HIS20 Lymphoma: Principles Of Diagnosis And Management Flashcards
Lymphoma
Neoplasm of Lymphoid system (***Peripheral lymphoid organ (spleen, thymus) + B, T, NK-origin)
—> Leukaemia: Neoplasm of ALL blood cells (in central lymphoid organ (BM))
In general Lymphoma refers to ***mature lymphoid neoplasm (vs Leukaemia: more immature)
Accurate diagnosis of Lymphoma requires integration of
- Clinical
- Morphologic (actual histopathology)
- Immunophenotypic (differential markers —> underlying cell of origin)
- Genetic features (gene mutations of lymphoma —> pathogenesis, prognosis, management treatment, targeted therapy)
B cell neoplasms
Central lymphoid tissue (BM): - Pro-B cells - Pre-B cells - Immature B cells (no CD20) —> Neoplasm of these cells —> Precursor B-cell neoplasm (e.g. B acute lymphoblastic leukaemia/lymphoma BALL)
Peripheral lymphoid tissue (LN / spleen):
- Naive B cells
- Mature B cells (have CD20)
- Plasma cells (lose CD20)
- Memory B cells (Marginal zone, have CD20)
(Interfollicular, Follicular, Perifollicular area)
—> Interfollicular area —> Pre-germinal centre (i.e. Mantle zone) neoplasm (e.g. Mantle cell lymphoma)
—> Follicular area —> Germinal centre neoplasm (e.g. Follicular lymphoma, ***Hodgkin lymphoma, Burkitt lymphoma)
—> Perifollicular area —> Post-germinal centre (e.g. Marginal zone lymphoma, Lymphoplasmacytic lymphoma)
T cell neoplasms
Central lymphoid tissue (BM, Thymus):
- Precursor T cell
- Double positive T cell
—> T acute lymphoblastic leukaemia/lymphoma (TALL)
Peripheral lymphoid tissue (spleen, LN, mucosa, skin):
- Mature T cell
- Th
- CTL
- NK cell
- (Cortical thymocytes —> γδ T cell residing in skin)
—> Mature T cell / NK cell leukaemia/lymphoma
(NK lymphoma —> mainly extranodal)
***Practical classification of Lymphoma
These are MATURE neoplasms
- B cell lymphoma / B lymphoproliferative disorder
- High-grade (rapidly proliferative, present acutely, rapidly enlarging lymphadenopathy)
—> Diffuse large B cell lymphoma
—> Burkitt lymphoma - Low-grade (indolent, may present with nodal disease, late presentation)
—> Follicular lymphoma
—> Chronic B cell lymphoproliferative disorder (e.g. CLL with circulating abnormal lymphoid cells)
- T cell lymphoma / T lymphoproliferative disorder
- NK/T cell lymphoma
- Hodgkin lymphoma (B cell origin)
- Classical Hodgkin lymphoma
- Nodular lymphocyte predominant Hodgkin lymphoma (very rare)
Principles of diagnosis of lymphomas
- Accurate history taking (onset, duration, progression)
- Physical examination (palpation of all lymphoid areas e.g. liver, spleen)
- Proper tissue diagnosis (need entire tissue, cells not ok)
- Adequate biopsy of the representative site is essential (adequate excision)
—> abnormal cells + surrounding architecture
—> Histologic, Immunohistochemical, Genetic assessment - NOT acceptable: simple cytological assessment (e.g. fine-needle aspirations)
Aims of investigations for lymphomas
- Accurate diagnosis
- treatment depends on diagnosis (i.e. different subtypes of lymphoma) - Staging
- prognosis
- treatment response - Complications of lymphoma
- infection
- mass effect compressing on surrounding structures
- ***Spontaneous tumour lysis syndrome (High grade B cell lymphoma / Burkitt lymphoma) —> high cell turnover —> lymphoma cell die and release cellular contents (e.g. urate: nephropathy, potassium: toxic to heart) - Prognosis
- ESR (early stage Hodgkin lymphoma)
- ***β2 microglobulin (Follicular lymphoma)
- LDH
- etc. - Suitability / fitness for treatment
