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Block 6: Microbio, ID, Derm, Heme-Onc > Myeloproliferative disorders, multiple myeloma, leukemia, lymphoma (Week 8) > Flashcards

Myeloproliferative disorders, multiple myeloma, leukemia, lymphoma (Week 8) Flashcards

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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

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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)

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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

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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

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5
Q

Clonal disorders of hematopoiesis

A

Acquired

Expansion of pluripotent hematopoietic stem cell

Abnormal production of mature blood cells

Predisposition to leukemia transformation

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6
Q

Myeloproliferative syndromes

A

Includes 4 myeloproliferative disorders plus more

CML

PV

ET

Myelofibrosis

Chronic monocytic leukemia

Chronic neutrophilic leukemia

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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

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8
Q

Atypical myeloproliferative diseases

A

Not the main 4!

Chronic neutrophilic leukemia

Chronic eosinophilic leukemia and hypereosinophilic syndrome

Systemic mastocytosis

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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

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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

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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…

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12
Q

Three phases of CML

A

1) Chronic phase
2) Accelerated phase
3) Blast crisis

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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 (?)

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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

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15
Q

Therapeutic milestones in management of CML

A

Hematologic remission

Cytogenetic remission

Molecular remission

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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

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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

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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

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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

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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

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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

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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

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23
Q

Other myeloproliferative diseases

A

Chronic idiopathic myelofibrosis

Hypereosinophilic syndrome

Chronic eosinophilic leukemia

Mastocytosis (cutaneous, systemic, or aggressive systemic)

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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

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25
Q

Mastocytosis

A

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

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26
Q

Acute myelogenous (non-lymphocytic) leukemia

A

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

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27
Q

Possible causes of acute leukemias

A

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

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28
Q

Symptoms of acute leukemias

A

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

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29
Q

Histology and cytochemistry to use for AML

A

Use to distinguish different types of AML (from ALL too):

Wright’s stain

Peroxidase

Sudan Black B

Periodic acid (Schiff)

Esterases

Muramidase

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30
Q

Different types of AML

A

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

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31
Q

Acute promyelocytic leukemia

A

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)

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32
Q

Chemotherapy stages

A

Induction: remission is induced by cytotoxic chemotherapy (this is hard for patient!)

Consolidation: sustains remission

Maintenance

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33
Q

Prognostic factors for remission and/or survival

A

Age

Prior radiation or chemotherapy

Karyotypic abnormalities, especially chromosomes 5 and 7

History of preleukemia

Gender

Leukocyte count at presentation

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34
Q

Acute lymphoblastic leukemia

A

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 survival; corticosteroids and vinca alkaloids, anthracycline antibiotics, L-asparaginase, CNS prophylaxis, cyclophosphamide

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35
Q

Distinct subtypes of ALL

A

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)

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36
Q

Do ALL and AML to the meninges/CNS?

A

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

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37
Q

Graft vs. leukemia with bone marrow transplant

A

No single population of immune cells identified (CD4, CD6, NK) that does the attacking

Introduction of autologous graft vs. leukemia (interferons, interleukins)

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38
Q

Why do people with leukemia get back pain?

A

Back pain is bone pain and this is because expansion of marrow pushes on periosteum which is innervated and creates pain

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39
Q

Where can you get lymphomas?

A

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)

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40
Q

What does a benign, reactive lymph node look like?

A

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

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41
Q

Normal parts of a lymph node

A

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

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42
Q

B cell markers

A

CD19

CD20

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43
Q

T cell markers

A

CD3

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44
Q

What are most common lymphomas derived from?

A

B cells which have passed through germinal centers of lymph nodes or spleed, where immunoglobulin genes complete diversification

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45
Q

Hodgkin’s Lymphoma

A

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

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46
Q

Reed-Sternberg cell

A

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

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47
Q

Subtypes of Hodgkin lymphoma

A

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]

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48
Q

Nodular sclerosis Hodgkin lymphoma

A

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

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49
Q

Lymphocyte rich (predominant) Hodgkin lymphoma

A

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

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50
Q

Mixed cellularity Hodgkin lymphoma

A

10%

More abundant RS cells and lymphocytes, epithelioid histiocytes, eosinophils and plasma cells

Intermediate prognosis

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51
Q

Lymphocyte depletion Hodgkin lymphoma

A

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

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52
Q

Nodular lymphocyte predominant Hodgkin lymphoma

A

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!)

