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Flashcards in Haematology Deck (40):
1

Haematology 1 - Haematology of systemic disease

 

What are the learning objectives for this lecture?

Learning objectives:

 

  • Understand the different mechanism whereby anaemia may be first presentation of a systemic disease or occult malignancy
    • Explain the term leuco-erythroblastic anaemia and list the important causes
    • Describe the relevant investigations to diagnose haemolytic anaemia and determine the cause
  • Set out an approach to investigate an elevated white cell count

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Haematology 1 - Haematology of systemic disease

 

 

What are the anaemias associated with cancer and systemic disease?

  • Iron deficiency
  • Anaemia of chronic disease
  • Leuco-erythroblastic anaemia
  • Acquired haemolytic anaemia: Immune mediated or non immune mediated (microangiopathic haemolytic anaemia)

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Haematology 1 - Haematology of systemic disease

 

What are Iron deficiency anaemia and anaemia of chronic disease?

How are tranferrein and ferritin used to destinguish the two?

Iron deficiency anaemia: A common microcytic anaemia. Happens with occult blood loss. Iron deficiency anaemia is due to bleeding until proven otherwise. Common causes are GI cancers, urinary tract cancers. Both this and anaemia of chronic disease are microcytic.

Anaemia of chronic disease: cytokines preventing the usual flow of iron into the body.

 

Lab findings show:

 

  • Ferritin: helps us to see how much iron is on the body (/inside the cells), in iron deficiency anemia Hb and ferritin are both low. Where as anaemia of chronic disease ferritin is high.

 

  • Transferrin: holds iron in the circulation and tends to be low in iron deficiency anaemia, since the body needs more iron and high in anaemia of chronic disease, since iron stores are fine the issue is cytokines preventing the usual flow of iron into the body.
    • The total iron binding capacity (TIBC) is an indirect measurement of transferrin, and follows the trend of raised in iron deficiency and low in anaemia of chronic disease.
    • Transferrin saturation is reduced in iron deficiency and normal in anaemia of chronic disease. Tells you how much transferrin in the serum is available to bind to iron.

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Haematology 1 - Haematology of systemic disease

 

 

What is Leuco-erythroblastic anaemia?

 

 

Morphological features in the blood film. Teardrop red blood cells (anisocytosis and poikilocytosis). Nucleated RBCs and immature myeloid cells.

 

The image on the right shows a normal blood film with biconcave RBCs and  you only see mature white blood cells the multinucleated cell is an example of a mature granulocyte. On the right you can see, a tear drop poikilocytes (RBCs with an irregular shape. The dark cell in the top left shows a nucleated red blood cell (NRBC). There is also an immature myelocytic cell on the right

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Haematology 1 - Haematology of systemic disease

 

What are the causes of leuco-erythroblastic anaemia? ​

 


When you see this type of anaemia, you are thinking about problems in the bone marrow since there are precursors in the blood.

 

 

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Haematology 1 - Haematology of systemic disease

 

What are the common features of Haemolytic anaemias?

Haemolytic anaemias (shortened red cell survival) common features:

 

  • Fistly there has to be an anaemia.
  • Reticulocytosis: healthy bone marrow responding to anaemia by putting out more precursor RBCs into the blood.
  • Raised bilirubin that is unconjugated
  • Raised LDH

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Haematology 1 - Haematology of systemic disease

 

What are the different types of Haemolytic anaemias?

(table)

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Haematology 1 - Haematology of systemic disease

 

How can  Adenocarcinomas have a low grade DIC effect on RBCs?

Can have an effect on red blood cells like that of cheese wire on cheese (with the RBCs being the cheese and the fibrin lines being the cheese wire).

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Haematology 1 - Haematology of systemic disease

 

What are the different Red cell changes in Cancer Elevated Haemoglobin?

True polycythaemia (raised red cell mass):

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10

Haematology 1 - Haematology of systemic disease

 

What are the white cell changes in systemic disease?

When looking at changes to white blood cells in the blood you need to consider any increases/decreases in their numbers, whether they are mature or immature, the types there are and their lineages. Types of disease that can affect white blood cells include:

 

  • Inflammatory
    • Autoimmune
    • Infective
  • Malignancy
  • Genetic
  • Metabolic

As is shown in the progressive chart above, the cells become more granulated and the nuclei become smaller as the white cells mature, you should not be seeing any of these immature myelocytes in the blood but should see a few of them in the bone marrow. Above the progressive chart you can see normal mature cells on the left, this is an example of chronic lymphocytic leukaemia and on the right shows acute myeloid leukaemia with immature myeloid cells in the blood.

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Haematology 1 - Haematology of systemic disease

 

What can cause Neutrophilia? 

