Neoplastic hematopathology Flashcards

Question 1

Q

Most common site of extranodal B cell lymphoma

Question 2

Q

B cell neoplasm demographics

Answer

A

Low grade more common in older adults; high grade in kids and young adults
Most B cell neoplasms have male predominance
- exceptions showing female predominance:
  - primary mediastinal lymphoma
  - follicular lymphoma
  - MALT lymphoma
DLBCL > FL > CLL > mantle cell lymphoma
CLL most common leukemia

Question 3

Q

CLL/SLL
- genetics

age
presentation
morphology (SLL and CLL)
immunophenotype
molecular and cytogenetics
transformation to

Answer

A

CLL has strongest genetic influence of all B cell neoplasms
- Familial clustering in 5%
- Risk in 1st degree relatives is 5x baseline
Median age = 65
Presentation
- Adenopathy, splenomegaly, PBL and BM involvement
- autoimmunity; positive DAT in 30%
- immunodeficiency; hypogammaglobulinemia in 30-50%
- M protein occasionally
Morphology
- SLL
  - Diffuse nodal involvement
  - small lymphs, occasional prolymphocytes
  - proliferation centers; many prolymphocytes (light and dark areas)
- CLL
  - small lymphs
    - prolymphs < 11%
    - 11-55% prolymphs = CLL/PLL
  - smudged cells in EDTA; not seen in heparin smears
  - lymphocyte count > 5 x 10⁹/L (monoclonal B cell lymphocytosis under this number)
Immunophenotype
- positive for
  - CD19
  - CD20 (dim)
  - CD22
  - CD5
  - CD43
  - CD23
  - sIg (dim)
  - CD79a
  - CD11c (dim and variable)
  - bcl-2
- Negative for
  - FMC-7
  - CD10
  - bcl-6
- CD38 and ZAP-70 expressed in half
Molecular and cytogenetics
- most common cytogenetic abnormality is trisomy 12
- # 1 FISH abnormality: del 13q (good)
  - others: tri 12, del(11q), del(14q), and del(17p)
  - 20% have normal FISH
Transformation:
- most common form is PLL
- Richter (large cell lymphoma)
- rarely transforms to Hodgkin

Question 4

Q

CLL prognosis adversely affected by

Answer

A

B symptoms
Diffuse pattern of marrow involvement
peripheral lymphocyte doubling time < 1 year
high initial lymphocyte count (>30,000)
unmutated Ig heavy chain gene variable region (IgVH)
- resemble pregerminal center B cells
- likely to progress
- candidates for treatment
- CD38 and ZAP-70 in > 30% of cells correlates with unmutated status
Chromosomal status by FISH
- Good: normal karyotype or del(13q) only
- Poor: 11q or 17p deletions

Question 5

Q

Mantle cell lymphoma

presentation
morphology
variants
immunophenotype
molecular and cytogentic
prognosis adversely affected by

Answer

A

Presentation
- adenopathy
- tends to involve Waldeyer ring and GI tract (lymphomatous polyposis)
Morphology
- diffuse or vaguely nodular lymph node effacement
- small to medium sized lymphocytes, irregular nuclear contour, small subtle nucleolus
- mitoses frequent
- admixed histiocytes and hyalinized vessels
- neither proliferation centers nor prolymphocytes
- variants: blastoid, pleomorphic, small cell, marginal zonelike
  - blastoid composed of large cells with high mitotic rate
  - blastoid and pleomorphic more aggressive
  - small cell variant resembles SLL; marginal zone like variant resembles MZL
Immunophenotype
- positive for: CD19, CD20 (bright), CD22, FMC-7, CD5, CD43, sIg (bright), bcl-1 (cyclin D1, prad 1), blc-2
- negative for: CD23, CD11c, CD10, CD99
Molecular and cytogenetic
- Positive for t(11;14)
  - rearrangment of JH region of IgH (14q32) to the CCND1 (11q13)
  - results in cyclin D1 (bcl-1) amplification
  - FISH is most sensitive
- most have additional abnormalities, often in chromosome 13
Prognosis adversely affected by mitotic rate > 10/HPF and Ki-67 > 40%

Question 6

Q

Follicular lymphoma

presentation
morphology
grading
diffuse growth
FL variants
in the marrow
immunophenotype
molecular and cytogenetic
prognosis adversely affected by

Answer

A

Presentation
- isolated lymphadenopathy without constitutional symptoms
Morphology
- nodular lymphoid proliferation: back to back, fused follicles with attenuated mantles
- often overruns capsule
- follicles lack polarity, tingible body macrophages, plasma cells, and have few mitoses
- 2 cell types: small cleaved cells (centrocytes) and large noncleaved cells (centroblasts)
Grading
- proportion of centroblasts in 10 fields
- grades 1 and 2 are low grade
- Grade 1: 0-5/HPF
- Grade 2: 6-15/HPF
- Grade 3
  - 3A: >15/HPF + some residual centrocytes
  - 3B: >15/HPF and no centrocytes
Diffuse growth
- lack of follicles and dendritic cells by CD21 and/or CD23 IHC
  - when low grade, called FL with focal diffuse growth
  - when high grade, called DLBCL
FL variants
- Intrafollicular FL (FL in situ)
  - intact interfollicular zones and open sinuses
  - follicles have cytologic features of FL: purely centroblasts and centrocytes that express bcl-2
- Isolated cutaneous FL
  - good px
  - lacks CD10 and bcl-2 expression
  - bcl-6 positive
  - lacks BCL2 rearrangement
- Isolated GI FL
  - good px
  - duodenum
- Pediatric FL is usually grade 3
In the marrow
- focal paratrabecular aggregates
- may be discordant with low grade in marrow and high grade in lymph node
Immunophenotype
- Positive: CD19, CD20 (bright), FMC-7, CD22, CD10, sIg (bright), bcl-2, and bcl-6
- Negative: CD5, CD43, CD11c, CD23
- Higher grade are less CD10 positive
- Ki-67 <20% in grades 1-2 and >20% in grade 3
- Background FDC express CD21 and CD23
Molecular and cytogenetic
- t(14;18)
  - FISH is most sensitive
  - Rearrangement of BCL2 on 18 with the J region of IgH on 14
  - Results in overexpression of bcl-2 protein with antiapoptotic properties
  - translocation not unique to FL and is most common encountered in B lineage lymphoma
  - bcl-2 overexpression also not unique to FL; bcl-2 overexpression in non-FL usually not associated with t(14;18)
Prognosis adversely affected by
- higher age, stage, and serum LDH
- bone marrow involvement
- B symptoms
- low performance status
- anemia