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53
Q

Clinical presentation of Hodgkin lymphoma

A

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

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54
Q

DDx of painless lymphadenopathy

A

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

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55
Q

Diagnosing Hodgkin lymphoma

A

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

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56
Q

Ann Arbor Staging System for Hodgkin and Non-Hodgkin lymphoma

A

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

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57
Q

Bad prognostic factors affecting outcomes in Hodgkin lymphoma (international prognostic score; IPS)

A

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)

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58
Q

How does Hodgkin lymphoma cause its effects?

A

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

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59
Q

What does blocking PD1 do?

A

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

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60
Q

Treatment for Hodgkin lymphoma

A

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%

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61
Q

ABVD chemotherapy

A

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

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62
Q

What is the overall cure rate for Hodgkin lymphoma?

A

85% of everyone

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63
Q

What’s the problem with treating Hodgkin lymphoma too aggressively?

A

Too much radiation causes secondary malignancy (leukemia, lung cancer, breast cancer)

We want to give just enough treatment to cure

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64
Q

Non-Hodgkin lymphomas

A

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)

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65
Q

Ways that Non-Hodgkin lymphomas are classified and named

A

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

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66
Q

Why do we get non-Hodgkin lymphoma?

A

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

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67
Q

Proto-oncogenes activated by faulty translocations causing non-Hodgkins lymphoma

A

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

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68
Q

Mutations involved in Burkitt’s lymphoma

A

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

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69
Q

Clinical features of non-Hodgkins lymphoma

A

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

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70
Q

Prognosis/outcomes in aggressive vs. indolent non-Hodgkin lymphoma

A

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

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71
Q

International prognostic index (IPI) for DLBCL non-Hodgkins lymphoma

A

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

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72
Q

Diffuse large B cell lymphoma

A

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

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73
Q

Gene expression profiling for Diffuse Large B cell Lymphoma

A

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)

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74
Q

Follicular lymphoma

A

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

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75
Q

Follicular lymphoma International Prognostic Index (FLIPI)

A

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

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76
Q

Marginal zone lymphoma

A

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

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77
Q

Small lymphocytic lymphoma

A

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)

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78
Q

Mantle cell lymphoma

A

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

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79
Q

Burkitt’s lymphoma

A

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%

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80
Q

T cell lymphomas (includes NK cell cases)

A

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)

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81
Q

Mycosis fungoides/Sezary syndrome

A

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)

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82
Q

CHOP treatment for non-Hodgkin lymphoma

A

Cyclophosphamide (DNA alkylating agent)

Doxorubicin (Hydroxydaunomycin; DNA strand breaks)

Vincristine (Oncovin; disrupts microtubules and mitosis)

Prednisone (corticosteroid; pro-apoptotic to lymphocytes)

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83
Q

How have we changed CHOP treatment in the past few decades?

A

We added anti-CD20 Rituximab to CHOP therapy

Made treatment much better

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84
Q

What is the idea behind using drug combinations for treatment?

A

Agents with different mechanisms of action but non-overlapping toxicities

CHOP is an example

85
Q

Rituximab (Rituxan)

A

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
Q

R-CHOP

A

Rituximab plus CHOP

Standard therapy for non-Hodgkin lymphoma

87
Q

Other than lymphoma, what can rituximab be used for?

A

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
Q

Most important in vivo mechanism we have against lymphomas

A

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
Q

Treatment for non-Hodgkin lymphomas

A

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
Q

Autologous stem cell transplantation

A

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
Q

What are new drugs for non-Hodgkin lymphoma targeting?

