Haematological malignancies Flashcards
Classification of haematological malignancies Lymphoproliferative disorders
How do hematological malignancies arise? Describe the pathogenesis in 3 steps
Acquired genetic alterations to long lived cell
Proliferative/survival advantage to that mutated cell
Produces malignant clone which grows to dominate the tissue
Pathogenesis of AML/ALL (acute hematological malignancies) [3]
Acute bone marrow failure is a characteristic feature of acute hematological malignancies. What are the 3 presenting features of acute bone marrow failure?
Mutation that affects myeloid differentiation > increased proliferation but blocked differentiation > accumulation of early myeloid/lymphoid progenitors which are useless (myeloidblasts/lymphoblasts)
Acute bone marrow failure:
- Anemia
- Thrombocytopenia bleeding
- Infection secondary to neutropenia mostly bacterial, fungal
Difference between mature haematological malignancies and early hematological ca [1]
What’s the difference between leukaemia & lymphoma?
Mature haem ca lead to increased proliferation of dysfunctional end cells with partial function but acute leukemias produce immature cancer cells.
They’re descriptive terms: Leukaemia refers to bone marrow/blood disease
Lymphoma refers to disease mostly in the lymphoid tissue
Classification of hematological malignancies:
Lymphoproliferative disorders [2]
Myeloproliferative disorders [3]
Myelomas
Lymphoproliferative disorders: Hodgkin’s lymphoma/NHL, leukemias (ALL, CLL)
Myeloproliferative disorders: Myelodysplastic syndromes, myeloproliferative syndromes, leukemias (AML, CML)
Name 2 significant NHL
Diffuse large B-cell lymphoma
Follicular lymphoma
Presentation of lymphomas [2]
- Enlarged lymph nodes ie lymphadenopathy
- With extra nodal or bone marrow involvement
Causes of lymphadenopathy (ddx) according to presentation: Localized and painful [1] Localized and painless [4] Generalised and painful/tender [1] Generalised and painless [4]
Localized and painful -bacterial infection in draining site Localized and painless - TB, rare infections - + rubbery - lymphoma - + hard - metastatic from draining site - Reactive Generalised and painful/tender [1] - viral infections eg EBV, CMV, hep, HIV Generalised and painless [4] - Lymphoma, leukemia - Connective tissue diseases eg sarcoidosis - Phenytoin causes pseudo lymphoma - Reactive
Systemic B symptoms [3]
Fever, Drenching Sweats
Weight loss > 10% in last 6 months, Fatigue
Pruritis
Ix of lymphadenopathy
Clinical exam and CT tells us where it is
Biopsy - tells us type
How is NHL classified [2]
NHL classified according to lineage and grade of disease
Describe high grade and low grade lymphoma (under NHL)
Low grade NHL:
- Indolent, asymptomatic
- Responds to chemotherapy but incurable
High grade NHL:
- Aggressive, fast growing
- Require combination chemo
- Curable but highly variable
Whats the commonest subtype of lymphoma? What type is it?
Second commonest? What type is it?
Describe treatment of both [2]
Diffuse large B-cell lymphoma - high grade
Follicular lymphoma - low grade
Combination chemotherapy: anti CD20 monoclonal ab + chemotherapy
Hodgkin lymphoma:
Give 5 risk factors
What histological finding is found on most classic hodgkin lymphoma cases?
Presentation [3]
EBV, HIV
Smoking
Familial and geographic clustering
Reed-stenberg cells - multinucleate giant cells
Presentation: bimodal, 30s & 70s
- Generalised, painless, unilateral lymphadenopathy
- B symptoms
- Alcohol pain
Hodgkin lymphoma
Ix [5]
Staging techniques [3]
Tx [3] what’s ABVD
Ix:
* FBC showing normocytic anemia, eosinophilia
* HIV testing
* LDH raised
* LN biopsy - Reed stenberg
* Staging: CXR, CT chest, bone marrow biopsy
Tx:
* ABVD
* Adriamycin
* Bleomycin
* Vinblastine
* Dacarbazine
* +/- radiotherapy
Leukemias: ALL
Clinical features [2]
Progression [1]
What will FBC reveal? [3]
Dx after bone marrow biopsy? [1]
- Commonest childhood leukemia
- 2-3 week history of bone marrow failure or bone/joint pain (a symptom of bone marrow necrosis)
- Hip pain/limp
- FBC: anemia, thrombocytopenia, raised WCC
- Dx: >20% lymphoblasts in bone marrow
ALL what are 2 signs of CNS involvement?
ALL poor prognostic factors [4]
CNS involvement: CN palsy, meningism
Increasing age, WBC
Immunophenotype
Philadelphia chromosome t(9;22); t(4;11)
Slow/poor response to tx
ALL treatment
3 approaches
4 modalities of standard treatment
Supportive treatment modalities…
Approach
Growth
Educational development
Social development
1. Induction chemotherapy, bone marrow debulking
2. Consolidation therapy
3. CNS directed tx as high incidence of mets here (methotrexate)
4. Maintenance therapy for 18m once normal hematopoiesis achieved
Why is CNS directed chemo a part of standard treatment of ALL? [2]
Name 2 side effects of radiotherapy in the CNS (traditionally used)
Method for less side effects [2]
Chemotherapy only partially penetrate into brain so leukemia might relapse into brain
Radiotherapy SE - HPO dysfunction, sexual dysfx
Intrathecal (spinal tap) chemotherapy under GA - less SE
Describe the two main side effects of CAR TCell therapy
- Cytokine release syndrome - mass release of cytokines from T cell causes widespread systemic inflammatory reaction causing fever, hypotension, SOB. Tocilizumab IL-6 inhibitor can dampen response.