Question 7

Q

Marginal zone lymphoma (MZL)

presentation
morphology
immunophenotype
molecular and cytogenetic

Answer

A

Presentation
- Nodal
- Extranodal (MALT)
- Splenic
Morphology
- Nodal
  - nodular or diffuse proliferation
  - small lymphs, rounded to indented nuclei, abundant pale cytoplasm (monocytoid)
    - associated with chronic antigenic stimulation
    - most common site is GI tract (especially stomach)
  - clonal plasma cells often present
- Extranodal (MALT)
  - variably destructive and/or tumefactive proliferation
  - monocytoid B cells and clonal plasma cells
  - lymphoepithelial lesions
  - reactive polyclonal germinal centers can be present
- Splenic
  - expansion of white pulp
  - involves splenic hilar lymph nodes often
  - liver sinusoids involved
  - peripheral blood involvement
    - splenic lymphoma with villous lymphocytes (SLVL)
    - resembles HCL but SLVL more likely to
      - display nucleoli
      - display polar villous projections
Immunophenotype
- Positive: CD19, CD20, CD21, CD79A, FMC-7, bcl-2, sIg (IgM)
- Negative: CD5, CD23, CD10, CD103, annexin A1, CD11c
- plasma cells contain monoclonal cytoplasmic light chains
- CD43 is negative generally, but positive in 30% of MALT lymphoma
Molecular and cytogenetic
- t(11;18) - rearrangement of API2 and MALT1 genes in stomach and lung
- t(14;18) - MALT1-IgH fusion: ocular, parotid, and cutaneous
- t(3;14) - FOXP1-MALT1 in ocular, thyroid, and cutaneous
- t(1;14) in lung and small bowel
- +3 and +18 in all sites
A monoclonal gammopathy is present in 30-50% of cases

Question 8

Q

Hairy cell leukemia

Presentation
Morphology
Immunophenotype
Molecular findings

Answer

A

Presentation
- neutropenia, monocytopenia, or aplastic anemia
- splenomegaly
- 4:1 male:female
Morphology
- blood smears
  - large lymphoid cells 2x the size of normal lymph
  - nuclei round to reniform with smooth contour
  - chromatin ground glass with indistinct to absent nucleoli
  - hairy projections are circumferential
- Tissue
  - Fried egg morphology
  - reticulin fibrosis, blood lakes, and mast cells
  - in spleen, cells infiltrate the red pulp
  - in liver cells are in sinusoids
- Ultrastructure
  - ribosome lamellar complexes
- Histochemistry
  - cells contain tartrate resistant acid phosphatase (TRAP)
  - weak TRAP nonspecific, but strong TRAP staining is specific
Immunophenotype
- Positive: CD19, CD20, CD22, sIg, CD11C (bright), CD25 (bright), CD103, DBA.44, annexin A1, cyclin D1 (dim, nuclear)
- Negative: CD5, CD43, CD23, CD10
- 10% are CD10+
No reproducible molecular findings

Question 9

Q

Prolymphocytic leukemia

Answer

A

presents abruptly with a very high white count > 100,000/uL, B symptoms, cytopenia, and splenomegaly
Definition: > 55% prolymphocytes (prominent nucleoli and a moderate quantity of cytoplasm)

Question 10

Q

Lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia

how to diagnose LPL
how to diagnose Waldentrom
associated with
morphology
molecular and cytogenetics

Answer

A

Lymphomas wtih plasmacytic features
- SLL/CLL, MCL, and MZL
- LPL diagnosed when these are excluded
Waldenstrom macroglobulinemia is LPL with an IgM monoclonal gammopathy and marrow involvement
Associated with HCV and cryoglobulinemia; may respond to anti viral therapy
Morphology
- small lymphs to plasma cells
- Dutcher bodies possible
- Lymph nodes
  - architecture may be normal or effaced
  - PAS+ material in sinuses
Immunophenotype
- Positive: CD19, CD20, CD38, sIg (bright), cIg (plasma cells)
- Negative: CD5, CD23, CD43, CD10
Molecular and cytogenetic
- t(9;14) involving PAX5 and C region of IgH

Question 11

Q

Heavy chain disease

Answer

A

only IgH are produced
Most common form is alpha H chain disease
- a form of MALT lymphoma also called immunoproliferative small intestine disease (IPSID) or Mediterranean lymphoma, associated wtih C. jejuni
gamma heavy chain disease (Franklin H chain disease) found in some cases of LPL
mu heavy chain disease found in some cases of CLL

Question 12

Q

Diffuse large B cell lymphoma

presentation
morphology
immunophenotype
molecular and cytogenetic
prognosis

Answer

A

Presentation
- rapidly enlarging lymph node or extranodal site
- localized at presentation, bone marrow involvement uncommon (10%)
Morphology
- diffuse nodal effacement by predominantly large cells (larger than a macrophage nucleus)
Immunophenotype
- positive: CD19, CD20, CD22, CD45, often bcl-2
- variable: CD10, CD5, and bcl-6
  - CD5 expressing cases must be distinguished from blastoid MCL (bcl-1+)
- Ki67 60-99%
Molecular
- BCL2 and BCL6 rarrangements present in 20-30%
  - BCL6 gene, 3(q27), rearranges with variety of partners, commonly t(3;14)
  - rearrangements of BCL6 more common in the ABC type
  - rearrangement of BCL2, t(14;18), more common in the GCB type
Prognosis
- germinal center-like has better response to treatment than activated B cell like (ABC)
- Germinal center-like type:
  - CD10+ BCL6+ MUM1 -
  - CD10+ BCL6 - MUM1-
  - CD10- BCL6+ MUM1-
- Non germinal center type
  - CD10 - BCL6+ MUM1+
  - CD10 - BCL6- MUM1+

Question 13

Q

Stepwise evaluation of DLBCL subtypes by IHC

Answer

A

CD10
- if positive, then it’s GC type
- if negative go to #2
BCL6
- if negative, then non GC type
- if positive, then go to #3
MUM1
- if positive, then non-GC
- if negative, then GC type