Neutrophilia: ​

  • Causes are usually a bacterial infection, tissue inflammation or steroids
  • Corticosteroids, patients on steroids can have artificially raised neutrophils
  • Underlying neoplasia
  • Tissue inflammation (e.g. colitis/pancreatitis)
  • myeloproliferative /leukemic disorders
  • Infection
    • Localised and systemic infections, acute bacterial, fungal, certain viral infections
    • Some do not produce a neutrophilia e.g. brucella, typhoid and lots of viral infections

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Haematology 1 - Haematology of systemic disease

 

How do you evaluate a neutrophilia?

Evaluation of a neutrophilia:

  • Reactive?: Presence bands, toxic granulation and signs of infection/inflammation
  • Malignant?:
    • Neutrophilia basophilia plus immature cells myelocytes and splenomegaly suggest a myeloproliferative CML
    • Neutrophilia plus myeloblasts = AML

 

Images shown here are of reactive neutrophilia on the right, since there is an appropriate increased level of neutrophils, with no signs of any immature myeloid cells. There is toxic granulation. As such, this is reactive neutrophilia.

The other image is of a chronic myeloid leukaemia, since there are myeloid cells shown in the film.

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Haematology 1 - Haematology of systemic disease

 

What are th causes of reactive eosinophilia? 

Reactive Eosinophilia:

  • Parasitic infestation
  • Allergic diseases (asthma)
  • Underlying neoplasms such as Hodgkin's lymphoma, which released eosinophil stimulating cytokines causing a reactive eosinophilia.

Chronic eosinophilic leukaemia:

  • Eosinophils part of the “clone” FIP1L1 PDGFRa Fusion gene

14

Haematology 1 - Haematology of systemic disease

 

What is Monocytosis?

Monocytosis:

Rare but seen in certain chronic infections and haematological disorders such as TB and chronic myelomonocytic leukaemia (MDS)

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Haematology 1 - Haematology of systemic disease

 

What are the causes of Lymphocytosis? 

 

Lymphocytosis:

Primary: monoclonal lymphoid proliferation e.g. CLL  i.e. this is not a reaction to an infections or another cause there is something in the cells that is making them proliferate

Secondary: also called reactive, polyclonal response to infection, chronic inflammation

Examples of reactive lymphocytosis are: EBV, CMV, Toxoplasma, infectious hepatitis. Rubella, herpes infections, autoimmune disorders and sarcoidosis.

When determining the genesis of a B cell lymphocytosis, looking at where there they are polyclonal or monoclonal. All B cells are either kappa or lambda. If there is a high number of both then this is likely to be a reactive lymphocytosis, whereas if there is a raised number of only 1 it is likely to be due to a lymphoma.

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Haematology 1 - Haematology of systemic disease

 

How do you evaluate Lymphocytosis? 

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Haematology 2 - Lymphoma Multidisciplinary

 

What are the learning objectives?

Learning objectives:

  • Know the aetiology, risk factors and genetic mechanisms of lymphoma
  • Histopathology (Dr Rashpal Flora)
    • Concept of equivalent normal counterpart cell
    • Classification: Hodgkin or Non Hodgkin Lymphoma
  • Clinical: Hodgkin, Non-Hodgkin and CLL
    • Tissue diagnosis WHO classification
    • Disease stage
    • Therapy
      • Watch and wait
      • intensive chemotherapy

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Haematology 2 - Lymphoma Multidisciplinary

 

What is the definition of Lymphoma? 

Definition:

 

A Neoplastic (meaning malignant) tumour of the lymphoid cells.They are usually found in lymph nodes, bone marrow, the blood. They can also appear in Lymphoid associated organs like the spleen or gut. Can also appear in the skin, usually these are T cell disease. They rarely appear other places like the CNS, ocular, breast etc.

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Haematology 2 - Lymphoma Multidisciplinary

 

What is the incidence of Lymphoma? 

How many different tpyes of lymphoma are there? Why are there so many?

Incidence:

Roughly 200 cases per million per year, in the UK this roughly equated to 10,000 new cases a year.

  • 80% is Non- Hodgkin's lymphoma
  • 20% is Hodgkin's Lymphoma


There are over 60 different types of Lymphomas, this is because you can have different cell origins behind the cancer, in different tissues and at different stages of the haemopoietic cell development. The earliest precursor is Acute Lymphoblastic Leukaemia (ALL) and the latest is Multiple Myeloma. As shown on the right, there are lots of different routes to lymphoma. Plasma cells will lead to Multiple myeloma, B precursor cells will lead to ALL and the mantle zone will lead to Mantle cell lymphoma.

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Haematology 2 - Lymphoma Multidisciplinary

 

What is the "downside" of an adaptive immune system?

