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Haematology 2 Flashcards

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1
Q

Features of myelodysplastic syndrome that just affects RBCs

A
  • anisocytosis
  • poikilocytosis
  • hypochromic
  • pyknotic
  • basophilic inclusions (Pappenheimer bodies)
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2
Q

What’s a Perls stain used for?

A

If coloured Prussian blue then granules are siderotic (iron). These are normally ‘bitten’ out by macrophages in the spleen.

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3
Q

What does pyknotic mean?

A

Irreversible condensation of chromatin in the nucleus of a cell undergoing necrosis or apoptosis. It is followed by karyorrhexis, or fragmentation of the nucleus.

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4
Q

Myelodysplastic syndromes can progress to….

A

AML

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5
Q

MDS diagnosis is based on…

A
  • Abnormal blood count.
  • Dysplastic features on bone marrow aspirate and trephine.
  • Increased blast count.
  • Abnormal karyotype.
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6
Q

Things that cause dysplastic features

A
  • Chronic inflammatory conditions
  • Nutritional deficiency
  • Hepatic or renal impairment
  • Alcohol
  • Endocrine disorders – hypothyroidism
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7
Q

What’s a normal amount of blast cells to find in bone?

A

< 5%

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8
Q

Diagnostic tests for MDS

A 
• Blood count and blood film
• Biochemistry
• Liver function
• Thyroid function test
• CRP ESR
• Autoimmune screen
• HIV and virology
• Bone marrow aspiration
    – Search for dysplastic changes and count the proportion of blasts
    – Mandatory cytogenetics
    – Trephine
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9
Q

Clinical features of MDS

A
  • Anaemia
  • Mouth ulcer (neutropenia)
  • Purpura (thrombocytopenia)
  • Pneumonia (neutropenia)
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10
Q

Two ways in which AML can occur

A 
De Novo AML 
Secondary AML (previous  MDS, Myeloproliferative Disorders)
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11
Q

What proportion of acute leukaemias are AMLs?

A

80%

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12
Q

Clinical features of AML

A
  • Anaemia – Pale, tired
  • Thrombocytopenia – bleeding and bruising
  • Neutropenia – infection
  • Catabolic state – weight loss, fevers, sweats
  • Organ infiltration - hepatosplenomegaly, gingival hypertrophy, and CNS infiltration
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13
Q

Types of bruising

A

Petechiae < 2mm

Purpura 3-5 mm

Ecchymosis >5mm

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14
Q

Infections in AML

A
  • Pseudomonas pyocyanea
  • Candidal septicaemia
  • HSV
  • Candida plaques
  • Aspergillomas in brain
  • Toxoplasma
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15
Q

Classification of AML

A

> 20% myeloid blasts in bone marrow

  1. Morphology
  2. Cytogenetic abnormalities- bone marrow aspirate- major impact on clinical outcome.
  3. Genetic abnormalities
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16
Q

FAB classification

A

French American British classification for AML based on morphology

MO - no evidence differentiation (blasts with no granules)
M1 – minimal differentiation
M2 – myeloid (granulocytic), myeloid blasts with granules
M3 - Acute Promyelocytic Leukaemia (APL, APML), abnormal promyeloblasts, lots of granules and folded nuclei
M4 – Myelomonocytic
M5 - M5a – monoblastic M5b – monocytic
M6 – erythroleukaemia
M7 – megakaryoblastic

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17
Q

Flow panel for B lymphoid

A

CD19, cCD22, cCD79a, CD10, CD19, anti-κ, anti-λ

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18
Q

Flow panel for myeloid cells

A

CD13, CD117, anti-cMPO, CD14, CD33

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19
Q

AML blast flow cytometery phenotype

A
  • Express CD33, CD117, CD15 CD56 and cMPO

- Does not express CD3, CD7 (T-cell), nor B-lymphoid markers like CD19 and CD10

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20
Q

Therapy for fit AML patients

A
  1. Combination chemotherapy to achieve complete remission (marrow blast count ≤5% with normal blood counts).
  2. APL (AML M3): Rx with All Trans Retinoic Acid. Arsenic is also used.
  3. Occasionally we give antibodies directed against leukaemic cells (anti-CD33 Mylotarg).
  4. In some patients we consider bone marrow transplantation. There are several types of transplant depending on source of donor stem cells and the type of chemo/radio therapy given.
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21
Q

Therapy for unfit AML patients

A
  1. Supportive care. Survival is only 2-3 months.
  2. Low dose chemotherapy – palliative.
  3. New agents – Epigenetic therapy. Azacitidine (causes DNA hypermethylation) and HDAC inhibitors. Anti-CD47 trial in Oxford
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22
Q

Prognosis for AML patients

A
  1. Age – elderly do worse – can not tolerate RX and disease is less sensitive to Rx.
  2. Performance status at time of therapy.
  3. De novo AML does better than secondary AML.
  4. Relapsed and refractory disease does worse.
  5. Cytogenetics and molecular mutations.
  6. Prior therapy
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23
Q

Common mutations in AML

A 
NPM1
FLT3
TDK
CEBPA
ITD
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24
Q

