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102 Cards in this Set

  • Front
  • Back
EBV is present in __% of endemic Burkitt lymphoma and ___% of sporadic and HIV-associated cases
100% endemic
25-40% HIV-related
<30% sporadic BL
The majority of B cell lymphomas related to iatrogenic immunosuppression are associated with ____
Primary effusion lymphoma is associated with what infectious agent?
Lymphoma associated with multicentric Castleman disase is associated with what infectious agent?
HCV is associated with what lymphoma?
lymphoplasmacytic lymphoma associated with type II cryoglobulinemia
Mature, naive B cells (aka ___ B cells) are often CD__+ and circulate in the blood and marrow, and in the lymph nodes they occupy ___ and ___.

Two neoplasms thought to correspond to these mature CD__+ B cells are ___ and ___
1. recirculating B cells
(consistent with the leukemic nature of CLL and MCL)

2. CD5+ mature B cells (sIg+)

3. PRIMARY lymphoid follicles and the mantle zones of SECONDARY lymphoid follicles

4. CLL/SLL (40-50% of cases are of a naive B cells type the others are of a memory B cell type) and most MCL
Once mature naive B cells encounter antigen, they undergo ___ with loss of___ expression; they then enter the FDC meshwork of the primary follicle, which then becomes a ___
blast transformation (centroblasts) with loss of Bcl-2 expression

secondary follicle with germinal center formation
Centroblast and centrocytes express markers of germinal center origin.
1. Bcl-6 (zinc finger transcription factor)

2. CD10
Centroblasts do or do not express sIg?
Many lack sIg!!
Two lymphomas that correspond to centroblastic stage of mature B cell development are __

How do they differ in regards to likely cell of origin?
large B cell lymphoma and Burkitt lymphoma

both are Bcl-6+ and have mutated Ig genes, additionally both correspond to proliferating cells (centroblasts) and are therefore clinically aggressive neoplasms

- Burkitt lymphoma more resembles a less mature stage (follicular B blasts) compared to the centroblast-like LBCL
Centroblasts mature to ___ (aka__) and select ones ultimately re-express ___ and turn off expression of __
1. centrocytes (cleaved follicle center cells)

2. Bcl-2 (select centrocytes are rescued by their higher affinity for antigen secondary to somatic mutation; thanks to lack of Bcl-2 expression in centroblasts, those centrocytes with decreased affinity die by apoptosis)

3. turn-off expression of Bcl-6 and differentiate into memory B cells or plasma cells
Lymphoma that corresponds to the centroblast/centrocyte stage of mature B cell development (predominantly centrocyte) is __
Follicular lymphoma

- clonal centrocytes that fail to undergo apoptosis due to continual expression of Bcl-2 secondary to t(14;18)

- since FL consists predominantly of centrocytes (non-proliferating, resting stage) they tend to be indolent (contrast with DLBCL and Burkitt lymphoma which are proliferative centroblastic cells)
Memory B cells reside in the ___ zone of the follicle
marginal zone (contrast to mantle zone which harbors mature naive B cells)
Memory B cell immunophenotype
IgM__ IgD__
pan B cell markers__
1. sIg+ (IgM+, IgD-) [contrast mature naive B cells (IgM+,IgD+)]

2. express pan-B antigens

3. CD5-, CD10-, Bcl-6-
Plasma cells naturally home to the ___
bone marrow
Memory B cell immunophenotype
IgM__ IgD__
pan B cell markers__
1. sIg+ (IgM+, IgD-) [contrast mature naive B cells (IgM+,IgD+)]

2. express pan-B antigens

3. CD5-, CD10-, Bcl-6-
Plasma cells naturally home to the ___
bone marrow
Plasma cell immunophenotype
CD79a+, CD138+

sIg- (while cIg+) and negative for the pan B antigens (CD20, CD22) but DO exrpress CD19 and CD79a


contrast with neoplastic plasma cells which:
CD20+ CD19- (switched)
Lymphomas that correspond to post-germinal center memory B cells
Marginal zone lymphomas of MALT, splenic, and nodal types

Each retains the natural homing tendency of the likely corresponding cell of origin
Mature B cell lymphomas

t(11;14) MCL
t(14;18) FL
t(8:14) BL
t(11;18) MZL

Place a proto-oncogene under the control of the Ig promoter on chromosome 14q:

Result in over-expression of an anti-apoptosis gene (BCL2 and API2):

Result in over-expression of genes associated with proliferation (CYCLIN D1 and MYC):
In the WHO classification, MATURE B cell neoplasms are categorized into 3 broad categories:
1. predominantly disseminated lymphoma/leukemia (present with bone marrow involvement +/- peripheral blood involvment)
- in general, these are relatively indolent