The “downside” of an adaptive immune system:

 

  1. Rapid cell proliferation in immune response to invading pathogens
    1. This increases the risk of DNA replication error
  2.  Dependent on apoptosis (90% are doomed to die by apoptosis, due to them having a bad fit to pathogens and/or your own body)
    1. Apoptosis in the germinal centre will turn the cells off
    2. Acquired DNA mutation in a proapoptotic gene can lead to cells that should die continuing survival.
  3. DNA molecules are recombinant for immunoglobulin diversity 1. Cut and rejoined plus 2. Undergo deliberate point mutation: this leads to the wide variety of T cell receptors. This means there is potential for new errors and point mutations.

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Haematology 2 - Lymphoma Multidisciplinary

 

How does Chromosomal translocation lead lead to lymphoma?

Chromosomal Translocations:

Essentially the translocations involve the Ig locus which has an Ig promoter that is very active in B cells. Translocation can bring intact oncogenes close to the Ig promoter, these can be antiapoptotic or proliferative.

This is deregulated proto oncogenes, the other type of chromosomal translocation you’ll see in Haem is fusion genes and they’ll come up later.

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Haematology 2 - Lymphoma Multidisciplinary

 

Do most cases have risk factors?

What are the 3 main causative factors behind the pathophysiology of lymphoma?

The majority of cases don’t have risk factors.

Aeitology:

  1. Constant antigenic stimulation
  2. Infection (direct viral infection of lymphocytes)
  3. Loss of T Cell function

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Haematology 2 - Lymphoma Multidisciplinary

 

How does constant antigenic stimulation lead to lymphoma?

Constant antigenic stimulation

Initially antigen dependent but eventually becomes autonomous, constantly proliferating cells that run long enough will eventually cause a mutation

  • H.Pylori: Gastric MALT (Mucosa associated lymphoid tissue) Marginal Zone NHL of stomach.  
  • Sjogren syndrome: Marginal Zone NHL of Parotid lymphoma
  • Coaeliac disease: if patients do not stick to a strict non gluten diet they are at risk of small bowel T cell lymphoma EATL (enteropathy associated T Cell Non Hodgkin's lymphoma)

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Haematology 2 - Lymphoma Multidisciplinary

 

How does infection (direct via lymphocytes) lead to lymphoma?

Infection (direct viral infection of lymphocytes):

  • Direct Viral integration:
  • HTLV1 infects T cells by vertical transmission, unlike H.Pylori which causes chronic antigen stimulation, this will directly infect T cells.
  • Caribbean and Japan carriers, this can develop into Adult t cell leukaemia (2.5% at 70 years)

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Haematology 2 - Lymphoma Multidisciplinary

 

How does Loss of T Cell function lead to lymphoma?

Loss of T Cell function:

Immunosuppression & EBV infection:

  • EBV infects B cells
  • We retain a carrier state and are chronically EBV infected, from time to time the EBV can go to a proliferative phase, when this happens the B cells will have EBV antigens on their surface.
  • Healthy carriers will have T cells that can recognise the EBV antigen on B cells should they be infected.
  • Suppression of normal T cell function leads to increased risk of B cell lymphomas, since they are less able to detect infected B cells.
    • HIV: 60 fold increase in lymphoma
    • Iatrogenic from organ transplants, called Post transplant lymphoproliferative disorder (PTLD).

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Haematology 2 - Lymphoma Multidisciplinary

 

Outline the lymphoreticular system

Generative LR tissue >> Bone marrow and thymus, generate and mature lymphoid cells

 

Reactive LR tissue >> lymph nodes and spleen, development of immune reaction


Acquired LR tissue >> extranodal lymphoid tissue (skin, stomach tissue) development of local immune system

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Haematology 2 - Lymphoma Multidisciplinary

 

Outline the WHO classification of Lymphoma

Which are the most common? 

 

B Cell Non- Hodgkin Lymphoma are the most common (85 to 80%). Shown below are the various types of lymphoma that emerge at different stages of cell maturation.

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28

Haematology 2 - Lymphoma Multidisciplinary

 

What is the histopathology of Follicular lymphoma?

Follicular lymphoma >> shows bcl2 expression which can be stained for. In a normal follicle this stain doesn’t show up

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Haematology 2 - Lymphoma Multidisciplinary

 

What is the histopathology of Small lymphocytic lymphoma/CLL?

Small lymphocytic lymphoma/CLL >> small lymphocytes, CD 5 and CD23+, shows no follicles whatsoever just sheets of these small lymphocytes.

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Haematology 2 - Lymphoma Multidisciplinary

 

What is the histopathology of Marginal zone lymphoma/ MALT lymphoma?

