Lymphoma Flashcards
Definition - normal sites, overlap with leukaemia
Malignancy of lymphocytes
Nodal: accumulate in LN and cause lymphadenopathy
Extra-nodal: involvement of lymphoid tissue outside LN e.g. tonsils or GI tract or infiltration outside lymphoid tissue e.g. nasopharynx, skin on both feet (mycosis fungoides)
Overlap between lymphoma and leukaemia
- lymphoma generally more mature lymphocytes and forms solid masses
- leukaemia more immature lymphocytes and involves PB and BM
- minority of lymphoma may spill into blood in leukaemia phase; T-ALL may present with mediastinal mass
- CLL and small lymphocytic lymphoma are the same biological disease
Classification of lymphoma and epidemiology
Hodgkin and Non-Hodgkin lymphoma
Non-Hodgkin more common than Hodgkin in HK (9th in incidence and 8th in mortality in 2016)
Hodgkin median age 40
Non-Hodgkin median age 63
Hodgkin Lymphoma - classical histology, immunophenotype
REED STERNBERG (RS) CELL (neoplastic cells)
- large bi-nucleated cell with inclusion-like nucleolus, giving an “owl eye” appearance
- possible mononuclear variants
- cell death and shrinking can form mummified cells
A/w INFLAMMATORY BACKGROUND of lymphocytes, plasma cells, eosinophils, histiocytes
Immunophenotype
- CD30, CD15
- B lymphoid lineage (“crippled” B cell)
EBV+ in 50%
Histological classification of Hodgkin lymphoma
- Nodular lymphocyte predominant
- POPCORN CELL/ L&H cell/ LP cell NOT RS CELLS!
- polypoid nuclei and inconspicuous nucleoli
- CD20 +ve B cells
- favourable prognosis - Classical (RS cells)
- nodular sclerosis (more common)
- —-> LACUNAR CELL VARIANT (more compact than RS showing retraction of cytoplasmic membrane)
- mixed cellularity
- lymphocyte rich
- lymphocyte depleted
Clinical features of Hodgkin Lymphoma - age, presentation, progression, lab results
Peak in young adults, M>F
Presentation
- painless, firm LN enlargement
- mediastinal involvement in nodular sclerosing type (particularly in young women)
- constitutional symptoms common
INITIALLY LOCALISED to a single peripheral LN region and spreads contiguously (stepwise spread)
Lab results:
- anaemia, EOSINOPHILIA, high ESR and CRP, high LDH
- should determine HIV status
Staging of Hodgkin Lymphoma
Ann Arbor staging
I = single LN region
II = 2 or more LN regions on same side of diaphragm
III = LN above and below diaphragm (including spleen)
IV = diffuse involvement of other extra-nodal tissues e.g. liver, BM, abdominal wall
A = absence, B = presence of constitutional symptoms
Treatment of Hodgkin Lymphoma
Combination of chemotherapy and radiotherapy – high cure rate
Early stage disease: excellent prognosis, don’t overtreat
Advanced stage: cyclical chemotherapy, assess treatment response by PET-CT
Relapsed and refractory disease: anti-CD30 Ab (brentuximab vedotin), Immunotherapy (PD-1 inhibitor), HSCT (usually autologous)
Non-Hodgkin Lymphoma categories and examples
Mature B cell neoplasms
- lymphoplasmacytic lymphoma
- follicular, mantle cell, diffuse large B-cell, burkitt lymphoma
- MALT lymphoma
(leukaemic types: CLL, hairy cell leukaemia)
T/NK cell neoplasms - Adult T cell leukaemia/lymphoma - NK/T cell lymphoma - Mycosis fungoides (leukaemic type: T-PLL)
NHL grading and prognosis
Low grade: CLL/Small lymphocytic lymphoma, follicular lymphoma
Intermediate grade: mantle cell lymphoma
High grade: diffuse large B-cell lymphoma
Highly aggressive: Burkitt lymphoma
Low grade disease = chronic and indolent but usually not treatable
High grade = high initial mortality but can be cured due to high proliferative activity being targeted by chemotherapy
B cell origin in B cell lymphoma
Identification of normal counterpart is useful in understanding lymphoma biology
Determining origin of diffuse large B cell lymphoma e.g. germinal centre vs activated B cell, is clinically important for prognostic and therapeutic purposes
Aetiology of NHL
Infection-related
e.g. HTLV-1, EBV, HHV-8, H.pylori
Immunodeficiency
- inherited
- acquired
Genetic predisposition
Diagnosis of NHL
Clinical
Radiological
Tissue diagnosis e.g. LN biopsy
PB and BM examination
Electron microscopy to confirm specific morphologies
Immunophenotyping – IHC on trephine BM or flow cytometry on PB/BM
–> normally use IHC since flow cytometry needs fresh cells (can use in leukaemic phase or if do FNA of LN)
Cytogenetics
