Malignancies Flashcards
1
Q
What is leukaemia?
A
Malignant progressive disease in which bone marrow and blood forming organs produce increased numbers of immature or abnormal leukocytes (suppressing other blood cells such as erythrocytes). Leukocytes are any WBC.
2
Q
What are lymphoid and myeloid cells?
A
.
3
Q
What are the four types of leukaemia?
A
- LYMPHOID (lymphocytes) or MYELOID (granulocytes, erythrocytes, monocytes, megakaryocytes)
- ACUTE (rapid increase in the number of immature cells) or CHRONIC (excessive build-up of relatively mature WBCs but are MONOCLONAL in origin)
4
Q
What are the risk factors for AML and ALL? (x4)
A
Radiation, viruses, chemotherapy drugs, genetic (associated more with ALL Down’s, neurofibromatosis type 1, Fanconi’s anaemia, xeroderma pigmentosum)
5
Q
What is the pathophysiology of ALL and AML?
A
Lymphoblasts in ALL and myeloblasts in AML, arrested during development with cytogenic abnormalities, chromosomal abnormalities and gene mutations, undergo malignant transformation and proliferation with subsequent replacement of normal marrow, leading to bone marrow failure, reduced haematopoiesis and infiltration into other tissues.
6
Q
What is the epidemiology of ALL: Common? Age?
A
Most common malignancy of childhood. 2-5 years old and also in elderly.
7
Q
What is the epidemiology of AML: Common? Age?
A
Most common of the acute leakaemias in adults. Increased incidence with age.
8
Q
What is the epidemiology of CLL: Age? Gender? Ethnicity?
A
Affects patients over 50. More common in males. Rare in Asians.
9
Q
What is the epidemiology of CML: Age? Gender?
A
Increases with age. 40-60 years old. More common males.
10
Q
What are the signs and symptoms of AML and ALL? (x3 and x7) Differentials? (x4 and x2)
A
- BONE MARROW FAILURE: anaemia, bleeding, opportunistic infections (from reduced WCCs). Anaemia can manifest with murmurs
- ORGAN INFILTRATION: tender bones, lymphadenopathy, hepatosplenomegaly, meningeal involvement (headaches, visual disturbances, nausea), skin infiltrations, painless unilateral testicular enlargement, pleural effusions
- ALL: if there is proliferation of T-cells, patients present with mediastinal compression. More likely to also see retinal haemorrhage/papilledema, leukemic infiltration in anterior chamber of eye and cranial nerve palsies
- AML: associated more with gum mucosa bleeding and swelling (hypertrophy), and DIC
11
Q
! What are the investigations for ALL? (x6) Diagnosis?
A
- FBC: normocytic anaemia with low reticulocyte count, low platelets, leucocytosis (remember this means high numbers), neutropenia, raised uric acid (from high cell turnover), high LDH
- BLOOD FILM: lymphoblasts, low reticulocytes
- BONE MARROW ASPIRATE/TREPHINE BIOPSY: hypercellularity with at least 20% lymphoblasts is diagnostic
- IMMUNOPHENOTYPING: use antibodies to identify cell surface antigens. This can determine whether leukaemia has lymphoid or myeloid lineage and therefore differentiate between ALL and AML respectively.
- CYTOGENETICS: karyotyping; identify CHROMOSOMAL abnormalities or translocations
- CYTOCHEMISTRY: B- and T-lineages show up with PAS stain and acid phosphatase respectively
12
Q
! What are the investigations for AML? (x6) Diagnosis?
A
- Differences with ALL highlighted in CAPITALS
- FBC: MACROcytic anaemia with low reticulocyte count, low platelets, leucocytosis (remember this means high numbers), neutropenia, raised uric acid (from high cell turnover), high LDH. MAY SEE DIC
- BLOOD FILM: HYPERGRANULATED MYELOBLASTS and AUER RODS (crystallisation of granules in granulocytes), low reticulocytes
- BONE MARROW ASPIRATE/TREPHINE BIOPSY: hypercellularity with at least 20% myeloblasts is diagnostic
- IMMUNOPHENOTYPING: classify lineage of abnormal clones
- CYTOGENETICS
- CYTOCHEMISTRY: myeloblasts granules are positive for Sudan black, chloroacetate esterase and myeloperoxidase, monoblasts are positive for butyrate esterase
13
Q
What investigations are used to assess symptoms of ALL and AML? (x3)
A
- LP and CSF analysis: for CNS involvement
- CXR: mediastinal lymphadenopathy, mediastinal compression and lytic bone lesions
- Bone radiographs: mottled appearance with ‘punched-out’ lesions from leukemic infiltration.
14
Q
What is the aetiology and pathophysiology of CLL? (x3)
A
- Malignant cells accumulate as a result of their inability to undergo apoptosis. This is associated with overexpression of BCL2 and Fas-inhibitory molecules, arising from chromosomal changes (e.g., trisomy 12, 11q and 13q deletions) and overexpression of certain microRNAs (that modulate the expression of genes post-transcription).