Question 14

Q

Primary DLBCL of the CNS

median age
location in brain
presentation
micro
FISH results

Answer

A

median age 60 years
supratentorial mass with radiographic features that mimic GBM
may present or recur as intraocular lymphoma
tumor cells often in perivascular cuffs and express pan B antigens
most cases have BCL6 rearrangement and overexpress bcl-6; BCL2 rearrangement is rare

Question 15

Q

T cell/histiocyte rich large B cell lymphoma (TCRBCL)

median age
micro
IHC
marrow

Answer

A

median 40 years (children to old age)
diffuse proliferation of small lymphocytes and histiocytes with scattered large B cells
Small lymphocytes are a mixture of CD4+ and CD8+ T cells
- absent are
  - CD57+ T cells
  - T cell rosettes
  - small B cells
  - CD21+/CD23+ FDC meshwork
Large B cells express pan B markers and bcl-6; some are EMA+
- Can be positive for CD10
- negative for CD15, CD30, and EBV
Involves marrow as paratrabecular lymphoid aggregates

Question 16

Q

Primary mediastinal (thymic) large B cell lymphoma

gender, age
micro
IHC
molecular

Answer

A

young adult women, F:M = 2:1
a sclerosing lymphoma with large B cells entrapped within bands of sclerosis
Positive: CD45, CD19, CD20, CD79a, CD30
NEGATIVE FOR surface Ig, CD10, CD5
Altered MAL gene, gains in 9p (locations of JAK2)
No rearrangement of BCL2 or BCL6

Question 17

Q

ALK+ large B cell lymphoma

Answer

A

Rare; immunoblastic/plasmablastic cells that express ALK

Question 18

Q

Plasmablastic lymphoma

IHC
patient population
site of involvement

Answer

A

rare; immunoblastic/plasmablastic cels
Positive: CD38, CD138, IRF4/MUM1, cIg, EBV
Negative: CD45, CD20, CD56 (in contrast to plasmayctoma)
Found in HIV+ adults and arises mostly in extranodal sites such as oral cavity mucosa

Question 19

Q

Intravascular large B cell lymphoma

aka
symptoms

Answer

A

aka angioendotheliomatosis, angiotropic lymphoma, and intravascular lymphomatosis
symptoms related to small vessel obstruction by large B cells
lymph node involvement rare

Question 20

Q

Primary effusion lymphoma

associated with
presentation
micro
IHC

Answer

A

Associated with HHV8 and HIV
Presents with effusion (pleural, pericardial, peritoneal)
- contains large B cells with immunoblastic/plasmablastic/anaplastic morphology and cytoplasmic vacuolization
negative for B/T/myeloid antigens (CD20, CD79, CD19, CD10, CD3, CD5, CD13, CD14, CD33)
Positive for CD45, CD30, CD38, CD138, EMA, HHV8

Question 21

Q

Leg type primary cutaneous DLBCL

Answer

A

rare; affects elderly women

Question 22

Q

EBV+ DLBCL of the elderly

affects what population
other EBV positive large B cell neoplasms

Answer

A

rare; affects elderly Asian adults
Other EBV+ large B cell neoplasms
- plasmablastic lymphoma
- PEL
- lymphomatoid granulomatosis
- DLBCL associated with chronic inflammation
- EBV+ DLBCL of the elderly
- EBV+ DLBCL, NOS

Question 23

Q

Lymphomatoid granulomatosis

Answer

A

Large B cells destructively invade vessel walls resembling vasculitis
many reactive T cells, plasma cells, histiocytes
granulomas are uncommon
most commonly affects lungs, upper aerodigestive tract, brain, kidneys, and liver
associated wtih EBV and immunodeficiency

Question 24

Q

DLBCL associated with chronic inflammation

Answer

A

forms within sites of longstanding inflammation (e.g., pyothorax)
EBV+

Question 25

Q

Lymphoproliferative disorders arising in primary immunodeficiency

Answer

A

Primary immunodeficiencies
- ataxia telangiectasia
- Wiskott Alrdich
- CVID
- X linked LP disorder (Duncan)
- Nijmegen chromosomal breakage syndrome
Most common LPDs
- DLBCL, LG, and T cell neoplasm

Question 26

Q

Most common lymphomas in HIV

Answer

A

BL
DLBCL (especially CNS)
PEL
plasmablastic lymphoma
HL

Question 27

Q

Posttransplant lymphoproliferative disorder

occurs how long after transplant?
heralded by?
risk factors
PTLD clone comes from donor or recipient?
does it involve the allograft?

Answer

A

Usually <1 year after transplant
EBV implicated in most (especially in 1st year)
Heralded by elevated EBV viral load
Late (>5 years out) PTLD is most aggressive and EBV-
Risk factors
- allograft
  - renal and BMT have lowest risk
  - heart-lung and liver-bowel have higher risk
- children
- EBV- at time of transplant
PTLD clone usually of recipient origin
often involves the allograft itself

Question 28

Q

Burkitt lymphoma/leukemia

Types
Morphology (tissue and blood)
Immunophenotype
vs DLBCL, NOS
vs B-LBL/B-ALL
molecular

Answer

A

3 clinicopathologic types of Burkitt lymphoma are recognized
- African (endemic): jaw mass in child, EBV+
- Western (sporadic): nodal, abdominal, less associated with EBV; kids and adults
- Burkittlike lymphoma: nodes, IC hosts
morphology
- tissue
  - diffuse proliferation; medium sized nuclei with 2-5 nucleoli
  - many tingible body macrophages, high rate of mits/apoptosis
- Wright stained blood
  - deep blue cytoplasm with lipid containing vacuoles
Immunophenotype
- positive: CD19, CD20, CD22, CD10, bcl-6, sIg, C-myc
- negative: CD5, CD23, Tdt, CD34, bcl-2
- Ki67 >99%
- vs DLBCL, NOS
  - BL positive for c-myc, negative for bcl-2, and Ki67 >99%
  - BL unlikely if CD10 negative, bcl-6 negative, or bcl-2 positive
  - BL unlikely if either BCL2 or BCL6 rearrangements are present
- vs B-LBL/B-ALL
  - BL is Tdt negative, CD20 positive, and sIg positive
Molecular
- rearrangement of C-MYC on chromosome 8
- t(8;14)
- Igkappa t(2;8)
- Iglambda t(8;22)