ATRA

A

all-trans-retinoic acid

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25
Mutations in signal transduction | pathways that promote proliferation.
JAK2 BCR-ABL CALR MPL
26
Types of s myeloproliferative | Neoplasms (MPNs)
White blood cells (myeloid) Chronic myelogenous leukaemia, BCR-ABL1 positive RBCs Polycythemia vera Megakaryocytes (secondary phenomenon - secondary scaring of bone marrow) Primary myelofibrosis Platelets Essential thrombocythemia
27
Concept of clonal disorder of myeloid lineage
A mutation arising in a single stem cell eventually causes “clonal dominance” and emergence of MPN
28
Basic Leukaemia Classification
Acute Leukaemia: Acute Myeloid Leukaemia (AML) Acute Lymphoblastic Leukaemia (ALL) Chronic Leukaemia: Chronic Myeloid Leukaemia (CML)- Classified as a myeloproliferative neoplasm Chronic Lymphocytic Leukaemia (CLL)
29
Laboratory Assessment of MPNs
- Full blood count - Blood film examination - Bone marrow aspirate and trephine: - Morphological assessment including cytochemistry (Blast %, Assess different lineages – number and appearance) - Flow cytometry - Cytogenetics - Molecular analysis: Blood or bone marrow
30
AML
In marrow: - Auer rods (abnormal lysosomes) - Myeloblasts - Monoblasts ``` Blood: Anaemia Neutropenia Thrombocytopenia > 30% myeloblasts ``` Adults
31
CML
Marrow: - Hypercellular marrow - Elevated eosinophils and basophils (deep purple) Blood: - WBC >200K-1000K - Some blast cells in blood - Increased eosinophils and basophils Splenomegaly Ages 20-50, rare in children
32
CLL
Smudge cells Condensed chromatin Scant cytoplasm Sustained abs Lymphocytosis >5000/uL Low platelets in 20-30% Most common leukemia in adults (2 x more common in men)
33
ALL
Condensed chromatin Scant cytoplasm Small nucleoli Anaemia Thrombocytopenia Variable WBCs > 30% lmphoblasts Children
34
CML – Essential investigations
Full blood count with differential count Bone marrow aspirate and trephine: - Cytogenetics (Philadelphia chromosome) - Real-time quantitative PCR (RQ-PCR) - Fluorescence in situ hybridization of 9;22 translocation
35
Phases of CML
Chronic Accelerated Blast transformation
36
Characteristics of Chronic phase CML
``` 20% asymptomatic Systemic unwell Abdominal discomfort Leucocytosis ±thromobocytosis ``` ``` Blood film neutrophilia, metamyelocytes, basophilia, Blasts <15% ``` BM exam Blast count<15% karyotype
37
Characteristics of Accelerated phase CML
``` Blood count Anaemia Persistent thrombocytopenia (<100 x 1^09 /L) ``` Blood film: Basophilia (>20%) Blasts seen (15-29%) BM exam : Blast count 15-29% Karyotype
38
Characteristics of Blast transformation CML
Blood count Anaemia Thrombocytopenia Blood film Basophilia ++ Blasts ``` BM exam Blast count ≥30% Karyotype 70% AML 30% ALL ```
39
When is it good to be positive for philadelphia chromosome?
In CML Poor prognosis if positive in PV, ET, PMF
40
Polycythaemia vera clinical presentation
Annual incidence 0.84/100000  Most commonly routine fbc, May be asymptomatic Symptoms that are not obviously related to MPD Abnormal fbc: high Hb high HCT high Plt count (50%) High Wcc Possible Symptoms: Headache, Dizziness, Visual disturbances, Parasthesias, Pruritus, Erythromelalgia, Gout, Haemorrhage, Chorea Median age 60 years Common Signs: Plethora 70%, Splenomegaly 70%, Hepatomegaly 40% Thrombosis in 25%, arterial or venous Budd Chiari syndrome particularly associated with PV Haemorrhage Abnormal fbc: high Hb high HCT high Plt count (50%) High Wcc
41
Causes of Congenital erythrocytosis
Associated with reduced P50: (partial pressure of oxygen at which 50% of haemoglobin is saturated with oxygen) •High-oxygen-affinity hemoglobinopathy (usually autosomal dominant) •2,3-Bisphosphoglycerate deficiency (usually autosomal recessive) •Methemoglobinemia Associated with normal P50: •VHL mutations including Chuvash polycythemia (usually autosomal recessive) •PHD2 mutations •HIF2a mutations •EPOR mutations (usually autosomal dominant)
42
Causes of Acquired erythrocytosis Clonal (polycythemia vera)
Hypoxia driven (Epo high): 1. Chronic lung disease 2. Right-to-left cardiopulmonary shunts 3. High-altitude habitat 4. Tobacco use/carbon monoxide poisoning 5. Sleep apnea/hypoventilation syndrome 6. Renal artery stenosis Hypoxia independent 1. Use of androgen preparations/erythropoietin injection 2. Post-renal transplant 3. Tumours: cerebellar, renal, liver Apparent erythrocytosis Not “true” polycythaemia Stress, alcohol, obesity, smoking, diuretics
43
Essential thrombocytosis (incidence, presenting features, diagnosis)
* Incidence: Annual incidence 1.03/100000 * Median Age: ~60 yrs (middle age). There is a second peak in women ~30 yrs of age * Presenting features: ~60% asymptomatic * Rest complications of the disease e.g. erythromelalgia, thrombosis, haemorrhage * 40% splenomegaly * Sustained platelet count >450x10^9/L * It is a diagnosis of exclusion
44
Differential diagnosis of raised platelet count
1 . Reactive --- infection, inflammation, malignancy, iron deficiency, haemorrhage drugs e.g. corticosteroids prior splenectomy history, examination, CRP, ferritin 2. Exclude mixed overlap MPD - PV/ET exclude primary myelofibrosis 3. Exclude CML -- clinical picture, blood count, blood film, karyotype bcr-abl testing 4. Exclude MDS -- rare overlap MDS/MPD, RARS, 5q- syndrome Practice of doing a bone marrow for PV/ET varies widely through out the country- In a young patient worth doing to document degree of fibrosis
45
Complications and prognosis for ET and PV
``` • Complications: Venous and arterial thromboembolic events. Haemorrhage 25-30% myelofibrosis 5-10% acute myeloid leukaemia ``` • Prognosis: median survival 10-15 years.
46
A patient has lab results showing increased haemoglobin, increased neutrophils, increased platelets, decreased EPO. On bone marrow biopsy, there was hypercellularity. Dx?
Polycythaemia vera
47
What would a bone marrow biopsy show in chronic myeloid leukaemia?
Hyperplastic marrow, with granulocytic proliferation
48
What is the treatment for myelofibrosis?
No treatment
49
How does transferrin respond to inflammation?
Decrease
50
How does albumin respond to inflammation?
Decrease
51
blood film shows a neutrophil with darker granules, vacuoles and a paler nucleus. What is the cause of this toxic change?
Infection
52
What procedure would be done in essential thrombocythaemia patients to reduce the risk of bleeding or clotting before surgery?
Platelet phoresis
53
A blood film has immature neutrophils with large nuclei and RBCs containing nuclei. What is the name of this picture?
Leukoerythroblastosis
54
Which disorder will have teardrop red cells evident on blood film?
