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279 Cards in this Set

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Diseases with prominent splenic involvment include:
- SMZL
- HCL
- hepatosplenic T cell lymphoma
- Mastocytosis
Rarely:
- LPL
- FL
Splenic MZL is an ___ low grade B cell lymphoma with primary presentation in the __
uncommon

spleen
SMZL is characterized by neoplastic small lymphocytes that surround and ___ the splenic white pulp germinal centers. These neoplastic small lymphs efface the ___ and merge with __
- surround and replace the splenic white pulp germinal centers
- efface the follicle mantle zone and merge with a peripheral marginal zone of larger cells (marginal zone-like cells - not true marginal zone)
SMZL often involves (sites of involvement):
spleen
splenic hilar lymph nodes (not peripheral lymph nodes)
bone marrow
blood (villous lymphocytes)
Virtually all patients with circulating villous lymphocytes have __, while not all patients with ___ have circulating villous lymphocytes
SMZL
Most patients with SMZL are ___(age)
over 50 (median age 68)
older adults
Pateints with SMZL present with __ without ___
splenomegaly without peripheral lymphadenopathy

spleen is large (often >1kg)
The clinical course of SMZL is ___ with a 5 year survival of __. Median time to progression is __
indolent

65-78%

5 years
Treatment of choice of SMZL is __
Splenectomy
In SMZL, gross cut surface of the spleen shows __
miliary small nodules
In SMZL, the splenic white pulp shows __
- nodular expansion with an APPARENT marginal zone pattern
- nodules may coalesce
- BIPHASIC PATTERN: small lymphs replace the white pulp germinal centers (may see residual GC centrally) with a rim of medium-sized cells, with more dispersed chromatin and abundant pale cytoplasm resembling normal marginal zone cells

- occasional transformed large cells in the peripheral rim
In SMZL, the splenic red pulp shows__
- prominent infiltration by small lymphs with micronodular aggregates of medium-sized cells

- red pulp is always involved
Less common findings in a spleen involved by SMZL include ___ and __
- plasmacytic differenitation
- epithelioid granulomas
Splenic hilar lymph nodes involved by SMZL show __
- stiking nodular pattern with dilated sinuses (WHO p136)
- as in the spleen, the nodules are formed on pre-exising lymphoid follicles, may see residual GC's
- HOWEVER, in the LN: the small lymphs replace the follicules with few interspersed transformed cells, BUT, no distinct marginal zone pattern is seen
Bone marrow involvment by SMZL shows a __ pattern
interstitial nodular pattern with intrasinusoidal infiltration
Immunophenotype in SMZL
- express B antigens: CD20+, CD22+, sIg+
- Bcl-2+ (but Bcl-6-, CD10-)

- negative for: CD5, CD10, CD23, CD43, CD103, Bcl-6, and cylcin D1

- absence of CD5 and CD43 help exlcude CLL and MCL (cyclin D1)
- absence of CD103 helps exclude HCL
- absence of CD10 helps exclude FL
SMZL differs from extranodal and nodal MZL
SMZL:
- lacks a true marginal zone growth pattern
- frequently express IgD (not seen in the others)
-
Difference between SMZL and splenic involvement by extranodal MZL, which is uncommon
In extranodal MZL, there is a true marginal zone pattern of involvement with preservation of the mantle zone and central GC
Hairy cell leukemia (HCL) is an ___ mature B cell lymphoma that manifests in the ___, ___, and ___
indolent

bone marrow, spleen, and blood
HCL is not responsive to standard NHL therapies, but __
long term remissions can be induced with HCL therpay
HCL is rare with only __ cases per year in the US
600-800
Typical patient with HCL
- middle aged (50 years old)
- male (M:F ration 4:1)
HCL presents with:
- splenomegaly (80% cases) with abdominal fullness
- pancytopenia (50%) (almost always monocytopenia)(25% present with only 1 or 2 cell lines suppressed)
- >50% have thrombocytopenia
- most have a normocytic, normochromic anemia
- hepatomegaly uncommon (20%)
- lymphadenopathy is rare

or

- asymptomatic
HCL typically involves the __ and ___, with typically small numbers of __
bone marrow and spleen

few circulating hairy cells in the blood (rarely frankly leukemic)
Bone marrow biopsy: HCL is often associated with a ___
dry tap due to reticulin fibrosis
Hairy cell morphology
- small lymphs (1-2 times the size of small lymphs)
- round, oval, or reniform nuclei
- chromatin is less dense than normal lymphs
- inconspicuous nucleoli
- abundant cytoplasm (clear to light blue) with circumferential hairy projections
In bone marrow core biopsy, the appearance of HCL
- usually hypercellular (but may be normo- or hypo-)
- intersitial, patchy to diffuse
- NO NODULAR AGGREGATES, if seen, suggest an alternate diagnosis
- "fried egg" appearance due to abundant cytoplasm
- reticulin fibrosis invariably
- extravasated RBCs often present
HCL can result in a hypocellular marrow that resembles __
- 10-20% have hypocellular marrow

- some cases are markedly hypocellular and resemble aplastic anemia due to cytokine production by the tumor cells

- avoid misdiagnosis by detection of CD20+ hairy cells

- typically other hematopoietic cells are almost always decreased in HCL; the granulocytes are most severely depressed
Cytochemical staining for __ is positive in most cases of HCL
TRAP
- tartrate-resistant acid phosphatase
- typically performed on blood smears, bone marrow aspirate smears or touch preps of bone marrow

- there is an immunostain for TRAP in paraffin-embedded tissue
HCL in the spleen primarily involves the ___ pulp
- red pulp, with atrophy of the white pulp
- Grossly, the splenic parenchyma is diffusely dark red and the spleen is markedly enlarged
- blood-filled pseudosinuses (blood lakes) lined by tumor cells are highly characteristic
Characteristic EM finding in HCL
ribosome lamellar complexes
Immunophenotype of HCL
bright CD45+ with increased forward and side scatter

CD19+
CD20+
CD22+
CD79a+

coexpress: CD103, CD25, FMC-7, and CD11c

monotypic Ig+

tyically CD5-
usually CD10-
In paraffin-embedded tissue, __ is a highly sensitive marker for HCL
DBA.44

- it is NOT specific for HCL
Hairy cell variant is a rare variant: similarities and differences
- in both: pateints present with anemia, thrombocytopenia, and splenomegaly, BUT, in HCLv there is a HIGH white cell count and NO monocytopenia

- HCLv cells resemble prolymphs with hairy projections:
1. are a little bigger
2. may have bilobed nuclei
3. coarse chromatin (compared to finer)
4. prominent nucelolus (versus inconspicuous nucleoli in classic HCL)
5. basophilic cytoplasm (compared to clear to light blue)

HCLv cell immunophenotype/cytochemical staining:
1. TRAP negative (typically)
2. CD25-, CD103-