Question 29

Q

Lymphoblastic leumkemia and lymphoma categories

Answer

A

B-ALL/LBL, NOS
B-ALL/LBL with recurrent cytogenetic abnormalities
T-ALL/LBL

Question 30

Q

LBL vs ALL

Answer

A

LBL: lesions involving tissue and sparing blood and marrow
ALL: marked involvement of marrow (>25%) and blood (>20%) regardless of tissue involvement
ALL: B lineage in 80%
LBL: T lineage in 80%

Question 31

Q

Clinical presentation and morphology of ALL/LBL and morphology and cytochemistry

Answer

A

B-ALL is most common malignancy in children; peaks at 3 years of age
T-LBL presents as anterior mediastinal mass; hypercalcemia is common
Morphology
- undifferentiated blasts
- cytochemically negative for MPO and SBB; PAS+ in blocklike/coarse granular pattern

Question 32

Q

B-ALL/LBL, NOS

immunophenotype
prognosis
hematogones vs ALL
molecular and cytogenetic

Answer

A

Immunophenotype
- positive: CD19, CD10, PAX5, CD34, CD99, HLA-DR, nuclear TdT
- Usually negative for CD20 and sIg
- absence of CD10 suggests MLL anomaly
- 30-50% express at least 1 myeloid antigen (CD13 or CD33)
Prognosis
- Good
  - lower initial white count
  - 2-10 years old
  - female
  - complete remission (day 14 marrow) following induction chemo
Hematogones vs ALL
- hematogones disperse, both in CD34 stained marrow sections and in flow plots
  - blasts cluster
- by flow cytometry, hematogones display a range of expression of CD10, CD20, Cd34, Tdt, sIg
  - blasts express a relativly uniform strength
Molecular and cytogenetic
- 6q
- 9p
- 12p
- “recurrent genetic abnormalities” absent

Question 33

Q

B-ALL/LBL with recurrent genetic abnormalities

Answer

A

Most common structural abnormality is t(9;22)(q34;q11)
- unfavorable
- minor breakpoint (m-bcr) rearrangement, chimeric protein of 190kD most common
t(v;11q23), usually t(4;11)
- MLL
- infants
- unfavorable
- overexpress FLT3
t(12;21)
- TEL-AML1 (ETV6-RUNX1)
- 25% of children
- good
Hyperdiploid
- >50
- 25% of children
- good
Hypodiploid
- <46
- <5% of children
- unfavorable
t(1;19)
- E2A-PBX1 (TCF3-PBX1)
- 5% of children
- unfavorable
t(5;14)
- IL3-IGH
- <1% of children and adults
- usual prognosis
- eosinophilia

Question 34

Q

T-ALL

immunophenotype
molecular
T-LBL vs thymoma

Answer

A

Immunophenotype
- positive: CD99, CD7, CD2, CD5, CD3 (cytoplasmic), and TdT (nuclear)
- CD34 variable; HLA-DR is usually negative
- CD4 and CD8 often both positive or both negative
- some express myeloid antigens (CD13 or CD33)
T-LBL vs thymoma
- Thymoma is EMA positive
- By flow, similar to distinction of hematogones and B-ALL
  - Thymoma: dispersal plots of CD4 vs CD8 and CD45 vs CD3
  - T-LBL: tight clustering in plots of CD4 vs CD8 and CD45 vs CD3

Question 35

Q

Plasma cell myeloma

age
race
gender
forms
renal manifestations

Answer

A

median 70 years
blacks > whites
males >females
forms
- symptomatic
- smouldering
renal manifestations
- hypercalcemia and/or hyperuricemia induced tubular injury
- AL amyloidosis most commonly found with lambda light chains
- Light chain deposition disease most commonly with kappa light chains
- myeloma cast nephropathy

Question 36

Q

Multiple myeloma

paraproteins

Answer

A

isotype (heavy chain) is most commonly IgG
- IgA (22%)
- none - light chain only (18%)
- IgD (1-2%)
- biclonal (1-2%)
- IgE (1-2%)
idiotype (light chain) is most commonly kappa
nonsecretory myeloma is found in 5% of cases

Question 37

Q

Multiple myeloma immunophenotype

Answer

A

positive: CD38, CD138, CD56, cytoplasmic lambda or kappa, and PCA1
negative: CD45, CD19, CD20, CD21, CD22, sIg
some are cyclin D1+ (bcl-1), correlating with t(11;14)
10-30% express myelomonocytic markers (CD117, CD33, CD13, CD11b, CD15)
10-50% express CALLA (CD10)
occasionally EMA and CD30+

Question 38

Q

Molecular and cytogenetics of multiple myeloma

Answer

A

most common abnormality is in IgH (14q32)
- 14q32 rearrangement found in >70% of myeloma and 50% of MGUS
t(11;14) produces CCND1/IgH fusion

Question 39

Q

Multiple myeloma prognosis (adverse)

Answer

A

adverse:
- higher levels of beta2 microglobulin
- high plasma cell labeling index
- high stage
- chromosomal abnormalities by FISH

Question 40

Q

Plasma cell leukemia

Answer

A

>20% or >2 x 10⁹/L plasma cells in the peripheral blood
1/2 of cases present de novo
present abruptly and follows an aggressive course
high incidence of monosomy 13
plasma cells often CD56 negative

Question 41

Q

Solitary cell leukemia

Answer

A

solitary osseous plasmactyoma arises most often in vertebrae, ribs, and pelvis
- 1/2 have detectable M protein
- Most develop MM within 10 years
Solitary extraosseous arises most commonly in the nasal cavity, oropharynx, or larynx
- most do not have a detectable M protein
- most do not develop MM

Question 42

Q

MGUS

prevelance
classification
risk for development of MM or other PCN

Answer

A

present in 3% of adults over the age of 50 years and 5% of adults over the age of 70 years
60% of patients with an M protein are classified as MGUS
1% progression per year to MM or another PCN
after 20 years, 1 in 3 develops overt myeloma

Question 43

Q

T cell neoplasms

Answer

A

5% of lymphoid neoplasms
incidence highest in Asia
- enteropathy associated T cell lymphoma strongly associated with Welsh and Irish ancestry
Most common T cell neoplasms, in decreasing order: PTCL NOS, AITCL, ALCL, ATCL