Myelofibrosis
55
A patient with a high haemoglobin and a high EPO level has what condition?
Secondary polycythaemia
56
A patient with high haemoglobin and a low EPO level has what condition?
Polycythaemia vera
57
A patient has a high serum iron, high ferritin and a high transferrin saturation. What is the diagnosis?
Haemochromatosis
58
A patient has had a gradual onset of headache, dizziness, weakness and sweating. On examination, he has red skin, splenomegaly and hepatomegaly. What is the diagnosis?
Polycythaemia vera
59
What is the treatment for essential thrombocythaemia?
Aspirin Hydroxyurea Anagralide
60
What cell is CRP synthesised by?
Macrophages
61
A patient has a slow onset of anaemia, weight loss and night sweats, as well as a massively enlarged spleen. They also experience episodic severe pain in the left shoulder. Dx?
Myelofibrosis
62
A patient has a blood screen showing increased platelet count, abnormal platelet morphology, marked increase in megakaryocytes, a mild anaemia and normal white blood cell count. Dx
Essential thrombocythaemia
63
What is the treatment for polycythaemia vera?
Aspirin | Phlebotomy
64
An asymptomatic patient with elevated platelets has a bone marrow biopsy which shows many enlarged, mature megakaryocytes. What is the likely diagnosis?
Essential thrombocythaemia
65
A patient has a slow onset disease, with bruising, fatigue, weight loss and splenomegaly. A blood screen shows increased WBCs, increased platelets, anaemia and high uric acid. Dx?
CML
66
What will a bone marrow biopsy show in myelofibrosis?
Collagen fibrosis | Increased reticulin
67
Prognosis of myelofibrosis?
Worse than ET/PV
68
Primary myelofibrosis (incidence, presentation)
Incidence: 0.47/100000 per year Clinical Picture: Primarily a disease of the elderly Systemic symptoms -- weight loss, night sweats low grade fever gout (often severe) Abdominal discomfort -- 90% splenomegaly -- massive splenomegaly 50% hepatomegaly Extra-medullary haemopoiesis
69
Blood film of primary myelofibrosis
- tear drop poilkiocytes - bizarre platelet morphology - megakaryocyte fragments - leucoerythroblastic Bone marrow exam is essential to make a firm diagnosis
70
Phases of myelofibrosis
``` Cellular phase: Hypercellular Left shifted Abnormal excessive mks - clusters of mk abnormal chromatin - cloud like, balloon shaped ``` ``` Fibrotic phase: Variable cellularity Abnormal Mks Increased blasts number Increased number and dilation of sinusoids New bone formation ```
71
Secondary myelofibrosis
``` Post ET Post PV Other haematological malignancy Malignancy Drugs ```
72
Causes of leucoerythroblastic blood film
Causes of a leucoerythroblastic blood picture can generally be divided into three main groups: ``` Conditions in which the bone marrow is under severe “stress” including: • severe sepsis • severe haemorrhage • severe haemolysis • advanced megaloblastic anaemia ``` Conditions in which the bone marrow is subject to abnormal infiltration including: • metastatic carcinoma • haemopoietic malignancies e.g. leukaemia • Myelofibrosis • osteopetrosis Conditions associated with extramedullary haemopoiesis including • advanced megaloblastic anaemia • myelofibrosis
73
Prognostic factors in myelofibrosis
``` Age > 65 years Constitutional symptoms Hb < 100 g/L WBC > 25 x 10^9/L Blast count >1% (blood) ```
74
Targeted treatment of JAK2
Ruxolitinib However, not used to treat myelofibrosis as minimal survival effect shown. It does prevent splenomegaly.
75
If you have a raised platelet count what tests would you to do determine cause?
Mutational analysis (PCR) for the JAK2 V617F mutation and for BCR-ABL fusion gene may help exclude a primary myeloproliferative disorder, though a bone marrow biopsy may be needed. General markers of inflammation (CRP, ESR) may be useful, as may serum ferritin (partly as it is an acute phase reactant, and partly because the platelet count will sometimes rise in iron deficiency). The remaining investigation will be determined by clinical history and examination.
76
What are the risks of an elevated platelet count?
Risks include thrombosis and, with marked elevated platelet counts, haemorrhage.
77
Which steps in the normal regulation of haemoglobin production can be disturbed to produce polycythaemia?
Hypoxia – patients with chronic hypoxaemia (e.g. cyanotic heart disease, chronic obstructive pulmonary disease) have a chronic stimulus to produce more erythropoietin and thus to promote erythrocytosis Oxygen sensing – rare forms of polycythaemia may result from defects in the HIF O2 sensing pathway (conceptually important, but small print from a clinical perspective). Erythropoietin excess – erythropoietin may be secreted in an unregulated fashion in patients with some renal tumours or polycystic kidney disease, resulting in polycythaemia Erythropoeitin sensing – rare defects in the epo receptor may result in polycythaemia Clonal bone marrow disorders – as in polycythaemia vera
78
Suggest three possible complications of an elevated haematocrit.
Thrombosis Haemorrhage Hyperviscosity
79
A 70-year-old woman with a ten-year history of polycythaemia vera is found no longer to require venesections to keep her haematocrit under control. - Suggest two possible complications that might give this picture. - What further laboratory tests might help clarify things?
1. Development of iron deficiency – great caution would be needed in replacing iron in this context as it might cause a rapid and uncontrolled increase in red cell mass. 2. Transformation into a myelofibrotic picture (‘burnt out’ polycythaemia) Suitable investigations would include inspection of the peripheral blood film (features of iron deficiency – microcytosis, pencil cells? Features of myelofibrosis – teardrop poikiocytes, nucleated red cells, occasional immature myeloid cells?), assessment of iron status (ferritin, serum iron and transferrin) and possibly a bone marrow aspirate and trephine.
80
A 38-year-old woman presenting with a short history of fatigue, mouth ulcers and petechial haemorrhage is found to have numerous featureless blasts on her peripheral blood smear, suggesting a diagnosis of acute leukaemia. - What tests will determine whether this is myeloid or lymphoblastic?
Inspection of the peripheral blood and bone marrow aspirate to assess the morphology of the blasts may help in some cases (e.g. granulated blasts suggest myeloid leukaemia) - but here we are told that the blasts are featureless. Immunophenotyping by flow cytometry is the key test, using either peripheral blood or aspirated bone marrow. Specific CD markers will define whether the blasts are from the myeloid or lymphoid lineage. This is important, because the drugs used to treat myeloid and lymphoid acute leukaemias differ.