A

Tyrosine kinases that are active in cancerous B cells

CAL-101 is a new drug that inhibits PI3 kinase delta

92
Q

Summary of therapies for aggressive vs. indolent B cell non-Hodgkin lymphomas

A

Aggressive: rituximab+CHOP, stem cell transplant, investigational

Indolent: rituximab alone, rituximab+bendamustine, soon PI3 kinase delta/Btk inhibitors

93
Q

Multiple Myeloma

A

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
Q

Criteria for diagnosis of MM

A

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
Q

Lab findings in multiple myeloma

A

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
Q

Different types of multiple myeloma

A

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
Q

Plasmacytoma

A

Isolated collection of plasma cells, plasma cell tumor

(NOT multiple myeloma)

98
Q

Plasma cell leukemia

A

Neoplastic plasma cells in the blood

99
Q

M protein

A

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
Q

Serum protein electrophoresis

A

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
Q

Clinical findings in multiple myeloma

A

Pathologic fractures

Pancytopenias

Increased infection

Renal failure

Hyperviscosity

102
Q

Why do you get more infections with multiple myeloma?

A

Lack of effective antibodies (only 1 kind made!)

Decreased opsonization

Neutropenia from marrow myeloma

Chemotherapy (steroids, neutropenia)

103
Q

Why do you get renal failure in multiple myeloma?

A

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
Q

Therapies for multiple myeloma

A

Bisphosphonates

Immunomodulatory drugs (thalidomide, lenalidomide)

Proteosome inhibitors

Others (HSP90 inhibitors, histone deacetylase inhibitors, anti-IL6 monoclonal antibodies)

105
Q

Waldenstroms Macroglobulinemia

A

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
Q

Top 5 cancer types in men and women

A

Men: prostate, lung/bronchus, colon/rectum, urinary bladder, melanoma of skin

Females: breast, lung/bronchus, colon/rectum, uterine corpus, thyroid

107
Q

Top 5 types of cancer killers in men and women

A

Men: lung/bronchus, prostate, colon/rectum, pancreas, liver/intrahepatic bile duct

Women: lung/bronchus, breast, colon/rectum, pancreas, ovary

108
Q

Which cancers do we screen for?

A

Established: colon, breast, cervical

Controversial, but supported by ACS: prostate

Not established: lung, ovarian

109
Q

Screening for breast cancer

A

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
Q

Why shouldn’t younger women get mammograms?

A

Because younger women have dense breast tissue because of estrogen

Dense breast tissue can look like tumor on mammogram so get false positives

111
Q

MRI for breast cancer screening

A

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
Q

Screening for colon cancer

A

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
Q

Screening for cervical cancer

A

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
Q

Prostate cancer screening

A

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
Q

Do most people with cancer have a family history?

A

No, only 5-10% of cancers are familial

116
Q

Familial cancers

A

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
Q

Environmental/industrial carcinogens

A

Arsenic: lung/skin

Asbestos: pleura, peritoneum, lung

Benzene: lymphoid tissue

Aminobiphenyl: bladder

Cadmium, Beryllium: lung

Hairdyes: bladder

Formaldehyde: nose/nasopharynx

Vinyl chloride: liver

118
Q

Carcinogenic medical agents

A

Estrogens: endometrial/breast

Anabolic steroids: liver

Tamoxifen: endometrium

Melphalan: lymphoid tissue

Busulphan: bone marrow

119
Q

Viruses associated with cancer

A

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
Q

Lifestyle factors that are carcinogens

A

Tobacco: lung, bladder, esophagus, mouth, larynx

Betel nut: oral cavity

Alcohol: esophagus, orla, pharynx, liver

UV radiation: melanoma, other skin cancer

121
Q

Cancer staging

A

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
Q

Tumor types not staged by TNM

A

Pediatric

Leukemia/lymphoma

CNS tumors

123
Q

Factors that are important in treatment and prognosis other than stage

A

Grade and type of tumor

Presence of biomarkers, gene mutations, amplifications, deletions

Age of patient, other medical conditions

124
Q

Clinical stage vs. pathologic stage

A

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
Q

Treatment approaches

A

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
Q

Judging response to therapy

A

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
Q

Oncologic emergencies

A

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
Q

Spinal cord compression

A

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
Q

New cancer drugs developed once we knew more about molecular underpinnings of cancer

A

ATRA: acute M3 leukemia (APL)

Gleevec: CML

Rituximab: non-Hodgkin lymphoma

Trastuzumab: Her2/neu + breast cancer

130
Q

HER2 breast cancer

A

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
Q

Trastuzumab (Herceptin)

A

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
Q

T-DM1 therapy for HER2 breast cancer

A

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
Q

Things to think about if you see a solitary “spot” or “bump”