2. Primary extranodal lymphomas (virtually always present in extranodal sites (extranodal MZL)
-less likely to disseminate, and when they do, it typically is to other extranodal sites and NOT to lymph nodes or bone marrow

3. predominantly nodal lymphomas (present with disseminated disease predominantly involving the lymph nodes, but often also involve extranodal sites and the bone marrow)
- DLBCL and FL make up the majority of these
The most common type of lymphoma worldwide is ___, in the US it is ___

An aggressive subtype of large B cell lymphoma that presents in young adults with a female predominance
primary mediastinal (thymic) large B cell lymphoma
Burkitt lymphoma is a highly ___ tumor of ___-sized, rapidly proliferating B cells, with a translocation involving __
1. aggressive
2. medium
3. t(8;14) c-myc oncogene
The major clinical subtypes of Burkitt lymphoma are
1. endemic
2. sporadic
3. immunodeficiency-related
Tumors with morphologic features intermediate between Burkitt lymphoma and large B cell lymphoma are considered a subtype of __
considered a subtype of BL (atypical Burkitt/Burkitt-like lymphoma)
Differences and similarities in the likely cell of origin for CLL/SLL and MCL
- both come from CD5+ mature B cells

- CLL/SLL: CD5+, CD23+ mature naive B cells from the blood, bone marrow, and/or within PRIMARY lymphoid follicles (prior to antigen exposure)
- NOTE: some CLL resemble memory B cells too!

- MCL: CD5+, CD23- mature B cells that arise from the mantle zone of secondary lymphoid follicles (after antigen exposure)
The cell of origin for large B cell lymphoma could be a __
1. B-immunoblast (prior to maturation to a plasma cell)
2. centroblastic
In general: prognosis and survival for CLL/SLL, FL, and smoldering myeloma
- indolent, incurable
- can watch the patient until they develop symptoms prior to treatment
-median survival 5+ years
MCL combines features of an indolent mature B cell lymphoma with those of an aggressive diesease
indolent and incurable, but also aggressive with a median survival of 3 years
MCL combines features of an indolent mature B cell lymphoma with those of an aggressive diesease
indolent and incurable, but also aggressive with a median survival of 3 years
CLL / SLL is a neoplasm of ___ small, round B lymphocytes (CD__+, CD__+) in the __, ___, and/or ___
1. monomorphic CD5+, CD23+
2. blood, marrow, and/or lymph nodes

(mature,naive B cells)
The small monomorphic round B cells of SLL/CLL are admixed with variable numbers of ___ that form __
1. prolymphocytes
2. pseudofollicles (proliferation centers)
In the US, CLL makes up __% of chronic lymphoid leukemias

Most patients are older than __

50 years old
What is the required PB lymphocyte count for a diagnosis of CLL
There isn't one!

Typically >10 but as long as the morphologic and immunophenotypic findings are present, a dx of CLL can be made with a lower lymphocyte count
CLL by definition involves the ___ and ___, but it often involves ____, ___, and ___, with occassional involvement of other ___
1. blood and marrow (leukemia!)
2. LN, liver, and spleen
3. other extranodal sites: skin, breast, CNS, ocular adnexae
Most CLL patients are clinically ___

some present with: fatigue, AIHA, infections, splenomegaly, hepatomegaly, lymphadenopathy, or extranodal infiltrates
Morphology of CLL in the lymph node
- enlarged nodes
- effacement of architecture with a pseudofollicular pattern of pale areas within a dark sea of monomorphic small cells with clumped chromatin, minimal mitotic activity (clouds in a dark sky) THIS PATTERN IS PATHOGNOMONIC FOR CLL/SLL!

- infltrate oftens spills out into the perinodal tissue

- few or minimal plasma cell component

- occasionally: interfollicular pattern
In CLL, the pseudofollicles (aka___) are made up of ___
1. proliferation centers
2. a continuum of small, medium and large cells including:
- prolymphocytes (medium-sized cells with dispersed chromatin and small nucleoli)
- para-immunoblasts (medium to large cells with dispersed chromatin, but central eosinophilic nucleoli and basophilic cytoplasm)
p.128 WHO
In the LYMPH NODE involved by CLL, the size of pseudofollicles (proliferation centers) and the number of paraimmunoblasts ___ correlate with clinical behvaior
does not!! (contrast with finding prolymphs in the peripheral blood, which does correlate with more aggressive disease)
In the spleen, CLL involves the ___ pulp
red and white pulp (white pulp predominantly)
In cases of CLL with a little more nuclear irregularity than usual, it may resemble ___. CLL is distinguished by __

CLL is distinguished by presence of pseudofollicles and/or prolymphs and para-immunoblasts
In CLL, the peripheral blood shows
- lymphocytosis with smudge or basket cells
In CLL, the % of prolymphocytes in the PB is usually <__%.