- CLL cells can infiltrate the lymphatic system and haematopoietic organs leading to hepatosplenomegaly, lymphadenopathy and bone marrow suppression
- CLL cells also involved in initiating antibody production by normal B cells, leading to autoimmune reactions such as autoimmune haemolytic anaemia and ITP
15
Q
What is the aetiology and pathophysiology of CML? Which cell type is most commonly affected?
A
- Associated with ionising radiation; not hereditary
- Malignant cells accumulate as a result of proliferation of stem cells. This is associated with chromosomal translocation t(9;22) resulting in Philadelphia chromosome and subsequent fusion of BCR and ABL genes. This results in transcription of a BCR-ABL protein which drives cell replication by increased tyrosine kinase activity.
- There is proliferation of mostly granulocytic stem cells.
16
Q
What are the three phases of CML?
A
(1) Relatively stable chronic phase (4-6 years), (2) accelerated phase (3-9 months), and then (3) AML.
17
Q
Note about CML and CLL and percentage of asymptomatic patients?
A
50% of patients are asymptomatic.
18
Q
What are the signs and symptoms of CLL? (x4)
A
- Systemic symptoms: lethargy, malaise, night sweats
- Non-tender lymphadenopathy – often SYMMETRICAL, hepatosplenomegaly
- BONE MARROW FAILURE: anaemia, bleeding, opportunistic infections. Anaemia can manifest with murmurs
- May present with signs of autoimmune conditions such as ITP (contributes to anaemia)
19
Q
What are the signs and symptoms of CML? (x7)
A
- Hypermetabolic symptoms: weight loss, malaise, sweating
- BONE MARROW FAILURE: anaemia, bleeding, opportunistic infections. Anaemia can manifest with murmurs
- Splenomegaly
- Occasionally presents with hyper-viscosity symptoms such as headaches and priapism
- Occasionally presents with gout (from raised uric acid associated with high cell turnover with stem cell proliferation)
- Abdominal discomfort and early satiety (from splenomegaly or splenic infarct from hyper-viscosity)
- May present with blast crisis (AML)
20
Q
! What are the investigations for CLL? (x5)
A
- BLOOD: high WCC WITH LYMPHOCYTOSIS, low Hb, low platelets
- IMMUNOGLOBULIN LEVELS: low serum immunoglobulins
- BLOOD FILM: see photo; large number of small lymphocytes with thin rims of cytoplasm and smudge cells (damage to lymphocytes during slide preparation). Signs of haemolysis may be present such as spherocytes
- IMMUNOPHENOTYPING
- CYTOGENETICS
21
Q
How is CLL staged?
A
CT scan. Higher stage correlates with lymphadenopathy and organomegaly.
22
Q
! What are the investigations for CML? (x3)
A
- BLOOD: high WCC, low Hb, thrombocytosis (in chronic and accelerated phases; thrombocytopenia in accelerated stage and blast crisis). HIGH URIC ACID, LOW NEUTROPHIL ALKALINE PHOSPHATASE, HIGH VITAMIN B12
- BLOOD FILM: high numbers of granulocytes, presence of immature band cells (lack of segmentation). No increase in erythrocytes, B cells or T cells
- CYTOGENETICS
23
Q
What do levels of uric acid reflect in cancers?
A
Reflects tumour burden. Higher turnover means higher uric acid.
24
Q
YEAR 2 RECAP: What are the causes of lymphocytosis? (x2 (x2 and x1))
A
- Lymphocytosis where cells are MATURE: means that the cause is REACTIVE (meaning secondary) to infection; or there is a PRIMARY DISORDER i.e. monoclonal lymphoid proliferation e.g. CLL (chronic lymphocytic leukaemia).
- Lymphocytosis where cells are IMMATURE: means that the cause is a PRIMARY DISORDER such as leukaemia or lymphoma e.g. acute lymphoblastic leukaemia (ALL).
25
YEAR 2 RECAP: How do the blood films of reactive and malignant lymphocytosis differ?
* REACTIVE: Lymphocytes differ in size – some small, some large – remember, marrow is polyclonal, so this is NORMAL. All cells are mature.
* MALIGNANT: marrow is monoclonal, so all cells look the same and immature cells are present. Larger cytoplasm (so, larger than mature cells) and presence of nucleoli still – shows immature.
26
YEAR 2 RECAP: How do you distinguish between a reactive polyclonal response and lymphoproliferative disorder (lymphocytosis)?
* ASSESS MATURITY IN BLOOD FILM: if there are immature lymphocytes, then the cause is a PRIMARY lymphoproliferative disorder (cancer such as ALL). If cells are mature, then the cause can be secondary (i.e. reactive polyclonal), or primary (i.e. CLL).
* SUMMARY: if mature, then we can’t differentiate between reactive polyclonal and lymphoproliferative. If immature, cause if lymphoproliferative.
* Next stage: DISTINGUISH PRIMARY AND SECONDARY REACTIVE: study clinical context, morphology, immunophenotype or gene rearrangement.