81
If acute myeloid leukaemia is confirmed, what additional tests are needed to define her prognosis?
The key prognostic test is cytogenetic analysis/karyotyping. Additional molecular tests include investigation for FLT3 mutation status. Details of prognostication in AML is beyond the Lab Med syllabus.
82
This is the formation of stacks of RBCs observed in peripheral blood
Rouleaux
83
Leukocyte Alkaline Phosphatase levels are elevated in....
Polycythemia vera
84
Where is the marginal zone and what do B-cells here do?
The marginal zone is the region at the interface between the non-lymphoid red pulp and the lymphoid white-pulp of the spleen. Protect against capsulated bacteria. In humans the splenic marginal zone B cells have evidence of somatic hypermutation in their immunoglobulin genes, indicating that they have been generated through a germinal centre reaction to become memory cells. Similar to B1 B cells, MZ B cells can be rapidly recruited into the early adaptive immune responses in a T cell independent manner.
85
Where do naive B-cells go?
From bone marrow to spleen where they become transitional B-cells. They then either stay in the spleen (MZ B-cells) or go to the lymphnodes (follicular B cells).
86
Where is the mantle zone?
The mantle zone (or just mantle) of a lymphatic nodule (or lymphatic follicle) is an outer ring of small lymphocytes surrounding a germinal center. It is also known as the "corona".
87
What are germinal centres and what happens?
Germinal centers or germinal centres (GCs) are sites within secondary lymphoid organs – lymph nodes and the spleen[1] where mature B cells proliferate, differentiate, and mutate their antibody genes (through somatic hypermutation aimed at achieving higher affinity), and switch the class of their antibodies (for example from IgM to IgG) during a normal immune response to an infection. They develop dynamically after the activation of follicular B cells by T-dependent antigen. As they undergo rapid and mutative cellular division in the dark zone, B cells of the germinal center are known as centroblasts. Once these B cells have stopped proliferating, they migrate to the light zone where they are known as centrocytes, and are subjected to selection by follicular helper T (TFH) cells in the presence of follicular dendritic cells (FDCs). Germinal centers are an important part of the B cell humoral immune response, acting as central factories for the generation of affinity matured B cells specialized in producing improved antibodies that effectively recognize infectious agents, and for the production of durable memory B cells. Histologically, the GCs describe microscopically distinguishable parts in lymphoid tissues.
88
What is a lymphoproliferative condition?
A Clonal Proliferation of Lymphocytes: T-cells or B-cells Clonal - all cells derived from one precursor cell May arise from a lymphocyte at any part of life cycle Maybe either: 1. Lymphomas - present as solid lumps e.g. Hodgkin’s 2. Leukaemias - presents with blood or bone marrow involvement e.g. ALL, CLL
89
What's the difference between CLL and SLL?
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are the same disease, but in CLL cancer cells are found mostly in the blood and bone marrow. In SLL cancer cells are found mostly in the lymph nodes. Chronic lymphocytic leukemia/small lymphocytic lymphoma is a type of non-Hodgkin lymphoma.
90
Classification of lymphomas
Lymphoma: Cancer of lymphocytes (T or B cells) Hodgkin lymphoma (young/curative) Non-Hodgkin Lymphoma (older people): - T-cell NHL - B-cell NHL (90%); high grade, low grade
91
Classes of Hodgkin Lymphoma
Classical Hodgkin Lymphoma Nodular sclerosing Lymphocyte rich Lymphocyte depleted Mixed cellularity
92
High grade B-cell NHLs
Diffuse Large B-cell (most common) Burkitt Lymphoblastic
93
Low grade B-cell NHLs
CLL Follicular Marginal zone
94
Features of high grade B-cell NHLs
- Rapidly progressive - Increases with age but do see in children - Usually no cause - HIV is a risk factor - Without treatment, survival only months - Treated with combination chemotherapy +monoclonal antibodies - Fequently curable with chemotherapy
95
Features of low grade B-cell NHLs
- Slowly progressive - Increases with age -never seen in children - Usually no cause -H pylori in gastric MALT lymphoma - Without treatment,may live for many years - Generally watch and wait but treatment variable: mono-agent chemo, multiagent chemo, antibodies, radiotherapy - Generally NOT considered curable with chemotherapy
96
Reed Sternberg cells
classical Hodgkin Lymphoma
97
Hodgkin cell of origin
Germinal centre
98
Ages of presentation of Hodgkin lymphoma
15-35 years | Second peak around 60 yrs
99
Virus associated with cHL
EBV (50%)
100
Presentation of Hodgkin lymphoma
Usually presents as a lump or with mediastinal mass May have ‘B symptoms’: fever, weight loss, night sweats Other symptoms: itch, alcohol-induced pain
101
Staging of Hodgkin lymphoma
Called the Ann-Arbor Classification system - applies to most lymphomas Stage I: single lymph node group Stage II: more than one lymph node group SAME side of the diaphragm Stage III: lymph node groups BOTH sides of the diaphragm (includes spleen) Stage IV: Extranodal involvement e.g. liver, bone marrow A or B added after to signify absence or presence of so-called B symptoms
102
Treatment and prognosis of Hodgkin lymphoma
Treatment very successful Combination chemotherapy +/- radiotherapy Now > 80% cured Concern now shifting towards late effects of treatment: Increased 2nd cancers and heart disease.
103
‘Diffuse infiltration by large, pleomorphic | lymphoid cells - stain positive for CD20’
Diffuse large B-cell lymphoma (CD20 positive)
104
Cell of origin for DLBCL
Germinal centre or just after
105
Where do plasma cells live?
Circulation and bone marrow
106
Most common lymphoma subtype
DLBCL
107
Where can DLBCL be found?
Nodal or Extra-nodal Extra-nodal: brain, testis, breast, bone....anywhere!
108
Risk factors of DLBCL
Age | HIV risk factor for CNS disease
109
Prognosis of DLBCL
``` Prognosis is variable - various factors identified which determine a worse prognosis. Together used to calculate the International Prognostic Index (IPI) • Age > 60 • Stage III or IV • LDH raised • ≥ 2 extranodal sites • Performance status > 2 ```
110
Treatment of DLBCL
Treatment is combination chemotherapy (usually CHOP) combined with the anti-CD20 monoclonal antibody rituximab
111
What's CHOP?
