplasm (CO poisoning, endocrine disorder)
Cerebellar hemangioma
Uterine myoma
19
Q
Rheologic problems in CML vs. PV
A
in CML, white blood cells stick to each other
In PV, just too many red cells but not sticking to each other
20
Q
Essential (primary) thrombocythemia
A
Excessive bone marrow production of platelets; have leukocytosis and marrow fibrosis as well
Presents age 50-70, usually asymptomatic
No chromosomal findings
Lab features: increased hematocrit, increased RBC mass, normal/increased plasma volume, occasionally microcytosis, neutrophilia, basophilia, thrombocytosis, hypercellular marrow, increased megakaryocytes, myeloid/erythroid hyperplasia (increase in all cell lines), absent stainable iron
Pathophysiology of ET: haven’t found mutation yet but JAK2 mutation in 30-50%, MPL 515 mutation in 1% (often with JAK2 mutation), endogenous erythroid colony (EEC) growth
21
Q
What else other than essential thrombocythemia (ET) can cause increased platelets (DDx for ET)
A
Reactive thrombocytosis due to:
Iron deficiency
Splenomegaly
Malignant neoplasms
Chronic inflammatory diseases
Polycythemia vera
CML
Agongenic myeloid metaplasia
22
Q
Clinical course of ET
A
Predictors of adverse events: age over 60, leukocytosis, smoking, DM
Thrombohemorrhagic risk: age over 60, platelets >1,500,000, cardiovascular risk factors
Risk of AML transformation
Rare to go to acute or blast crisis
23
Q
Other myeloproliferative diseases
A
Chronic idiopathic myelofibrosis
Hypereosinophilic syndrome
Chronic eosinophilic leukemia
Mastocytosis (cutaneous, systemic, or aggressive systemic)
24
Q
Hypereosinophilic syndromes
A
Sustained eosinophilia (>1500), typically in absence of clonality
Chronic eosinophilic leukemia if >5% marrow blasts or >2% circulating blasts
End-organ manifestations of tissue infiltration
Absence of secondary causes of eosinophilia (allergy, metazoan parasitic infection, hypersensitivity pneumonitis, collagen vascular disease, neoplasia, CML, mastocytosis, AML, other myeloproliferative disease)
Chromosomal abnormalities (interstitial deletion of chromosome 4q12, FIP1L1-PDGFRalpha fusion tyrosine kinase)
Clinical manifestations if untreated: infiltrative cardiomyopathy, peri-myocarditis, intramural thrombi, mononeuritis multiplex, peripheral neuropathy, central and cerebellar dysfunction, pulmonary infiltrates/fibrosis/effusions/emboli, GI, arthritis, myositis
25
Mastocytosis
Distinguished by site and degree of involvement (**cutaneous**, **systemic**, **aggressive** systemic)
Somatic clonal mutations may involve c-kit (D816V) of FIP1L1-PDGFRalpha
Clinical manifestations
Elevated serum tryptase
26
Acute myelogenous (non-lymphocytic) leukemia
AKA acute non-lymphoblastic leukemia
Increased **myeloblasts** in marrow (**\>20%** needed for diagnosis but usually \>50%)
AML more common in older people (**60** median); more **male**
Clinical findings: **fatigue**, infection, **bleeding**, adenopathy, LUQ discomfort, **leukostasis**, rectal lesions, **splenomegaly**, lymphadenopathy, gingival hypertrophy, ecchymoses, neuro abnormalities, granulocytic sarcoma neutrophilic dermatosis, CHF
Lab findings: **high** **WBC**, **blasts** in peripheral blood, low hemoglobin, low platelets, high LDH, hypercellular marrow, marrow blasts \>20%; possibly hyperuricenia, renal insufficiency, hypokalemia, hyper/hypocalcemia, CSF pleocytosis, coagulopathy, anergy
27
Possible causes of acute leukemias
**Viruses** (HTLV-1 with adult T-cell leukemia/lymphoma)
**Drugs** and **radiation** cause increased risk of leukemia (usually AML)
Cytotoxic **chemotherapy** or immunosuppression increases risk for leukemia
**Genetic disorders** with chromosomal instability (Klinefelter's, Fanconi's anemia, Down's syndrome) increase risk for development of leukemia
28
Symptoms of acute leukemias
Result of failure of normal hematopoiesis: **malaise**, **fever**, **infections**, **bleeding**
Fever, pallor, petechiae, possibly hepatosplenomegaly, skin infiltrates or nervous system disease
Lab findings: **hypercellular** bone marrow with **blast** cells, blasts in peripheral blood but **pancytopenia of mature blood elements**
29
Histology and cytochemistry to use for AML
Use to distinguish different types of AML (from ALL too):
Wright's stain
Peroxidase
Sudan Black B
Periodic acid (Schiff)
Esterases
Muramidase
30
Different types of AML
**M1-7**
Clinically distinct with unique drivers/mutations and maybe unique therapies
There are favorable and unfavorable genotypes
M1: deletion on 5 or 7 (bad prognisis); no differentiation
M2: deletion on Y; with differentiation
**M3**: acute promyelocytic leukemia (**APL**) with t(15;17) involving **retinoic acid receptor**-alpha binding protein
M4: trisomy 4 and trisomy 8 (good prognosis); acute myelomonocytic leukemia
M5: trisomy 8 (good prognosis); acute monocytic leukemia
M6: acute erythroid leukemia
M7: acute megakaryocytic leukemia
31
Acute promyelocytic leukemia
**M3 type of AML**
**DIC**
Distinct cytogenetic features = **t(15;17)** or t(11;17)
Distinct histological features = azurophilic granules, **Auer rods**
Distinct molecular features = **PML (oncogene)-RARalpha**
Treatment: **all trans retinoic acid** (which makes cells differentiate into neutrophil which die), **arsenic trioxide**, anthracycline-based chemotherapy (might not be used soon)
32
Chemotherapy stages
**Induction**: remission is induced by cytotoxic chemotherapy (this is hard for patient!)
**Consolidation**: sustains remission
**Maintenance**
33
Prognostic factors for remission and/or survival
Age
Prior radiation or chemotherapy
Karyotypic abnormalities, especially chromosomes 5 and 7
History of preleukemia
Gender
Leukocyte count at presentation
34
Acute lymphoblastic leukemia
**Lymphoblasts** of **B cell** type (null pre-pre B, Pre-B, B, and **sometimes T cell**)
Most common cancer in **children**
High N:C ratio
Characteristic pre-B cell markers: **CD10 (CALLA)**, **tDt** (remember, this DNA enzyme induces hypervariability in immunoglobulin so tells you this cancer cell evolved early in development)
**Sanctuary** disease sites: CNS, testis
Treatment: survival only 3-6 month with no therapy but with maintenance antimetabolite therapy have **\>50% chance of 5 year surviva**l; **corticosteroids** and **vinca** **alkaloids**, anthracycline antibiotics, **L-asparaginase**, CNS prophylaxis, **cyclophosphamide**
35
Distinct subtypes of ALL
**Childhood** ALL: **L1** phenotype; **CD10+**, hyperdiploid
**Adult** ALL: **L2** phenotype; 30% are **Philadelphia chromosome +**
**Burkitt's** lymphoma/leukemia: **L3** phenotype; **c-myc** juxtaposed to IgH or kappa or lambda; t(8;14) or t(2;8), t(8;22)
36
Do ALL and AML to the meninges/CNS?
**ALL can enter spinal fluid** since lymhpoid cells (B cells) go to meninges
AML cannot enter spinal fluid because myeloid cells don't usually go to meninges
37
Graft vs. leukemia with bone marrow transplant
No single population of immune cells identified (CD4, CD6, NK) that does the attacking
Introduction of autologous graft vs. leukemia (interferons, interleukins)
38
Why do people with leukemia get back pain?