Bone marrow:
1. only moderated reticulin fibrosis
2. aspirates obtained easily (NO dry tap)
HCLv is resistant to therapy including __ while classic HCL is responsive
IFN-alpha
SLVL(SMZL) vs. HCL
1. the villous projections of villous lymphocytes are often polarized
2. villous lymphs have less cytoplasm than hairy cells
3. Bone marrow involvement by SLVL is characterisitcally nodular and interstitial (NO! nodules in HCL)
4. Villous lymphs are CD103- and CD25-
In HCL, cyclin D1 is overexpressed in 50-75% of cases, but __
this is NOT associated with t(11;14)
Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) comprised of morphologically _____ small B cells including:
heterogeneous

- marginal zone cells (monocytoid B cells)
- small lymphocytes
- scattered immunoblasts
- varible plasma cells
In extranodal MZL of MALT, the infiltrate is within the ___
marginal zone of reactive B-cell follicles!! (unlike SMZL, with infiltration of the germinal center and a marginal zone-like pattern)
In MZL of MALT, the neoplastic cells typically infiltrate the ___ forming ___
epithelium

LELs
A special type of MALT lymphoma occuring more commonly in young adults near the Mediterranean is known as ___
IPSID (alpha heavy chain disease)
MALT lymphoma is a disease of ___, comprising __% of B-cell lymphomas, but __% of primary GASTRIC lymphomas
adults (median age 63)

7-8% of B-cell lymphomas

up to 50% primary gastric lymphomas
Many cases of MALT lymphoma are associated with a prior history of ___ with the development of ___
prior chronic inflammation often with autoimmune disorders
-H.pylori gastritis
-Sjogrens syndrome
-Hashimoto thyroiditis

= development of extranodal lymphoid tissue (MALT)
In MALT lymphomas, the neoplastic cells may colonize the germinal centers, morphologically this detected by the absence of a ___ in the GCs
starry sky (TGM's are normally present in uninvolved reactive GCs)
Patients with ___ and ___ are at an increased risk of developing MALT lymphoma
1. Sjogrens/lymphoepithelial sialadenitis(SS/LESA)
- 85% of lymphomas developing in this setting are MALT lymphomas
- have a 44-fold increased risk of lymphoma!!

2. Hashimoto thyroiditis
- 3-fold increased risk of lymphoma in general
- 70-fold increased risk of thyroid lymphoma
- 94% of patients with thyroid lymphoma have thryoiditis in the adjacent gland tissue
IPSID may be associated with chronic ___
intestinal infection

- some cases are reversible with antibiotic therapy early in the course
MALT lymphoma most commonly occur in the ___, however other sites include:

IPSID occurs in ___
GI tract 50% (stomach most common site in GI tract 85%)

IPSID typically involves the small intestine and colon

other sites include:
- lung 14%
- ocular adnexae
- head and neck
- breast
- thyroid
- skin
MALT lymphomas: bone marrow involvement is __
uncommon (20%)
Plasmacytic differentiation can be seen in MALT lymphomas, and a serum paraprotein (M-component) is ___ present. What about IPSID?
rarely (despite plasmacytic differentiation)

exception: IPSID aka alpha HCD!! produces truncated IgA heavy chain that is detectable in the serum
In H. pylori-related gastric MALT lymphomas, the proliferation of the neoplastic B cells requires ___
activate T cells, stimulated by H. pylori antigens
In some cases of cutaneous extranodal MZL, ___ is a possible source of antigenic stimulation driving the lymphoma
Borrelia burgdorferi
MALT lymphoma cells infiltrate around ___ B-cell follicles, external to a ___, from which they ___
1. reactive
2. preserved mantle zone (unlike SMZL, loss of the mantle zone)
3. spread out to form large confluent areas of lymphoma that eventually overrun most of the follicles
Characteristic marginal zone B cell morphology
- small to medium-sized, slightly irregular nuclei
- inconspicuous nucleoli
- moderately abundant pale cytoplasm (gives the monocytoid appearance)

Note: they may just resemble small lymphocytes too!!
lymphoepithelial lesion (LEL) is defined as an aggregate of __ or more ____ cells within the epithelium, resulting in __
aggregate of 3 or more marginal zone B cells within the epithelium, resulting in distortion and destruction of the epithelial cells

epithelial cells often show eosinophilic degeneration
In a MALT lymphoma, in which the lymphoma cells colonize the germinal centers, this can sometimes resemble___
follicular lymphoma
MALT lymphomas are by definition a ___ cell lymphoma, if there are large aggregates or sheets of transformed cells then it should be designated __
small cell lymphoma

DLBCL with note of accompanying MALT lymphoma
Morphologically, IPSID and typical MALT lymphomas are ___
similar

Note: IPSID may have striking plasmacytic differentiation
MALT lymphoma can involve lymph nodes?
YES

-as usual, the lymphoma cells infiltrate the marginal zone of reactive follicles
- aggregates of marginal zone cells in the paracortical areas and perisinusoidal areas

- varying degress of plasmacytic differentiation too
Characteristic immunoprofile for MALT lymphoma?
NO!

Absence of characteristic marker of other B cell neoplasms is useful

CD21 and CD35 will highlight tumor cells plus show the FDC meshwork of residual/colonized germinal centers
Two common cytogenetic abnormalities in MALT lymphoma
1. trisomy 3 (most common) 60%

2. t(11;18)(q21;q21)
API2/MLT fusion
- apoptosis inhibitor gene (API2)
- associated with resistance to H. pylori therapy
t(11;18)(q21;q21) in gastric MALT lymphomas is good or bad?
Not so good.
Associated with resistance to H. pylori therapy
Prognosis for MALT lymphoma
indolent (slow to disseminate)

risk of transformation to large B-cell lymphomas
MALT lymphoma is sensitive to ___
radiation therapy

Gastric MALT lymphoma - H. pylori treatment
Criteria for differential diagnosis of gastric MALT lymphoma
see WHO p. 160
includes:

Score 0(nml) to 5 (MALT lymphoma)

0: normal

1: chronic active gastritis without lymphoid follicles or LELs

2: chronic active gastritis with florid lymphoid follicle formation No LELs!!

