Haematological malignancies

Question 1

What is ‘leukaemia’ and what are the two classes?

Answer 1

The term “leukaemia” refers to a malignant neoplastic process involving one of the white blood cell lines (neutrophils, lymphocytes, monocytes etc).

Depending on the cell line that is affected it could be classified into Myeloid (neutrophils) or Lymphocytic (lymphocytes) leukaemia

Question 2

Name the two lymphocytic leukaemias

Answer 2

Acute lymphoblastic leukaemia (ALL)

Chronic lymphocytic leukaemia (CLL)

Question 3

Name the two myeloid leukaemias

Answer 3

Acute myeloid leukaemia (AML)

Chronic myeloid leukaemia (CML)

Question 4

Describe AML

Answer 4

This is the commonest acute leukaemia of adults. This neoplastic proliferation of blast cells is derived from marrow myeloid elements. It progresses rapidly: death in approx. 2 months if untreated and approx. 20% survive for 3 years with treatment.

Question 5

AML symptoms (using subtypes)

Answer 5

Acute promyelocytic leukaemia (subtype) : DIC occurs due to build-up of dysfunctional retinoic acid receptors and an increase in auer rods (increased coagulation risk)

Acute monocytic leukaemia : gym hypertrophy

Acute megakaryoblast leukaemia: associated with down’s syndrome (before the age of 5)

General: anaemia, infection or bleeding, hepatosplenomegaly, CNS involvement (rare)

Question 6

AML diagnosis and complications?

Answer 6

Diagnosis:
• WCC is often raised but can be normal or even low.
• Bone marrow biopsy: myeloperoxidase enzymes and auer rods

Complications
• Infections (esp. Septicaemia) – related to disease and during treatment
• AML often causes fever so if often misdiagnosed as an infection

Question 7

AML treatment?

Answer 7

• Supportive care
• Chemotherapy – results in long periods of marrow suppression with neutropenia + low platelets
• Bone marrow transplant
ATRA - binds to retinoic acid receptors to cause the cells to mature and eventually die.

Question 8

Describe CML

Answer 8

CML is characterised by an uncontrolled clonal proliferation of myeloid cells. It accounts for 15% of leukaemia. It is a myeloproliferative disorder. It occurs most often between 40-60years with a slight male predominance and is rare in childhood.

Question 9

Which protein is often found in CML?

Answer 9

Philadelphia chromosome (Ph) is present in >80% of those with CML. Those without pH have a worse prognosis.

Ph chromosome codes for a protein (tyrosine kinase) that causes immature myeloid cells to reproduce quicker and therefore build up and cause hepatosplenomegaly.

Question 10

CML symptoms and signs?

Answer 10

Symptoms: Weight loss, tiredness, fever, sweats. There may be features of gout (due to puring breakdown), bleeding (platelet disfunction) and abdominal discomfort (splenic enlargement).

Signs: splenomegaly, hepatomegaly, anaemia, bruising

Question 11

CML diagnosis and treatment?

Answer 11

Diagnosis:
• WBC increases
• ↓Hb (anaemia), ↑urate, ↑vitamin B12
Philadelphia chromosome on genetic testing

Treatment:
• Imatinib (tyrosine kinase inhibitor) – specific genotype-related drug
• Other chemotherapy drugs
• Stem cell transplantation

Question 12

Describe ALL

Answer 12

Acute lymphoblastic leukaemia is very rare and is equally as common in children as in adults. Although rare, acute lymphoblastic leukaemia is the most common type of childhood leukaemia

Acute Lymphoblastic Leukaemia has a peak incidence of 2-5 years, affects slightly more boys than girls and accounts for 80% of childhood leukaemia’s.

It is the most common malignancy affecting children. There is not a strong family correlation, although some genetic disorders, such as Down’s syndrome (after the age of 5), increase the likelihood of developing the disease.

B-cell ALL is the most common type of ALL. It causes a translocation of chromosomes:
• t(12:21) = mostly affects children
• t(9:22) = mostly affects adults (Philadelphia chromosome)

T-Cell ALL is less common but accumulates in the thymus gland and is most common in teenagers. This is often called acute lymphoblastic lymphoma because a mass is formed i.e. lymphoma.

Dx: TdT protein found in nucleus indicates that cells are lymphoblasts
.

