Aggressive Lymphoma Flashcards
(35 cards)
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Definition of Burkitts Lymphoma
A mature, aggressive CD10+ B cell neoplasm composed of monomorphic, medium-sized cells with basophilic cytoplasm, a GCB phenotype, high proliferation index and IG::MYC rearrangement
eg. t(8;14)
Essential role of EBV in early pathogenesis, causing B cells to evade apoptosis
Diagnostic criteria Burkitts Lymphoma
Essential:
* Medium-sized, monomorphic lymphoma cells with basophilic cytoplasm and multiple small nucleoli
* CD20+, CD10+. Absent (rarely weak) expression of BCL2. Ki67 >95%
* Usually strong MYC expression (>80% of cells), and/or demonstration of MYC breakage or IG::MYC translocation
Desirable:
Starry-sky pattern, cohesive growth pattern
BCL6+, TdT-, CD38+
Exclusion of BCL2 and BCL6 rearrangements (mainly required in adult BL)
Burkitt Lymphoma - morphology
Monomorphic medium-sized lymphoid cells with basophilic cytoplasm, round nuclei with finely clumped and dispersed chromatin, and multiple basophilic nucleoli
Should not be pleomorphic
Cellular cohesion
Abundant mitoses and apoptosis
‘starry sky’ pattern on trephine (from macrophages with apoptotic debris)
Coagulative necrosis is common
Reactive small lymphocytes are rare
Burkitt Lymphoma IHC and flow
Pan B cell antigens (CD19+, 20+, 79a+, 22+, PAX5+)
CD10+ is positive; BCL6, CD38 are also positive
MYC expression in >80% of cells is seen in almost ALL cases
Ki67 is >95%
BCL2 and TdT negative; weak BCL2 is seen in 20% of cases and does not exclude the diagnosis
Burkitts Lymphoma Cytogenetics and Molecular
Cytogenetics
* MYC breakage, **IG::MYC translocation ** via MYC/IGH dual fusion probe
* 80% of cases involve **t(8;14) **
* Less commonly, the MYC gene is translocated to the IGL or IGK locus (can use IGK and IGL break apart probes)
* Rarely, a cryptic insertion of MYC into IGH may occur
Molecular
* TCF3 (transcription factor) and ID3 (its negative regulator), which activates the PI3K is commonly mutated, as is CCND3
* **TP53 **mutation/deletion is seen in 25-50% of cases
High grade B cell lymphoma with chromosome 11q abberation
Lymphoma with intermediate/blastoid or Burkitt-like morphology
Typical immunophenotype (B cell markers are positive, CD10+, BCL6+, BCL2-)
Chromosome 11q gain/loss, telomeric loss or telomeric LOH pattern
Exclusion of a MYC translocation
DLBCL NOS
NHL accounting for 30% of cases (most common)
> can be de novo or arise from indolent disease
Essential:
* Large B cell lymphoma with a diffuse or vaguely nodular growth pattern
* Mature B cell phenotype
* Exclusion of other specific entities of large B cell lymphoma
Desirable:
* cell of origin subtyping (ABC vs GCB)
* Reporting of MYC and BCL6 rearrangements
* Genetic testing, if relevant for clinical decision making
Approximately 60% of DLBCL are GCB subtype and 40% are ABC subtype
ABC vs GCB
Distinction between Germinal Center B-cell (GCB) and Activated B-cell (ABC) subtypes in DLBCL is crucial because it reflects underlying biology, prognosis, and treatment response.
ABC has less favourable outcome
*if have MUM1 expression are ABC
(mum teaches you ABCs)
*BCL6+ and CD10+ are GCB type (don’t need both positive to be GCB - see flow chart)
BCL2 is found in both GCB and ABC subtypes
DLBCL NOS IHC and flow
pan-B cell markers (CD19+, CD20+, CD22+, CD79a+, PAX5+) but may lack one or more of these antigens
SIg+ in 50-75% of cases
CD30+ in 10-20%
CD5+ in 5-10% of cases
MYC
Considered positive if staining in ≥40% of cells
BCL2
Considered positive if staining in ≥50% of cells
BCL6
Considered positive if staining in ≥30% of cells; part of the Hans classifier (see below)
Ki67 is usually >80%; it can be lower, closer to 40%
Should be TdT negative; if positive, MYC/BCL2 rearrangements should be sought
DLBCL morphological variants
Centroblastic - MOST common
- Medium-sized to large lymphoid cells with oval-round, vesicular nuclei containing fine chromatin
- 2-4 nuclear membrane-bound nucleoli
- Scant and amphophilic or basophilic cytoplasm
- Usually GCB subtype
Immunoblastic
- >90% of cells are immunoblasts; cells with a single, centrally-located nucleolus and an appreciable amount of basophilic cytoplasm
- Plasmablasts may also be present (cells with an eccentric nucleus with single nucleolus)
Anaplastic
- Large to very large cells with bizarre, pleomorphic nucleoli that may resemble Reed-Sternberg cells, or the nenoplastic cells of anaplastic large cell lymphoma
- Show a sinusoidal/cohesive growth pattern and may mimic undifferentiated carcinoma
DLBCL
Cytogenetic, FISH and molecular
Somatic mutations
- EZH2 and GNA13 are seen almost exclusively in GCB subtype
- MYD88 and CD79B are characteristic of ABC subtype
Chromosomal translocations
* BCL2 rearrangement is seen in 40% of GCB subtypes (and is associated with BCL2+ and CD10+)
* BCL6 rearrangement is associated with ABC subtype
* MYC rearrangement occur at equal frequency in ABC and GCB subtypes
Prognostic features
Cell of origin (GCB vs ABC)
- ABC confers poorer prognosis
?immunoblastic
MYC/BCL2 double expressor
MYC, BCL2, NCL6 translocations
EBV
Proliferative rate
Mutational alterations
Summary of changes of classification of LBCL WHO4th to 5th
Some entities in differential diagnosis of DBLCL NOS
High-grade B-cell lymphoma with MYC and BCL2 rearrangement
* BCL2+, MYC+, TdT+/-
Large B-cell lymphoma with 11q alterations
* Burkitts morphology but 11q abberation
* CD10+, BCL6+, BCL2+/-
Large B-cell lymphoma with IRF4 rearrangement
* Strong MUM1 (IRF4) IRF4 rearrangment
ALK-positive large B-cell lymphoma
T cell/Histiocyte Rich large B cell lymphoma
THR-LBCL
An aggressive B-cell lymphoma with <10% large neoplastic B cells and a diffuse background of T cells and histiocytes, without small B cells
> tumour cells always DISPERSED and never form aggregates or sheets
> no eosniophils or plasma cells
Has clinical, immunophenotypic and molecular overlap with NLPHL
Accounts for < 10% of DLBCL.