- specific SE of Multiagent chemotherapy (cardiac, lung assessment) - Complications of treatment
- ***Spontaneous tumour lysis syndrome - Assessing response to treatment
- usually via imaging
***Investigations in lymphomas
- Complete blood count + Blood film
- T cell lymphoma: Eosinophilia (∵ IL-5 production)
- ***Hodgkin lymphoma: Eosinophil count ↑ - Bone marrow aspiration and Trephine biopsy (for staging)
- CXR (look for disease-related complications, active / prior infections)
- e.g. enlarged mediastinal LN —> Hodgkin lymphoma - ***Serum protein electrophoresis (SPE) (比Leukaemia多左呢樣)
- Plasma cell myeloma, lymphoma —> immunoclonal Ig (Paraproteins) —> Clonality of disease —> marker for disease response
- give diagnostic information - Serum electrolytes (Na, K, Ca, PO4)
- deranged in tumour lysis syndrome (K, PO4 ↑ —> arrhythmia) - LDH, Urate levels
- ↑ in ↑ cell turnover
- High LDH, Urate: high grade, highly proliferative
- Risk of tumour lysis syndrome —> Nephropathy - Liver and renal function tests
- Renal function: tumour lysis syndrome - ESR (prognostic marker for early stage of ***cHL)
- β2-microglobulin (prognostic marker for ***Follicular lymphoma)
- Whole body 18-FDG positron emission tomography - computerised tomography (PET-CT) (for staging)
- label glucose with radioactive isotope
—> taken up by lymphoma cells
—> lymphoma cells are metabolically active depending on subtype
—> locate lymphoma cells
***Pre-treatment investigations
- ECG, Transthoracic echocardiogram (Anthracyclines —> risk of cardiotoxicity)
- Lung function studies (Bleomycin used in Hodgkin lymphoma —> risk of pulmonary fibrosis)
- Hepatitis B and C serology (Immunosuppression —> risk of reactivation)
- HIV serology (Lymphomas may be a presenting feature fo HIV AIDS)
- G6PD assay (Co-trimoxazole used for PJP —> risk of oxidative haemolysis)
Staging of lymphoma - Ann Arbor staging
Stage 1: involvement of single LN region / single extralymphatic site (stage 1E)
Stage 2: Involvement of >= 2 LN regions on ***same side of diaphragm (may include localised extralymphatic)
Stage 3: Involvement of LN regions on ***both sides of diaphragm (may include spleen (3s) / localised)
Stage 4: Diffuse extralymphatic disease (e.g. in liver, BM, lung, skin)
Extralymphatic = Extranodal
***Principles of management of lymphomas
-
**Multi-agent cytotoxic chemotherapy (achieve maximal cell death within short time)
+/- **Monoclonal Ab (e.g. Anti-CD20 in CD20+ B cell lymphoma) - ***Multiple cycles with Interim / End-of-treatment assessment by Imaging +/- Biomarkers
- Initial cycle: maximal cell death
- Subsequent cycles: wipe out remaining abnormal lymphoma cells - Immuno-conjugates
- monoclonal Ab delivering toxin to target abnormal lymphoma cell - Checkpoint inhibitors (in certain subtypes of lymphoma)
- Supportive care with prevention of tumour lysis syndrome
- Management of disease/treatment complications
- Haematopoietic Stem Cell Transplantation (usually Autologous HSCT)
- reserved for selected relapsed patients who are chemo-sensitive
Case 1
- 63 yo man
- weight loss
- rapidly enlarging bilateral cervical LN for 1 month
- history of hypertension since 50 yo —> well controlled with 1 anti-hypertensive
- bilateral multiple firm and non-tender cervical LN of 3-5 cm in size (1cm already palpable)
- CBC, LRFT, serum electrolytes normal
- LDH, urate levels ↑↑
- Excisional LN biopsy
Histology:
- Effaced nodal architecture (loss of follicular area etc.)