Back pain is **bone pain** and this is because **expansion of marrow** pushes on periosteum which is innervated and creates pain
39
Where can you get lymphomas?
**Anywhere** in the body that there is a lymphocyte, which is anywhere in the body!
Lymph nodes, spleen, bone marrow, thymus, Peyer's patches, MALT, even extralymphatic sites because there are lymphocytes there!
However, most begin in lymph nodes (where there are most lymphocytes)
40
What does a benign, reactive lymph node look like?
Widely spaced irregularly shaped **follicles** with distinct darkly stained mantle zones and pale, expanded germinal centers
Follicles aren't packed together, they're respecting their neighbors
41
Normal parts of a lymph node
Paracortex has B cells in follicles and T cells in interfollicular zones
Medulla has T cells, plasma cells, histiocytes and B cells
**Paracortical** area has mostly **T cells**
**Secondary follicle** has mostly **B cells**
42
B cell markers
CD19
**CD20**
43
T cell markers
CD3
44
What are most common lymphomas derived from?
**B cells** which have passed through germinal centers of lymph nodes or spleed, where immunoglobulin genes complete diversification
45
Hodgkin's Lymphoma
Usually begins in lymph nodes in neck or chest and then spreads to adjacent nodes then to liver, spleen and bone
Bimodal age distribution (**20's** then **60's**) = "disease of young and old"
**Slow**, continguous progressive lymphadenopathy
Only a few malignant **Reed-Sternberg cells** amongst other **inflammatory** **cells** (this is different from other tumors)
First cancer found to be **curable** in advanced stages using combination chemotherapy
46
Reed-Sternberg cell
Malignant cell of **Hodgkin's disease**
Large, **binucleate** or bilobed with 2 halves as mirror images with prominent **nucleoli** (owl's eyes)
**Transformed B cell**, crippled by bad immunoglobulin gene rearrangements but rescued from apoptosis by multiple mutations/activations promoting cell growth and survival (NFkB or EBV!)
No B cell (CD20) or T cell (CD3) markers but do have **CD15** and **CD30**
47
Subtypes of Hodgkin lymphoma
1) **Nodular sclerosis** Hodgkin lymphoma
2) **Lymphocyte rich** (predominant) classical Hodgkin lymphoma
3) **Mixed cellularity** Hodgkin lymphoma
4) **Lymphocyte depleted** Hodgkin lymphoma
[5) **Nodular lymphocyte-predominant** Hodgkin lymphoma]
48
Nodular sclerosis Hodgkin lymphoma
Most **common** (75%)
Partially nodular pattern with **fibrous** **bands** separating nodules
Rare RS cells often of the **"lacunar"** variant with partial cytoplasmic loss when fixed
**Women** \> men
Primarily young adults
**Excellent** prognosis
49
Lymphocyte rich (predominant) Hodgkin lymphoma
5%
RS cells in background of predominantly lymphocytes, with rare or no eosinophils
May have nodular pattern without fibrosis
\<35 year old males
**Excellent** prognosis
50
Mixed cellularity Hodgkin lymphoma
10%
More abundant **RS** cells and **lymphocytes**, epithelioid histiocytes, eosinophils and plasma cells
**Intermediate** prognosis
51
Lymphocyte depletion Hodgkin lymphoma
5% (rare)
Presence of **fibrosis**, **necrosis** and **paucity of inflammatory cells**
**Large numbers of RS cells** (25%), at times in sheets and bizarre forms
Older males with disseminated disease
**Poor** prognosis
52
Nodular lymphocyte predominant Hodgkin lymphoma
5%
Not a standard Hodgkin lymphoma, **more like indolent non-Hodgkin lymphoma** and that's how it's treated
Partially nodular growth pattern with many lymphocytes and distinct type of cells (L&H variants with popcorn shaped nucleus)
**CD20+** (unlike other Hodgkin lymphomas!)
53
Clinical presentation of Hodgkin lymphoma
**Painless adenopathy** in neck or axilla
Systemic complaints **(fever, fatigue, night sweats, weight loss, pruritus)**
Chest symptoms from mediastinal mass (chest pressure, pain, dry cough) that can extend into lung parenchyma
Adenopathy with **rubbery textured, firm, nodes** (only tender if grew fast)
**Pain** and **itching** at tumor sites with **alcohol** ingestion
**Hepatosplenomegaly** in advanced cases
Most advanced: lung, bone marrow, destructive bony lesions
54
DDx of painless lymphadenopathy
**Hodgkin/Non-Hodgkin lymphoma**
**Metastases** from other primary tumors
**EBV** (mononucleosis)
**Toxoplasmosis**
**Tuberculosis** or atypical mycobacterial infection
Systemic **lupus** erythematosis
**Drug reactions** causing lymph node hyperplasia
55
Diagnosing Hodgkin lymphoma
Do **excisional** **biopsy**, not fine needle aspiration because need larger sample (only a few RS cells!)
Immunohistochemistry for CD3, CD15, CD20, CD30, kappa and lambda light chains
History of **"B symptoms"** (fatigue, night sweats, weight loss)
Physical exam: lymph nodes, tonsils, base of tongue (Waldeyer's ring), spleen, liver, chest
Lab studies: CBC, differential count, platelets, ESR, LDH, hepatic panel, albumin, BUN, creatinine
Radiographs: CT of neck, chest, abdomen, pelvis; PET
Bone marrow biopsy (if advanced stage cytopenias present)
Fertility: pregnancy test, cryopreservation of semen
56
Ann Arbor Staging System for Hodgkin and Non-Hodgkin lymphoma
**Stage I**: involvement of a **single** **lymph** **node** (I) or involvement of a **single extralymphatic organ or site** (IE; spleen, thymus, Waldeyer's ring)
**Stage II**: involvement of **two** **or more lymph node regions on the same side of the diaphragm alone** (II) or with involvement of limited contiguous extralymphatic organ or tissue (IIE)
**Stage III**: involvement of **lymph node regions on both sides of the diaphragm** (III) which may include spleen (IIIS) and/or limited contiguous
**Stage IV**: **multiple** or **disseminated** foci of involvement of one or more extralymphatic organs or tissues with or without lymphatic involvement
A: asymptomatic
B: fevers \> 38 C, drenching night sweats, loss \>10% body weight
57
Bad prognostic factors affecting outcomes in Hodgkin lymphoma (international prognostic score; IPS)
IPS is 1 point per adverse factor:
Male
\>45
Stage IV
Anemia (\<10.5)
**Elevated WBC** (\>15 x 109)
**Low lymphocytes** (\<0.6 x 109 or \<8% of WBC diff)
Low serum albumin (\<4)
58
How does Hodgkin lymphoma cause its effects?
**Affects** **inflammation** locally and at a distance: attracts eosinophils, neutrophils, mast cells, fibroblasts (to lay down fibrous stroma causing nodular sclerosis)
**Attracts** **lymphocytes** (T cells) and then **inactivates them** via **PDL1/PD1** (this is why patients are immunosuppressed)
Chemokines and cytokines at a distance mess up function of the **liver**, cause anemia even if bone marrow not infiltrated
59
What does blocking PD1 do?