Question 13

Describe CLL

Answer 13

Accumulation of mature B cells that have escaped programmed cell death and undergone cell-cyle arrest in the G0- G1 phase. It is the commonest leukaemia

The exact causal mutation is unknown, but it affects either B-cell lymphocytes (usually) or T-cell lymphocytes.

Question 14

CLL symptoms and signs?

Answer 14

often asymptomatic and an incidental finding. Increased number of infections (leukopenia), fatigue (anaemia), bleeding (thrombocytopenia). If severe = weight loss, sweats, anorexia. Enlarged, rubbery, tender nodes. Splenomegaly, hepatomegaly

Question 15

CLL tests and complications

Answer 15

Tests:
• Increased lymphocytes
• Later- anaemia, low neutrophils and low platelets.
• Blood smear: smudge cells (immature B cells that have broken during the smear)
• Genetic testing: chromosome abnormalities

Complications:

1. Autoimmune haemolysis
2. Increased risk of infection due to hypogammaglobinaemia (reduced IgG)
3. Marrow failure
4. Can develop into a lymphoma

Question 16

CLL treatment and prognosis?

Answer 16

Treatment: consider drugs if symptomatic or if immunoglobulin gene are unmutated.
• Chemotherapy
• Steroids – help autoimmune haemolysis
• Radiotherapy – treat lymphadenopathy and splenomegaly
• Supportive care: transfusions (anaemia), IV immunoglobulin if recurrent infections arise
• Stem cell transplant

Prognosis: 1/3 never progress, 1/3 progress slowly and 1/3 progress actively.

Question 17

What is a lymphoma?

Answer 17

Lymphomas are malignancies that involve the lymphocytes. Lymphocytes are present in the circulation, bone marrow, lymph nodes and other organs that form the reticulo-endothelial system such as the liver and spleen. Characteristically, lymphomas are solid tumours involving the lymph nodes and when there is involvement of other organs it is referred to as extra-nodal involvement. Extra-nodal involvement may even include remote sites such as the skin, brain, bowels and bone. Lymphomas are closely related to lymphoid leukaemias, which originate in the marrow and therefore typically involves circulating lymphocytes. Lymphomas are a part of the broad spectrum of haematological malignancies

Question 18

What are the two types of lymphomas?

Answer 18

Malignant Lymphomas are when the normal lymphoid structure is replaced by a collection of malignant cells.

They can be divided into 2 groups.

1. Hodgkins Lymphoma – characterised by the presence of Reid Sternberg cells (RS)
2. Non Hodgkins Lymphoma -Characterised by diffuse or nodular abnormal lymphocytes.

Question 19

How are lymphomas staged?

Answer 19

Stage 1: One group of lymph nodes is affected.

Stage 2: Two or more groups of nodes are affected, but the lymphoma is restricted to one side of the diaphragm only

Stage 3: Lymphadenopathy is evident on both sides (above and below) of the diaphragm.

Stage 4: The lymphoma has spread beyond the lymph nodes to other organs such as the spleen, bone marrow, liver or lungs.

As well as giving each stage a number, a letter code – A or B, is added to each of the above stages to indicate whether or not the patient has systemic symptoms (such as weight loss, fevers or night sweats).

Question 20

What is non-hodgkin’s lymphoma?

Answer 20

“Non-Hodgkin’s lymphoma” is an umbrella term used to describe a range of lymphomas described since the time of Thomas Hodgkin. These “non-Hodgkins lymphomas” have little in common with each other and hence the term is gradually being abandoned in the scientific literature.
In 1996 an attempt was made to classify Non-Hodgkin’s lymphomas into four grades: Low grade, Intermediate grade, High grade, and Miscellaneous based on their prognosis. This has now been superseded by newer classifications based on cell morphology and surface markers.

Question 21

How are non-hodgkin’s lymphomas graded?

Answer 21

In addition to Staging, the histological sub-type of lymphoma is very important. The subtype determines the behaviour, treatment and prognosis of the lymphoma. There are a number of different subtypes of non hodgkins lymphoma but put simply they may be graded into high grade or indolent lymphomas based on the histology:

Indolent: These tumours grow slowly and may not require treatment for long periods. When they do need treatment they are likely to respond well to chemotherapy but they are very rarely cured. Follicular lymphomas are low-grade Non-Hodgkins Lymphomas.

