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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What are lymphoproliferative disorders (LPDs)?

- Malignant neoplasms of lymphoid cells

(Distinct types of LPDs reflect different lymphocytic developmental stages)


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

- Lymphoblastic lymphoma


- B cell NHL


- 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


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

- Lymphoblastic lymphoma


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

- B-cell NHL


Plasma cell:

- Lymphoplasmacytic lymphoma

- Myeloma 


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

- Leukemia

- Lymphoma

- (multiple) Myeloma


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


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


Describe B Symptoms as seen in LPDs.


- 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)


What are some constitutional symptoms of LPDs?

Non-B but "constitutional" symptoms:

- Anorexia

- Fatigue

- Pruritus


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


- May cause early satiety or abdominal discomfort

- Can lead to hypersplenismpancytopenia


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

- Can be associated in fast-growing LPD


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


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)


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

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


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)


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


Genetics of CLL


- 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


High levels of Bcl-2 -> resistance to apoptosis

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


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


What is this? 


- 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)


What immune markers are present in CLL?

- CD19

- CD20

- CD23

- CD5! (even through typically T cell marker)


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%)


Staging of CLL?

- By affected organ system/symptoms (Rai)

- By nodal location/general system (Binet) 


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


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)!!


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


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


- Del11q, del17p


- 2-3 yrs


What is Richter Transformation?

Occurs in who/how many?


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


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)


Etiology of NHL



- Iatrogenic (e.g. after organ transplant)

- Congenital immunodeficiencies

DNA repair defects:

- Ataxia telangiectasia

- Xeroderma pigmentosum



- HTLV-1


- HHV-8

Chronic inflammation and antigenic stimulation

- H. pylori

- Sjogren's syndrome

- Hashimoto thyroiditis


The following viruses typically cause what type of NHLs?


- HTLV-1


- 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


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


Genetics of NHL? Associated with what types of NHLs?


- IgH promoter and Bcl-2

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


- 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


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


When in the staging workup for NHL should a LP be done?

- T cell lymphoblastic lymphoma

- Aggressive lymphoma with positive marrow

- AIDS lymphoma (usually aggressive lymphomas)


Staging of NHL?

Same as CLL

- Done by no. of affected LNs




What is the most important split/categorization of NHLs?

Indolent vs. aggressive


Characteristics of Indolent vs. Aggressive/highly aggressive NHL?


- Life expectancy in years, untreated

- 85-90% present in Stage III or IV

- Incurable in advanced stages

- Much more common in older people

Aggressive/Highly aggressive:

- Life expectancy in weeks, untreated

- Potentially curable even in advanced stages

- B symptoms much more frequent


Simplified method of classifying NHLs: B cell and T-cell for:

- Indolent (low grade)

- Aggressive (intermediate grade)

- Highly aggressive (high grade)


Which are more common, B or T cell NHLs?

B cell (85%)


What are the most common types of (tumor? NHL?) in the US?

- Diffuse large B-cell (31%)

- Follicular (22%)

- Small lymphocytic/CLL (6%)

- Mantle cell (6%)

- Peripheral T cell (6%)

- MALT (5%)

- Others (each under 5%)


What are the indolent subtypes of B cell lymphoma?

- Follicular lymphoma

- Small lymphocytic lymphoma

- Marginal zone (MALT) lymphoma


Characteristics of follicular lymphoma?

- How aggressive

- How common

- Rate of growth

- Median survival

- Possible outcomes

- Paradigm of indolent lymphoma

- Most common indolent lymphoma

- Slow growing, but not curable with standard therapy when advanced

- Median survival 8-10 yrs

- About 40% transform to more aggressive form (diffuse large B cell lymphoma)


What is this?

Follicular lymphomas

- Resembles germinal centers of lymphoid particles


What is this?

Small Lymphocytic Lymphoma

- CLL but in the lymph nodes...


What are the main characteristics of MALT lymphomas?

- What does it stand for; other names?

- Arise where? Affect what tissues?

- May be caused/predisposed by what?