3: suspicious lymphoid infiltrate, probably reactive

4: suspicious lymphoid infiltrate, probably lymphoma

5: MALT lymphoma - see dense, diffuse infiltrate of marginal zone cells in lamina propria w/ prominent LELs
Nodal MZL lymphoma is ___. It is a primary nodal B cell neoplasm that morphologically resembles___ but without__
Rare (1.8% of lymphoid neoplasms)

nodal involvement by SMZL or extranodal MZL (MALT lymphoma), but without extranodal disease
There are two morphologic types of nodal MZL described:
1. resembles nodal involvement by SMZL

2. resembles nodal involvement by MALT lymphoma
In patients with MALT lymphoma, Hashimoto thyroiditis, or Sjogrens syndrome, instead of a diagnosis of nodal MZL, the diagnosis should be __
MALT lymphoma with secondary lymph node involvement
Follicular lymphoma (FL) makes up __% of NHL in the US, and __% of low grade B-cell lymphomas.
35%

70%
Follicular lymphomas is a disease of ___ people, median age __. Rarely, it occurs in __
middle age to older
59 years old
<20 years old
Follicular lymphoma: site(s) of involvment: predominately ___, but also __
1. lymph nodes
2. spleen, bone marrow (40% at diagnosis!!), blood

3. uncommon in extrahematopoietic tissues, but if so it is usually associated with widespread lymph node involvement too!!
Follicular lymphoma in the skin?
FL is the one of the most common primary cutaneous B cell lymphoma
Patients with FL usually present with __
- widespread disease with BM involvement in 40% and splenomegaly is common.

- despite widespread disease, patients are usually asymptomatic other than LAD

- LAD may wax and wane

- some patients present with constitutional symptoms
Follicular lymphomas has at least a partially ____ pattern. The pattern is described as ___
1. follicular

2. pattern:
- follicular (>75% follicular)
- follicular and diffuse (25-
75% follicular)
- minimally follicular (<25% follicular)

There is at least some follicular pattern present
In FL, the neoplastic follicles are:
1. poorly defined
2. often lack a mantle zone
3. are closely packed
4. efface the nodal architecture, with occasional perinodal extension
5. nonpolarized
6. lack a starry sky appearance (tingible body macs)
7. follicles are often smaller than reactive follicles
In FL, the neoplastic cells can infiltrate the ___ areas, however this does not qualify as a ___ pattern
interfollicular areas

diffuse
Most cases of FL are composed of two cell types
1. centrocytes (cleaved FCC)
- small to medium-sized cells
- nuclei can be angulated, elongated, twisted, or cleaved
- inconspicuous nucleoli
- scant pale cytoplasm

2. centroblasts (noncleaved FCC)
- large transformed cells
- usually round or oval nuclei
- vesicular chromatin
- one to three peripheral nucleoli
- narrow rim of cytoplasm
In FL, the ___ usually predominate.
-centrocytes predominate, however, centroblasts are always present in the minority
FL is graded (WHO recommendation) using a 3-tiered system, based on ___
1. proportion of centroblasts

Histologic grading can predict clinical outcome

Count 10 hpf's: 1 hpf for 10 separate follicles.

grade 1: 0-5 centroblasts/hpf
grade 2: 6-15 centroblast/hpf
grade 3: >15
In FL, if a discrete area of grade 3 is present in a background of grade 1 or grade 2, then the diagnosis should reflect:
each grade, giving the relative proportion for each grade
The follicles selected for grading FL should be __
representative

Not those with the most centroblasts!!
In FL, when looking for centroblast (in grading), be sure not to count __ or __as centroblasts
1. follicular dendritic cells
WHO p.164
- often binucleated
- central esoinophilic nucleolus (versus multiple distinct nucleoli often peripherally located)
- CD21+ CD23+
2. large centrocytes (larged cleaved cells)
FL, for research purposes, grade 3 can be divided into
grade 3a
- centrocytes present
grade 3b
- solid sheets of centroblasts
Any areas of DLBCL within FL is considered__
transformation to a higher grade lesion

report the relative proportions of FL and DLBCL
Immunophenotype for FL
sIg+
pan B antigen +
CD10+
Bcl-2+
Bcl-6+

CD5-
CD43- (see note)

CD21+ CD23+ FDCs present in follicular areas

Note: some grade 3 FL are CD43+
Cutaneous follicular lymphoma is frequently Bcl-2___
Bcl-2 negative!!
The most common cytogenetic abnormality in FL __
t(14;18)(q32;q21)
BCL2/IgH
In FL, histologic grade correlates with prognosis
grade 1 and 2: indolent, not curable

grade 3: more aggressive with potential for cure with aggressive therapy (similar to DLBCL)
Grade 3, FL has a ___ prognosis compared to DLBCL
slightly better

- grade 3, FL is treated similar to a DLBCL
In FL, how does the presence of large diffuse areas in grade 1 or 2 lesions effect prognosis?
It does not.

But: in grade 3, it is more common to find large diffuse areas, and SOME studies show a worse prognosis
___% of FL cases transform or progress to LBCL most often DLBCL
25-35%
Cutaneous follicle center lymphoma is often Bcl-2 __ and typically involves the __ region of the body
- Bcl-2 negative
- head and neck
- remain localized!! amenable to local therapy

- true relationship with nodal FL is unknown
Diffuse follicle center lymphoma is __
- a FL without a follicular pattern!!
- so we cannot call it a FL
- rare
- has the mix of centrocytes with minor component of centroblasts
- both the small and large cell must have the SAME immunophenotype as a typical FL
Diffuse follicle center lymphoma (FCL) should be grade similar to FL, but one big difference is __
1. grade similar to a FL for grades 1 and 2, BUT:
- IF centroblasts predominate ((OR)) the small lymphs turn out to be T cells!! then it is a DLBCL
In FL, how does bone marrow involvement effect prognosis?
It does not seem to effect prognosis.
FL is rare in children, but if it occurs, it is similar to ___
primary cutaneous FL
BOTH:
- usually lack BCL2 gene rearrangement and are Bcl-2-
- head and neck region involved
- disease is apparently curable
In FL, the neoplastic follicles ___ the nodal architecture, with occasional __
efface

extension into perinodal tissue
In FL, the small cleaved cells are still __X the size of small lymphocytes
2X

slightly larger abnormally shaped cells
Bone marrow involvement by FL characteristically occurs in a ___ location
paratrabecular
Grade 3b FL is a special category that differs from other FL's
- less often CD10+ (50% vs 100%)
- t(14;18) less common (22% vs 73%)
- appears to be more biologically related to DLBCL

BUT: there is no difference in survival between grade 3a and 3b
FL with diffuse component: for grade 1 and 2, diffuse component does not seem to effect ___ (unless it occupies __%), but in grade 3___ (from Fletcher)
1. prognosis
2. 25-50% diffuse
3. in grade 3 FL, any area of diffuse should lead to a diagnosis of "FL with DLBCL" instead of "FL, grade 3, follicular and diffuse"

Note: Contrast with WHO:
- even large diffuse areas in a grade 1 or 2 does not seem to affect prognosis; but it says that some studies do show the degree of nodularity does have an impact on survival, so they recommend reporting the % of diffuse and follicular components
In situ follicular lymphoma?
- partial node involvement
- usual reactive follicles present
- some follicles have germinal centers with aggregates of bcl-2+ follicle center cells (monoclonal)
- some pts have FL in other nodes, if not, 23% will develop FL