Causes **regression of solid tumors** of Hodgkins lymphoma
Causes strong immune response against tumor cells because tumor cells express PD1 which dampens the immune response (normally on APCs) to allow RS cells to "hide" from immune system
60
Treatment for Hodgkin lymphoma
**Early** stage disease (Stages I-IIA): **4 cycles of ABVD** chemotherapy + **involved field radiation**
**Advanced** stage disease (Stages IIB-IV): **6-8 cycles of ABVD**; or **BEACOPP** for high-risk cases (IPS\>4) which adds **etoposide** (topoisomerase inhibitor), **cyclophosphamide** (alkylator), oncovin, procarbazine (alkylator), **prednisone** (corticosteroid)
**Relapsed**/refractory disease: **"salvage" chemotherapy** and autologous or allogenic **stem cell transplantation**; can be curative in 25-50%
61
ABVD chemotherapy
**Adriamycin**: anti-tumor antibiotic, anthracycline, causes DNA strand breaks
**Bleomycin**: anti-tumor antibiotic, can cause pulmonary toxicity
**Vinblastine**: vinca alkaloid, microtubule inhibitor
**Dacarbazine**: alkylating agent
62
What is the overall cure rate for Hodgkin lymphoma?
**85%** of everyone
63
What's the problem with treating Hodgkin lymphoma too aggressively?
Too much radiation causes **secondary malignancy** (leukemia, lung cancer, breast cancer)
We want to give just enough treatment to cure
64
Non-Hodgkin lymphomas
**8x as common** as Hodgkin lymphoma
Youngest median age of all common cancers (42 years)
Fatal in many cases, but about half can be cured with modern chemotherapy and anti-CD20 antibody therapy
More than **30 sub-types** (includes B cell, T cell and NK cell mature (peripheral) neoplasms)
65
Ways that Non-Hodgkin lymphomas are classified and named
1) Appearance of nodal architecture
2) Appearance of cells; what they look like compared to cells in normal lymphoid tissue compartments; stage of differentiation
3) Immunophenotype (B cell, T cell, NK cell)
4) Anatomic location where they arise and reside
66
Why do we get non-Hodgkin lymphoma?
When **rearranging immunoglobulin DNA** (rearrangements and hypermutations) we can make mistakes that cause non-Hodgkin lymphoma
Immunoglobulin promoter/enhancer elements brought next to genes controlling cell growth
Faulty translocations activate proto-oncogenes
67
Proto-oncogenes activated by faulty translocations causing non-Hodgkins lymphoma
1) **Transcription** **factors**: **c-myc** in Burkitt's lymphoma; **bcl-6** in diffuse large B cell lymphoma
2) **Cell cycle regulators**: **cyclin D1** in mantle cell lymphoma
3) **Anti-apoptotic proteins**: **bcl-2** in Follicular lymphoma
68
Mutations involved in Burkitt's lymphoma
Translocation of heavy chain **IgH on chromosome 14** in front of **c-myc on chromosome 8** = **t(8;14)**
Or could be lambda light chain from chromosome 22 = **t(8;22)**
Or could be kappa light chain from chromosome 2 = **t(8;2)**
Rapidly growing tumor
69
Clinical features of non-Hodgkins lymphoma
**Painless** enlargement/lump, sweats, fatigue
**Aggressive**: (ex: **diffuse large B cell lymphoma**) **rapid** growth, maybe **pain**, extranodal site (lung, kidney, stomach, bones), **acute** illness, impaired functional status
**Indolent**: (ex: **follicular lymphoma**, small lymphocytic lymphoma, marginal zone lymphoma) **slow** insidius growth, often **asymptomatic**, usually limited to nodal sites, **cytopenias** from bone marrow involvement is common
70
Prognosis/outcomes in aggressive vs. indolent non-Hodgkin lymphoma
**Aggressive**: **curable** in half of cases, or **death** within 1-3 years
**Indolent**: responds to therapy initially but nearly always recurs, so "incurable" but average **survival** **~13 years**
71
International prognostic index (IPI) for DLBCL non-Hodgkins lymphoma
Bad for prognosis:
Age \> 60
LDH \> normal
Performance status \>/= 2
Ann Arbor stage III or IV
Extranodal involvement \> 1 site (not independent predictor in age \<60)
Note: number of points here can predict survival time
72
Diffuse large B cell lymphoma
Most **common** subtype of non-Hodgkin lymphoma (34%)
60% present with nodes only; 40% have extranodal involvement
Cells are large, have **open chromatin** pattern
**CD20+** in virtually all cases
Half cured by **R-CHOP**; recurrent cases treated with autologous **stem cell transplantation**
Gene expression profiling defines distinct biologic and prognostic categories
73
Gene expression profiling for Diffuse Large B cell Lymphoma
Did gene expression study and found that DLBCL fell into 2 subtypes: **germinal** **center** **type** and **activated B cell type**
**Germinal center type had better outcome**
Don't routinely do whole genome study for patients, but can look at a few markers to decide what category they fall into and change treatment (aggressive therapy vs. rituximab-CHOP)
74
Follicular lymphoma
**Indolent** non-Hodgkin lymphoma
**Asymptomatic** at diagnosis, grows slowly
**CD20+** in virtually all cases
Highly responsive to **rituximab** anti CD20 antibody therapy
Despite good response to initial therapy, usually "incurable" median survival 13+ years
Approximately 25% experience "transformation" to higher grade lymphoma with poor prognosis
75
Follicular lymphoma International Prognostic Index (FLIPI)
Poor prognisis if:
Age \>60
Ann Arbor stage III, IV
**Hemoglobin level \<12**
Serum LDH level \>ULN
**Nodal sites \> 5**
Note: number of factors predicts risk group
76
Marginal zone lymphoma
3rd most common non-Hodgkin lymphoma
**Indolent**, slow-growing, asymptomatic at diagnosis, good prognosis
Small to medium-sized cells that infiltrate around **"marginal zone" of reactive B cell follicles**
**"Triple negative"** lymphoma because CD5, 10, 23 negative
**CD20+** and highly responsive to **rituximab** anti-CD20 antibody therapy
**Gastric MALT lymphoma** (driven by cytokines released during H. pylori infection --\> promote B cell proliferation and survival --\> MALT lymphoma --\> treat H. pylori infection --\> lymphoma goes away!)
Other MALT sites: salivary glands, lung, head and neck, conjunctiva, skin, thyroid, breast
77
Small lymphocytic lymphoma
Only 6% of non-Hodgkin lymphomas
**Nodal/solid tumor** counterpart to chronic lymphocytic leukemia (CLL)
CD20 low, CD5+, CD23+
Typically **widespread involvement** of nodes, liver, spleen, bone marrow, peripheral blood
Treated with **rituximab** anti CD20 antibody but less responsive than follicular lymphoma
Richter's transformation in approximately 5% (survival less than 1 year)
78
Mantle cell lymphoma
6% of non-Hodgkin lymphoma cases
Cells resemble normal **mantle zone B cells** that surround germinal centers (small, monotonous, are CD20+, CD5+, CD23-)
Characteristic **t(11;14)** Ig heavy chain gene translocation activates **cyclin D1** oncogene which promotes cell cycle progression
Often involves extranodal sites: bone marrow, spleen, liver, GI tract; lymphomatous polyposis (submucosal nodules on colon)
5 year survival is 50%, but improved with new therapies
79
Burkitt's lymphoma
Only 3% of non-Hodgkin lymphoma cases
Driven by Ig/**c-myc** oncogene chromosomal translocation: **t(8;14)** or others
High-grade, very rapid growth
Cells medium-sized, diffuse, monotonous with numerous mitoses and infiltrating macrophages giving **"starry sky"** pattery at low power
sIgM+, CD20+, CD10+
Endemic form from Africa, in jaw and **EBV+**
Sporadic form from North America, extranodal/abdominal mass and only 30% are EBV+
Presents in young patients or **HIV+**
Requires immediate hospitalization and chemotherapy, including **intrathecal** **methotrexate**
Treatment often complicated by **tumor lysis syndrome** (hyperuricemia, uric acid nephropathy, hyperkalemia, hyperphosphatemia, hypocalcemia
3 year overall survival 50%
80
T cell lymphomas (includes NK cell cases)
11% of non-Hodgkin lymphoma cases
Over 20 different subtypes
Most are CD3, 4, 5+
Tend to be more **aggressive** with extranodal involvement and poorer survival than B cell non-Hodgkin lymphomas
Most are cutaneous T cell lymphomas (CTCL)
Ex: **mycosis fungoides (MF)/Sezary syndrome** (leukemic phase, when cells get into blood)
81
Mycosis fungoides/Sezary syndrome
Type of **T cell lymphoma**
Diffuse **erythroderma** because cells spread out and home to skin and cause itchy flaky skin
Form **mushroom-like tumors**
Sezary syndrome is just the point where the cells get to the **blood**, so you have diffuse erythroderma PLUS 20% of lymphocytes are sezary cells (have cerebreform/brain-like nuclei)
82
CHOP treatment for non-Hodgkin lymphoma
**Cyclophosphamide** (DNA alkylating agent)
Doxorubicin (**Hydroxydaunomycin**; DNA strand breaks)
Vincristine (**Oncovin**; disrupts microtubules and mitosis)
**Prednisone** (corticosteroid; pro-apoptotic to lymphocytes)
83
How have we changed CHOP treatment in the past few decades?