- ICANS
Caused by endothelial dysfunction and blood brain barrier breakdown. Occurs 5 days after therapy. Manifests as agitation, seizures, cerebral oedema, aphasia, deterioration of handwriting, prognosis usually good. Intracerebral haemorrhage.
Supportive treatment modalities in ALL [4]
Replacement therapy of blood cells
Growth factors to alleviate profound myelosuppression
Ab, anti fungal for opportunistic infection
Allopurinol
Why is allopurinol required in induction therapy?
Rise in uric acid levels during induction therapy
CLL
Histological findings [1]
Immunophenotyping characteristics [4]
Variable presentation and often asymptomatic. But what are 4 frequent findings?
Smear cells B cell markers CD19, 20, 23, 5 Frequent findings: - Bone marrow failure - Lymphadenopathy - Splenomegaly - Fever, sweats
CLL
What are 3 less common findings
2 associated findings
Less common findings
* Hepatomegaly
* infections
* Weight loss
Associated findings:
1. Immune paresis - loss of normal immunoglobulin production resulting in hypogammaglobulinemia
2. Hemolytic anemia
Binet classification system is used in CLL
Stage A - <3 lymph node areas
Stage B - 3 or more LN areas
Stage C - Stage B + anemia or thrombocytopenia
CLL Tx [3]
- Fludarabine, cyclophosphamide and rituximab (FCR)
- Patients with good performance status and the p53 deletion are given alemtuzumab (a monoclonal
antibody that binds to the CD52 protein on the surface of lymphocytes). - Ibrutinib is now considered second line in recurrence after FCR
- Patients with poor performance status are given chlorambucil.
Indications of treatment in CLL [5]
Progressive bone marrow failure
Progressive splenomegaly
Lymphocyte doubling time <6m or >50% increase over 2m
Systemic symptoms, massive lymphadenopathy
Autoimmune cytopenias
Emergency presentation of HL [2]
Infection
SVC obstruction
SVC obstruction signs in HL [5]
- Increased JVP
- Sensation of head fullness
- Dyspnoea
- Blackouts
- Facial edema
NHL - Diffuse large B-cell lymphoma treatment [5]
RCHOP 21 Rituximab Cyclophosphamide Doxorubicin Vincristine Prednisolone
ALL associations
◆ Down syndrome;
◆ Fanconi anaemia;
◆ Klinefelter syndrome;
◆ exposure to chemicals;
◆ paternal exposure to radiation.v
CLL prognostic factors
Poor prognostic factors (median survival 3-5 years)
- male sex
- age > 70 years
- lymphocyte count > 50
- prolymphocytes comprising more than 10% of blood lymphocytes
- lymphocyte doubling time < 12 months
- raised LDH
- CD38 expression positive
- TP53 mutation
What is seen on blood smear in ALL?
Blast cells
What suggests good prognosis in ALL?
FAB L1 type
Pre-B phenotype
Low initial WCC
Deletion of 9p
What suggests poor prognosis in ALL?
FAB L3 type T or B cell surface markers Philadelphia translocation Age <2 or >10 Male CNS involvement High initial WCC >100
What is the most common type of AML?
M3 - acute promyelocytic
What translocation is seen in APML?
t(15;17) - fusion of PML and RAR-alpha genes
What is seen in BM biopsy in AML?
Auer rods
What is the treatment of APML?
All-trans retinoic acid (ATRA) and anthracycline chemotherapy
What are the poor prognostic features of AML?
> 60 years
20% blasts after first course of chemo
Deletion of chromosome 5 or 7
In which leukaemia are smudge cells seen on blood film?
CLL
What are the complications of CLL?
3 points
Hypogammaglobulinaemia leading to secondary bacterial infection
Warm autoimmune haemolytic anaemia
Richter’s transformation
What is Richter’s transformation?
Leukaemia cells enter lymph node and change into high grade fast growing NHL
Ritcher’s transformation is indicated by one of the following symptoms:
lymph node swelling
fever without infection
weight loss
night sweats
nausea
abdominal pain
What is a complication of CML?
Blast transformation to AML in 80% and ALL in 20%
What mutation is common in hairy cell leukaemia?
BRAF
How is hairy cell leukaemia diagnosed?
Dry tap despite BM hypercellularity. A dry tap obtained on bone marrow aspiration is considered a failure to aspirate marrow particles. However, it is often related to an underlying bone marrow pathology that hinders successful aspiration of hematopoietic cells.
TRAP stain +ve
What is the treatment of hairy cell leukaemia?
First line: Cladribine, pentostatin, rituximab
Immunotherapy is second-line: rituximab, interferon-alpha
How is Hodgkin’s lymphoma diagnosed?
LN biopsy - Reed Sternberg cells
Raised LDH
Normocytic anaemia
Eosinophilia
How is Hodgkin’s lymphoma staged?
Ann-Arbor
Stage I-IV for lymph nodes
A = pruritus
B = all other B symptoms
What are 3 common types of B cell lymphoma?
Mantle Cell
B-cell follicular
Diffuse large B cell
What mutations are seen in Mantle cell and B cell-follicular lymphoma?
Mantle cell: t(11;14) –> over-expression of BCL-1
B-cell follicular t(14;18) –> over expression of BCL-2
25% of low grade B cell follicular lymphoma transform to what?
Diffuse large B cell
What are the 2 types of Burkitt’s lymphoma?
Endemic African: maxilla/mandible
Sporadic: ileocaecal
What is seen on lymph node biopsy in Burkitt’s lymphoma?
Starry sky - lymphocyte sheets interspersed with macrophages containing dead apoptotic tumour cells
What is the treatment of Burkitt’s lymphoma?
CYC, MTX, cytosine arabinoside, vincristine
What is the treatment of T and NK cell lymphoma?
VHOP