- may represent early involvement by FL or a preneoplastic event
sIg can be negative in some cases of FL, especially if composed of mostly __
large cells
Bcl-2 is postivie in ___% of FL cases, it is more likely to be negative in __
85% bcl-2+

cases composed predominately of large cells are more likely to be negative
Ki-67 (proliferation) index is usually __ in FL compared to reactive follicular hyperplasia
lower
In FL, deletions of __ and __ are associated with __
6q and 17p

- shorter survival
- higher probability of transformation to DLBCL

Note: only 10% of FL cases have t(14;18) as the sole abnormality.
FL, with marginal zone differentiation
- at periphery of the follicles there is a pale rim of monocytoid B cells
- these cells are CD10- and bcl-6-
- not clear whether or not it is clinically significant
In MALT lymphoma, multifocal disease (involving more than on mucosal or extramucosal sites) is associated with what cytogenetic abnormalities?
- gastric lymphomas: t(11;18)(q21;q21)

- extragastric lymphomas: trisomy 18

NOTE: there is no significant differences in survival between localized and disseminated disease!!
___% of gastric MALT lymphomas associated with H. pylori show complete remission with antibiotics
70-80%

- regression usually occurs within a few weeks (up to 1 year in some)

- NOTE: molecular evidence residual tumor lags behind clinical remission and may persist
In gastric MALT lymphomas, bcl-10 aberrant nuclear positivity is associated with ___
t(11;18) and lack of a response to anti-Helicobacter therapy

In normal B lymphocytes, including those lacking t(11;18), bcl-10 immunoreactivity is limited to the cytoplasm
extranodal MZL is bcl-2__, in cases of colonization of ___, this may resemble FL
bcl-2+

germinal centers by MZL

BUT: CD10-, bcl-6-
t(11;18)(q21;q21)
- gastric MALT lymphomas
- lack of response to anti-Helicobacter therapy
- API2 gene on 11q21 fused with MALT1 gene on 18q21
- fusion protein directly activates NFkB, bypassing normal signaling pathways
t(11;18) in gastric MALT lymphomas and transformation to a large cell lymphoma?
t(11;18) seems to protect it from large cell transformation
Mantle cell lymphoma (MCL) has a striking ___ predominance (gender)
male (7:1)
patients with mantle cell lymphoma often present with
lymphadenopathy, often with extranodal involvement (spleen and GI)
lymphomatous polyposis
ileocecal involvement by MCL, with formation of multiple polyps
Lymph nodes with MCL show a
- diffuse, vaguely nodular to nodular, or mantle zone pattern
- NO proliferation centers
- NO (or minimal) transformed cells
- scattered, solitary epithelioid histiocytes are an IMPORTANT clue to MCL
- blood vessels often hyalinized

- monotonous lymphoma cells with folded nuclei
immunophenotype of mantle cell lymphoma
B-antigen positive
CD5+
CD23-

CD10-
bcl-6-

Cyclin D1+
Cyclin D1 can be seen in:
-MCL
-rare CLL/SLL
-some HCL
-some plasma cell myeloma/plasmacytoma
Cylcin D1 negative (by IHC)MCL?
7% cases
Dx based on:
- morphology
- CD5+
- expression of other cyclins
In MCL, the Ig genes can be mutated (20-30%) or unmutated (70-80%), but unlike CLL/SLL___
In MCL, there is no clinical difference between the two
__% of MCL exhibit t(11;14)
50-65% although >90% are positive for cyclin D1 by IHC!!

Additonally, by FISH for 11q13 translocations, practically all cases are positive

Suggests that cryptic translocations or other mechanisms are involved in CYCLIN DI dysregulation
cyclin D1 is also known as __
bcl-1
PRAD1
Blastoid/pleomorphic MCL has a __ prognosis compared to classic MCL
worse
blastoid MCL is TdT__
negative

distinguishing it from B-LBL
MCL is characterized by a ___ population of ____ to ___-sized B lymphocytes with ___ nuclei. NO ___ are present.
- monomorphous
- small to medium
- irregular

- NO proliferation centers (pseudofollicles), transformed neoplastic cells (centroblasts), or paraimmunoblasts
Most commonly involved extranodal sites for MCL are ___and ___
GI tract and Waldeyer's ring
Lymphomatous polyposis can involve __ part of the GI tract
any!!

Fletcher (ileocecal)
MCL often presents with __ splenomegaly
massive

LAD, hepatosplenomegaly, bone marrow involvement
Some patients with MCL have a marked lymphocytosis that can mimic __
prolymphocytic leukemia
- the circulating MCL cells can be morphologically indistinguishable from prolymphocytes!!
MCL is characterized by a ___ population of ____ to ___-sized B lymphocytes with ___ nuclei. NO ___ are present.
- monomorphous
- small to medium
- irregular

- NO proliferation centers (pseudofollicles), transformed neoplastic cells (centroblasts), or paraimmunoblasts
Most commonly involved extranodal sites for MCL are ___and ___
GI tract and Waldeyer's ring
Lymphomatous polyposis can involve __ part of the GI tract
any!!

Fletcher (ileocecal)
MCL of presents with __ splenomegaly
massive

LAD, hepatosplenomegaly, bone marrow involvement
Some patients with MCL have a marked lymphocytosis that can mimic __
prolymphocytic leukemia
Is mantle cell lymphoma graded?
No
But, if blastoid features are present, it is noted in the diagnosis
In mantle cell lymphoma, transformation to a typical large cell lymphoma ___ occur
does NOT

- but may see subsequent blastoid variant with recurrence
CD5- MCL cases may be more ___
indolent than typical CD5+ MCL
the most consistently reported adverse histopathological prognositic finding in MCL is
a high mitotic rate (not well defined!!)

high mitotic rate: >10/10hpf to 20-30/10hpf
MCL, blastoid variant has two subtypes:

Any difference in survival?
1. Usual
- resembles lymphoblasts (high mitotic rate >10/10hpf, usually at least 20-30/10hpf)

2. Pleomorphic
- heterogenous cells
B symptoms in a pt with CLL at presention
predicted to have a shorter survival.

- remember, many patients are incidently discovered
The ddx in young patients with suspected CLL is with NLPHL
the lymphs in NLPHL do not express CD5 and CD43 and are polytypic not monotypic as in CLL
DLBCL, the lymphoma cells are equal to or exceed the size of a ___
normal macrophage!! or 2X the size of a normal lymphocyte
DLBCL sites of involvment:
1. extranodal:
- most common site is GI (stomach and ileocecal region)
- any site could be the primary
- up to 40% of cases, the disease is limited to extranodal sites
2. nodal
3. bone marrow
- primary BM or PB involvement is RARE!!
Most DLBCL arise __
de novo