Increased numbers of prolymphs in the PB correlates with __, ___, and __
1. <2%

2. more aggressive disease
3. p53 abnormalities
4. trisomy 12
CLL with increased prolymphocytes (CLL/PL) is a variant of CLL characterized by __
>10% but <55% prolymphocytes in the PB at the time of diagnosis

If there is a history of CLL/SLL, then you are dealing with progression or transformation
Patterns of bone marrow involvement by CLL (seen in core biopsy) and correlation with prognosis
1. nodular (paratrabecular aggregates are NOT typical)
2. intersitial
3. diffuse
4. or a combination

early CLL: nodular and interstitial patterns

advanced CLL: diffuse
In CLL, Richter syndrome is characterized by __
Occurs in 3-10% of cases, usually resulting in death within 1 year

Transformation to a DLBCL
- confluent sheets of large cells that are often centroblastic or immunoblast-like
- may be clonally related to CLL or may be a clonally unrelated (new) tumor!


- (rarely) prolymphocytic transformation
Para-immunoblasts versus immunoblasts
Para-immunoblasts refers the the larger cells seen in proliferation centers in CLL / SLL

Immunoblasts are normal antigenically stimulated larger B cells
Do you ever see Reed-Sternberg-like cells in CLL?
Possibly. (RARELY)

- CLL can be assoicated with HL!! In which case you would see scattered RS cells and variants in a background of CLL or may see discrete areas of classical HL

- could just see Reed-Sternberg-like cells in CLL, that are EBV+ while the CLL is EBV-, additionally, the mixed inflammatory background typical of HL is missing
Immunophenotype of CLL/SLL
coexpress: CD5+, CD23+ (usually), and CD43+

B antigens: CD19+, dimCD20+, dimCD22+, CD79a+, and dim sIg (IgM or IgM and IgD)


cycln D1-
FMC7- (typically)
In CLL, CD38+ is associated with __
unmutated Ig variable genes and a worse prognosis
Based on mutational status of Ig VH genes, CLL can be divided into two types
1. 40-50% WITHOUT Ig VH gene somatic mutations - consistent with mature naive B cell

2. 50-60% WITH Ig VH gene somatic mutations, consistent with a POST-germinal center mature memory B cell (more favorable prognosis)
In CLL, the most common cytogenetic abnormalities involve ___
deletions of 13q12-14, 11q, and 17p

trisomy 12q
In CLL, trisomy 12q is associated with __
unmutated IgVH gene (naive B cell type) and a more aggressive clinical course
In CLL, abnormalities of 13q12-14 are assoicated with a ___ survival time
In CLL, indicators of a worse prognosis include:
1. ZAP 70 protein expression
2. CD38+
3. trisomy 12q
4. del(11q22-23) (MLL gene)
5. del(17p)p53 gene mutation or deletion
6. high WBC count >50
7. high % of circulating prolymphs (>10%)
8. Ki-67 index >25%

Note: abnormalities of 13q12-14 are associated with a better prognosis!
In CLL, (del)11q22-23 is associated with extensive ___ and ___ survival
lymphadenopathy and poor survival
In CLL, ZAP 70 protein expression is assciated with __
unmutated IgVH gene
rapid disease progression
poor survival
Difference between SLL and CLL?
predominantly LN, splenic and hepatic involvement with little to no marrow or blood involvement (lacking leukemic phase)

CLL is the opposite
An arbitrary peripheral blood lymphocyte count used to distinguish CLL and SLL
>10 x10^9/L
In advanced stage CLL, there is __ and ___ due to ___
anemia and thrombocytopenia due marrow infiltration
In CLL, hypo- or hyper- gammaglobulinemia is common?

- associated with increased risk of infection
Immune dysregulation associated with CLL increases the risk for ___ and __
autoimmne hemolytic anemia (AIHA) and autoimmune thrombocytopenia
M-spike associated with CLL?
Some patients do have a paraprotein, but it is in low concentration (contrast to that of myeloma and Waldenstroms macroglobulinemia)
The natural clinical progression of CLL
Indolent, but ultimately results in diffuse marrow infiltration with gradual deterioration in general health and secondary immunodeficiency
When is therapy offered to patients with CLL
If symptomatic or there is evidence of disease progression
In CLL with transformation to large B cell lymphoma, marrow involvment is typically ___
seen late in the course, commonly found at autopsy
In the peripheral blood, the conditions most commonly confused with CLL
lymphoplasmacytic lymphoma
small cell variant of T-PLL
In prolymphcytic transformation of CLL, the DDX includes:
- transformed CLL
- de novo T-PLL
- de novo B-PLL

In transformed CLL, the prolymphocytes are typically <55% of the total LYMPHOID population (compared to de novo PLL) and more atypical
How can you distinguish de novo DLBCL and LBCL secondary to transformed CLL
You cannot based on morphology or immunophenotype