Question 44

Q

Peripheral T cell lymphoma

Answer

A

Any T cell neoplasm that does not fit any other clinicopathologic entity
Most common T cell lymphoma
Morphology
- diffuse proliferation of polymorphic small and large lymphoid cells
- neoplastic lymphs may have cloverleaf nuclei
- admixed eos, plasma cells, and/or histiocytes
- postcapillary venules may be prominent
Immunophenotype
- CD4+
- CD8-
- Loss of one or several pan T cell markers
- CD25-

Question 45

Q

Adult T cell leukemia/lymphoma

Caused by
Clinical presentation
Morphology
Immunophenotype

Answer

A

Caused by HTLV-1
- endemic in southwest Japan, Oceania, and the Caribbean
- rare in North America
- Lifetime risk of ATCL in HTLV-1 positive people is 5% (greater for men than women)
Clinical presentation
- LAD and HSM
- visceral involvement (CNS, lungs, GI tract)
- rash
- hyperCa
- lytic bone lesions
Morphology
- nuclear irregularity with cloverleaf or flower forms
Immunophenotype
- positive: CD2, CD3, CD5, CD4, and CD25
- negative: CD7 usually and CD8

Question 46

Q

Angioimmunoblastic T cell lymphoma (AITCL)

associated with
age
presentation
morphology
immunophenotype

Answer

A

EBV associated neoplasm affecting older adults
Clinical presentation
- abrupt onset
- constitutional symptoms: fever, night sweats, weight loss
- generalized LAD
- pruritic rash
- pleural effusion
- Coombs+ autoimmune hemolytic anemia
- cold agglutinins
- anti-smooth muscle antibody
- RF
- polyclonal hypergammaglobulinemia
Morphology
- diffuse nodal effacement with prominence of postcapillary venules
- immunoblasts, lymphs, plasma cells, eos, aggregates of cells with clear cytoplasm
- deposition of PAS+ extracellular material, and a mixed lymphoid infiltrate
- absence of apparent follicles; CD21 displays hyperplastic follicular dendritic cells
Immunophenotype
- positive: CD4, most pan T markers (CD2, CD3, CD5, CD7) and TFH markers (CD10, bcl-6, CXCL-13)
- negative: CD8, loss of one or several pan T cell markers (CD2, CD3, CD5, CD7)
- EBV is present in B cells

Question 47

Q

Anaplastic large cell lymphoma

population
morphology
prognosis
immunophenotype
molecular

Answer

A

children and young adults
- 50% of childhood high grade lymphomas
morphology
- diffuse proliferation with many large lymphs, some of which are anaplastic
- anaplastic cells cluster near blood vessels
- small cell variant is composed of large, but not anaplastic lymphoid cells; may be mistaken for PTCL
prognosis depends on expression of Alk; Alk+ has best prognosis
- WHO classification has separate categories for Alk+ and Alk- ALCL
- Alk- ALCL has worse prognosis than Alk+ but better than PTCL NOS
Immunophenotype
- positive: CD30 (membranous and golgi), clusterin, EMA, CD45
- often positive for myeloid antigens (CD13, CD33)
- often positive for T cell antigens (CD4)
- Alk expression correlates with t(2;5)
  - with usual t(2;5) NPM-ALK, Alk is expressed in cytoplasm and nucleus
  - variant translocations result in various patterns of Alk expression
- negative for B cell antigens, CD15, and EBV
Molecular and cytogenetics
- t(2;5) in >95%
  - ALK (anaplastic lymphoma kinase) gene on 2p23 and NPM (nucleophosmin) on 5q
- clonal TCR rearrangement in 90%

Question 48

Q

Large granular lymphocytic leukemia (LGL leukemia)

define

Tc cytotoxic LGL leukemia:

presentation (clinical, labs)
immunophenotype
cytogenetics

Answer

A

> 6 month increase (>2 x 10⁹) in LGL
- may be T cells or NK cells
Tc cytotoxic LGL leukemia
- neutropenia
- splenomegaly
- polyclonal hypergammaglobulinemia
- older men
- associated with rheumatoid arthritis
- usually indolent; more aggressive if CD56+ blast-like cells present
Immunophenotype
- positive: CD2, CD3, CD8, CD16, CD57, granzyme M, granzyme B
- negative: CD4, often negative/dim for CD7 and or CD5
TCR rearranged

Question 49

Q

NK cell LGL leukemia

presentation
IHC
molecular

Answer

A

neutropenia, anemia, fever, jaundice, HSM
EBV negative (in contrast to aggressive NK cell leukemia)
Immunophenotype
- positive: CD2, CD16, CD56
- variable: CD7, CD8, CD57
- negative: surface CD3 (cytoplasmic epsilon chain of CD3 is positive) and CD4
TCR germline

Question 50

Q

Aggressive NK cell leukemia

Answer

A

aggressive EBV associated neoplasm
Asians
mean age 40

Question 51

Q

Nasal type NK/T cell leukemia

Answer

A

extranodal, usually nasal, EBV associated neoplasm
angioinvasive growth pattern
more common in Asians, Native Americans

Question 52

Q

Enteropathy associated T cell lymphoma

associated with
sites affected
MHC type
immunophenotype

Answer

A

high grade T cell lymphoma in patients with longstanding celiac sprue
often preceded by refractory sprue with mucosal ulceration (ulcerative jejunoileitis)
jejunum and/or ileum
like sprue, Welsh and Irish ancestry common
- most have the HLADQA1*0501, DQB1*0201 genotype
CD3+, CD30+, and usually CD4-/CD8-

Question 53

Q

Hepatosplenic T cell lymphoma types

Answer

A

gamma-delta type
- young males
- B symptoms
- HSM
- cytopenias
- CD8+ cytotoxic T cells that express gamma delta TCR and isochrome 7q
alpha-beta type
- female
- wider age distribution

Question 54

Q

Cutaneous T cell lymphoma

IHC
micro
define MF
define Sezary

Answer

A

CTCL is a CD4+ T cell neoplasm with epidermotropic growth pattern
- small to large lymphoid cells with cerebriform nuclei
MF is CTCL which involves lymph nodes
Sezary syndrome is CTCL involving peripheral blood