But, can represent progression or transformation of a less aggressive lymphoma
DLBCL that arise in the setting of immunodeficiency are often ___-related
EBV

- immunodeficiency is a risk factor
DLBCL patterns of involvement within nodal and extranodal tissues
variety
- complete to partial effacement
- interfollicular
- sinusoidal

- often infiltrates perinodal tissues

- +/- broad bands of sclerosis
DLBCL is composed of large __ lymphoid cells
transformed
The DLBCL variants are described but not very reproducible, therefore, the pathtologist can use the term __
DLBCL only or use one of the variant types
The most common morphologic variant of DLBCL is the ___
centroblastic variant
- medium to large cells
- oval to round, vesicular nuclei
- fine chromatin
- 2-4 membrane bound nucleoli
- scant cytoplasm
Immunoblastic DLBCL:
- features
- DDX
- majority (>90%) of the cells have a single, central, nucleolus
- moderate basophilic cytoplasm
- NOTE: centroblasts MUST be <10% of cells

DDX: plasmablastic variant of plasma cell myleoma
T-cell/histiocyte rich DLBCL
- majority of the cells are __
- majority of the cells are T-cells w/ or w/out histiocytes
- <10% large neoplastic B cells!!!
t-cell/histiocyte rich DLBCL can raise a DDX including:
1. NLPHL
- in T-cell/histiocyte rich DLBCL, small B cells are rare, but if present, along with fewer large neoplastic B cells and a vague nodularity, may suggest NLPHL
2. HL
The pleomorphic variant of DLBCL can mimic __
1. carcinoma (if growing in cohesive pattern, especially if there is a sinusoidal pattern of growth)
2. RS cells of HL
3. ALCL ( T cell lymphoma)
Immunophenotype of DLBCL
1. express various pan B markers
- may lack one or more too!
2. sIg+ 50-75%
3. cIg+ in ones with plasmacytic differentiation
4.+/- CD30+!!! (as is ALCL)
5. +/- CD5+ (these are cyclin D1 negative distinguishing them from blastoid MCL)
6. many are bcl-6+
7. occasionally CD138+ (if immunoblastic variant, could be confused with plasmablastic variant of plasma cell myeloma)
8. Ki-67 index is high >40%, upto >90% in some cases
Most anaplastic DLBCL variants are CD30__.
CD30+

- as is ALCL
___% of DLBCL exhibit t(14;18)
20-30%
Bcl-2+ is seen in ___% of DLBCL and may be associated with __
30-50% cases are bcl-2+

worse prognosis
Bcl-6 translocation in DLBCL may be associated with a __ prognosis
better
Plasmablastic variant of DLBCL is ___ and typically presents in the __, in the setting of __.
RARE

oral cavity

HIV infection

- 60% EBV+
- lymphoma cells are CD20- and CD45-
- they are CD138+
How can you distinguish a plasmblastic DLBCL from a variant of plasma cell myeloma?
In plasmablastic DLBCL
- CD20- (vs CD20+)
- CD45-
- CD138+
- lack of mature monoclonal plasma cells
- high proliferation index
- clinical picture (HIV, oral cavity)
DLBCL usually presents with __, but __ is common
lymphadenopathy, but extranodal presentation is common too
If DLBCL is detected in a staging marrow, it is IMPORTANT to determine __
- is it marrow involvement by DLBCL or is it involvement by an occult follicular lymphoma

REASON:
- marrow involvement by DLBCL is a dismal px (stage IV)
- marrow involvement by FL DOES NOT affect the prognosis, BUT it suggests that the disease is more likely to relapse after complete remission, in the form of FL
DLBCL is an aggressive disease that is fatal if untreated, but __
- is potentially curable with aggressive therapy
- 50% cases can achieve long term disease-free survival
DLBCL treatment includes:
1. CHOP:
- cyclophosphamide
- doxorubicin
- vincristine
- prednisone

2. CHOP + rituximab
Morphologically, a DLBCL and peripheral T cell lymphoma can __ be distinguished
can NOT!
__% of DLBCL are bcl-6+ and CD10+
40% CD10+
60% bcl-6+

- follicle center cell origin
DLBCL: __% are bcl-2+ and are associated with __
50% bcl-2+
associated wtih resistance to CTX
3 molecular pathways to the development of DLBCL
1. transformation pathway
- involves activation of BCL-2 w/ or w/o P53 mutation

2. de novo pathway involving BCL-6 rearrangement

3. de novo pathway with retained germline BCL-6 and BCL-2, via some unknown mechanism
Immunophenotypic findings with poor prognostic significance in DLBCL
- bcl-2 + (single strongest independent unfavorable prognostic factor)

- bcl-6-

- CD5+

- HLA-DR-

- ki-67+ >60-80%
Germinal center cell differentiation in DLBCL is associated with a __ prognosis
better

What about t(14;18)?
3 subtypes of DLBCL with distinct features include:
1. mediastinal (thymic) large B-cell lymphoma (Med-DLBCL)

2.Intravascular large B-cell lymphoma

3. Primary effusion lymphoma
Med-DLBCL occurs in which age group and gender?
young women

30-50's

F>M

anterior mediastinal mass
Med-DLBCL are EBV__
EBV negative
Med-DLBCL consists of __
variably sized neoplastic B cells with abundant pale cytoplasm and sclerosis

- classic clear cell appearance and delicate interstitial fibrosis
Med-DLBCL may contain eosinophils, fibrosis, and interspersed benign lymphs suggesting a dx of __
HL (NS type)

- NOTE: the lymphoma cells are often CD30+ (often weak), BUT CD45+, CD20+, CD15- and EBV- !!
Immunophenotype of Med-DLBCL
CD19+, CD20+
CD10-
CD5-
CD30+ (70%)(patchy and weak, focal to diffuse)
CD15-

CD23+ (70%)
In med-DLBCL (thymic large B-cell lymphoma) a cytokeratin can highlight __
- thymic remnants infiltrated by tumor cells

- WARNING: thymic remnants may appear n clusters mimicking carcinoma
Unlike most lymphomas, med-DLBCL may spread to the __
CNS (26% cases either at presentation or relapse)
Med-DLBCL therapy is different compared to DLBCL
- it is not as responsive to standard DLBCL therapy (CHOP)
- require multimodality therapy often with XRT
- can achieve 10 yr disease-free survival up to 78%
Med-DLBCL consists of __
- medium to large cells
- mod to abundant pale, clear, or amphophilic cytoplasm
- intermingled RS-like cells, highly pleomorphic cells, and small lymphs
the sclerosis in med-DLBCL leads to a ___ pattern that can mimic __
compartmentalized pattern

mimic carcinoma or seminoma

NOTE: sclerosis is NOT essential for the diagnosis
CD23 and sIg are typically __ in med-DLBCL and __ in non-mediastinal DLBCL
med-DLBCL CD23+ (70%) and sIg-

nonmed-DLBCL CD23- (only 10% CD23+) and sIg+
med-DLBCL distinguished from a mediastinal lymph node invovled by DLBCL
LN w/ DLBCL
- M>F
- older age
- sIg+
- CD23-

med-DLBCL:
- young women
- CD23+
- sIg-
DDX of med-DLBCL
1. thymoma, thymic carcinoma
- presence of well-formed Hassall corpuscles favor lymphoma!! Rarely seen in thymoma