(C)yclophosphamide, an alkylating agent which damages DNA by binding to it and causing the formation of cross-links (H)ydroxydaunorubicin (also called doxorubicin or adriamycin), an intercalating agent which damages DNA by inserting itself between DNA bases (O)ncovin (vincristine), which prevents cells from duplicating by binding to the protein tubulin (P)rednisone or (P)rednisolone, which are corticosteroids.
112
What causes the starry sky appearance in Burkitts lymphoma?
Macrophages embedded in monomorphic lymphoid infiltrate Black sky= burkitt cells White stars= macrophages
113
What's unusual about Burkitts lymphoma?
Every single cell is cycling. | 100% proliferation index
114
What's tumour lysis syndrome?
If chemo is very successful there's a large amount of cell death and contents is dumped into cells. Hyperkalemia Hyperphosphatemia Hypocalcemia Hyperuricemia and hyperuricosuria (purine degradation) The most common tumors associated with this syndrome are poorly differentiated lymphomas (such as Burkitt's lymphoma), other Non-Hodgkin Lymphomas (NHL), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML).
115
Most common childhood cancer
ALL Numerous blast cells in bone marrow Immunophenotype- lymphoid
116
ALL cell of origin
hematopoietic progenitor cells
117
Child presents with Presents with: • pancytopenia, Anaemia, Thrombocytopenia, Leucopenia • bone pain (limping with no obvious cause) • Non-specifically unwell
ALL
118
Poor prognostic factors of ALL
* High WCC at presentation * Infant or adolescent * Specific cytogenetic abnormalities e.g. Ph chromosome * Slow response to chemotherapy * High ‘minimal residual disease’ at end of induction treatment * Male sex (testis act as a sanctuary) Overall cure rate > 80% Adult ALL much less common and survival much worse
119
Peak age of ALL presentation
1-9 years
120
Childhood ALL treatment
* Long and complex - 2 years girls; 3 years boys * involves multi-agent chemotherapy * CNS directed Rx and important component * Maintenance treatment * A lot of steroids: psych disturbance, avascular necrosis
121
Proportion of different lymphomas
``` 30% Large B cell 22% follicular 14% Hodgkins 8% marginal zone 7% PTCL 6% mantle cell 6% SLL/CLL 6% mediastinal 2% anaplastic ```
122
PTCL
Peripheral T-cell lymphoma
123
Features of low grade B cell NHL
- Slowly progressive Increases with age (never seen in children) - Usually no cause (H pylori in gastric MALT lymphoma) - Without treatment, may live for many years - Treatment variable: mono-agent chemo, multiagent chemo, antibodies, radiotherapy - Generally NOT considered curable with chemotherapy - Auto-immune phenomena
124
Deletion of 11q
CLL
125
CLL cell of origin
Transitional B cell or Marginal zone B cell
126
Most common adult leukaemia in the Western world
CLL | (3-6/100,000); 15% of patients are diagnosed under the age of 65
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B-symptoms, lymphadenopathy, splenomegaly
CLL
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Complications of CLL
Complications: – increased risk of infections mainly with encapsulated bacteria – Autoimmune complications: ITP, AIHA
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Staging for CLL
Binet staging stage A: (raised WBC count) - fewer than three areas of enlarged lymphoid tissue - no anaemia - no thrombocytopaenia * lymphadenopathy in the neck, axiallary, inguinal as well as the splenic invovement, are each considered as "one group," whether unilateral (one-sided) or bilateral (on both sides) stage B: (lymphadenopathy) - three or more areas of enlarged lymphoid tissue - no anaemia - no thrombocytopaenia stage C: (marrow failure) - patients have anaemia and/or thrombocytopaenia regardless of lymphadenopathy
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Prognosis for CLL
Stage A 11 years Stage B 7 years Stage C 3 years ``` CLL is incurable for most patients 1/3 of patients do not require treatment Treatment is with chemo-immunotherapy Focus on quality of life Bone marrow transplantation for a minority of younger patients ```
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CLL treatment
There are a number of different medicines for CLL, but most people will take three main medications in treatment cycles lasting 28 days. These medicines are: fludarabine – usually taken as a tablet for three to five days at the start of each treatment cycle cyclophosphamide – also usually taken as a tablet for three to five days at the start of each treatment cycle rituximab – given into a vein over the course of a few hours (intravenous infusion) at the start of each treatment cycle Fludarabine and cyclophosphamide can usually be taken at home. Rituximab is given in hospital, and sometimes you may need to stay in hospital overnight. A number of different medicines can also be tried if you can't have these medicines, you've tried them but they didn't work, or your CLL has come back after treatment. These include bendamustine, chlorambucil, ibrutinib, idelalisib, obinutuzumab, ofatumumab and prednisolone (a steroid medication).
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Fludarabine
Fludarabine is a purine analog, and can be given both orally and intravenously. Fludarabine inhibits DNA synthesis by interfering with ribonucleotide reductase and DNA polymerase. It is active against both dividing and resting cells. Being phosphorylated, fludarabine is ionized at physiologic pH and is effectually trapped in blood. This provides some level of specificity for blood cells, both cancerous and healthy.
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cyclophosphamide
The main effect of cyclophosphamide is due to its metabolite phosphoramide mustard. This metabolite is only formed in cells that have low levels of ALDH. Phosphoramide mustard forms DNA crosslinks both between and within DNA strands at guanine N-7 positions (known as interstrand and intrastrand crosslinkages, respectively). This is irreversible and leads to cell apoptosis.
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bendamustine
Bendamustine is a white, water-soluble microcrystalline powder with amphoteric properties. It acts as an alkylating agent causing intra-strand and inter-strand cross-links between DNA bases. After intravenous infusion it is extensively metabolised in the liver by cytochrome p450. More than 95% of the drug is bound to protein – primarily albumin. Only free bendamustine is active. Elimination is biphasic with a half-life of 6–10 minutes and a terminal half-life of approximately 30 minutes. It is eliminated primarily through the kidneys.