M>F
Immunophenotype
- Pan B cells
- BCL6+
- Background of CD68+, CD163+ histiocytes and CD3+ CD5+ T cells
- Cells are usually CD30- and CD10-
Intravascular large B cell lymphoma
An extranodal large B-cell lymphoma characterized by **selective growth of lymphoma cells within the lumina of capillary vessels **
Pan B cell markers are positive
usually widely disseminated and can present in any organ. LN are usually spared.
Difficult to detect on traditional imaging
Poor prognosis
Assoc with MYD88 and CD79B hotspot mutations
ALK positive LBCL
Aggressive neoplasm of ALK positive monomorphic large immunoblastic like cells most with have plasma cell phenotype.
Essential:
- Large cell morphology
- Plasmablastic immunophenotype (plasma cell-associated markers such as CD138, MUM1, VS38c, BLIMP1, XBP1 positive and CD20 negative/weak)
- ALK expression
Desirable:
- ALK genetic alterations (usually translocations)
- No EBV
Immunophenotype
Negative for pan B cell antigens
**Positive for plasma cell markers CD138, VS38c, BLIMP1, XBP1, MUM1 **
CD45 is weak or negative
CD30 is negative
Most tumours express cytoplasmic immunoglobulin
ALK positive, with a cytoplasmic staining pattern
Always EBV and HHV8 negative
Most common ALK rearrangement
- t(2;17) (ALK:CLTC)
Lymphomatoid granulomatosis
EBV associated angiocentric, angiodestructive B cell lymphoproliferative disorder involving extranodal sites, composed of EBV+ atypical large B cells usually admixed with a large number of reactive T cells.
EBV associated
EXTRANODAL DISEASE
RARE
DLBCL with MYC and BCL2 rearrangment
An aggressive mature B-cell lymphoma with structural chromosomal aberrations, with breakpoints at both MYC and BCL2 loci
- MYC at 8q24
- BCL2 at 18q21
With or without BCL6 rearrangement
Morphology and phenotype consistent with aggressive B cell lymphoma
> 90% of tumours have a GCB phenotype
Flow/IHC
- Pan B cell
- CD10+
- MYC in ~80%
- BCL2 ~90%
Essential diagnosis:
- intermediate/blastoid morphology not consistent with either DLBCL or Burkitt lymphoma
- lack TdT and CD34 (exclude B-ALL), lack of Cyclin D1 (to exclude MCL)
- Absence of 11q abberations
difference between double hit vs double expressor
double hit lymphomas = double expressors
BUT
most double expressors ARE NOT double hit
(the majority are ABC subtype DLBCL and do not harbour translocations)
EBV positive diffuse large B cell lymphoma
EBV positive DLBCL is RARE large B cell lymphoma in which majority of neoplastic cells harbour EBV.
Affected patienst DO NOT have history of lymphoma or underlying immunodeficiency/dysregulation.
Thought to arise from IMMUNOSENESCENCE
DLBCL of immune-privileged sites
Large B cell lymphomas that arise as primary tumours of the** CNS, vitreoretina and testis** of immunocompetent patients and CONFINED to these spaces.
Excluded from this category are: tumours of the dura, choroid. Secondary involvement, and tumours occurring in immune deficiency/dysregulation-related settings
DLBCL of immune privileged sites - Lab tests
IHC and flow
* Pan B cell markers
* Express MUM1, BCL2, BCL6 (ABC phenotype)
* High Ki67 (>80-90%)
* CD10 is positive in <10% of cases
Molecular
* MYD88 (>50% of cases) and CD79B mutations
* Look for rearrangements which make disease improbably ie BCL2, CCND1, 11q abberations
Plasmablastic lymphoma
Usually occur in immune deficiency/dysregulation ie. HIV, post transplant
Poor survival
Predominantly EXTRANODAL
Diagnosis
Essential
* Lymphoma with plasmablastic/immunoblastic morphology
* Expression of **plasma cell-associated antigens (e.g. MUM1, CD138, BLIMP1) **
* Negativity for CD20, PAX5, ALK and KSHV/HHV8
Desirable
* EBV (EBER) in ~60% of cases
* Detection of **MYC rearrangements **
* Detection of monoclonal IG rearrangements