Question 55

Q

Nodular lymphocyte predominant Hodgkin lymphoma

morphology
NLPHL vs TCRBCL
NLPHL vs CHL

Answer

A

morphology
- nodular or vaguely nodular
- RS cells rare to absent
- L&H cells with large vesicular convoluted (popcorn) nucleus
- progressive tranformation of germinal centers thought to be precursor lesion
NLPHL vs TCRBCL
- Meshwork of follicular dendritic cells, highlighted by CD21 or CD23 IHC
- predominance of CD20+ B cells
- wreath of CD3+/CD57+ T cells
NLPHL vs CHL
- neoplastic cell in NLPHL
  - L&H cells express CD45, CD20, surface Ig, bcl-6, and EMA, OCT2, BOB1 (latter two stains incorrectly described in Compendium)
  - L&H cells negative for EBV

Question 56

Q

Classic Hodgkin lymphoma

Immunophenotype
Age
Presentation
Bone Marrow

Answer

A

Immunophenotype
- positive: CD15, Cd30
- often positive for fascin, IRF4/MUM1, PAX5 (weak), EBV, antigens (LMP-1, EBER1/2)
- negative: CD45, CD20, bcl-6, ALK, EMA
- 10-20% are CD20+
- background lymphs predominantly T cells
Incidence: bimodal (15-25 years and after age 50)
Clinical presentation:
- localized LAD
  - cervical lymph nodes most often, followed by mediastinum
  - spread via contiguous lymphatic sites; noncontiguous spread in LD
- B symptoms
Bone marrow
- LD and HIV-associated have highest involvement
- 10% overall
- atypical mononuclear CD30+ cells

Question 57

Q

Nodular sclerosis HL

site affected
micro
variant
ISH
background

Answer

A

Mediastinum
Micro
- nodular with bands of sclerosis
- RS cells, Hodgkin cells, and lacunar cells
- lacunar appearance due to formalin fixation artifact
syncytial NS an aggressive form of CHL that presents at high stage with bulky mediastrinal disease, composed of sheets of RS cells and RS variants; may have necrosis
25% EBV positive
background is mixed

Question 58

Q

Mixed cellularity HL

site affected
age
associated with
micro
ISH

Answer

A

peripheral nodes
25-45 years
HIV associated
developing nations
diffuse proliferation of lymphs, eos, histiocytes, and plasma cells with varying numbers of classic RS cells and mononuclear Hodgkin cells
75% EBV positive

Question 59

Q

Lymphocyte rich CHL

compared wtih NLPHL
site affected
age
micro
ISH

Answer

A

similar NLPHL but has typical immunophenotype of CHL
peripheral nodes
35-55 yo
Micro
- R-S cells
- Hodgkin cells
- popcorn cells
50% EBV positive

Question 60

Q

Lymphocyte depleted HL

site affected
percentage of CHL
age
associated with
micro
ISH
prognosis

Answer

A

retroperitoneum
<1% of CHL
30-40 years
HIV associated
Developing nations
RS cells and variants > 15/HPF
Pleomorphic cells
mixed background
50% EBV positive
relatively aggressive

Question 61

Q

Blast equivalents

Answer

A

promonocyts in diagnosis of acute monocytic or myelomonocytic leukemia
promyelocytes in APL
erythroblasts in pure erythroleukemia

Question 62

Q

MDS and splenomegaly

Answer

A

Usually splenomegaly is not present in MDS

Question 63

Q

Secondary MDS caused by

Answer

A

chemotherapy (alkylating agents)
- associated with 5q or 7q
radiation
benzenes
Fanconi anemia

Question 64

Q

MDS morphology

general marrow findings
blast %
dispoiesis in erythroid, myeloid, and meg lines

Answer

A

Marrow is usually hypercellular; sometimes abnormal localization of immature precursors
blasts < 20%
dyspoiesis present in at least one cell line
- erythroid
  - PB: anemia, basophilic stippling, poikilocytosis, and macrocytosis
  - Marrow: megaloblastoid change and/or nuclear lobation, internuclear bridging, multinuclearity, karyorrhexis, ringed sideroblasts (at least 5 siderosomes surrounding at least 1/3 nucleus), cytoplasmic PAS+, cytoplasmic vacuoles
  - Functional: increased susceptibility to complement mediated lysis, increased HbF, abnormal expression of red cell antigens, acquired enzyme defects (e.g., pyruvate kinase deficiency), acquired thalassemia
- Granulocytic (myeloid)
  - PB: neutropenia, abnormal cytoplasmic granulation, or abnormal nuclear segmentation (including pseudo Pelger-Huet anomaly)
  - Marrow: megaloblastoid maturation, abnormal cytoplasmic granulation
  - Functional: increased susceptibility to bacterial infection
- Megakaryocytic dyspoiesis:
  - PB: thrombocytopenia, variable size, variable granulation
  - Marrow: micromegs, multinucleated megs, hypolobated megs
  - Functional: abnormal platelet aggregometry
Heathly marrow contains dyspoietic cells (<5% of any cell line)
Dyspoiesis must be >10% in a cell line to diagnose dysplasia

Answer 64

A

B12 and folate deficiency
alcohol
HIV
lead
arsenic
copper deficiency/zinc intoxication (prominent erythroid vacuolization and iron laden plasma cells are clues)
medications
- INH
- chloramphenicol
- chemo

Answer 65

A

30-40% of low grade (RA, RARS) have cytogentetic abnormalities
70-80% of high grade have abnormalities
most common is complex karyotype (2 or more clonal abnormalities)
2nd most common is isolated 7 or 7q-
3rd most common is isolated 5q-
- disproportionately affects elderly women
- anemia, normal to elevated platelets, micromegs in bone marrow
- indolent clinical course

Answer 66

A

primary features
- persistent absolute monocytosis (>1 x 10⁹/L)
- marrow dysplasia
- <20% blasts (blasts + promonocytes)
- absence of Philadelphia chromosome
- HSM
- anemia
- thrombocytopenia
- abnormal monocyte morphology
2 types
- CMML-1: blasts and promonocytes < 5% in PB and <10% in marrow
- CMML-2: 5-19% in PB , 10-19% in marrow
Molecular and cytogenetic
- JAK2 mutation in some
- if eosinophilia is present, rearrangement of PDGFRA and PDGFRB should be excuded