We added anti-CD20 **Rituximab** to CHOP therapy
Made treatment much better
84
What is the idea behind using drug combinations for treatment?
Agents with **different mechanisms** of action but **non-overlapping toxicities**
CHOP is an example
85
Rituximab (Rituxan)
Genetically engineered chimeric murine/human antibody (IgG1)
Binds the **CD20** antigen on surface of normal and malignant B cells
First FDA-approved monoclonal antibody for treatment of cancer
Minimal toxicity
50% have remission that lasts at least 1 year
Giving rituximab with CHOP chemotherapy was very good
86
R-CHOP
**Rituximab** plus CHOP
Standard therapy for **non-Hodgkin lymphoma**
87
Other than lymphoma, what can rituximab be used for?
**Kills B cells**, so can be used in **autoimmune** diseases that are the result of over-active B cells (antibody-mediated auto-immune diseases: ITP, hemolytic anemia, RA, SLE, pemphigus, cryoglobulinemia, organ transplantation)
However, sometimes the auto-antibodies are so well established that rituximab doesn't work that well
88
Most important in vivo mechanism we have against lymphomas
Antibody-dependent cellular cytotoxicity (**ADCC**): antibody binds tumor cell, then binds Fc portion on NK cell and NK cell carries out perforin-granzyme-mediated lysis of tumor cell
Some apoptosis and antiproliferation and complement-mediated cytotoxicity used to kill tumor cells, but these are just minor mechanisms
T cell immunity probably not involved in killing lymphoma tumor cells
Note: ritubimab uses ADCC because is an antibody that binds tumor cell and then the NK cell to cause perforin-granzyme-mediated lysis of tumor cell
89
Treatment for non-Hodgkin lymphomas
**Follicular lymphoma 1st line**: watch and wait, **rituximab**, R-CVP, R-bendamustine, R-fludarabine
**Follicular lymphoma 2nd line**: one of above, radioimmunotherapy (Zevalin, Bexxar), **R-CHOP**
**Follicular lymphoma 3rd, 4th line**: one of above, investigational agents, **salvage** regimen, autologous or allogenic **stem cell transplant**
**DLBCL 1st line**: **R-CHOP**, R-EPOCH (high-risk), CODOX-M/IVAC (for c-myc translocation in Burkitt's)
**DLBCL relapse/2nd line**: R-ICE, R-ESHAP, R-EPOCH, Gemzar/navelbine, oxaliplatin (if respond, autologous transplantation; if no response or BM+ consider allogenic transplant), investigational agents
90
Autologous stem cell transplantation
Used to treat **recurrent aggressive lymphomas** after failure of R-CHOP
1) **Collect stem cells** from patients bone marrow or blood when they are in remission
2) **Cryopreserve** stem cells
3) Give patient **very high dose chemotherapy** to try to kill cancer cells
4) **Reinfuse thawed stem cells** into patient, and they populate empty bone marrow to regenerate blood and immune cells
91
What are new drugs for non-Hodgkin lymphoma targeting?
**Tyrosine kinases** that are active in cancerous B cells
CAL-101 is a new drug that **inhibits PI3 kinase delta**
92
Summary of therapies for aggressive vs. indolent B cell non-Hodgkin lymphomas
**Aggressive**: **rituximab+CHOP, stem cell transplant,** investigational
**Indolent**: **rituximab alone, rituximab+bendamustine**, soon PI3 kinase delta/Btk inhibitors
93
Multiple Myeloma
Multifocal neoplastic proliferation of **plasma cells** (clonal)
**Crowding out** of normal marrow cells causes pancytopenia, **anemia**, **infections** (with encapsulated bacteria if asplenic), **bleeding**
(Don't need to know this but also the plasma cells produce IL-6 which causes anemia of chronic disease)
**Bone lesions are "punched out"** (tumor causes bone resorption by growing but also making IL-1 and other bone resorbing factors)
Increased cell turnover (uric acid and calcium phosphate deposits)
At least one **CRAB** end-organ manifestation
94
Criteria for diagnosis of MM
**Monoclonal plasma cells** in bone marrow
Monoclonal protein present in **serum** and/or **urine**
At least 1 **CRAB** organ dysfunction (calcium increase, renal insufficiency, anemia, bone lesions)
95
Lab findings in multiple myeloma
Elevated **serum protein** (+/- hyperviscosity)
**Hyperglobulinemia** (but **effective** **hypoglobulinemia** and increased infections)
**Monoclonal** **spike on** SPEP and IEP
**Rouleaux** formation of RBCs on smear (Ig stacks on RBCs, no more negative charge to repel each other)
Ig coats coagulation factors (get excess **bleeding**)
**Excess light chains** in urine and serum (Bence Jones protein) may cause renal failure and amyloidosis
96
Different types of multiple myeloma
**IgG**: most common, classical findings
IgM: hyperviscosity; usually Waldenstrom's Macroglobulinemia which is NOT multiple myeloma
**IgA**: may have flame cells (secretory part)
IgD: may not detect globulin on routine protein electrophoresis so need to do immune electrophoresis with IgD (rare)
IgE: may present with plasma cell leukemia (very rare)
**Light chain only**: usually missed on serum electrophoresis so need to do urine protein electrophoresis and light chain typing to see monoclonal light chain
Null chain: no production or secretion of abnormal antibody but have neoplastic proliferation of plasma cells in marrow (usually hypogammaglobulinemic)
97
Plasmacytoma
Isolated collection of plasma cells, plasma cell tumor
(NOT multiple myeloma)
98
Plasma cell leukemia
Neoplastic plasma cells in the blood
99
M protein
M protein = **paraprotein** = **immunoglobulin** that is over-produced by plasma cells of multiple myeloma
Found in serum or urine or both at time of diagnosis in 97% of patients
Amount of M protein correlates with number of malignant cells in the body
100
Serum protein electrophoresis
Test done to investigate multiple myeloma
Can determine **amount of M protein** (paraprotein, immunoglobulin) in blood
With MM, have **spike at m**, and no broad gamma peak like usual
101
Clinical findings in multiple myeloma
**Pathologic fractures**
**Pancytopenias**
**Increased infection**
**Renal failure**
**Hyperviscosity**
102
Why do you get more infections with multiple myeloma?
