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1

What is lymphadenopathy?

Enlarged lymph nodes

2

What does painful LAD signify?

Acute infection

3

What does painless LAD signify?

Chronic inflammation, metastatic carcinoma, or lymphoma

4

What are the three small cell lymphomas?

(1) Follicular
(2) Mantle
(3) Marginal

5

Follicular lymphoma

Neoplastic small B cells
CD20+
Follicle-like nodules in cortex AND medulla
Mostly adults (~60 years)
Germinal B-cell markers: CD10, BCL6

6

What do follicular lymphoma B-cells have that reactive germinal cell center B-cells (follicular hyperplasia) do not have?

Neoplastic cells have BCL2 (no apoptosis), whereas normal cells do not (want apoptosis)

Reactive have TINGIBLE BODY MACROPHAGES, whereas lymphoma cells do not

Neoplastic follicles are homogenous; reactive follicles have light/dark zones

Follicles through entire lymph node in neoplasia (not just cortex), and no other structures

7

What is the gene translocation in follicular lymphoma?

t(14;18)
Ig heavy chain (IGH) + BCL2

Ig heavy chain is obviously heavily expressed in B cells, so BCL2 (when translocated) becomes over-expressed

8

What does BCL2 do?

Main function: stabilizes mitochondrial membrane. Prohibits Cytochrome C from leaking from mitchondria into cytoplasm --> blocks apoptosis

In the follicle of the lymph node, where there are developing B cells, you want apoptosis!

9

Mantle cell lymphoma

Neoplastic small B cells
CD20+
Mantle zone of lymph node
Mostly adults (~60 years)

10

What is the gene translocation in mantle cell lymphoma?

t(11;14)
Cyclin D1 on Chr 11 translocates to Ig heavy chain locus on Chr 14

Overexpression of cyclin D1 promotes G1/S transition in cell cycle

11

Burkitt Lymphoma

Neoplastic intermediate B cells
CD20+
Associated with EBV
Classically presents as an extranodal mass in child or YA

12

Endemic Burkitt Lymphoma

Malarial belt of Africa
In jaw
4-7 years of age

13

Sporadic Burkitt Lymphoma

Mostly children or YA
Ileocecal area (abdomen)

14

What genetic causes drive Burkitt Lymphoma development?

t(8;14)
Translocations of c-myc on Chr 8

Overexpression of c-myc oncogene promotes cell growth

15

What does Burkitt Lymphoma look like on histology?

Starry skies :)

16

How is Hodgkin Lymphoma different from NHL?

NHL: large mass of malignant cells
Hodgkin: rare neoplastic Reed-Sternberg cells

17

What do Reed-Sternberg cells do and cause?

Secrete cytokines that draw in other inflammatory cells, which then results in production of a mass

Cytokines --> 'B' symptoms (fevers, chills, night sweats) --> also attract lymphocytes, plasma cells, macs, and eos

May lead to fibrosis

18

Describe Reed-Sternberg cells

Large B cell
Multilobed nuclei and prominent nucleoli ("owl eyes")
CD15+ and CD30+

19

Nodular sclerosis HL

Classical presentation: enlarging cervical neck/mediastinal LN in a YA, usually female

Lymph node is divided by broad bands of fibrosis

RS cells sit in big open spaces = lacunar cells

20

Mixed cellularity CHL

More often on or below both sides of the diaphragm

On histology, RS cells + mixed cells in background --> abundant eosinophils (IL-5)

21

Lymphocyte rich CHL

Nodular growth pattern
Classic RS cells very rare
Best prognosis

22

Lymphocyte depleted CHL

Least frequent subtype (~1%)
Paucity of lymphocytes
Numerous RS cells, which appear bizarre
Worst prognosis :(

23

Plasma cell neoplasm

Clonal proliferation of plasma cells
Express one Ig or protein
Mostly bone marrow, but also elsewhere

24

What are two germinal B cell markers?

BCL6 and CD10

25

Plasma cell myeloma (multiple myeloma)

Bone marrow-based
M protein in serum/urine
Clinical features: bone pain in the back or extremities (osteoporosis)
Radiologic features: lytic bone lesions, osteoporosis, fractures

26

What is an M protein?