- When detected?

- Mucosa-Associated Lymphoid Tissue tumor

- Aka extra-nodal Marginal Zone Lymphoma

- Most MALT lymphomas arise in the stomach

---Associated with gastritis due to Helicobacter pylori (cured in many cases with Abx)

- Any mucosa can by affected: bronchus, salivary glands, eye adnexa, etc…

- Often caught at early stages


Management for indolent NHL?

10-15% in Stage I or II (potentially curable)

Tx: Local radiotherapy

85-90% Stage III or IV (incurable; dz return treated or not and treatment has not been shown to prolong survival)

Tx: observation is appropriate unless there is reason to treat…


What are reasons to treat in advanced indolent lymphomas?

- Constitutional (B) symptoms

- Cytopenias

- Organ dysfunction

- Anatomic obstruction

- Painful/massive lymph nodes

- Cosmetic considerations


Treatment options in advanced indolent lymphomas?

Several options, but 1st line therapy is usually chemoimmunotherapy:

- CD20 antibody (rituximab) combined with

- Cyclophosphamide, Vincristine (Oncovin), Prednisone, Bendamustine

--- R-CVP, R-B, R-CHOP, …

Other possibilities include:

- Immunotherapy alone

- Radioimmunotherapy (131I, 90Y CD20 Ab conjugates)

- Radiation therapy to problematic site of disease

- PI3K inhibitors (idelalisib)


Aggressive subtypes of B-cell lymphoma include what?

- Diffuse Large B-cell lymphoma

- Mantle cell lymphoma


Characteristics of Diffuse Large B-cell lymphoma?

- How common

- Mean age of presentation

- Organs involved

- Sign

- Outcome

- Most common NHL

- Mean age of presentation: 64 (55% male)

- Bone marrow involved infrequently (15%)

- LDH elevated in most cases

- All indolent lymphomas can transform to DLBCL


What is this? 

Diffuse Large B-cell lymphoma


Treatment options for early stage aggressive lymphomas?

~50% in stage I or II

- potentially curable

- disseminates through bloodstream early (hematogenous spread of disease, with no predictable pattern)

- must use systemic chemotherapy (R-CHOP × 6 cycles; R-CHOP × 3 cycles followed by radiotherapy)


Treatment options for advanced stage aggressive lymphomas?

Also potentially curable

- Systemic chemotherapyR-CHOP is usual first line

± Intrathecal chemotherapy (in AIDS patients and CNS involvement)

± Radiotherapy (for Spinal cord compression, bulky disease)


What is the R-CHOP Regimen?

- Rituximab (anti-CD20 monoclonal antibody)

- Cyclophosphamide

- Hydroxydaunorubicin (Adriamycin™)

- Oncovin™ (vincristine)

- Prednisone


What is the international prognostic index (IPI) based on?

- Age > 60

- PS > 1


- Extranodal sites > 1

- Stage III/IV (pic 10)


What is Mantle Cell Lymphoma?

- Pathology

- Curable?

- Hallmark genetics

- Disease occurs where/affects what organs

- Treatment

- Pathology looks indolent, behaves aggressively; thought to be incurable

- Hallmark: t(11;14), cyclin D1 overexpression

- Nodal and extranodal disease (gut, bone marrow, blood, …)

- Regimens with cytarabine seem to be better

- Responds well to BTK inhibitors (ibrutinib)


What are highly aggressive subtypes of B-cell lymphoma?

Burkitt Lymphoma


What is Burkitt Lymphoma?

- Epidemiology

- Linked to what cause

- Growth rate

- Presents how

- Treatment

- African variety: jaw tumor, strongly linked to Epstein-Barr Virus infection (in U.S., about 50% EBV infection)

- May present as abdominal mass

- Most rapidly growing human tumor

- Treated with multidrug regimen similar to pediatric leukemia/lymphoma regimens


What genetic abnormalities are associated with Burkitt Lymphoma?


- t(2;8)

- t(8;14)

- t(8;22)


What is this?

Burkitt Lymphoma