**Lack of effective antibodies** (only 1 kind made!)
**Decreased opsonization**
**Neutropenia** from marrow myeloma
**Chemotherapy** (steroids, neutropenia)
103
Why do you get renal failure in multiple myeloma?
Myeloma kidney: light chains inhibit renal tubular function (**Bence Jones protein**)
Amyloidosis (light chain deposits)
Uric acid and calcium deposits
Renal infiltrates by plasma cells
Infections (?)
104
Therapies for multiple myeloma
**Bisphosphonates**
**Immunomodulatory** drugs (thalidomide, lenalidomide)
**Proteosome inhibitors**
Others (HSP90 inhibitors, histone deacetylase inhibitors, anti-IL6 monoclonal antibodies)
105
Waldenstroms Macroglobulinemia
Lymphoid-plasmacytoid cells (look like combo between plasma cell and lymphocyte) in bone marrow and/or blood that clonally produce **IgM pentamers**
**Hyperviscosity** (large amounts of IgM pentamer in plasma): fatigue, malaise, SOB, neuro symptoms, bleeding, headache, vision
No bone lesions
**NOT multiple myeloma**
106
Top 5 cancer types in men and women
**Men**: prostate, lung/bronchus, colon/rectum, urinary bladder, melanoma of skin
**Females**: breast, lung/bronchus, colon/rectum, uterine corpus, thyroid
107
Top 5 types of cancer killers in men and women
Men: **lung/bronchus**, prostate, colon/rectum, pancreas, liver/intrahepatic bile duct
Women: **lung/bronchus**, breast, colon/rectum, pancreas, ovary
108
Which cancers do we screen for?
Established: **colon, breast, cervical**
Controversial, but supported by ACS: prostate
Not established: lung, ovarian
109
Screening for breast cancer
Self breast exam optional
**Clinical breast exam** every 3 years starting at age 20 and every year after age 40
**Mammogram** yearly after age **40**
Women at high risk (\>20% lifetime) should get yearly MRI and mammogram
110
Why shouldn't younger women get mammograms?
Because younger women have **dense** breast tissue because of estrogen
Dense breast tissue can look like tumor on mammogram so get **false positives**
111
MRI for breast cancer screening
More **sensitive** than mammogram but **less sepcific**
Since more false positives, only want to do this on **high risk patients** because don't want to do useless biopsies for confirmatory testing
112
Screening for colon cancer
Start at age **50**
Yearly fecal occult blood and flex sig q5 years
Double contrast barium enema q5 years
Colonoscopy q10 years
If high risk (family hx, personal hx polyps, IBD), more frequent and may start younger
113
Screening for cervical cancer
**Pap** smears start yearly 3 years after vaginal intercourse and no later than 21yo
Yearly screening regular pap or q2 years with liquid based pap
Age 30 and 3 normal pap in a row, can screen q2-3 years or every 3 years if add HPV DNA test
If DES (diethylstilbestrol) exposure before birth, HIV, immunosuppression, continue annual screening
If 70+ yo with 3 normal paps in a row and no abnomal in last 10 years can stop screening
114
Prostate cancer screening
**PSA blood test** and digital rectal exam (**DRE**) yearly starting at age 50
High risk men (AA, family history) start screening at age 40-45
Discuss risks/benefits (limitations to testing) but should offer to patients
115
Do most people with cancer have a family history?
No, only 5-10% of cancers are familial
116
Familial cancers
Li Fraumeni (chk2, p53): sarcoma, breast, brain, leukemia
Cowden (PTEN): multiple hamartomas, breast, thyroid
BRCA1 (chrom 17): ovarian and breast; prostate/colon?
**BRCA2** (chrom 13): breast (males), pancreatic
MEN I (chrom 11): pituitary, thymic, pancreatic islet cell
MEN II (chrom 10, RET): medullary thyroid, pheo
FAP/Gardner's syndrome: colon
HNPCC/Lynch syndrome (chrom 3): colon, uterine, GBM?
Von Hippel Lindau (VHL): hemangiomas, renal cell
Ataxia-telangiectasia: lymphoma, gastric, brain, uterine, breast?
117
Environmental/industrial carcinogens
Arsenic: lung/skin
Asbestos: pleura, peritoneum, lung
Benzene: lymphoid tissue
Aminobiphenyl: bladder
Cadmium, Beryllium: lung
Hairdyes: bladder
Formaldehyde: nose/nasopharynx
Vinyl chloride: liver
118
Carcinogenic medical agents
**Estrogens**: endometrial/breast
Anabolic steroids: liver
**Tamoxifen**: endometrium
Melphalan: lymphoid tissue
**Busulphan**: bone marrow
119
Viruses associated with cancer
**Kaposi's sarcoma** (HIV, HHV-8)
**Non-Hodgkin lymphoma** (EBV and HIB for Burkitt's; HIV and HHV-8 for primary effusion lymphoma)
CNS lymphoma
**Hodgkins lymphoma** (EBV)
**Nasopharyngeal carcinoma** (EBV)
**Cervical cancer** (HPV 16, 18, 33, 39)
Liver cancer (Hep B and C)
H pylori (gastric lymphoma and cancer)
**Adult T cell leukemia/lymphoma** (HTLV-1)
120
Lifestyle factors that are carcinogens
Tobacco: lung, bladder, esophagus, mouth, larynx
Betel nut: oral cavity
Alcohol: esophagus, orla, pharynx, liver
UV radiation: melanoma, other skin cancer
121
Cancer staging
Cancer stage tells you degree of **localization/spread**
Helps determine **prognosis** (better than grade!) and thus treatment
Imaging modalities for staging: **PET**, **CT** (large mets and bleeds), **MRI** (catch more subtle findings), bone scan, ultrasound, plain X-rays
**T** (tumor size 1-4), **N** (regional lymph node involvement 0-3), **M** (metastases X,0,1)
Stage 0: Tis, N0, M0
Stage I: **T1**, N0, M0
Stage II: T0-2, **N0-1**, M0
Stage III: T0-3, **N1-2**, M0
Stage IV: anyT, anyN, **M1**
122
Tumor types not staged by TNM
Pediatric
Leukemia/lymphoma
CNS tumors
123
Factors that are important in treatment and prognosis other than stage
Grade and type of tumor
Presence of biomarkers, gene mutations, amplifications, deletions
Age of patient, other medical conditions
124
Clinical stage vs. pathologic stage
**Clinical stage**: **PE** and **imaging** (use little c); guides presurgical ("neoadjuvant") chemotherapy choices
**Pathologic stage**: **histologic** examination of tissue (use little p); helps determine prognosis and guides whether patient should receive post-surgical ("adjuvant") chemotherapy
Clinical exam might not identify pathologic disease
125
Treatment approaches
**Surgery**
**Radiation**: external beam, RFA, stereotactic radiosurgery/Gamma knife
**Chemoembolization**
**Chemotherapy**
Novel **biological** **agents**: immune therapy (interferon, vaccines, gene therapy), anti-angiogenesis, targeted agents (monoclonal antibodies, tyrosine kinase inhibitors)
**Palliation**
126
Judging response to therapy
Complete response (CR): disappearance of all lesions
Partial response (PR): \>30% decrease from baseline (RECIST), \>50% decrease from baseline (WHO)
Overall response rate (ORR): %PR + %CR
Progressive disease (PD): \>20% increase over smallest sum observed or appearance of new lesions (RECIST), \>25% increase in one or more lesions or appearance of new lesions
Stable disease (SD): neither PR nor PD criteria met
127
Oncologic emergencies
**Superior vena cava syndrome**
**Spinal cord compression**
**Electrolyte disturbances** (tumor lysis, low Na, high Ca, hyperuricemia, etc)
**Cardiac tamponade** (malignant effusion)
**Venous thromboembolism**
**Febrile neutropenia**
128