A monoclonal protein --> a polypeptide subunit of the Ab
Can be detected in urine

27

What is the definition of an acute leukemia?

A neoplastic proliferation of blasts

Defined as an accumulation of >20% blasts in the bone marrow

28

What is the hallmark of a lymphoblast?

(+) for TdT in the nucleus

TdT = DNA polymerase

29

What is the classic hallmark of a myeloblast?

Presence of myeloperoxidase (MPO)

Cytoplasm --> can crystallize into an AUER ROD

30

Describe ALL

Acute lymphoblastic leukemia
+TdT
75% in kids <6 yrs
Associated with Down Syndrome (after the age of 5)

31

Describe (in-depth) the subclassifications of ALL

B-ALL:
80-85% of cases of ALL
Typical ALL of childhood

T-ALL:
Around 25% of cases
More frequently in adolescent and YA
Often presents as a mediastinal mass (thymus region)

32

What markers do B-ALL cells express?

CD19 and CD22

Usually do not express CD20 or surface Ig (mature markers)

33

What are the 3 common cytogenetic abnormalities seen in B-ALL, and what are the age groups associated with them?

t(12;21)
25% of childhood B-ALL
Very favorable prognosis

t(9;22) --> BCR-ABL1
(p190 breakpoint instead of p210 in CML --> Ph+ ALL)
25% of adult ALL (more common in adults)
Worst prognosis

translocation of 11q23 --> MLL
Neonates & young infants
Poor prognosis

34

What are the surface cell markers of T-ALL?

CD3 and CD7

35

What is the full name of T-ALL? And why?

T acute lymphoblastic lymphoma

Lymphoma because the cells are forming a mass ("-oma") in the mediastinum. Leukemia = they're floating around.

36

What are prognostic factors in ALL?

Worse prognosis:
Infant (10 yo)
Very high WBC count
T-lymphoblastic
Hypodiploidy (<46)
Slow response to Rx
Min. residual disease

Better prognosis:
1-10 yo
B-lymphoblastic
Hyperdiploidy (51-65)

37

Describe AML

Acute myeloid leukemia
Elderly (~65)
**AUER RODS (from MPO)**

38

What are the cytogenetic classifications of AML? What are the typical patient ages and prognoses?

t(8;21)
Younger patients
Relatively good prognosis

inv(16) or t(16;16)
Younger patients
Relatively good prognosis

t(15;17) --> PML-RARA
aka acute promyelocytic leukemia (APL)

t(1;22)
Mostly seen in infants with Down Syndrome
Relatively good prognosis

Abnormalities of 11q23 --> MLL
Poor prognosis (similar to cases of ALL with abnormalities of MLL)

39

What is MLL?

Mixed lineage leukemia

40

Why is APL important?

Acute promyelocytic leukemia

Abnormal promyelocytes predominate instead of blasts

Important because:
(1) The gene fusion fuses retinoic acid receptor-alpha (RARA) gene to another gene.
RARA is needed for differentiation of promyelocytes. Fused protein = block in differentiation.

However, block can be overcome with high doses of all-trans retinoic acid (ATRA) + arsenic salts --> give 'em Vitamin A (ATRA), not chemotherapy!

(2) Sometimes --> DIC :(((( (b/c of Auer rods)

41

What is a myelodysplastic syndrome?

Cytopenias with hypercellular bone marrow (basically, pre-leukemia)

Abnormal maturation with increased IMMATURE CELLS (blasts) - but 20% blasts)

42

What are the two main categories of therapy-related AML? What is their prognosis?

Alkylating agents or radiation
2-8 years later
Usually progresses to AML via an MDS stage
Whole or partial losses of Chr 5 and/or 7

Topoisomerase inhibitors
1-2 years later
de novo AML
rearrangement of MLL gene (11q23)

All have very poor prognosis

43

What are 3 molecular markers currently used to predict prognosis in patients with AML? Which one trumps the other two?