Answer 67

A

neutrophilia
spectrum of neutrophils, metamyelocytes, myelocytes, and promyelocytes
marrow dysplasia
<20% blasts
absence of Philadelphia chromosome
most have cytogenetic anomalies, especially +8 or del(20q)
some have JAK2 mutations

Answer 68

A

monocytosis and/or granulocytosis
HSM
B symptoms
may have anemia, thrombocytopenia, increased HbF
may have monosomy 7
in vitro spontaneous formation of granulocyte macrophage colonies that are hypersensitive to GM-CSF is confirmatory
nearly 10% of patients have NF-1

Answer 69

A

t(9;22)
ABL locus at 9 and BCR at 22
chimeric Bcr-Abl protein with enhanced tyrosine kinase activity
major breakpoint cluster p210 fusion protein
uncommonly occurs at mu-BCR breakpoint with p230 fusion protein
- associated with thrombocytosis and more mature leukemic neutrophils
uncommonly m-BCR breakpoint with p190 fusion protein associated with
- CML with marked monocytosis
- Ph+ ALL

Answer 70

A

Indices
- leukocytosis with neutrophilia, monocytosis, basophilia, eosinophilia
- thrombocytosis common
neutrophils immature, and myelocyte proportion is high
marrow
- hypercellular with high M:E ratio and small hypolobated dwarf megs
- mild reticulin fibrosis and thickening of paratrabecular generative cuffs
splenomegaly
low leukocyte alkaline phosphatase (LAP) score
elevated B12

Answer 71

A

Marked by at least one of the following:

progressive basophilia (>20%)
progressive thrombocytopenia (<100 x 10⁹/L) or thrombocytosis (<1000 x 10⁹/L)
clonal cytogenetic progression (+8, i17q, +19, 2nd Ph chromosome)
increasing blasts: > 10% (but less than 20%)

Answer 72

A

>20% blasts in blood or marrow, a tissue infiltrate of blasts (chloroma), or a prominent focal accumulation of blasts in the marrow biopsy (filling an intertrabecular space)
70% AML, 30% ALL
often additional cytogenetic abnormalities

Answer 73

A

Most powerful prognostic factor is response to TKI therapy as measured by RT-PCR
- imatinib resistance present in 5% of cases
- resistance often result of mutations within BCR-ABL gene; tyrosine kinase domain and the P loop

Answer 74

A

presentation
- HTN
- thrombosis
- pruritis
- plethora
- erythromelalgia
- headache
- splenomegaly
Phases
- Proliferative (chronic)
  - erythrocytosis, sometimes with neutrophilia, basophilia, and/or thrombocytosis
  - marrow hypercellular, usually with megakaryocytic hyperplasia; iron decreased
- Spent phase (postpolycythemic myelofibrosis with myeloid metaplasia)
  - peripheral myelophthisic pattern, marrow reticulin fibrosis, and extramedullary hematopoiesis
Cause of death: thrombosis is #1, acute leukemia is #2
JAK2 mutation
- >90% of PV and over 50% of ET and PMF
- involved in stimulating the STAT pathway
- most common mutation is G to T at nt 1849 resulting in val to phe at codon 617
- 2nd activating mutation within JAK2 exon 12 in some cases
mutations in MPL is present in some PMF and ET, but are not seen in PV

Answer 75

A

bimodal ages: 30 and 60
longest survival of the MPNs with the lowest transformation to acute leukemia
presents as isolated thrombocytosis
marrow:
- large, hyperlobated megs that are paratrabecular and display emperipolesis
- iron usually present (helpful to exclude iron deficiency)

Answer 76

A

Cellular phase (prefibrotic)
- anemia, mild leukocytosis, thrombocytosis
- marrow hypercellular
- megs abnormal (aberrantly lobulated with clumped, inky chromatin) in clusters adjacent to sinuses and trabeculae
Fibrotic phase
- leukoerythroblastic pattern in PB
- marrow is inaspirable
- reticulin fibrosis, intrasinusoidal hematopoiesis
- abnormal clustered megs

Answer 77

A

Male:female = 9:1
ages 25-45
PB eosinophilia (>1.5 x 10⁹/L) with tissue infiltration and damage
- heart
- GI
- lung
- CNS
eos may be hypogranular, but granules highlighted by cyanide resistant MPO stain
must exclude allergic reaction, parasitic infection, collagen vascular disease, mastocytosis, other hematolymphoid neoplasms (PDGFRalpha, PDGFRbeta, and FGFR1 rearrangement)
must have evidence of clonality, such as increased blasts or clonal cytogenetic abnormality; without this the diagnosis is hypereosinophilic syndrome

Answer 78

A

Most common type of acute leukemia in adults and infants < 1 year of age
- median age 65 years
Presentation
- leukocytosis or pancytopenia or soft tissue mass (chloroma)
  - blasts usually present in PB
Diagnosis
- blasts >20%
- blasts <20% if there is pure erythroleukemia, myeloid sarcoma, or defining genetic abnormalities
- blast count may include promyelocytes in APML or promonocytes in acute monocytic leukemia
Immunophenotype
- positive: CD13, CD33, HLA-DR, CD34, and CD45 (dim)
- some express CD7 or CD19
Classfied:
- AML with recurrent genetic abnormalities
- AML arising secondary to therapy
- AML with myelodysplasia related changes
- AML, NOS

Answer 79

A

young adults
very chemosensitive
involves AML1 (RUBX1) and ETO (RUNX1T1) genes
AML1 encodes alpha chain of core binding factor (CBFalpha)
blasts have azurophilic granularity, sometimes with large granules (pseudo Chidiak Higashi) and Auer rods
favorable prognosis
Immunophenotype:
- positive: CD34, CD13, CD33, CD56, HLA-DR, CD19
- high rate of activating KIT mutations in relapsed cases

Answer 80

A

M4-like
increased/abnormal eosinophils
involves MYH1 (myosin) and CBFBeta genes
blasts with myelomonocytic differentiation and abnormal eosinophils
eos with large granules with alpha napththyl acetate esterase
usually no eosinophilia in PB
Immunophenotype:
- positive: CD13, CD33, CD14, CD64, CD11b, HLA-DR, lysozyme, and CD2
younger adults
chemosensitive
favorable prognosis