2. germinoma
- due to the packeted pattern and clear cell morphology
- absence of glycogen!! and marked nuclear irregularities favor lymphoma

3. syncytial variant of NS Hodgkin lymphoma
Intravascular large B-cell lymphoma is a ___ disease characterized by the presence of ___ cells within the lumina of __
extremely rare (only a few cases reported!!)

lymphoma cells only in the lumina of small vessels, particularly capillaries
Intravascular large B-cell lymphoma can involve any __ site. It is a subtype of ___ DLBCL. Sites involved include __
- any extranodal site
- it is a subtype of extranodal DLBCL
- brain, bone marrow, skin,...
intravascular large B-cell lymphoma is aka ___
- intravascular lymphomatosis
- malignant angio-endotheliomatosis
In cases of intravascular large B-cell lymphoma, despite the almost exclusive intravascular proliferation, there usually is no __
circulating lymphoma cells in the PB
bone marrow morphologic examination for intravascular large B-cell lymphoma is often __, however ___ is often ___
negative

molecular evidence is often present
In intravascular large B-cell lymphoma the tumor cells plug the lumina of __
small and medium-sized vessels

vascular occlusion leads to infarcts in multiple organ systems
TCRBCL (T cell rich large B cell lymphoma): the __ cells make up >90% of the cells
T-cells

in cases with a rich histiocyte or epithelioid histiocyte component, the term T-cell rich/Histiocyte rich B-cell lymphoma is used
In TCRBCL the background T-cells are often CD__+
CD8+
Primary effusion lymphoma (aka__) is a type of __ without a ___
body cavity-based lymphoma

large B cell lymphoma without a detectable tumor mass and presenting as a serous effusion

HHV8+

a/w immunodeficiency
primalry effusion lymphoma most often occurs in two patient populations:
1. young HIV+ homosexual men with HHV8
2. non-immunodeficient elderly men in areas with high HHV8 prevalance (Mediterranean)
Primary effusion lymphoma most commonly involves the __, __, and __ cavities
pleural, pericardial, and peritoneal

other sites: soft tissues, GI tract, other
Primary effusion lymphoma cells are positive for ___ and often coinfected with ___
HHV8+

EBV
In cytology, primary effusion lymphoma cells appear __
- large cells
- prominent nucleoli
- nuclei round to irregular
- cytoplasm can be abundant, deeply basophilic, and contain vacuoles!!
Immunophenotype for primary effusion lymphoma
CD45+
CD19-
CD20-
CD22-
CD79a-
CD3-
CD138+
+/-CD30 (activation marker)
+/-HLA-DR (activation marker)
CD10-
bcl-6-
The B cell nature is supported by Ig gene rearrangements
primary effusion lymphoma typically remains ___
localized to the body cavity or origin
median survival for primary effusion lymphoma is
6 months
In cases of primary effusion lymphoma, a pleural biopsy may show__
- lymphoma cells adherent to the pleural surface often embedded in fibrin and occasionally invading the pleura
In primary effusion lymphoma, abberrant CD3__ has been reported
CD3+

- in combination with the often absent pan B cell markers, this can make assigning the appropriate lineage difficult
Although the majority of primary effusion lymphomas remain localized to the ___, there have been reported cases of ___
- body cavity of origin

- extracavitary solid form, WITHOUT effusion, involving lymph nodes or extranodal sites
Main differences between classic primary effusion lymphoma and the extracavitary solid form are __
- slightly higher frequency of B cell antigen and sIg expression
- better survival (but still poor px) 11 mos vs 3 mos
Primary effusion lymphoma is a very aggressive disease, with a median survival of __ and __% 1 year survival
- 6 months
- 39%
Primary effusion lymphoma cells are large cells with voluminous, ___ ____ and a pale ___.
- voluminous basophilic cytoplasm
- pale Golgi zone
Using gene expression profiling, primary effusion lymphoma closely resembles that of a ___
- malignant plasma cells
- may be a form of malignant plasmablastic neoplasm
HHV8+ germinotropic large B cell lymphoma:
- occurs in __ host
- presents with __
- has a ___ response to CTX and/or XRT
- lymphoma cells infiltrate and replace ___
- immunophenotype __
- occurs in immunocompetent hosts
- present with LAD
- favorable response to CTX and XRT
- prexisting follicles are partially or completely replaced by large, pleomorphic lymphoma cells
- plasmablastic immunophenotype:
CD20-
CD79a-
CD10- (germinal center marker)
bcl-6- (germinal center marker)
-Ig light chain restricted
HHV8-associated lymphomas include:
- primary effusion lymphoma (HHV8+EBV)
- germinotropic large B cell lymphoma (HHV8+EBV)
- plasmablastic lymphoma associated with multicentric Castleman disease (HHV8)
- some cases of sporadic plasmablastic lymphoma
Lymphomas associated with HHV8 tend to have ___ features
plasmablastic
ALK+ large B-cell lymphoma is a __ disease. Occurs mostly in __ ___. It presents with __. It has a ___ clinical course
- very rare!
- adult men
- marked LAD in multiple sites
- very aggressive clinical course
As with ALCL, ALK+ large B cell lymphoma obliterates the lymph node architecture with frequent involvement of the ___. The lymphoma cells are ___ and may appear __, mimicking a __
- sinusoids (sinusoidal pattern)
- lymphoma cells are large, with large vesicular nuclei, prominent nucleoli and abundant amphophilic cytoplasm
- may appear cohesive, mimicking a carcinoma!!
Immunophenotype of ALK+ large B cell lymphoma
CD45+ (68%)
CD20+ (5%)
CD79a+ (10%)
- variably positive for pan B-cell markers (more often negative)

IgA+ (50%)
CD138+ (100%)
EMA+ (100%)

ALK+ (100%)
CD30+ (24%) (unlike ALCL)
CD4+(71%)

B cell nature supported by finding Ig gene rearrangment
ALK staining in ALK+ large B-cell lymphoma is __
- CYTOPLASMIC and granular
- rarely nuclear and cytoplasmic
ALK expression in ALK+ large B cell lymphoma is most often due to t(__,__)
- t(2,17), rarely t(2,5)
- contrast with t(2,5) in ALCL
Large B cell lymphomas with plasmablastic features are CD20__
CD20-
Plasmablastic lymphoma is an uncommon and highly aggressive form of ___ that encompasses ___
- large B-cell lymphoma
- encompasses more than one entity (heterogeneous group)
Originally defined cases of plasmablastic lymphoma were thought to occur in two settings__
1. oral cavity and jaw of HIV+ pts
2. in setting of multicentric Castelman disease