Spinal cord compression
Most commonly associated with **prostate**, **breast**, **lung** cancer (also renal cell, lymphoma and myeloma)
Most common and earliest symptom is **pain** (precedes neurological compromise by 7 weeks, worse lying down)
Motor weakness 60-85%
Sensory defects
Bowel/bladder incontinence or dysfunction (late sign)
Imaging (best is MRI, can also do CT myelogram)
Treatment: urgent **surgical decompression** and/or RT
129
New cancer drugs developed once we knew more about molecular underpinnings of cancer
**ATRA**: acute M3 leukemia (APL)
**Gleevec**: CML
**Rituximab**: non-Hodgkin lymphoma
**Trastuzumab**: Her2/neu + breast cancer
130
HER2 breast cancer
**HER2** is overexpressed in 25% of breast cancers
HER2 is a protein on the surface of cancer cells
Functions: growth and proliferation, differentiation, cell survival, motility, angiogenesis
131
Trastuzumab (Herceptin)
Breast cancer drug that **targets Her/neu protein** expressed on surface of breast cancer cells
Is an anti-HER2 antibody that binds HER2 and **kills cells** that express it (possibly through ADCC, but also other mechanisms)
132
T-DM1 therapy for HER2 breast cancer
**Trastuzumab with a very toxic chemical emtansine stably linked to it**
Binds to HER2 using trastuzumab, then gets **endocytosed** and toxic emtansine is **released** into cell to kill it (inhibit MT polymerization, etc)
133
Things to think about if you see a solitary "spot" or "bump"
Melanoma
Basal Cell Carcinoma (BCC)
Squamous Cell Carcinoma (SCC)
Actinic Keratosis (AK)
134
Benign growths
Ephilides (freckles)
Lintigines
Nevi
Seborrheic keratoses
Acrochordons
Cherry angiomas
Dermatofibromas
Sebaceous hyperplasia
Keloids
Epidermal inclusion cysts
Milia
Lipomas
135
Actinic keratosis (AK)
**Solar keratosis**
Common cutaneous growth, seen in fair-skinned adults
Seen in sun-exposed areas
**Potential** to develop into **squamous cell carcinoma** (only \<5% though)
Clinical features: rough, pink or tan scaly papules, 3-10mm, can become thicker or hyperkeratotic
Treatment: Cryotherapy, curettage, chemical peel, dermabrasion, topical chemo (5FU) or immunotherapy (imiquimod), photodynamic therapy
136
Basal cell carcinoma (BCC)
**Most common malignancy in US**
Areas of chronic sun exposure, lighter skin types
Can be locally destructive
**Rare reports of metastasis** but if leave alone for 10-20 years, will metastasize
General clinical presentation: **telengectasias** and blood vessels around nodule with round borders
Types: **nodular** BCC, **pigmented** BCC, **superficial** BCC
Pathogenesis: sporadic BCCs have mutations in p53 tumor suppressor gene; sporadic and hereditary have mutation in PTC tumor suppressor gene
Treatment: curettage, electrodissection, excision, Mohs micrographic surgery, radiation, cryotherapy, photodynamic therapy, topical 5FU or imiquimod, laser surgery
137
Different types of BCC
**Nodular** BCC: most common, usually on head and neck; firm, **waxy** papule or nodule, pearly border, can ulcerate, telangiectasias on surface
**Pigmented** BCC: common in asians, latinos, AAs; make melanin so **brown** or black and look a lot like melanoma; similar morphology as nodular BCC
**Superficial** BCC: scaly pink to red-brown patch, usually on trunk; can look like **ecxema**, **psoriasis** or Bowen's disease, can ulcerate
**Morpheaform** or **Sclerosing** BCC: less common; poorly defined firm papules or plaque; scar-like appearance, usually not ulcerating; **borders** **extend** beyond what you can see
138
Squamous cell carcinoma (SCC)
Malignant skin tumor of keratinizing cells of epidermis or appendages
Second most common cutaneous malignancy
**Metastatic potential**
Risk factors: UV exposure, fair skin, radiation, arsenic, inflammation/burn scars, HPV, immunosuppression, history of actinic keratosis
Pathogenesis: defects in p53 tumor suppressor gene, 10-50% have mutation in RAS tumor oncogene
Treatment: excision, Mohs micrographic surgery, laser surgery, radiotherapy, cryotherapy, curettage and electrodessication, phototherapy, topical chemotherapy (5FU)
139
Types of SCC
SCC **in-situ**: Bowen's disease, Erythroplasia of Queyrat
**Keratoacanthoma**
**Verrucous carcinoma**
140
High risk SCC tumors
Size **\>2cm**
**Recurrent**
On **ears, scalp, temple, lip**
Histologic features: **perineural** **invasion**, poorly differentiated, increased **depth** of invasion
141
Melanocyte
Cell that **produces pigment**
Determines color of skin
They distribute **melanosomes to keratinocytes**; basal cells pick up melanin from melanocytes too
Derived from **neural** **crest**, migrate to skin (hair follicles), eye, inner ear, medulla oblongata
Normally located in **basal** **layer** **of epidermis** (1 for every 10 basal cells)
Everyone has **same number**, but melanocytes produce **different numbers of melanosomes** and that determines skin color
142
Diseases of defective melanocyte migration
**Piebaldism** (patches of white hair/skin)
**Waardenburg's syndrome** (patches of white hair/skin, deafness, diff colored eyes, megacolon)
**"Mongolian spots"** = dermal melanocytosis (when dermal melanocytes don't die like they're supposed to and cause nevus of Ota on head and neck, blue nevi on distal extremities, presacral areas)
143
Oculocutaneous albinism
Defect in **tyrosinase** (produced by melanocytes and converts **tyrosine to melanin**)
**Autosomal recessive**
Normal number of melanocytes but **no melanin**
Get **nystagmus**, and **white hair** and **light eyes**
144
Vitiligo
Just a **cosmetic** problem
**Acquired loss of melanocytes**
Irregular patches of decreased pigment
145
Benign pigmented lesions
**Flat** lesions: ephelides (freckles), lentigines, cafe au lait macules, some nevi
**Raised** lesions: melanocytic nevi, congenital nevi, dysplastic nevi
146
Ephelides
Freckles
Normal number of melanocytes, increased melanin
147
Lentigo (lentigines)
**Lentigo simplex** if at birth
**Solar lentigo** (liver spots?) if from chronic sun exposure
Hyperpigmented macules and patches on skin or mucosa
May involve an increase in the number of melanocytes
Multiple lentigines can be marker for disease (Peutz-Jeghers Syndrome --\> intestinal polyps and increased incidence of malignancies)
148
Cafe au lait macules
Seen in 10-20% of population
Often appear during early childhood
Smooth bordered, light to dark brown patch
Normal melanocyte density, **increased melanin**
**No malignant potential**
Multiple cafe au lait macules can be marker for disease (Neurofibromatosis type I)
149
Melanocytic nevus ("mole")
May be flat or raised
Evenly pigmented (flesh to dark brown colored)
Even borders
Neoplastic collection of nested melanocytes
Hard to **distinguish** from **seborrheic keratosis**
150
Congenital nevus
Present at birth
Often **larger** than melanocytic nevi
Often have associated **hair** **growth**
Large or multiple congenital nevi may be associated with leptomeningeal involvement and resultant CNS defects