Marginal zone lymphoma/ MALT lymphoma >> arises at extranodal sites (lung, gut spleen) thought to be due to chronic antigen stimulation, therefore can be treated with non chemo drugs if you treat the underlying cause (such as removing the helicobacter infection)

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Haematology 2 - Lymphoma Multidisciplinary

 

What is the histopathology of Mantle cell lymphoma?

Mantle cell lymphoma >> cyclin D1 expression, characterised by a 11/14 translocation

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Haematology 2 - Lymphoma Multidisciplinary

 

What is the histopathology of Burkitt’s lymphoma?

Burkitt’s lymphoma >> jaw or abdominal mass in children/young adults, EBV associated. Has a “starry sky appearance”. The macrophages containing apoptotic debris are “stars” in the night sty. The “night” is formed from lymphoma cells.Characterised by c-myc translocation.

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Haematology 2 - Lymphoma Multidisciplinary

 

What is the histopathology of Diffuse large B cell Lymphoma?

 

Diffuse large B cell Lymphomas >> High grade rapidly growing, has very large B cells, more than 4 times normal size. P53 positive

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34

Haematology 2 - Lymphoma Multidisciplinary

 

What is the histopathology of T cell lymphomas ?

T cell lymphomas >> in B Cell lymphomas you often see background reactive normal cells alongside the neoplasm. Background cells are negative in T cell lymphomas, which are also more aggressive. Different types include:

  • Adult associated leukaemia >> ​Caribbean and Japan, associated with HTLV-1 infection
  • Enteropathy associated T cell lymphoma >> Some patients with long standing coeliac disease
  • Cutaneous T cell lymphomas >> mycosis fungoides
  • Anaplastic large cell lymphoma (bottom right):
    • Lymphoma of children and young adults, has large epithelioid” lymphocytes
    • Appear “bean shaped”
    • Alk-1 protein expression

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Haematology 2 - Lymphoma Multidisciplinary

 

What is the histopathology of Hodgkin lymphoma?

Hodgkin lymphoma >> more often localised to a single nodal sight

 

Classical:

  • Predominated by “Reed-Sternberg” and Hodgkin cells with eosinophils. With an owl's eye appearance due to the multinucleated cells.
  • Nodular sclerosis
  • Mixed cellularity
  • Lymphocyte rich and lymphocyte depleted

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Haematology 2 - Lymphoma Multidisciplinary

 

What is the histopathology of Non-Hodgkin lymphoma?

Non-Hodgkin lymphoma >> more often involves multiple lymph nodes

Clinicall:

  • Isolated lymphadenopathy
  • Indolent and B cell rich

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Haematology 2 - Lymphoma Multidisciplinary

 

What are the main features of and types of Hodgkin lymphoma?

Hodgkin Lymphoma:

 

  • Reed-Sternberg cells, 15% of Lymphoma and 1% of all cancer.
  • Bimodal age incidence, most common between 20 and 29 years and over 60
  • Painless enlargement of lymph nodes
  • Constitutional symptoms; fever night sweats, weight loss (the B symptoms) pruritus may be present
  • Can be divided into Nodular (80%, good prognosis, peak incidence in young women)
  • Mixed cellularity (17%) good prognosis
  • Lymphocyte rich (Good prognosis)
  • Lymphocyte depleted (poor prognosis)

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Haematology 2 - Lymphoma Multidisciplinary

 

How is Hodgkin lymphoma staged?

Staging :

Following a pathological diagnosis, a FDG-PET/CT scan (will do a CT scan and combines it with a glucose linked compound that is absorbed but not excreted) will be used alongside the biopsy for a diagnosis.

 

Quite simple and regularly appears in exams.

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39

Haematology 2 - Lymphoma Multidisciplinary

 

What is the treatment of Lymphoma?

What is it a balance between?

Treatment:

  • Chemotherapy: often use combination chemotherapy to target multiple pathways of cells. ABVD, meaning adriamycin, bleomycin, vinblastine DTIC, AVBD is given at 4 week intervals and HL was the first disease to be cured by chemotherapy (MOPP was the original treatment that made people infertile. ABVD doesn’t). It is BEST to CURE USING JUST chemotherapy to reduce the risk of treatment related cancers later on.
  • Radiotherapy: HL is very responsive to radiotherapy, older therapy used to have large field, now has much smaller fields.
    • For young people getting the therapy this will causes a 1 in 4 risk of causing breast cancer over 25 years.
  • Often given together

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Haematology 2 - Lymphoma Multidisciplinary

 

What is the prognosis of Lymphoma?

Prognosis:

Dependent on stage at presentation and stage. Cure rate is over 80% for patients with stage 1 or 2. But only 50% for those with stage 4. Remember this is a balance between the risk that is posed by the disease and the risk of treatment related complications.

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