NOW:
- can occur in both immunocompromised and immunocompetent hosts
- involves lymph nodes and extranodal sites (GI, upper respiratory tract, bone, soft tissues)
4 types of large B-cell lymphoma with plasmablastic features include:
1. plasmablastic lymphoma
2. primary effusion lymphoma
3. ALK+ large B-cell lymphoma
4. HHV8+ germinotropic large B-cell lymphoma
Two histologic types of plasmablastic lymphoma are__
- prototype characterized by large blastic cells only
-- eccentric, vesicular, round to ovoid nuclei with prominent nucleoli
-- abundant cytoplasm and a paranuclear hof

- second type has evidence of plasmacytic differentiation
-- immunoblasts and plasmablasts
-- some plasma cells present
plasmablastic lymphoma immunophenotype
- usually CD20- and PAX-5-
- +/- CD45, CD79a, Ig, and EMA
- CD38+
- CD138+
- MUM-1+

- Ki-67+ >90%!!
plasmablastic lymphoma:
EBV__
HHV8__
- EBV+ in many cases (50-74%)
- HHV8+ in only some sporadic cases
- NOTE: plasmablastic lymphoma associated with multicentric Castleman is HHV8+!!
Distinguishing plasmablastic lymphoma from the plasmablastic type of plasmacytoma/myeloma?
- can be difficult
- plasmablastic lymphoma is closer to lymphoma than myeloma and is NOT associated with a M-spike
Two histologic types of plasmablastic lymphoma are__
- prototype characterized by large blastic cells only
-- eccentric, vesicular, round to ovoid nuclei with prominent nucleoli
-- abundant cytoplasm and a paranuclear hof

- second type has evidence of plasmacytic differentiation
-- immunoblasts and plasmablasts
-- some plasma cells present
plasmablastic lymphoma immunophenotype
- usually CD20- and PAX-5-
- +/- CD45, CD79a, Ig, and EMA
- CD38+
- CD138+
- MUM-1+

- Ki-67+ >90%!!
plasmablastic lymphoma:
EBV__
HHV8__
- EBV+ in many cases (50-74%)
- HHV8+ in only some sporadic cases
- NOTE: plasmablastic lymphoma associated with multicentric Castleman is HHV8+!!
Distinguishing plasmablastic lymphoma from the plasmablastic type of plasmacytoma/myeloma?
- can be difficult
- plasmablastic lymphoma is closer to lymphoma than myeloma and is NOT associated with a M-spike
Burkitt lymphoma (BL) is a __ lymphoma that often presents at ___ or as an __
- aggressive
- extranodal sites or as an acute leukemia
There are __ clinical variants of Burkitt lymphoma
3 clinical variants of BL:

1. endemic BL
- equatorial Africa and Papua New Guinea
- most common malignancy in chldren in these regions
- peak incidence 4-7 yo
- M:F 2:1

2. sporadic BL
- worldwide
- mainly children and young adults
- 30-50% of childhood lymphomas
- median age of adults pts: 30 yo

3. immunodeficiency associated
- associated with HIV
- EBV+ in 25-40% of cases
Burkitt lymphoma often presents in __ sites; a three clinical variants are associated with a risk of __ involvement
- extranodal sites with some variation according to the clinical variants
- all three variants are at risk for CNS involvement

1. endemic BL:
- present in jaw and other facial bones (orbits) in 50% cases

2. sporadic BL:
- majority present with abdominal masses (ileo-cecal most common)

3. immunodeficiency-associated BL
- lymph node and bone marrow involvement are common

NOTE:
- RARE for BL to present as pure acute leukemia (Burkitt leukemia)
- leukemic phase usually seen with bulky disease
Most patients with BL present with a __ tumor burden, due to __
- high tumor burden
- short doubling time of the tumor
Bone marrow involvement by Burkitt lymphoma is a __
- poor prognostic sign
- seen in pts with high tumor burden
Patients with BL who have bulky disease will have the following serum marker abnormalities
- high uric acid
- high LDH
BL is clinically staged. Most patients present with __ stage disease
- advanced stage disease III and IV/IV
With the start of therapy for BL, patients are at risk for __
- tumor lysis syndrome
- release of intracellular components

- severe hyperkalemia with possible cardiac arrest
- hyperphosphatemia with secondary hypocalcemia
- precipitation of uric acid, xanthine, and/or phosphate in renal tubules causing severe renal failure
EBV is positive in % of endemic, sporadic, and immunodeficiency-associated BL cases
- endemic: 100%, EBV+ in the majority of tumor cells too!

- sporadic: <30% (EBV is less commonly associated with sporadic cases)

- immunodeficiency-associated: 25-40%


EBV is not essential for the development of BL, but likely plays a co-factor role
Genetic abnormalities involving the __ gene at locus __ is essential for BL pathogenesis
- MYC
- 8q24
Classic Burkitt lymphoma cells are ___ in size and shape, the nuclei contain ___, and the nuclear diameter is approximately that of __
- uniform in size and shape
- multiple small basophilic nucleoli
- starry sky histiocyte nucleus
On touch imprints, classic Burkitt lymphoma cells have cytoplasm that is __ and contains __
- deeply basophilic cytoplasm
- abundant lipid vacuoles in the cytoplasm
Nodal involvement is __ in endemic and sporadic BL
- RARE!!
- can see uninvolved nodes surrounded by tumor
Morphologic types of Burkitt lymphoma include (3)
- Classical BL
- BL with plasmacytoid differentiation
- atypical Burkitt/Burkitt-like
Classical BL morphology
- medium-sized cells (about the size of a starry sky histiocyte nucleus)
- DIFFUSE monotonous pattern of infiltration
- rounded nuclei with clumped chromatin
- mutiple basophilic nucleoli
- deeply basophilic cytoplasm with lipid vacuoles

- extremely high proliferation index

- starry sky pattern
BL with plasmacytoid differentiation is characterized by __ and is seen more common in ___ BL
- some tumor cells with plasmacytoid features: eccentric nucleus with a single central nucleolus and monotypic intracytoplasmic immunoglobulin

- seen more commonly in immunodeficiency-associated BL
Atypical Burkitt/Burkitt-like lymphoma is characterized by ___ and requires ___
- predmoninantly MEDIUM-sized cells
- high proliferative index (nearly 100% required)
- greater nuclear pleomorphism
- fewer more prominent nucleoli
- less consistent starry sky pattern
- DX requires proven or strong presumptive evidence of MYC translocation
Immunophenotype of BL
sIgM+ (monoclonal)
CD19+
CD20+
CD22+
CD79a+