A

Melanoma

Basal Cell Carcinoma (BCC)

Squamous Cell Carcinoma (SCC)

Actinic Keratosis (AK)

134
Q

Benign growths

A

Ephilides (freckles)

Lintigines

Nevi

Seborrheic keratoses

Acrochordons

Cherry angiomas

Dermatofibromas

Sebaceous hyperplasia

Keloids

Epidermal inclusion cysts

Milia

Lipomas

135
Q

Actinic keratosis (AK)

A

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
Q

Basal cell carcinoma (BCC)

A

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
Q

Different types of BCC

A

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
Q

Squamous cell carcinoma (SCC)

A

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
Q

Types of SCC

A

SCC in-situ: Bowen’s disease, Erythroplasia of Queyrat

Keratoacanthoma

Verrucous carcinoma

140
Q

High risk SCC tumors

A

Size >2cm

Recurrent

On ears, scalp, temple, lip

Histologic features: perineural invasion, poorly differentiated, increased depth of invasion

141
Q

Melanocyte

A

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
Q

Diseases of defective melanocyte migration

A

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
Q

Oculocutaneous albinism

A

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
Q

Vitiligo

A

Just a cosmetic problem

Acquired loss of melanocytes

Irregular patches of decreased pigment

145
Q

Benign pigmented lesions

A

Flat lesions: ephelides (freckles), lentigines, cafe au lait macules, some nevi

Raised lesions: melanocytic nevi, congenital nevi, dysplastic nevi

146
Q

Ephelides

A

Freckles

Normal number of melanocytes, increased melanin

147
Q

Lentigo (lentigines)

A

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
Q

Cafe au lait macules

A

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
Q

Melanocytic nevus (“mole”)

A

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
Q

Congenital nevus

A

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
Q

ABCDE of melanoma

A

Asymmetry

Border

Color

Diameter

Evolution

152
Q

Dysplastic nevus

A

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
Q

Risk factors for melanoma

A

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
Q

Xeroderma pigmentosum

A

Autosomal recessive

Defective DNA repair

Numerous skin cancers at a young age

155
Q

Genes involved in development of melanoma

A

BRAF mutations (80% of melanomas have activating mutation)

CDKN2A mutation (involved in regulating cell cycle; mutations can be familial)

156
Q

Types of melanoma

A

Lentigo maligna and other melanomas in situ

Lentigo maligna melanoma

Superficial spreading melanoma

Nodular melanoma

Acral lentiginous melanoma

157
Q

Lentigo maligna (a type of melanoma in situ)

A

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
Q

Lentigo maligna melanoma

A

5-15% of melanomas

Elderly patients with sun damaged skin

Identical to lentigo maligna but possesses vertical growth phase

159
Q

Superficial spreading melanoma

A

Most common type of melanoma (60-70%)

Most frequently found on back in men and on legs in women

Fulfills ABCDEs

160
Q

Nodular melanoma

A

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
Q

Acral lentiginous melanoma

A

Rarest type of melanoma (5-10%) but common in dark skinned patients

45% of melanomas in Asians

Occurs on palms and soles

162
Q

Subungual melanoma

A

Variant of acral lentiginous melanoma

Can present as hyperpigmented streak on nail plate (longitudinal melanonychia)

Hutchinson’s sign: pigmentation of proximal nail fold

163
Q

Amelanotic melanoma

A

Melanoma that stopped making melanin

Dangerous!

164
Q

What determines prognosis of melanoma?

A

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
Q

What do metastases tell you about prognosis?

A

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
Q

Management of melanoma

A

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
Q

New treatments for melanoma

A

Ipilumimab: anti-CTLA4 antibody

Vemurafenib: B-RAF inhibitor

TLR agonists like imiquimod for lentigo maligna and cancer vaccines are experimental/off-label

168
Q

Seborrheic keratoses

A

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
Q

Dermatofibroma

A

Common scar-like firm papules, mostly fibroblasts, often on limbs

170
Q

Skin tag

A

Acrochodon

171
Q

Two very common subcutaneous nodules

A

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
Q

Defining characteristics of marrow stem cell

A

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
Q

3 types of stem cell transplant

A

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
Q

Indications for stem cell transplantation

A

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
Q

Conditions that can be treated with stem cell transplant

A

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
Q

Graft versus tumor effect

A

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
Q

Where does graft versus host disease occur?