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chlorambucil
Chlorambucil produces its anti-cancer effects by interfering with DNA replication and damaging the DNA in a cell. The DNA damage induces cell cycle arrest and cellular apoptosis via the accumulation of cytosolic p53 and subsequent activation of Bax, an apoptosis promoter. Chlorambucil alkylates and cross-links DNA during all phases of the cell cycle, inducing DNA damage via three different methods of covalent adduct generation with double-helical DNA: 1. Attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA. 2. DNA damage via the formation of cross-links which prevents DNA from being separated for synthesis or transcription. 3. Induction of mispairing of the nucleotides leading to mutations. The precise mechanisms by which Chlorambucil acts to kill tumor cells are not yet completely understood.
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ibrutinib
Ibrutinib (Imbruvica) is a small molecule drug that binds permanently to a protein, Bruton's tyrosine kinase (BTK), that is important in B cells; the drug is used to treat B cell cancers like mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström's macroglobulinemia, a form of non-Hodgkin's lymphoma. Ibrutinib has been reported to reduce chronic lymphocytic leukemia cell chemotaxis towards the chemokines CXCL12 and CXCL13, and inhibit cellular adhesion following stimulation at the B cell receptor (BCR). Additionally, ibrutinib down-modulates the expression of CD20 (target of rituximab/ofatumumab) by targeting the CXCR4/SDF1 axis. Together, these data are consistent with a mechanistic model whereby ibrutinib blocks BCR signaling, which drives cells into apoptosis and/or disrupts cell migration and adherence to protective tumour microenvironments.
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idelalisib
* Targeted, potent, highly selective, small-molecule, oral inhibitor of PI3Kδ * Inhibits proliferation and induces apoptosis in many B-cell malignancies * Inhibits homing and retention of malignant Bcells in lymphoid tissues, reducing B-cell survival
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obinutuzumab
humanized anti-CD20 monoclonal antibody Obinutuzumab binds to CD20 on B cells and causes these cells to be destroyed by engaging the adaptive immune system, directly activating intracellular apoptosis pathways, and activating the complement system.
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ofatumumab
Ofatumumab (trade name Arzerra, also known as HuMax-CD20) is a fully human monoclonal antibody (for the CD20 protein) which appears to inhibit early-stage B lymphocyte activation. It is FDA approved for treating chronic lymphocytic leukemia that is refractory to fludarabine and alemtuzumab (Campath) and has also shown potential in treating follicular lymphoma, diffuse large B cell lymphoma, rheumatoid arthritis and relapsing remitting multiple sclerosis. Ofatumumab is a humanised anti-CD20 monoclonal antibody whose epitope is distinct from that of rituximab. The CD20 antigen is expressed on solely B cell lymphocytes. Compared with rituximab, ofatumumab binds more tightly to CD20 with a slower off-rate. It causes cytotoxicity in the cells that express CD20 by means of complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC).
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56 year old man notices persistent lymph nodes in his neck. He is otherwise well. Initial investigations including a FBC are normal. A CT scan reveals the presence of widespread lymphadenopathy. Lymphnode biopsy: Closely packed follicles with a mixture of centrocytes and centroblasts
Follicular Lymphoma
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Follicular Lymphoma-cell of origin
Germinal centre
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Features of follicular lymphoma
FL acounts for 20% of all lymphomas Median age of presentation: 60 Mostly widespread disease at presentation • Patients are often asymptomatic or present with painless lymphadenopathy • Can transform into high grade diffuse large B-cell lymphoma • Rising in incidence (4% per year) • Median age of onset is 60 • Accounts for 70% of low grade lymphomas • Slight female:male predominance • Less common in Asian and African Americans
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Staging of follicular lymphoma
* Staging according to Ann-Arbor Classification system * Histological grading (grade 1-3) depending on the number of centroblasts * About 80% of cases are positive for the t(14;18)(q32;q21) leading to overexpression of bcl-2 * However: this t(14;18) is also found in normal population in low levels
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Prognosis of follicular lymphoma
International prognostic index * Age greater than 60 years * Stage III or IV disease * Elevated serum LDH * ECOG ( Eastern Cooperative Oncology Group) performance status of 2, 3, or 4 * More than 1 extranodal site * Newer prognostic models incorporating clinical and genetic features One point for each. More points is worse
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Follicular lymphomas express
Bcl2
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Grades of follicular lymphoma
Grade I: 0-5 centroblasts/HPF(high power field), “Small cleaved follicle cells”, Centrocytes Grade II: 6-15 centroblasts/HPF, Mixed Grade III: >15 centroblasts/HPF, “large blastic follicle cells”, Centroblasts
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Treatment for follicular lymphoma
* Treatment is only required for symptomatic disease * Modern treatment is with chemoimmunotherapy (rituximab, CHOP) * High-grade ‘transformation’ is treated with more intensive therapies
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Acrocyanosis
Acrocyanosis is persistent blue or cyanotic discoloration of the extremities, most commonly occurring in the hands, although it also occurs in the feet and distal parts of face.
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A 75 year old lady is admitted via A&E with breathlessness and discoloration of her hands, feet and ear lobes. Fundoscopy showing: Dilated veins, haemorrhages, Venous sausaging Protein electrophoresis: Showing a monoclonal band in gamma position Bone marrow infiltration by lymphoplasmacytoid cells
Lymphoplasmacytic lymphoma (LPL)and Waldenström macroglobulinemia. Waldenstrom describes the disease and problems relating to the IgM paraprotein problems. The IgM paraprotein can have cryoglobulin activity and cause autoimmune symptoms, neuropathy and coagulopathy