27
YEAR 2 RECAP: How does immunophenotyping differentiate between primary and secondary reactive lymphocytosis?
Polyclonal cells, in response to infection, show BOTH kappa and lambda short chains on immunoglobulins, while monoclonal shows kappa OR lambda, but not both – because the cause is cancer which causes monoclonal production in the bone marrow (production of lymphocytes from the tumour). It is similar with T cells – recombinant configurations vs identical configurations of T cell receptor.
28
What is lymphoma?
Malignancy of lymphoid cells originating in lymph nodes or other lymphoid tissues
29
What is the aetiology of Hodgkin’s lymphoma?
Environmental trigger in a genetically susceptible individual, usually infectious. Indeed, EBV genome can be detected in 50% of patients but role is unclear.
30
What is the aetiology of non-Hodgkin’s lymphoma? (x4)
* Accumulation of genetic lesions (chromosomal translocations, inactivation of tumour suppressor genes) including by oncogenic viruses such as EBV and AIDS. HTLV-1 has been implicated in T cell lymphoma and HHV-8 in body-cavity-based lymphomas.
* Radiotherapy and chemotherapy
* Immunosuppressive agents
* Autoimmune disorders such as SLE
31
What is the pathophysiology of Hodgkin’s lymphoma?
B cell malignancy without immunoglobulin expression and defined by presence of Reed-Sternberg cells in lymph nodes. It is believed that viral factors (EBV) have a role in allowing abnormal B cells to evade apoptosis.
32
What is the pathophysiology of non-Hodgkin’s lymphoma for each cell type?
* 85% B cell, 15% T cell and NK cell malignancies with HUGE phenotypic and prognostic range. There are so many different types including Burkitt’s, diffuse large B-cell and mantle cell.
* B cells mature in the bone marrow and migrate to secondary lymphoid tissues for differentiation. B cell lymphoma arises anywhere during these processes of MATURATION. For example, mutations can happen at the stage of early precursors in the bone marrow and therefore also cause ALL. Equally, mutations can happen in mature antigen-naïve B cells in lymph nodes with no corresponding ALL.
* T cells migrate early to the thymus to mature. As such T cell lymphomas arise in the thymus
33
What is the epidemiology of Hodgkin’s lymphoma: Age? Gender?
Peaks between 20-30 and over 50 years. More common in males.
34
What is the epidemiology of non-Hodgkin’s lymphoma: Age? Gender? Where?
Increasing incidence with age. More common in males. More common in West.
35
What are the signs and symptoms of Hodgkin’s lymphoma? (x5)
* Lymphadenopathy: painless enlargement. May become painful after alcohol ingestion
* ‘B’ symptoms: fevers over 38 degrees, night sweats and weight loss
* Pruritus
* Signs of mediastinal lymphadenopathy: cough, dyspnoea, superior vena cava syndrome, chest pain
* Hepatosplenomegaly in advanced disease
36
What are the signs and symptoms of non-Hodgkin’s lymphoma? (x2 +5)
* Lymphadenopathy: painless enlargement
* ‘B’ symptoms (less commonly): fevers over 38 degrees, night sweats and weight loss
* EXTRA-NODAL DISEASE (MORE COMMON THAN IN HODGKIN’S):
* Skin rashes: Mycosis fungoides (well-defined hard scaly plaque-like lesions with ulcerated nodules caused by cutaneous T-cell lymphoma; see photo) or Sezary syndrome (red, itchy rash caused by T cell lymphoma)
* Meningeal involvement: headache and mental changes
* Hepatosplenomegaly: lymphoma infiltration
* Bone marrow infiltration: anaemia, infections, purpura
* Lung/pleural infiltration: SOB, cough
37
What are the investigations for Hodgkin’s lymphoma? (x4) Diagnosis?
* BLOOD: anaemia of chronic disease, lymphocytosis, reactive neutrophilia and eosinophilia (low if bone marrow infiltration), raised ESR/CRP, raised LDH
* LYMPH NODE BIOPSY: Reed-Sternberg cell presence is diagnostic – abundant pale cytoplasm and two or more oval lobulated nuclei containing ‘owl-eye’ eosinophilic nucleoli (see photo)
* PET scan, CXR, CT of thorax, abdomen and pelvis to assess spread
* BONE MARROW ASPIRATE or BIOPSY: not common, detect Hodgkin’s cell in bone marrow infiltration
38
What are the investigations for non-Hodgkin’s lymphoma? (x4)
* BLOOD: anaemia, lymphocytosis, PANCYTOPENIA, THROMBOCYTOPENIA, raised ESR/CRP, raised LDH, deranged LFTs from liver involvement, Ca2+ may be raised
* BLOOD FILM: left shift from bone marrow involvement
* LYMPH NODE, SKIN or BONE MARROW ASPIRATION/BIOPSY: diagnostic through immunophenotyping, histopathological evaluation and cytogenetics
* CXR, CT and PET to assess extent of infiltration
