8/17- Lymphoproliferative Disorders I: CLL, SLL, Follicular Lymphomas, Malt, Mantle Flashcards Preview

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Flashcards in 8/17- Lymphoproliferative Disorders I: CLL, SLL, Follicular Lymphomas, Malt, Mantle Deck (58)
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1

What are lymphoproliferative disorders (LPDs)?

- Malignant neoplasms of lymphoid cells

(Distinct types of LPDs reflect different lymphocytic developmental stages)

2

Distinct types of LPDs reflect different lymphocytic developmental stages; what stages are involved in the following LPDs? (Not important)

- Lymphoblastic lymphoma

- ALL

- B cell NHL

- CLL

- Lymphoplasmacytic lymphoma

- Myeloma

- Lymphoblastic lymphoma: stem cell, pre-pre B cell, Pre-B cell

- ALL: stem cell, pre-pre B cell, Pre-B cell

- B cell NHL: immature B cell, mature B cell, activated B cell

- CLL: immature B cell, mature B cell, activated B cell

- Lymphoplasmacytic lymphoma: plasma cell

- Myeloma: plasma cell

Alternatively:

Stem cell, pre-pre B cell, Pre-B cell:

- Lymphoblastic lymphoma

- ALL

Immature B cell, mature B cell, activated B cell:

- B-cell NHL

- CLL

Plasma cell:

- Lymphoplasmacytic lymphoma

- Myeloma 

3

LPD encompasses what broad categories (mostly dependent on presentation rather than cell types involved)?

- Leukemia

- Lymphoma

- (multiple) Myeloma

4

What are some common manifestations of LPD (excluding plasma cell disorders)?

- Lymphadenopathy

- B Symptoms (fever, night sweats, weight loss)

(- Constitutional symptoms)

- Liver and spleen enlargement

- Extranodal tumors

- Cytopenias

5

Describe lymphadenopathy as seen in LPDs.

- Minimal to massive

- Usually nontender, rounded, discrete, and freely mobile: "rubbery" (can be tender if growth is fast, i.e. acute leukemia)

- Can -> obstruction or mass effect, esp if growth is fast

6

Describe B Symptoms as seen in LPDs.

Fever

- Temp > 38'C or 100.4'F

Drenching sweats

- Especially at night

Unintentional weight loss

- More than 10% of usual body weight over last 6 mo

(Name derives from original Ann Arbor lymphoma staging system for Hodgkin lymphoma)

7

What are some constitutional symptoms of LPDs?

Non-B but "constitutional" symptoms:

- Anorexia

- Fatigue

- Pruritus

8

Describe Liver and Spleen Enlargement as seen in LPDs.

Diffuse enlargement seen more often with slow-growing LPD; focal lesions more common with fast-growing LPD

Splenomegaly

- May cause early satiety or abdominal discomfort

- Can lead to hypersplenismpancytopenia

Hepatomegaly

- Usually not associated with liver dysfunction in slow-growing LPD

- Can be associated in fast-growing LPD

9

Describe extranodal tumors as seen in LPDs.

Rarer than nodal disease

- More common with certain types of LPD

Can occur anywhere lymphoid tissue exists (GIT, skin...) and even where it usually does not (CNS)

Symptoms due to mass effect or wall erosion

10

Describe cytopenias as seen in LPDs.

Inflammatory state:

- Anemia of inflammation

Bone marrow infiltration:

- Most frequent with advanced disease

- Causes pancytopenia: anemia, thrombocytopenia, neutropenia

Autoimmune phenomena (rare, variable incidence)

- Autoimmune hemolytic anemia (AIHA)

- Immune thromboctyopenic purpura (ITP)

- Pure red cell aplasia (PRA)

11

Broadly, chronic lymphocytic leukemia (CLL) is a ___ LPD

Broadly, chronic lymphocytic leukemia (CLL) is an indolent LPD

12

Overview of CLL. Epdemiological importance?

Neoplasm of small, mature-appearing lymphocytes that slowly accumulate in:

- Blood

- Lymph nodes

- Spleen

- Bone marrow

MOST COMMON type of leukemia in the W world (about 1/3 of all leukemias in the US)

13

Epidemiology of CLL?

MOST COMMON type of leukemia in the W world

- About 1/3 of all leukemias in the US Increasing incidence with age

- 90% of cases occur over the age of 50

- Median age at diagnosis is 65 yo

Males > Females (2:1)

No known environmental or occupational risk factors

Possible genetic factors

- Very low incidence in Asia

- Still low in people of Asian descent who move to the US

14

Genetics of CLL

FISH:

- Deletion in long arm of c. 13 (55%)

- Deletion in long arm of c. 11 (18%)

- Trisomy 12 (16%)

- Deletion in short arm of c. 17 (7%)

So: d13q > d11q > tri12 > d17p

Also:

High levels of Bcl-2 -> resistance to apoptosis

- CLL cells are not very metabolically active, but they still accumulate

15

Diagnosis of CLL

Persistent monoclonal lymphocytosis > 5e9/L

- Absolute lymphocyte count (ALC) generally > 10e9/L and can be > 100e9/L

Peripheral blood is enough (BM exam not required)

Mature small lymphocytes with smudge cells in smear

16

What is this? 