Molecular genetics – FISH/PCR for fusion genes, electrophoresis for IgH/TCR gene rearrangements, NGS for IgH/TCR gene rearrangement or mutation profiling or IGHV somatic hypermutation in CLL
Differential Diagnosis of small B cell lymphoma and how to differentiate
CLL, Follicular lymphoma and MCL
CLL: CD5 +ve, CD23 +ve, Cyclin D1 -ve
Follicular: CD5 -ve, CD23 +/-ve, Cyclin D1 -ve
MCL: CD5 +ve, CD23 -ve, Cyclin D1 +ve
Clonality testing in NHL diagnosis - purpose, methods
Purpose: distinguish between reactive lymphadenopathy (e.g. infection, AI disease) and lymphoma
Methods:
- light chain restriction in B cell lymphoma
- IgG or TCR gene rearrangement in B/T cell lymphoma by gel electrophoresis (PCR) or NGS
- other clues e.g. detectable chromosomal translocation by FISH e.g. IGH-BCL2 t(14;18) in follicular lymphoma, other clonal cytogenetic abnormality
FISH is preferred for translocation (instead of PCR) since the use of large directly labelled fluorescent DNA probes can cover scattered genetic breakpoints
Follicular Lymphoma - epidemiology, course, appearance, immunophenotype, cytogenetics, prognosis
Middle aged, elderly - median age 60yrs
Indolent clinical course (low grade)
Median survival 10 yrs
Grading 1-3
Follicular pattern, cleaved cells/BUTTOCK CELLS
Immunophenotype:
- CD10, 19, 20
- BCL2+, BCL6+
Cytogenetics:
- t(14;18) IGH-BCL2 with BCL2 overexpression
May transform into high grade lymphoma
Mantle Cell Lymphoma - origin, nuclear appearance, immunophenotype, cytogenetics
From pre-germinal centre cells (mantle zone)
Irregular nuclear contour
Immunophenotype:
- CD19
- CD5+ve, CD23-ve, Cyclin D1 +ve
Cytogenetics:
- t(11;14) IGH-BCL1 with BCL1 (cyclin D1) overexpression
Lymphoplasmacytic lymphoma - associated syndrome, clinical manifestation, origin of cells, diagnostic test for mutation
A/w monoclonal IgM paraprotein and Waldenstrom macroglobulinaemia
Hyperviscosity syndrome common
Post-germinal centre B cell with characteristics of IgM baering memory B cells
Diagnostic test: MYD88 L265P mutation in 93% cases
Extranodal marginal zone B cell lymphoma of MALT i.e. MALT lymphoma - severity, most common site, associated pre-existing diseases
Low grade, indolent course
- MC at stomach (other sites e.g. GI, lung, H+N, skin etc)
Lymphoepithelial lesions, lots of mucosal infiltration
A/w pre-existing inflammatory or AI disease e.g. H.pylori chronic gastritis, Sjogren syndrome, Hashimoto thyroiditis
Diffuse large-B cell lymphoma - severity, aetiology, histology
Common
Classical high grade lymphoma
Nodal or extranodal
Can present as de novo or as progression from low grade lymphoma
Appearance (applicable to all lymphomas): destructed lymphoid architecture
+ diffuse proliferation of large sized neoplastic B cells
Heterogenous disease entity
Burkitt Lymphoma - severity, variants, common site, associated infection, morphology, cytogenetics
High grade, clinically aggressive
3 variants: endemic, sporadic, immunodeficiency associated
Site: jaws, other facial bones in 50% of endemic cases
ASSOCIATED WITH EBV INFECTION
Morphology: STARRY SKY pattern
Cytogenetics:
- t(8;14) IGH-MYC fusion
- biologically identical to ALL-L3
Extranodal NK/T cell lymphoma, nasal type - prevalence, commonest site, associated infection, characteristic pathology
High prevalence in HK
More prevalent in asia, central/south america
Extranodal: nasal cavity as commonest site
CONSTANTLY ASSOCIATED WITH EBV
- FISH detection of EBER (EBV early RNA)
Angiocentric and angiodestructive
- invasion around blood vessels and destruction of vessels –> necrosis due to ischaemia
Anaplastic large cell lymphoma - age group, severity, appearance, immunophenotype, cytogenetics
Common in children and young adults
Aggressive disease with systemic symptoms and extranodal involvement
Appearance: large sized, bizarre cells with WREATH-LIKE nucleus
Immunophenotype (T cell)
- CD3, CD30
- ALK+ve
Cytogenetics
- t(2;5) NPM1-ALK fusion
Treatment of NHL
Combination chemotherapy and localised radiotherapy
HSCT
Monoclonal Ab
- anti-CD20 for B cell lymphoma in general
- anti-CD30 for anaplastic large cell lymphoma
- anti-CD52 for selected cases
Molecular targeted drugs
- ALK inhibitor for anaplastic e.g. crizotinib
- BCL2 inhibitor e.g. venetoclax
- BTK inhibitor Ibrutinib for B cell lymphoma e.g. lymphoplasmacytic
Immunotherapy
- PD1 inhibitors
- CAR-T cell therapy
