W7L11 - Introduction to Lymphoid Neoplasia

Question 1

Neoplasms of Lymphoid Cells

Answer 1

Encompass a large number of complex disorders that includes:
- solid lymphoid neoplasms affecting a wide range of tissue types (‘lymphoma’)
- haematopoietic lymphoid neoplasms predominantly affecting blood and bone marrow (‘leukaemia’)
- neoplasms that exhibit characteristics of both (‘leukaemia/lymphoma’)
Broadly classified into:
- mature lymphoid neoplasms (well differentiated, mature)
- precursor lymphoid neoplasms = acute lymphoblastic leukaemia/lymphoma (poorly differentiated, immature)

Question 2

WHO B-Lymphoblastic Leukemia/Lymphoma Examples

Answer 2

B-lymphoblastic leukemia/lymphoma, NOS
B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities
Provisional entity: B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like
Provisional entity: B-lymphoblastic leukemia/lymphoma with iAMP21

Question 3

WHO Lymphoblastic Leukemia/Lymphoma Examples

Answer 3

T-lymphoblastic leukemia/lymphoma
Provisional entity: Early T-cell precursor lymphoblastic leukemia
Provisional entity: Natural killer (NK) cell lymphoblastic leukemia/lymphoma

Question 4

Acute Lymphoid Leukemia (ALL) - Clinical

Answer 4

ALL occurs predominantly in children 2-9 years old
Patients usually present with:
- lymphadenopathy, hepatosplenomegaly
- coagulopathy
- circulating blasts
- cytopenia due to replacement of bone marrow
Combination chemotherapy induces remission of 80-90%
Relapse often occurs during adulthood
Stem cell transplant is often the best option for extended remission in adults

Question 5

ALL FBC Results

Answer 5

FBC
- anaemia, thrombocytopenia
- [WBC], [blast] variable
- eosinophilia, basophilia, cyclic neutropenia
Varied blast morphology
Typically
- round, high N:C, varied size
- nucleolus: inconspicuous/prominent
- nuclear membrane smooth (cleaved, convoluted)
Phenotype cannot be predicted from morphology

Question 6

ALL Cytochemical Stains

Answer 6

Typically replaced by immunophenotyping
Negative
- sudan black B
- myeloperoxidase
- chloroacetate esterase
Focal positive
- non-specific esterase

Question 7

ALL Immunophenotyping

Answer 7

Precursor B-cell immunophenotype is found in approximately 80% of both childhood and adult ALL, and precursor T-cell immunophenotype in most of the remainder
In general, ALL shows aberrant antigen expression compared to normal precursor B-cells
Terminal deoxynucleotidyl transferase (TdT) expression is found in more than 95% of ALL cases
Myeloid-associated antigens expression (e.g. CD13, CD33) is found in approximately 30% to 35% of ALL cases
No significance is attached to the expression of myeloid antigens in ALL

Question 8

ALL - Cytogenetics

Answer 8

Overall 70-90% of ALL have a demonstrable cytogenetic abnormality
Crucial for diagnosis of many B-lymphoblastic leukaemia/lymphoma with recurrent genetic abnormalities
Used to inform treatment & prognosis

Question 9

B-Cell Lymphoblastic Leukemia/Lymphoma (B-ALL)

Answer 9

Most cases in children ~95% of ALL in children 2-9 y.o.
Can occur in infants (<2 y.o.)
Clinical Signs
- pallor, bruising, bone pain, lymphadenomegaly, splenomegaly
FBC
- varied
Morphology
- blasts relatively small & monomorphic (80%)
- blasts larger & pleomorphic (20%)

Question 10

B-cell Lymphoblastic Leukaemia/Lymphoma with Recurrent Genetic Abnormalities

Answer 10

B-ALL with BCR-ABL1
- associated with Philadelphia chromosome
- older ages affected
- poor prognosis
B-ALL with KMT2A rearrangement
- infant, older children, adults; 20-25% ALL cases
- poor prognosis
B-ALL with ETV6-RUNX1
- 25% childhood; 3% adult ALL
- prognosis is relatively good
B-ALL with TCF3-PBX1
- ~5-10% childhood ALL,  ~3% Adult ALL
- precursor B-cell phenotype
- poor prognosis

Question 11

B-cell Lymphoblastic Leukaemia/Lymphoma with Alterations in Chromosome Number

Answer 11

B-ALL with hyperdiploidy
- 51-65 chromosomes
- commonest form of childhood ALL in developed countries
- ~25% childhood ALL; ~7-8% of adult ALL
- associated with t(12;21)(p13;q22)
- karyotyping may show gains of chromosomes 4, 6, 10, 14, 17, 18, 21, X
- typically relatively good prognosis (children 10 year survival >90%)
B-ALL with hypodiploidy
- less than 46 chromosomes
- uncommon 1-5% of B-ALL cases
- typically have a poor prognosis