**Large** congenital nevi (\>20cm) are associated with increased risk of **melanoma**
151
ABCDE of melanoma
Asymmetry
Border
Color
Diameter
Evolution
152
Dysplastic nevus
Clark's or Atypical nevus
**Melanoma can arise** from dysplastic nevus (or de novo)
But dysplastic nevus is **not necessarily a pre-cancer**
Can be difficult to distinguish clinically and histologically from melanoma
Can be a marker for melanoma risk
153
Risk factors for melanoma
**Intermittent** high intensity **UV exposure** (history of sunburns)
**\>50 melanocytic nevi**
Family or personal **history** of melanoma or dysplastic nevi
**Giant** congenital nevus
**Lighter** skin
DNA repair defects
154
Xeroderma pigmentosum
Autosomal recessive
Defective DNA repair
**Numerous** skin cancers at a young age
155
Genes involved in development of melanoma
**BRAF** mutations (80% of melanomas have activating mutation)
**CDKN2A** mutation (involved in regulating cell cycle; mutations can be familial)
156
Types of melanoma
**Lentigo maligna** and other melanomas in situ
**Lentigo maligna melanoma**
**Superficial spreading melanoma**
**Nodular melanoma**
**Acral lentiginous melanoma**
157
Lentigo maligna (a type of melanoma in situ)
**Irregularly pigmented** macule or patch (often fulfills ABCDEs)
Sun-exposed areas in elderly patients
Progresses to **lentigo maligna melanoma in 2-5%**
Thinned epidermis, solar elastotic changes in dermis
Proliferation of irregular and atypical melanocytes in epidermis
**No invasion** of atypical melanocytes into dermis
158
Lentigo maligna melanoma
5-15% of melanomas
Elderly patients with sun damaged skin
Identical to lentigo maligna but possesses **vertical growth phase**
159
Superficial spreading melanoma
Most **common** type of melanoma (60-70%)
Most frequently found on **back** in men and on **legs** in women
Fulfills ABCDEs
160
Nodular melanoma
Second most common type of melanoma (15-30%)
Rapidly **developing** nodule (may not satisfy ABCDs)
Can be ulcerated and bleed
Mostly in **vertical growth phase**
161
Acral lentiginous melanoma
**Rarest** type of melanoma (5-10%) but common in dark skinned patients
45% of melanomas in Asians
Occurs on **palms and soles**
162
Subungual melanoma
**Variant of acral lentiginous melanoma**
Can present as hyperpigmented streak on **nail plate** (longitudinal melanonychia)
Hutchinson's sign: pigmentation of proximal nail fold
163
Amelanotic melanoma
Melanoma that stopped making melanin
Dangerous!
164
What determines prognosis of melanoma?
**Breslow depth**
Measured from stratum granulosum (down past epidermis)
Determines how likely it is to spread and what surgery they need
Note: Clark's levels are NOT what determines prognosis
165
What do metastases tell you about prognosis?
**Lymph node** metastasis means **5 year survival is 66%**
**Extra-nodal** metastasis means **5 year survival 10%** (most often to lungs, liver, brain, or bone)
166
Management of melanoma
**Surgical** **excision** with margins dependent on thickness
**Sentinel lymph node biopsy** controversial but frequently done on tumors \>1mm thickness
Elective lymph node dissection not performed routinely
**Adjuvant** or palliative chemotherapy (IFN-alpha, dacarbazine (DTIC) or temozolomide)
167
New treatments for melanoma
**Ipilumimab**: anti-CTLA4 antibody
**Vemurafenib**: B-RAF inhibitor
TLR agonists like imiquimod for lentigo maligna and cancer vaccines are experimental/off-label
168
Seborrheic keratoses
Very common
**Waxy**, scaly, greasy stuck on verrugous, papules to small plaques
**Benign** keratinocyte neoplasms
Everywhere except palms and soles
Sometimes become itchy/irritated or inflamed
Can look like **nevi**
169
Dermatofibroma
Common scar-like **firm papules**, mostly fibroblasts, often on limbs
170
Skin tag
Acrochodon
171
Two very common subcutaneous nodules
**Lipoma**: benign fat tumor; excise if symptomatic, patient worried or diagnosis unclear
**Epidermoid** **cyst**: "sebaceous cyst" or epiderman inclusion cyst (EIC); subcutaneous nodule with punctum; excise don't drain; can ignore if diagnosis clear and patient unconcerned
172
Defining characteristics of marrow stem cell
1) **Renewal** capacity
2) Great **proliferative** and **differentiative** potential
3) **Quiescent** but easily induced into cell cycle
4) Capable of giving rise to **variety** of nonhematopoietic cells when microenvironment is altered
173
3 types of stem cell transplant
1) **Autologous** (own cells; just in order to be able to give high dose chemo then replace your bone marrow afterward)
2) **Allogenic** (someone elses; in order to give you a new immune system)
3) **Syngenic** (from identical twin)
174
Indications for stem cell transplantation
1) Restore hematopoiesis after myeloablative chemotherapy to **intensify dose for chemotherapy** responsive tumor (can use autologous tx)
2) **Treat** intrinsic bone marrow disorders (aplastic anemia, some metabolic genetic diseases)
3) **Correction** of immune defect (SCID)
4) Break tolerance to tumor by engraftment of donor immune system with **graft versus tumor attack** of malignancy
5) Break tolerance to **autoimmune** disease
6) Vehicle for **gene therapy**
7) Induce **immune tolerance** to permit solid organ transplantation
175
Conditions that can be treated with stem cell transplant
Leukemia/lymphoma: **AML, ALL, CML, CLL,** JMML, **Hodgkin lymphoma, Non-hodgkin lymphoma**
**Multiple myeloma,** amyloidosis
Marrow failure: **aplastic anemia**, Fanconi anemia
Immune deficiencies: **SCID**, Wiskott-Aldrich
Hemoglobinopathies: **beta-thal major, sickle cell**
Inherited metabolic syndromes: Hurler syndrome, adrenoleukodystrophy
Myelodysplastic syndromes: refractory anemias, CMML, IMF
176
Graft versus tumor effect
**Donor cells attack recipient's tumor**
May be mediated by donor T cells attacking minor histocompatibility antigens (MHAs) on recipient tumor cells
**CML** has good GVT effect but ALL does not
177
Where does graft versus host disease occur?
Acute GVHD in skin, gut, liver
178
Brentuximab Vedotin
AKA Adcetris
Anti **CD30** antibody
Drug used for **Hodgkin lymphoma**
Antibody is **linked to MMAE** which is a potent antitubulin agent
179
Ibritumomab
AKA Zevalin
First **radio-immunotherapy** treatment approved by FDA
**CD20** antibody linked to radionucleotide that emits beta radiation
Approved for relapsed/refractory low grade **follicular** or **transformed B cell non-Hodgkin lymphoma**
180
Genetic changes leading to cancer
Oncogenes
Tumor suppressor genes
DNA hypomethylation
Remember, **multi-step process**
181
Infectious agents in carcinogenesis
HPV
EBV
HTVL1
HIV
Hep B and C
HHV8
H. pyori
182
Therapeutic targets of antineoplastic therapy
Cell differentiation (ex: all-trans retinoic acid or arsenic trioxide in PML)
Cell proliferation (ex: block cell division with antimetabolite, induce dormancy)
Cell death
Vascular proliferation
Unique molecular targets ("rational drug design")