- Sheets of large abnormal lymphoid cells
- Immunohistochemistry:
—> CD19 +ve, CD20 +ve, CD79a +ve, PAX5 +ve (all biomarkers of B cell lymphoma)
—> T cell, NK cell markers -ve - Conclusion:
- Diffuse Large B cell Lymphoma (DLBCL) - Subsequent investigations:
- PET-CT: Hypermetabolic LN in bilateral cervical, thoracic and intraabdominal regions
- BM biopsy: Not involved by lymphoma
—> Ann-Arbor Stage 3B disease (B: B symptoms e.g. significant fever, weight loss)
- ECG, Echocardiogram normal
- CXR clear
- HBsAg +ve —> HBV carrier, Anti-HCV -ve, Anti-HIV 1/2 Ab -ve
- HBV DNA undetectable —> inactive HBV
- G6PD normal - Treatment:
- Patient started on Entecavir prophylaxis —> suppress HBV
- DLBCL treated with R-CHOP
—> R: Rituximab (Anti-CD20)
—> C: Cyclophosphamide
—> H: Doxorubicin
—> O: Vincristine
—> P: Prenisolone - Outcome:
- Complete response (CR) after 3 cycles of R-CHOP
- Completed 6 cycles of R-CHOP and remained in complete remission
Rituximab
Anti-CD20 —> Bind to CD20
MOA: 1. Activate complement system —> MAC —> cellular lysis 2. ADCC 3. Other direct effects —> activate apoptotic pathway
Case 2
- 30 yo woman
- non-smoker, good past health
- dry cough for 2 months
- fever, night sweats
- recent appetite loss and weight loss of 10kg over 2 months
- 3-cm palpable Left Supraclavicular fossa LN + rubbery in consistency
- liver, spleen not palpable
- CVS, respiratory exam unremarkable
- no upper limb / facial swelling
- Chest X-ray: Mediastinal mass
Differential diagnoses: - ***LN - lymphoma / metastatic LN (commonest)
- Thymoma
- Germ cell tumour
- Others: retrosternal goitre, dilated aortic arch, neurofibroma
- Histology (Excisional biopsy of L SCF LN):
- Distorted nodal architecture
- Typical multinucleated giant cells (Reed-Sternberg cells present)
- Prominent infiltration by inflammatory cells (eosinophils, reactive lymphocytes, plasma cells) - Suggestion
- Classical Hodgkin lymphoma - Immune-histochemical study:
- **CD30 immunostain highlighted malignant Hodgkin and Reed-Sternberg cells (also **CD15) —> Hodgkin lymphoma
- Malignant cells -ve for other B / T cell markers (e.g. no CD20) - Diagnosis:
- Classical Hodgkin Lymphoma
—> 4 subtypes: Nodular sclerosis subtype commonest
—> **Lower cervical lymphadenopathy + **Mediastinal lymphadenopathy - Staging:
- Ann Arbor Stage 2B - Further investigations:
- CBC: Eosinophilia (∵ Reed-Sternberg cells secrete IL-5)
- LRFT normal, serum electrolytes normal
- LDH, Urate ↑ - Pre-treatment test:
- Baseline ECG, Echocardiogram normal (Adriamycin: cardiotoxic)
- Lung function normal (Bleomycin: pulmonary fibrosis)
- HBsAg -ve, Anti-HBs +ve, Anti-HBc -ve, Anti-HCV Ab -ve, Anti-HIV 1/2 Ab -ve - Treatment:
- Oocyte preservation (Gonadotoxicity of chemotherapy) before starting chemotherapy with Adriamycin, Bleomycin, Vinblastine, Dacarbazine (ABVD) - Outcome:
- Cycle 1 ABVD started with adequate hydration and Febuxostat (prevent tumour lysis syndrome)
- CBC, LRFT monitored regularly in between cycles (∵ potential neutropenia due to chemotherapy)
- NO cardiac / respiratory symptoms during treatment
- Interim assessment PET-CT after 2 cycles of ABVD showed complete response (CR)
- Complete 4 cycles of ABVD + end-of-treatment PET-CT showed continual remission
- Opted not to radiotherapy to chest (∵ risk of breast cancer, coronary vessel problem) - Subsequent
- Patient relapsed disease 8 months after remission with nodal involvement at bilateral cervical, mediastinal, intraabdominal LN on PET-CT
- Re-biopsy of cervical LN
—> confirmed recurrent Classical Hodgkin Lymphoma (nodular sclerosis type)
—> need to change therapy
—> Immuno-conjugate Brentuximab vedotin (Anti-CD30 monoclonal Ab linked to MMAE)
- Failed to achieve a response after 3 cycles of Brentuximab vedotin
—> Check-point inhibitor Pembrolizumab (Anti-PD1) as salvage treatment - Complete response achieved after 4 cycles of pembrolizumab
—> Treatment was continued
Brentuximab vedotin
Anti-CD30 monoclonal Ab
—> linked to ***Monomethyl auristatin E (MMAE, a microtubule-disrupting cytotoxic agent)
MOA: 1. Bind to ***CD30 receptor on Reed-Sternberg cells —> internalisation —> MMAE released —> microtubule disruption —> Cell cycle arrest and apoptosis 2. ADCC 3. Immunogenic cell death 4. Bystander effect
Check-point inhibitor Pembrolizumab (Anti-PD1)
Tumour cell express PD-L1 (a check-point)
—> bind to ***PD-1 (a receptor present in all normal T cell)
—> inhibit T cell killing of tumour cell
Check-point inhibitor (Anti-PDL1 / Anti-PD1):
Blocking PD-L1 / PD-1
—> allows T cell killing of tumour