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LPL/Waldenstrom cell of origin
Lymphoplasmacytoid cell (comes out of lymph node after class swithching)
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Features of LPL/Waldenstrom
Rare lymphoma of patient over the age of 60 years Familial predisposition About 80% of patients have a mutation in the MYD88 gene (L265P) Association with HCV infection Bone marrow involvement common Patients present with: Fatigue, anaemia, cryoglobulinaemia and hyperviscosity: breathlessness, headaches, visual disturbance, strokes, neuropathy
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cryoglobulinaemia
Ig precipitates at low temperatures and causes vasculitis.
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Treatment of LPL/Waldenstrom
Not all patients require treatment at diagnosis Emergency treatment of hyperviscosity: plasma exchange Chemo-immunotherapy, more novel targeted therapies Antibody properties of IgM paraprotein
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A 65 year old man presents to his GP with chronic indigestion. More recently, he has experienced some upper abdominal pain after heavy meals. A full blood count shows a microcytic anaemia. The GP refers him for upper GI endoscopy. Treatment
Urease positive (detect carbon dioxide when take urea capsule) H. pylori causing MALT Treat with 2 antibiotics and PPI
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MALT Lymphoma- cell of origin
Marginal zone
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Causes of MALT
Accumulation of MALT Chronic inflammation MALT lymphoma (t(11;18) ``` Infectious organism: •H pylori (gastric) •Chlamydia psittaci (ocular) •Campylobacter jejuni (small intestine) •Borrelia Burgdorferi (cutaneous) ``` ``` Autoimmune diseases: Sjogren Syndrome (salivary glands) Hashimoto thyroiditis (thyroid) ```
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What's an M-spike?
In myeloma, there is a loss of polyclonal immunoglobulins, and development of monoclonal immunoglobulins, which results in an “M-spike” The loss of polyclonal immunoglobulins results in infectious complications
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What's MGUS?
Monoclonal Gammopathy of Undetermined Significance NOT CANCER, common in elderly * Monoclonal protein present, but < 3 g/dL * Monoclonal bone marrow plasma cells present, but < 10% * No features of symptomatic disease (“CRAB” features)
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What are CRAB features?
C: Calcium elevation > 11.5 mg/L or ULN R: Renal dysfunction (serum creatinine > 2 mg/dL) A: Anaemia (Hb < 10 g/dL or 2 g < normal) B: Bone disease (lytic lesions or osteoporosis)
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What factors increase the risk of progression from MGUS to MM?
* serum M-protein ≥15g/l * non-IgG subtype * abnormal SFLC ratio (<0.26 or >1.65) ``` 20yr risk ofprogression(%): Score 0 5% Score 1 21% Score 2 37% Score 3 58% ```
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SFLC
Serum free light chains
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Criteria for Smouldering (asymptomatic) myeloma
``` As for MGUS, but:  Monoclonal protein level higher at > 3g/dL AND/OR  Monoclonal plasma cells present at a higher percentage, at > 10% BUT  No symptoms attributable to myeloma present (see CRAB features) ``` Cancer that doesn't require treatment
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Stepwise progression of MGUS
MGUS Smoldering MM Active MM Extra medullary
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Criteria of multiple myeloma diagnosis
 Increased monoclonal plasma cells in the bone marrow and/or biopsy proven plasmacytoma AND  Monoclonal protein present in the serum and/or urine AND  Symptoms related to 1 or more of CRAB criteria
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Clinical features of myeloma
 Bone pain: often with loss of height  Constitutional: weakness, fatigue, and weight loss  Anaemia  Renal disease: renal tubular dysfunction  Infections: neutropenia/hypogammaglobulinaemia  Hypercalcaemia: myeloma cells secrete osteoclast-activating factors  Hyperviscosity: 2% with myeloma; 50% with macroglobulinaemia  Neurologic dysfunction: spinal cord or nerve root compression
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International staging system (ISS) for MM
``` 1 Serum ß2 microglobulin <3.5 mg/dL + Serum albumin ≥ 3.5 g/dL 2 Not 1 or 3* 3 Serum ß2 microglobulin >5.5 mg/dL ```
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Example of IMiDs and side effects
Thalidomide (neuropathy, constipation, sedation, DVT) Lenalidomide (myelosuppression, skin rash, DVT) Pomalidomide
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Examples of protease inhibitors
Velcade Bortezomib Carfilzomib
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Manifestations of myeloma bone disease and treatment
``` bone pain fractures osteoporosis significant kyphosis loss of height ``` * Bisphosphonate therapy * Orthopaedic intervention * Vertebroplasty * Radiotherapy
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Myeloma renal disease
• “Myeloma kidney” – Normal glomerular function – Concentrated light chains precipitate in tubules – Monoclonal light chains seen in UPEP with immunofixation • Glomerular lesions – Deposits of amyloid or light chain deposition disease – Nonselective leakage of all serum proteins – UPEP preponderance of albumin
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UPEP
Urine protein electrophoresis
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In MM where would you find casts and what are they composed of?
DCT mainly consisting of immunoglobulin light chain known as Bence Jones protein, but often also contain Tamm–Horsfall protein.
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What's THP?
Tamm–Horsfall glycoprotein (THP), also known as uromodulin
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What's the most abundant protein excreted in ordinary urine?
Uromodulin
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Function of THP
THP is a GPI-anchored glycoprotein. It is not derived from blood plasma but is produced by the thick ascending limb of the loop of Henle of the mammalian kidney. While the monomeric molecule has a MW of approximately 85 kDa, it is physiologically present in urine in large aggregates of up to several million Da. When this protein is concentrated at low pH, it forms a gel. Uromodulin represents the most abundant protein in normal human urine (results based on MSMS determinations). It is the matrix of urinary casts derived from the secretion of renal tubular cells. Uromodulin excretion in urine follows proteolytic cleavage of the ectodomain of its glycophosphatidylinositol-anchored counterpart that is situated on the luminal cell surface of the loop of Henle. Uromodulin may act as a constitutive inhibitor of calcium crystallization in renal fluids. The excretion of uromodulin in urine may provide defense against urinary tract infections caused by uropathogenic bacteria