CLL

- Smudge cells! (bottom R): burst upon smear

- Chromatin is relatively condensed

- Very small amounts of cytoplasm

- Markers of B cells shown: CD19, 20, 23, and 5 (even though 5 is T cell marker, it shows up here in CLL)

17

What immune markers are present in CLL?

- CD19

- CD20

- CD23

- CD5! (even through typically T cell marker)

18

Clinical presentation of CLL?

- Asymptomatic lymphocytosis with or without lymphadenopathy (>80%) and splenomegaly (~50%); rarely cause complications

- Recurrent infections due to immune deficiency

- Anemia, thrombocytopenia from advanced disease in marrow OR autoimmune disease!

- B symptoms and other constitutional symptoms (fatigue, anorexia) are rare (10-20%)

19

Staging of CLL?

- By affected organ system/symptoms (Rai)

- By nodal location/general system (Binet) 

20

CLL Management- when to treat?

- Observation is appropriate if patient is asymptomatic

Treatment for CLL is indicated for:

- Progressive disease

- B symptoms

- Cytopenias

If cytopenias are due to autoimmune phenomena, treatment of the autoimmune disease alone (e.g., steroids) may suffice

21

Should elevated WBC be treated in CLL?

Not necessary to treat the elevated white count by itself

- Pts can have very high wight counts (200-800K) without any systemic symptoms or evidence of leukostasis

- This is in contrast to other types of leukemia (like AML)!!

22

CLL Treatment

- Chemotherapy: chlorambucil, bendamustine, cyclophosphamide, fludarabine

- Antibodies: anti-CD20 (rituximab, ofatumumab); anti-CD52 (alemtuzumab)

- Combinations: fludarabine + cyclophosphamide + rituximab (FCR), bendamustine + rituximab

- B-cell receptor signaling inhibitors: BTK* inhibitors (ibrutinib), PI3K* inhibitors (idelalisib)

*BTK: Bruton tyrosine kinase

*PI3K: phosphoinositide 3-kinase

23

Prognosis of CLL?

- Years of life

- Genetic characteristics

Favorable: Stage 0/A

- Isolated del13q - > 10 yrs

- Treatment may not be necessary

Neutral: Stage I-II/B

- Normal tri12

- 5-8 yrs

Unfavorable:

- Del11q, del17p

- III-IV/C

- 2-3 yrs

24

What is Richter Transformation?

Occurs in who/how many?

Dx?

Transition from an indolent leukemia to an aggressive lymphoma

- Rapidly enlarging nodes, B symptoms, rising LDH

Occurs in about 1-10% of all CLL pts

- Can occur at any time during course of CLL

Requires repeat LN biopsy to confirm Dx

25

What are Non-Hodgkin Lymphomas (general definition/characteristics)?

- How common

- How to diagnose

- Malignant neoplasms of lymphocytes (predominantly nodal accumulation)

- Most prevalent hematologic malignancy (8th cancerous COD)

- Pathology (excisional biopsy preferred) is essential for Dx

- Distinct types of lymphomas reflect different lymphocytic developmental stages (including stages of lymphoid follicle maturation)

26

Etiology of NHL

Immunosuppression

- HIV/AIDS

- Iatrogenic (e.g. after organ transplant)

- Congenital immunodeficiencies

DNA repair defects:

- Ataxia telangiectasia

- Xeroderma pigmentosum

Viral

- EBV

- HTLV-1

- HCV

- HHV-8

Chronic inflammation and antigenic stimulation

- H. pylori

- Sjogren's syndrome

- Hashimoto thyroiditis

27

The following viruses typically cause what type of NHLs?

- EBV

- HTLV-1

- HCV

- HHV-8

- EBV: Burkitt lymphoma (and Hodgkin lymphoma)

- HTLV-I: adult T-cell leukemia/lymphoma

- HCV: splenic marginal zone lymphoma

- HHV-8: primary effusion lymphoma

28

The following chronic inflammation and antigenic stimulation situations are associated with what types of NHLs?

- H. pylori

- Sjogren's syndrome

- Hashimoto thyroiditis

- H. pylori: gastric MALT lymphoma

- Sjogren's syndrome: MALT and other lymphomas

- Hashimoto thyroiditis: MALT and other lymphomas

29

Genetics of NHL? Associated with what types of NHLs?

t(14;18)

- IgH promoter and Bcl-2

- 85% of follicular lymphomas and 28% of higher grade NHL

t(11;14)

- IgH promoter and Cyclin D1

- about 100% of mantle cell lymphomas

t(8;14), t(2;8), t(8;22):

- IgH/K/gamma and c-Myc

- about 100% of Burkitt lymphomas

30

Clinical features of NHLs

(Same as for CLL)

- Lymphadenopathy

- Splenomegaly or hepatomegaly

- B symptoms (fever, night sweats, wt loss > 10%)

- Cytopenias (anemia, thrombocytopenia)

- Organ dysfunction

- Rarely: autoimmune phenomena