183
Sanctuary site
Chemotherapy from IV does not get to these sites
**CNS, testes, ovary**
184
Terminology of antineoplastic therapy
**Adjuvant**: given when you don't see disease but hope to get rid of it (like consolidation in leukemia)
**Neoadjuvant**: give before definitive resection and radiation (cosmetically don't want to remove huge tumor)
**Salvage**: attempt to alleviate, but probably not saving patient's life?
**Induction**: induce remission--get as low cancer cell count as possible
**Consolidation**: keep giving chemo after induction even if don't see the disease in order to hopefully get rid of it
**Maintenance**: maintain low level of cancer cells
185
Diseases for which chemotherapy is given with curative intent
Gestational trophoblastic disease, testicular cancer, **Hodgkins lymphoma**, **diffuse large B cell lymphoma**, **Burkitt's lymphoma**, **ALL**, **AML**, pediatric tumors (Wilms, neuroblastoma, osteosarcoma), **breast cancer**
186
Diseases for which chemotherapy is given to prolong life or palliate symptoms
Small cell lung cancer, **indolent lymphoma** and **CLL**, metastatic carcinoma, endometrial carcinoma, **Kaposi's sarcoma**, **multiple myeloma**, bladder cancer, **mycosis fungoides**, **hairy cell leukemia**, malignant melanoma
187
DIseases for which chemotherapy is not given
Adenocarcinoma of **stomach**, **pancreas**, **liver**, **bile** **ducts**, **thyroid**
Carcinomas of unknown primary origin
188
Alkylating agents as antineoplastic drugs
Highly reactive compounds with ability to add alkyl groups (carbon chains) to DNA (attack the nitrogen) --\> breaks in DNA molecule or **crosslinks** **DNA** strands --\> interferes with DNA replication
"Nitrogen mustard"
**Cyclophosphamide, ifosfamide**
**Busulfan**
**Nitrosureas**
**Cisplatin, carboplatin**
Toxicities: hair loss, nausea, vomiting, mouth ulcers
189
Specific toxicities of some alkylating agents
**Cyclophosphamide**, ifosfamide: **hemorrhagic cystitis**
**Busulfan**: **pulmonary** toxicity (all "B" drugs!)
**Cisplatin**: **ototoxicity, nephrotoxicity**
**Carboplatin**: **myelosuppression**
190
Antineoplastic antibiotics
Derived from soil fungus Streptomyces
Mechanisms: **intercalate** DNA to uncoil helix, form **free** **radicals**, **chelate** important metal ions, **inhibit** **topoisomerase** --\> all decrease DNA replication/cell division
**Dactinomycin**
**Doxorubicin, daunorubicin**
**Bleomycin**
**Etoposide, teniposide**
**Idarubicin**, mitoxatrone, mitomycin C
Toxicities: cardiotoxicity, alopecia, myelosuppression, pulmonary (for B drugs)
191
Microtubule inhibitors
Vinca alkaloids: **vincristine, vinblastine**
Taxanes (from Yew tree): **paclitaxel (Taxol), docetaxel** **(Taxotere)**
192
Specific toxicities of microtubule inhibitors
**Vincristine**: **neurotoxicity** (areflexia, peripheral neuritis (because neurons are longest MTs in the body!)), paralytic ileus
**Vinblastine**: **bone marrow suppression** (blasts bone marrow)
193
Specific toxicities of epipodophyllotoxins
Remember, these are topoisomerase II inhibitors (**etoposide**, **teniposide**)
**Myelosuppression**, GI irritation, alopecia
Can induce acute lymphoblastic leukemia (**ALL**)!
194
Camptothecins
Inhibit topoisomerase
**Topotecan, irinotecan**
Toxicities: myelosuppression, cholergic
195
Antimetabolites as antineoplastic drugs
**Structural analogues** of normal metabolites that are required for cell function and replication
Interact with cellular enzymes:
1) **Substitution** for a normal metabolite in key molecule making molecule **function abnormally**
2) Competition for **active** site to occupy/block active site of key enzyme
3) Competition at **allosteric** stie to alter catelytic rate of a key enzyme
Examples: methotrexate, 5-FU, 6-MP, 6-TG, ara-C
196
Methotrexate (MTX)
Folic acid analog that **inhibits dihydrofolate reductase** to decrease dTMP and DNA and protein synthesis
Rescue molecule leucovorin (analog of fully reduced folate) is absorbed by all cells except cancer cells (yay!)
Toxicities: myelosuppression (reversible with leucovorin rescue), fatty liger, mucositis, teratogenic, pulmonary
197
5-fluorouracil
Pyrimidine analog bioactivated to 5F-dUMP which **inhibits thymidylate synthetase** to decrease dTMP, DNA and protein synthesis
Uses: colon cancer
Toxicities: myelosuppression (rescue with thymidine), photosensitivity, GI and mucosal, hand-foot syndrome
Related drugs: FUDR, capecitabine
Note: can be used synergystically with MTX
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Other antimetabolites
Gemcitabine
**Cytarabine**: pyrimidine antagonist to inhibit DNA; used for AML, ALL, non-Hodgkin lymphoma
**6 mercaptopurine**: purine (adenine) analog used for leukemia and lymphoma (not CLL or Hodgkin)
**6 thioguanine**: purine (guanine) analog used for ALL
Allopurinol: xanthine oxidase inhibitor for gout (not anticancer!)
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Purine nucleoside analogues that operate on ribonucleotide reductase and adenosine deaminase
**Fludarabine**: inhibits ribonucleotide reductase and DNA polymerase alpha
**Pentostatin**: inhibits adenosine deaminase
**Cladribine**: causes DNA strand breaks and apoptosis
Potent marrow suppressants and immunosuppressants
200
Hormonal agents for antineoplastic agents
Appear to function by interacting and binding to specific receptors on cell membrane, in cytoplasm on in nucleus of target cell --\> structural rearrangement --\> bind to DNA --\> **not fully understood**, but involve **receptor** transformation/activation, altering **autocrine**/**paracrine** survival mechanisms of cancer cells
Ex: tamoxifen, megestrol acetate, prednisone, dexamethasone, leuprolide and goserelin, arimidex, octreotide acetate
201
Tamoxifen
Multiple mechanisms of action
Liver biotransformation
SERM (**selective estrogen receptor modulator**): antagonist in breast and agonist in bone
Favorable side effect: prevent osteoporosis, prevent breast cancer?
Toxicity: may increase the risk of endometrial cancer, hot flashes
202
Corticosteroids
Complex mechanisms of intracellular activities
**Lymphocytolytic**
Potently immunosuppressive (duh)
Side effects: glucose intolerance (hyperglycemia), osteoporosis, opportunistic infection, fluid retention, fat redistribution, psychiatric
203
Antiandrogens
Direct: flutamide, bicalutamide
Indirect: LHRH/GnRH agonists (leuprolide, goserelin)
204
Aromatase inhibitors
Aminoglutethimide
Arimidex
205
All-trans retinoic acid
AKA Tretinoin, **ATRA**
Used to treat acute promyelocytic leukemia (**APL**; t(15;17) creates PML-RARalpha transgene and chimeric protein)
ATRA binds RARalpha and **degrades this abnormal receptor**, which induces **differentiation of myeloblasts to neutrophils**
May cause differentiation syndrome (huge increase in neutrophils)
High likelihood of long-term leukemia-free survival with this
206
Imatinib (Gleevec)
**Tyrosine kinase inhibitor** that acts specifically on the Philadelphia chromosome bcr-abl tyrosine kinase that is constitutively active
Used to treat **CML** (obvi)
207
EGFR inhibitors
Small molecular inhibitors: **gefitinib** and **erlotinib** in lung cancer
Monoclonal antibodies: **cetuximab** and **panitumumab** in colon cancer
ErbB2 (Her2neu) inhibitors: **trastuzumab** and **lapatinib**
208
Conjugated antibodies
**Radioimmunoconjugates**: tositumomab and Iodine I 131 Tositumomab; Ibritumomab tiuxetan