Answer 81

A

Acute promyelocytic leukemia

promyelocytes
- cytoplasm varies from intensely granulated to agranular (microgranular variant)
- microgranular variant has occasional Auer rods and is strongly MPO positive
often have DIC
respond to tranretinoic acid (ATRA)
Immunophenotype:
- positive: CD33, CD13, CD15 (DIM)
- negative: HLA-DR and CD34
t(15;17) results in RARalpha next to PML
variant translocations: t(11;17) and t(5;17)
- insensitive to ATRA
middle age
favorable prognosis

Answer 82

A

common in children
MLL anomalies
monoblastic differentiation (M5-like)
immunophenotype:
- positive: CD4, CD14, CD64, CD11b, lysozyme
- negative: usually CD34
intermediate prognosis

Answer 83

A

multilineage dysplasia
RS
increased platelets
erythroid hyperplasia
Topo II: 11q23 (MLL) or 21q22 (RUNX1)
Therapy + 5 years
poor prognosis

Answer 84

A

any morphology, especially M4 with basophilia
DEK/NUP214
children and adults
poor prognosis
immunophenotype:
- positive: CD34, HLA-DR, CD13, CD33
- Tdt +/-

Answer 85

A

megakaryocytic (M7-like)
RBM15/MKL1
infants
intermediate prognosis
immunophenotype:
- positive: CD13, CD33, CD41, CD61
- negative: CD34, HLA-DR

Answer 86

A

M0, M1, or M7-like
thrombocytosis
giant agranular platelets
RPN1/EVI1
adults
poor prognosis

Answer 87

A

Agranular cytoplasm
- <3% blasts stain with SBB, MPO, and NSE
- myeloid differentiation demonstrable only by immunophenotyping (or ultrastructural cytochemical reactions)
Immunophenotype
- positive: CD13, CD33, CD117, CD34, HLA-DR
- negative: CD14, CD15, CD11b
- Tdt+ in up to 30% of cases
Poor prognosis

Answer 88

A

3-10% of blasts show maturation (stain with MPO, CAE, or SBB)
rare Auer rods and/or granulation
usually express CD34, CD13, CD33, HLA-DR, CD117
poor prognosis

Answer 89

A

maturation in greater than 10% of blasts
monocytic differentiation in <20% of nonerythroid cells
cytoplasmic granulation and Auer rods frequent
rule out t(8;21)
immunophenotype:
- positive: HLA-DR, CD13, CD33, CD117, CD15
- may or not be CD34 positive
Variable prognosis

Answer 90

A

at least 20% of nonerythroids have monocytic differentiation
at least 20% of nonerythroids have neutrophilic differentiation
immunophenotype
- positive: CD13, CD33, CD4, CD14, CD64, CD11b
- smaller population may be CD34+
variable prognosis

Answer 91

A

monocytic differentiation in over 80% of nonerythroid cells (including monoblasts, promonocytes, and monocytes)
acute monoblastic leukemia
- >80% of monocytic cells are monoblasts
acute monocytic leukemia
- <80% monoblasts
Immunophenotype
- postiive: HLA-DR, CD4, CD14, CD64, CD11b, lysozyme
- variable expression of CD13, CD33, CD117
- variable but usually negative CD34
younger people
often have soft tissue infiltration (gingival, CNS)
poor prognosis

Answer 92

A

2 subtypes
- erythroleukemia
  - >50% of all nucleated cells are erythroids and >20% of nonerythroids are myeloblasts
- pure erythroid leukemia (true erythroleukemia, acute erythremic myelosis)
  - >80% of all nucleated cells are erythroid precursors; without excess myeloblasts
peripheral anemia, not erythrocytosis, with numerous circulating nucleated RBCs
marrow erythroids dysplastic and megaloblastoid
erythroid cytoplasm may have vacuoles and PAS positivity (like ALL blasts)
Immunophenotype
- Myeloblasts variably positive for CD34, HLA-DR, CD13, CD33, CD117
- Erythroids: HLA-DR, CD34, glycophorin (CD235a), and CD71 (may be aberrantly dim)
cases wtih >50% erythroids but <20% myeloblasts may be classified as MDS (RAEB)
poor prognosis

Answer 93

A

>50% of blasts megakaryocytic, either by platelet peroxidase (PPO) technique (electron microscopy with staining for peroxidase), or by immunophenotyping (CD41 or CD61)
associated with
- mediastinal germ cell tumors (Isochromosome 12p)
- often AML and transient myeloproliferative disorders in Down syndrome are often megakaryoblastic
poor prognosis

Answer 94

A

1/2 ALL and 1/2 AML
DS associated ALL
- generally similar to non-DS ALL
DS associated AML
- increased chemosensitivity, particular to MTX
- relatively favorable prognosis
- peaks between 1-5 years of age
- blasts express CD11b and CD13; negative for CD34
Transient myeloproliferative disorder (TMD)/transient abnormal myelopoiesis (TAM)
- 10% of neonates with DS
- 1st week of life usually
- may be trisomy 21 mosaic or confined to the clone itself
- marked leukocytosis and HSM
- difficult to distinguish from congenital acute leukemia
- in most cases, complete resolution without therapy
- still at high risk for AML during childhood
- TMD blasts negative for CD11b and CD13, positive for CD34
somatic mutations in the GATA1 gene in blasts of both TMD and DS associated AML

Answer 95

A

arbitrarily defined as an acute leukemia presenting before 4 weeks of age
must be distinguished from a leukemoid reaction and TMD (need FISH/cytogenetics)
most commonly myeloblastic (AML)
- vast majority are monocytic/monoblastic
commonly with leukemia cutis, often described as “blueberry muffin” babies
10% have abnormalities of 11q23 (MLL) gene

Answer 96

A

systemic mastocytosis
- skin
- spleen
- bone marrow
- GI tract
elevated
- serum tryptase
- urine N-methylhistamine (NMH)
- urine prostaglandin D2
- histamine (hypereosinophilic states can also increase histamine)
Morphology
- in marrow, spindled or round cell infiltrates, often with fibrosis and eosinophils
Immunophenotype
- positive: LCA, CD11c, CD33, CD43, CD117, FceRI
- unlike benign mast cells, malignant mast cells express CD25 and CD2 with decreased CD117
- CD25 expression correlates with CKIT mutation
molecular
- CKIT mutation, most commonly D816V

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Neoplastic hematopathology Flashcards

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