High-grade: These tumours grow quickly and are frequently symptomatic. However, they are more likely to be completely cured than low-grade lymphomas with chemotherapy. Diffuse large B-cell lymphomas and Burkitt lymphomas are examples of high-grade Non Hodgkins lymphoma.

Question 22

What is hodgkin’s lymphoma?

Answer 22

In Hodgkin’s lymphoma, characteristic cells with mirror-image nuclei are found called Reed-Sternberg cells

Question 23

What are the symptoms and signs of hodgkin’s lymphomas?

Answer 23

Symptoms:
• Enlarged, painless, non-tender rubbery superficial lymph nodes – typically cervical (60-70%), btu also axillary or inguinal.
•Node size may in crease and decrease spontaneously and nodes can become matted.
• 25% have constitutional upset e.g. fever, weight loss, night sweats, pruritus, and lethargy.
• There may be alcohol-induced lymph pain.

Signs: 
• Lymph node enlargement
• Cachexia
• Anaemia
• Splenomegaly or hepatomegaly

Question 24

How is hodgkin’s lymphoma diagnosed?

Answer 24

Tissue diagnosis: lymph node biopsy if possible. Image-guided needle biopsy, paratomy or mediastinoscopy may be needed to obstain a sample.

Bloods: FBC, ESR, LFT, LDH, urate, Calcium
Increased ESR and decreased Hb indicate a worse prognosis.

Question 25

How is hodgkin’s lymphoma staged?

Answer 25

Staging (Ann Arbor system)
Influences treatment and prognosis. Done by CXR CT/PET scan of thorax, abdominal, pelvis +/- marrow biopsy.

I) Confined to single lymph node region
II) Involvement of two or more nodal areas on the same side of the diaphragm
III) Involvement of nodes on both sides of the diaphragm
IV) Spread beyond lymph nodes e.g. liver or bone marrow

Question 26

How is hodgkin’s lymphoma treated?

Answer 26

Chemoradiotherapy

Question 27

What is a myeloma?

Answer 27

Myeloma is a cancer of plasma cells in the bone marrow. Myeloma can develop wherever there are plasma cells i.e. pelvis, spine, ribcage etc. As it can occur in several places in the body, it is often called multiple myeloma. Myelomas arises due to an abnormal proliferation of a single clone of plasma or lymphoplasmacytic cells leading to a secretion of Immunoglobulin(Ig) or an Ig fragment, causing the dysfunction of many organs.

Question 28

What are the symptoms of a myeloma?

Answer 28

• Osteolytic bone lesions causing backache, pathological fractures and vertebral collapse. Lesions are due to increased osteoclast activation from signally to myeloma cells.

Symptomatic Hypercalcaemia

Symptoms of anaemia, infection and bleeding: Anaemia, neutropenia or thrombocytopaenia may results from marrow infiltration by plasma cells.

Recurrent bacterial infections

Renal impairment – due to light chain deposition in the loop of Henle

Question 29

How is a myeloma tested for

Answer 29

Have a high index of suspicion in back pain or bone pain which is not improving.
• Normocytic normochromic anaemia
• Persistently raised ESR
• Increased urea and creatinine
• Increased calcium
•X-ray: ‘punched out’ lesions, e.g. pepper-pot skull, vertebral collapse, fractures or osteoporosis
• CT/ MRI to detect lesions not seen on X-ray

Question 30

What is the diagnostic criteria for a myeloma?

Answer 30

I. Monoclonal protein band in serum or urine electrophoresis
II. Plasma cell increase on marrow biopsy
III. Evidence of end-organ damage from myeloma (hypercalcaemia, renal insufficiency, anaemia)
IV. Bone lesions: a skeletal survey after diagnosis detects bone disease: x-ray of chest, all of spin, skull and pelvis

Question 31

How is a myeloma treated?

Answer 31

Analgesia: to treat bone pain (avoid NSAIDs due to renal impairment)

Bisphosphonate – to reduce fracture rates and bone pain

Local radiotherapy

Orthopaedic procedures – vertebroplasty and kyphoplasty – useful in vertebral collapse.

Transfusion – treat anaemia

Treat renal failure with IV fluids or dialysis + Treat infections with broad-spectrum antibiotics
• Chemotherapy

Question 32

What are the complications of a myeloma?

Answer 32

1. Hypercalcaemia
2. Spinal cord compression
3. Hyperviscosity
4. Acute renal injury