A

Acute GVHD in skin, gut, liver

178
Q

Brentuximab Vedotin

A

AKA Adcetris

Anti CD30 antibody

Drug used for Hodgkin lymphoma

Antibody is linked to MMAE which is a potent antitubulin agent

179
Q

Ibritumomab

A

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
Q

Genetic changes leading to cancer

A

Oncogenes

Tumor suppressor genes

DNA hypomethylation

Remember, multi-step process

181
Q

Infectious agents in carcinogenesis

A

HPV

EBV

HTVL1

HIV

Hep B and C

HHV8

H. pyori

182
Q

Therapeutic targets of antineoplastic therapy

A

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
Q

Sanctuary site

A

Chemotherapy from IV does not get to these sites

CNS, testes, ovary

184
Q

Terminology of antineoplastic therapy

A

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
Q

Diseases for which chemotherapy is given with curative intent

A

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
Q

Diseases for which chemotherapy is given to prolong life or palliate symptoms

A

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
Q

DIseases for which chemotherapy is not given

A

Adenocarcinoma of stomach, pancreas, liver, bile ducts, thyroid

Carcinomas of unknown primary origin

188
Q

Alkylating agents as antineoplastic drugs

A

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
Q

Specific toxicities of some alkylating agents

A

Cyclophosphamide, ifosfamide: hemorrhagic cystitis

Busulfan: pulmonary toxicity (all “B” drugs!)

Cisplatin: ototoxicity, nephrotoxicity

Carboplatin: myelosuppression

190
Q

Antineoplastic antibiotics

A

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
Q

Microtubule inhibitors

A

Vinca alkaloids: vincristine, vinblastine

Taxanes (from Yew tree): paclitaxel (Taxol), docetaxel (Taxotere)

192
Q

Specific toxicities of microtubule inhibitors

A

Vincristine: neurotoxicity (areflexia, peripheral neuritis (because neurons are longest MTs in the body!)), paralytic ileus

Vinblastine: bone marrow suppression (blasts bone marrow)

193
Q

Specific toxicities of epipodophyllotoxins

A

Remember, these are topoisomerase II inhibitors (etoposide, teniposide)

Myelosuppression, GI irritation, alopecia

Can induce acute lymphoblastic leukemia (ALL)!

194
Q

Camptothecins

A

Inhibit topoisomerase

Topotecan, irinotecan

Toxicities: myelosuppression, cholergic

195
Q

Antimetabolites as antineoplastic drugs

A

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
Q

Methotrexate (MTX)

A

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
Q

5-fluorouracil

A

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

198
Q

Other antimetabolites

A

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!)

199
Q

Purine nucleoside analogues that operate on ribonucleotide reductase and adenosine deaminase

A

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
Q

Hormonal agents for antineoplastic agents

A

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
Q

Tamoxifen

A

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
Q

Corticosteroids

A

Complex mechanisms of intracellular activities

Lymphocytolytic

Potently immunosuppressive (duh)

Side effects: glucose intolerance (hyperglycemia), osteoporosis, opportunistic infection, fluid retention, fat redistribution, psychiatric

203
Q

Antiandrogens

A

Direct: flutamide, bicalutamide

Indirect: LHRH/GnRH agonists (leuprolide, goserelin)

204
Q

Aromatase inhibitors

A

Aminoglutethimide

Arimidex

205
Q

All-trans retinoic acid

A

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
Q

Imatinib (Gleevec)

A

Tyrosine kinase inhibitor that acts specifically on the Philadelphia chromosome bcr-abl tyrosine kinase that is constitutively active

Used to treat CML (obvi)

207
Q

EGFR inhibitors

A

Small molecular inhibitors: gefitinib and erlotinib in lung cancer

Monoclonal antibodies: cetuximab and panitumumab in colon cancer

ErbB2 (Her2neu) inhibitors: trastuzumab and lapatinib

208
Q

Conjugated antibodies

A

Radioimmunoconjugates: tositumomab and Iodine I 131 Tositumomab; Ibritumomab tiuxetan

Block 6: Microbio, ID, Derm, Heme-Onc (10 decks)

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