Requires history of CLL or coexisting typical CLL at time of diagnosis

Definitive proof of transformation can be provided by gene rearrangement studies
B-PLL is a ___ disease (median age is ___); it is characterized by prolymphocytes comprising __, and PLL must be distinguished from ___
extremely rare (median age 70, older than CLL)

>55% of total lymphocytes are prolymphocytes in the blood (often >90%!)

exluding CLL/PL and transformed CLL
In B-PLL, most patients have marked ___ and a rapidly ___ lymphocyte count in the PB
marked splenomegaly

rapidly rising lymphocyte count (usually >100 x 10^9/L)
A medium-sized lymphocyte is __ the size of a normal lymphocyte
In B-PLL, the lymph nodes show
diffuse or vaguely nodular involvement by similar appearing cells, without proliferation centers as seen in CLL
The morphologic DDX of B-PLL
CLL with increased prolymphs
blastoid MCL
splenic MZL
Immunophenotype of B-PLL
(contrast with CLL)
strong sIg

strong B antigen expression

CD23- (typically)
CD5+ (only 33% cases)

Contrast to CLL with:
dim sIg
coexpress CD5+, CD23+
In B-PLL, sites of involvement include:
Bone marrow

minimal lymphadenopathy or hepatomegaly

(contrast with CLL/SLL which is typically dominanted by a leukemic or lymphomatous presentation)
B-PLL responds to therapy of CLL?

Survival is short
Splenectomy in B-PLL may do what for the patient?
Improve general condition, but does not delay disease progression
In the spleen invovled by B-PLL, the __ pulp is involved
red and white pulp
The DDX for B-PLL
CLL with prolymphocytic transformation

- some transformed CLL cases retain the typical CLL immunophenotype
- others acquire a B-PLL immunophenotype, requiring history for distinction
Lymphoplasmacytic lymphoma (LPL) is a rare neoplasm of B cells with varying degrees of ___ inlcuding ___, ____ and ___
B cells with varying degrees of plasmacytic differentiation including:
small B cells, plasmacytoid lymphs, and plasma cells
LPL usually involves the __,___, and __
PB, BM, and spleen
LPL is a disease of __ people
older (median age 63)
Majority of patients with LPL have a __ in the serum
monoclonal IgM paraprotein (>3gm/dl) - Waldenstroms macroglobulinemia
Waldenstroms macroglobulinemia is or is not specific for LPL
Is not!

Other entities associated with an IgM paraprotein:
- splenic MZL
- rarely extranodal MZL
__ % of patients with LPL exhibit hyperviscosity syndrome

- RBC sludging
- rouleaux
- reduced visual acuity
- risk of stroke
Most cases of LPL are associaed with Waldenstroms macroglobulinemia, the cases that are not, typcially __
produce IgM, but are nonsecretors
The monoclonal IgM of Waldenstroms macroglobulinemia can have __ and __ activity
Deposits of monoclonal IgM associated with Waldenstroms macroglobulinemia can present in ___ and result in __
- in GI tract: diarrhea
- skin
- peripheral nerves: neuropathy
CLL/SLL, paraimmunoblastic variant morphologically could be confused with __

CLL with sheets and/or aggregates of paraimmunoblasts

Worse prognosis
In CLL, the gene involved in (del)11q23 is
ATM gene (mutated in ataxia telangiectasia)
LPL is a diagnosis of ___

rule out other known types of lymphoma
LPL is a disease of the ___ and __
middle aged and elderly
In LPL, the nodal architecture is usually __ and the sinuses are __
effaced by mix of small lymphs, plasmacytoid lymphs, and plasma cells w/ Dutcher bodies

distended with proteinaceous fluid (Ig)
B cell lymphomas that can demonstrate maturation to plasmacytoid lymphs and plasma cell include:
- FL

LPL - is restricted to those without features of the other lymphomas (neoplastic follicles of FL, proliferation centers of CLL, marginal zone or monocytoid B cells of MZL)
PB smear in LPL would show
-WBC count typically lower than that of CLL
-mix of small lymphs, plasma cells, and plasmacytoid lymphs
BM in LPL typically has a ___ and/or ___ pattern of involvement
nodular and/or diffuse interstitial involvement
Immunophenotype of LPL
- cIg+ (usually IgM)
- some sIg+
- express B antigens (CD19+, CD20+, CD79a+)
- usually CD5-. CD10-, CD23-
- nuclear Bcl-10+ (55%)
LPL is an __ disease with a median survival of __

When is treatment offered?
5 years

Treatment offered when symptomatic
In LPL, IgM-related complications (neuropathy, GI, viscosity) can be treated with __
Diseases with prominent splenic involvment include:
- hepatosplenic T cell lymphoma
- Mastocytosis
-B-PLL (often present with splenomegaly!)
- FL