Question 12

T-cell Acute Lymphoblastic Leukaemia/Lymphoma

Answer 12

~10-15% of all ALL cases for both children & adults
Most commonly affects male adolescents
Clinical Signs
- mediastinal mass, lymphadenopathy, hepatosplenomegaly
FBC
- leukocytosis
Blast morphology
- varied

Question 13

Leukaemia of Mature Lymphoid Cells

Answer 13

Many types (~100) of neoplasms of mature lymphoid cells are recognised
General categories
- mature B-cell neoplasms
- mature T & NK neoplasms

Question 14

Mature Lymphoid Neoplasms

Answer 14

Group of haematological disorders typically characterised by persistent lymphocytosis
Classified using
- morphology
- immunophenotype
- cytogenetics
- genetics
Examples of mature lymphoid neoplasms:
- chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL)
- B-cell prolymphocytic leukaemia (B-PLL)
- hairy cell leukaemia (HCL)
- T-cell prolymphocytic leukaemia (T-PLL)

Question 15

Chronic Lymphocytic Leukaemia/Small Lymphocytic Lymphoma (CLL)

Answer 15

Mature B-cell neoplasm
Most common category of leukaemia in the western world
Predominantly occurs in older people
Male: Female (2:1)
Patients often asymptomatic => discovered during routine assessment (70-80%)
Often present with general malaise & fatigue
Commonly has tissue infiltration
- lymphadenomegaly
- hepatomegaly

Question 16

CLL - FBC

Answer 16

Lymphocytosis typically 10-150 x 10^9/L
(WHO 2016 requires > 5.0 x 10^9/L clonal B cells)
Round to ovoid lymphocytes, slightly larger than normal lymphocytes with coarsely clumped chromatin & absent-inconspicuous nucleolus
“Smear/smudge” cells
Neutropenia, thrombocytopenia
~10% have AIHA
Cryoglobulins, ↑ viscosity

Question 17

CLL - Bone Marrow Results

Answer 17

Hypercellular
Increased M:E ratio
Infiltration of ‘normal morphology’, mature lymphocytes (B-cells)
May replace other elements of the bone marrow

Question 18

CLL - Prognostic Factors

Answer 18

IGHV mutational status
- mutated vs. unmutated
- most important independent biological prognostic factor
TP53 status
- no abnormalities vs. del(17p) and/or TP53 mutation
Serum β2-microglobulin concentration
- ≤ 3.5 mg/L vs. > 3.5 mg/L
Clinical stage
- Binet A or Rai 0 vs. Binet B–C or Rai I–IV
Age
- ≤ 65 years vs. > 65 years

Question 19

CLL - Genetics

Answer 19

There are no recognized disease-defining mutations
However there are a large number of mutations that occur with a relatively low frequency
Some, such as TP53, NOTCH1, SF3B1, & BIRC3 are of clinical interest because they may provide prognostic information

Question 20

Transformation of Mature Lymphoid Neoplasms

Answer 20

Transformation into higher grade B-cell neoplasm occurs in ~10% cases CLL
‘Richter syndrome’

Question 21

B-cell Prolymphocytic Leukaemia (B-PLL)

Answer 21

Rare, chronic, B-lineage lymphoproliferative disorder
Clinical signs
- middle aged-older adults
- splenomegaly
FBC
- WBC > 100 x109/L
- prolymphocytes >55%
- anaemia; AIHA; thrombocytopenia
Morphology
- round-ovoid nucleus
- single prominent nucleolus
- moderate blue cytoplasm
Trisomy 12

Question 22

Hairy Cell Leukemia (HCL)

Answer 22

Uncommon, chronic, B-lineage lymphoproliferative disorder
Peak incidence: 40-60 y.o.
M:F 4:1
BRAF V600E mutations are found in > 97% cases of HCL
FBC
- variable [lymphocytes], lymphopenia-lymphocytosis
- neutropenia, thrombocytopenia, anaemia, AIHA
Morphology
- classic appearance of the hairy cell has elongated cytoplasmic projections distributed around the circumference of the cell.

Question 23

T-Cell Prolymphocytic Leukaemia (T-PLL)

Answer 23

Rare, affects elderly and more commonly males
Clinical Signs
- hepatosplenomegaly, lymphadenopathy & effusions
FBC
- variable lymphocytosis (up to 900 x10^9/L)
- anaemia, thrombocytopenia (~30%)
Cytogenetics: various, often involving chromosome 14q11