CD10+
Bcl-6+

CD21+ (endemic BL, but usually CD21- in sporadic BL)

In cases of BL with plasmcytoid differentiation: monotypic cIg+

Ki-67+ (nearly 100% of cells)

CD5-
CD23-
Bcl-2- (cells are growing fast and dying fast)

In contrast to blasts of precursor B-ALL, BL has a mature B-cell phenotype

bright CD45+
CD34-
TdT-
sIg+
mature B-cell markers (CD19+, CD20+, CD22+, CD79a+)
somatic mutations of the Ig genes in BL is consistent with a __ stage of differentiation
germinal center
Translocations associated with Burkitt lymphoma
- all cases involve MYC gene (8q24) translocations
- t(8;14)(q24,q32) MOST COMMON
- t(2;8) and t(8;22) are less common
MYC translocations are __ specific for BL
- NOT entirely
- seen in some cases of secondary B-LBL following follicular lymphoma
BL presenting with CNS and/or bone marrow involvement is stage __
stage IV/IV
endemic and sporadic BL is a highly aggressive but potentially __ disease
- curable
- with intensive CTX: 80-90% survival
- children do better than adults
Poor prognositc findings in BL
- CNS and/or BM involvement
- high serum LDH
- unresected tumor >10cm

- still potentially curable
Relapse of BL typically occurs within __ yr(s), after __yr(s) without relapse, the patient can be considered cured
- 1yr if it is going to happen
- after 2 yrs of no replapse = cure!
Burkitt lymphoma is one of the most rapidly growing human tumors, with a potential doubling time of __
24-48hours
BL makes up a __ proportion of NHL cases in AIDS patients compared to the general population
- higher %
- 24-40% of NHL in AIDS vs <5% of NHL in general pop
BL morphology is characterized by __
- a monotonous infiltration of medium-sized cells with round nuclei, coarse chromatin, 2-5 basophilic nucleoli and an appreciable rim of basophilic cytoplasm
- frequent mitotic figures
- apoptotic cells
- TBM

- nuclear and cytplasmic borders often show molding and squaring off (distinctive feature) - best seen in formalin fixed tissue

- some cases show necrosis and granulomatous response
Granulomatous response in Burkitt lymphoma is associated with EBV_, __stage disease, and __ px
- EBV+
- early stage
- good px
CD21 is the __ receptor
C3d/EBV receptor
Lymphomatoid granulomatosis (aka___) is an __ and __ lymphoproliferative disease involving __ sites
- LYG (aka angiocentric immunoproliferative lesion)
- angiocentric and angiodestructive lymphoproliferative disease
- extranodal sites
LYG is dominated by reactive __
T-cells
LYG can evolve into a __
EBV+ DLBCL
LYG must be distinguished from __, which also has an angiodestructive growth pattern and EBV+
extranodal NK/T cell lymphoma, nasal-type
Lymphomatoid granulomatosis is a __ rare disease the mainly affects __
RARE
- mostly adults (can be seen in immunodeficient children)
- M:F 2:1
Lymphomatoid granulomatosis most often involves __, but other sites include___

LYG RARELY invovles __ and __
- lung (MOST COMMON)
- brian, kidney, skin, GI, upper respiratory tract

RARE: lymph node and spleen
LYG usually present with __
- symptoms related to pulmonary involvement (cough, CP, dyspnea)
- constitutional symptoms are common (fever, malaise, weight loss, GI)

- RAREly asymptomatic
Lymphomatoid granulomatosis is a __-driven lymphoproliferative disorder. Patients who are __ are at increased risk of developing LYG
- EBV-driven
- immunodeficient (including iatrogenic and hereditary causes)
LYG most commonly present with ___
- mulitple pulmonary nodules that vary in size
- larger lesions may exhibit central necrosis and cavitate
- lesion usually involve mid and lower lung fields
Morphologically, LYG is charactrerized by __
- angicentric and angiodestructive POLYMORPHOUS lymphoid inflitrate
- admixed plasma cells, immunoblasts, and histiocytes
- NO SIGNIFICANT NEUTROPHILIC OR EOSINOPHILIC COMPONENT
- NO WELL-FORMED GRANULOMAS
- SMALL number of EBV+ B cells in a prominent inflammatory background
- vascular changes: lymphocytic vasculitis, which can lead to tissue necrosis
The EBV+ B cells in LYG may resemble __
- RS cells, but classic RS should NOT be seen in LYG
Grading of lymphomatoid granulomatosis is based on the proportion of __ relative to __
- EBV+ B cells to reacitve background lymphocytes
LYG is graded I-III
Grade I
- large transformed lymphoid cells are RARE to ABSENT
- ISH: EBER1/2 probe - detect infrequent EBV+ cells (<5/hpf); some cases EBV-
- NO prominent necrosis

Grade II
- occasional large transformed lymphoid cells or immunoblasts seen
- polymorphous background
- necrosis more commonly seen
- ISH: readily detected EBV+ cells (5-20/hpf)

Grade III
- readily identified histologically as MALIGNANT
- numerous large lymphoid cells
- STILL MAINTAINING INFLAMMATORY BACKGROUND
- may see markedly pleomorphic and RS-like cells
- ISH: extremely numerous EBV+ cells (may see sheets of cells!)
- BASICALLY A SUBTYPE OF LARGE B-CELL LYMPHOMA
Grade III LYG should be considered a ___, however some cases may __
- type of large B cell lymphoma
- some cases may spontaneous regress with immunotherapy or alteration in immune status
LYG immunophenotype
EBV+ cells:
CD20+
CD79a+/-
CD30+/- but CD15-

LMP-1+

Background lymphocytes:
CD3+ T cells (mostly CD4+)
By molecular techniques, most grade II or III LYG demonstrate __
- PCR: CLONALITY (sometimes different clones in different anatomic sites)
- southern blot analysis: clonality of EBV
In cutaneous LYG a ___ response is more commonly seen; the infiltrate is seen in the __
- granulomatous
- infiltrate present in subcutis +/- fat necrosis
LYG: demonstration of clonality seen in __ cases of grade II and III disease. What about grade I disease?
- most cases of grade II and III disease exhibit clonality

- less consistent in grade I disease

- NOTE: some cases may be polyclonal
Postulated cell of origin for LYG
Mature B lymphocyte, transformed by EBV
Natural history of LYG is ___.
VARIABLE
- may wax and wan, with spontaneous remission without therapy
- MOST cases - the disease is aggressive with median survival less than 2 yrs
Most common cause of death secondary to LYG
progressive pulmonary involvement
Grade III LYG show some response to ___ CTX, while grade I and II disease may respond to ___
- aggressive CTX for grade III disease
- interferon alpha 2b for grade I and II