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Co-factors for Acute Kidney Injury in Myeloma
``` • Drugs – NSAIDS – Diuretics • Hypercalcaemia • Sepsis • Volume depletion/dehydration • Operative stress ```
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Solitary Plasmacytoma of Bone
``` • ~3% of plasma cell neoplasms • One isolated bony lesion of plasma cells • Uninvolved marrow <5% plasma cells • M-protein present ~25% cases – Disappears following treatment • Curable with local radiation therapy – Median OS 10 years – Multiple myeloma develops in 50-60% ```
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Extramedullary Plasmacytoma
• ~3% of plasma cell neoplasms • Isolated plasma cell tumors of soft tissues – Upper respiratory tract common • Uninvolved marrow, negative skeletal survey • M-protein present ~25% cases – Disappears following treatment • Curable with local radiation therapy/ surgery
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What's amyloidosis?
Extracellular tissue deposition of low molecular weight fibrils. These fibrils are insoluble, linear, rigid and measures approximately 7.5 to 10mm in width. – Beta-pleated sheets, bind Congo red – Damage tissue structure and organ function
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Precursor proteins of amyloidosis
• Precursor proteins involved – Monoclonal immunoglobulin light chains: Primary (AL) Amyloidosis – Serum amyloid A protein: Reactive or Secondary (AA) Amyloidosis – Beta-2 microglobulin: Dialysis (DA) Amyloidosis – Transthyretin, apolipoprotein A-I, Alzheimer amyloid precursor protein, prion protein, Prolactin, Atrial natriuretic protein, Procalcitonin, Insulin, Keratin…
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Amyloidosis: Presentation
• Nephrotic syndrome • Refractory CHF, Arrhythmia, Heart block • Orthostatic hypotension, Peripheral neuropathy • Bleeding diathesis (Raccoon eyes) – Factor X deficiency, liver disease • GI bleeding, Gastroparesis/Dysmotility, Malabsorption • Macroglossia, Carpal tunnel syndrome, Organomegaly • Skin thickening/waxy, easy bruising
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Prognosis of AL
Poor, cardiac involvement makes it worse
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What's a SAP scan?
* Serum Amyloid protein purified from normal people labelled with 123Iodine. * Given intravenously * Poor definition in GI tract and heart * Useful for staging and assessment for response * Only performed at the Royal Free Hospital
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Characteristics common to all amyloid subtypes
* Hematoxylin and Eosin (HE) staining results in amorphous eosinophilic appearance when viewed on light microscopy. * Congo red staining results in bright green fluorescence/birefringe apple green color when viewed under polarized light.
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Waldenstrom’s macroglobulinaemia
* Cells: lymphocytes, lymphoplasmacytoid cells, plasma cells, excess mast cells in association with lymphoid aggregates * BM: interstitial pattern with diffuse or nodular infiltrates, excess mast cells in association with lymphoid aggregates * LN/SP: diffuse pattern
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Clinical manifestations of WM
``` ↓HCT, ↓PLT, ↓WBC Hyperviscosity Syndrome: Epistaxis, HA, Impaired vision >4.0 CP IgM Neuropathy (22%) Cryoglobulinaemia (10%) Cold Agglutinaemia (5%) Fatigue Adenopathy splenomegaly≤15% ```
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Adenopathy
Large or swollen lymph nodes | Synonymous with lymphadenopathy.
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Histological features of Follicular lymphoma
‘Follicles’ of centrocytes (cleaved follicle centre B-cells) of monomorphic appearance, surrounded by non-malignant lymphoid cells, often with little interfollicular tissue. This is a low grade lymphoma, so the proliferation rate of the malignant cells is low.
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What's a paraprotein?
Production of a single immunoglobulin from a clone of lymphoid cells results in a strong narrow band on the electrophoresis strip – this is the paraprotein (also known as an M protein)
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A patient has a paraprotein. Explain what additional laboratory investigation this patient should have.
Investigation for end-organ damage: - FBC - renal function - calcium - skeletal survey for lytic lesions - Urine should be examined for Bence-Jones proteins (free light chains). - Free immunoglobin light chains in the peripheral blood can also be assayed, and are now often used in monitoring patients with myeloma.
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What is the underlying genetic basis of Waldenstrom’s macroglobulinaemia?
This is another example of how exome sequencing has enhanced our understanding of the pathophysiological basis of disease. The great majority of cases of WM are characterised by a somatic mutation in the MYD88 gene – a mutation that results in uncontrolled activation of two kinases (Interleukin-1 receptor associated kinase and Bruton’s tyrosine kinase) and subsequent NF-kB pathway activation. Although the molecular details here are beyond the requirements of the lab medicine course, it is important to recognise that a proper understanding of haematological diseases moves beyond the clinical picture and the orphological appearance of the cells into an appreciation of the genetic and biochemical disturbances in each cell. Emphasizing the clinical significance of these findings, Bruton’s tyrosine kinase has recently been exploited as a target for the treatment of some lymphomas.
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A 55-year-old woman presents with night sweats, a cough, and cervical lymphadenopathy. A lymph node biopsy demonstrates diffuse large B-cell lymphoma. - What tests need to be performed to complete her staging investigations?
Bone marrow trephine biopsy and staging CT of neck, chest, abdomen and pelvis

Haematology (5 decks)

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