****1. FLT3******
Prognosis: POOR

2. Nucleophosmin-1 (NPM1) mutation
Prognosis: GOOD

3. CEBPA mutation
Prognosis: GOOD

(#2 & #3 = as long as #1 is absent)

44

Describe CLL

Chronic lymphocytic leukemia

Neoplastic proliferation of naive B cells

Cells co-express CD5 and CD20
(CD5 normally on T cells)

Negative for CD10 (not germinally-derived)

Smudge cells

45

What is SLL?

Small lymphocytic lymphoma

Occurs when CLL spreads to lymph nodes --> generalized lymphadenopathy

46

What is a myeloproliferative neoplasm?

A neoplastic proliferation of MATURE myeloid cells (megakaryocytes, monocytes, RBCs, and granulocytes)

Causes an increase in errybody. However, named based on predominant cell.

47

What are some complications of MPNs?

(1) Increased risk for hyperuricemia and gout
(2) Progression to marrow fibrosis
(3) Transformation to acute leukemia

48

Describe CML

Chronic myeloid leukemia

Increase in *granulocytes* --> leukocytosis. Markedly hypercellular bone marrow.

BCR-ABL1 gene transfusion! (p210)

Tyrosine-kinase inhibitors (TKIs) (like imatinib) have dramatically improved prognosis = 5-year overall survival rates around 80-85%

49

What are 2 reasons for hepatosplenomegaly frequently seen in MPNs?

(1) Sequestration of extra blood cells
(2) Extramedullary hematopoiesis --> blood cells are made in liver (like they were in fetal stage)

50

Describe polycythemia vera

Neoplastic proliferation of mature myeloid cells, especially RBCs

Associated with JAK2 mutation

Most serious complication are arterial or venous thrombosis

51

Which thromboses should raise the suspicious of PV?

Mesenteric vein, portal vein, or splenic vein

52

What are the phases of PV?

(1) Polycythemic phase
= increased blood counts

(2) Spent phase
= extensive marrow fibrosis with corresponding fall in blood counts

53

What is Budd-Chiari Syndrome?

Thrombosis in/occlusion of the hepatic vein

Classically presents as abdominal pain, ascites, and liver enlargement

(#1 cause of this = PV)

54

Treatment of PV?

Phlebotomy

2nd line: hydroxyurea

55

Essential Thrombocythemia

Persistent thrombocytosis

JAK2 mutations present in 50% of cases

Increased risk of bleeding (if they don't work at all) and/or thrombosis (if there are too many & they all work)

56

What is a sign of essential thrombocythemia on histology?

Clusters of very large megakaryocytes

57

Primary Myelofibrosis (PMF)

Megakaryocytic hyperplasia (and, to lesser extent, granulocytic), but NO RBCs

JAK2 mutations in 50% of cases

Results in marrow fibrosis --> extramedullary hematopoiesis in spleen --> splenomegaly

Leukoerythroblastosis = more immature cells in the blood (both red and white), b/c forced out from spleen

58

What type of cells occur on a smear in myelofibrosis?

Tear drop cells (dacrocytes)

(Small # of RBCs in fibrotic marrow have to squeeze to get out)

59

What type of cytopenia is suspicious for MDS (myelodysplastic syndrome)?

Persistent cytopenia in 2+ lineages in a patient of advanced age

60

What are four possible causes of secondary myelodysplasia that might mimic MDS?

1. Vitamin deficiency (B12, folate, etc.)
2. Toxin exposure (e.g., heavy metals)
3. Exposure to certain drugs
4. Viral infections

61

What are 3 viruses known to have oncogenic effects in some types of lymphomas?

(1) Epstein-Barr virus (EBV): Some cases of classical Hodgkin lymphoma, some cases of Burkitt lymphoma, some other B cell non-Hodgkin lymphomas

(2) Human T cell leukemia virus-1 (HTLV-1): Causative factor in adult T cell leukemia/lymphoma (ATLL)

(3) Kaposi sarcoma herpesvirus/Human herpesvirus-8 (KSV/HHV-8): Primary effusion lymphoma

62

Contrast the incidence of leukemias & lymphomas in children vs. adults

In childhood:
Leukemia is the most common childhood cancer by type.
Lymphoma is the third most common childhood cancer by type.

In adults:
Non-Hodgkin’s lymphoma is 7th most common
Leukemia is 10th most common