Haematology II: Leukaemia & Lymphomas

• What are leukaemias?


  Malignant neoplasms of haemopoietic stem cells which result in diffuse replacement of bone marrow and normal blood precursor cells by neoplastic cells
• What does this bone marrow failure lead to?

  Anaemia, neutropenia and thrombocytopenia

  
  

  Leukaemic cells can then spill over into blood & may infiltrate organs
• How are leukaemias classified?

  They're classified on basis of cell type involved and its maturity i.e.

  forcell type:Myeloidcell lineLymphoidcell line

  And formaturity:Acuteleukaemia (>50% of cells present are myeloblasts or lymphoblasts in bone marrow at clinical presentation)

  Chronicleukaemia (cells are more differentiated)
• What is the diagnosis of leukaemias based on?

  Blood film

  
  

  Diagnosis suggested due to abnormal WCC, as well as presence of immature blast cells which are not normally present in the peripheral blood,
• How is a leukaemia diagnosis confirmed?

  Bone marrow aspirate (if it's hypercellular and there are numerous blast cells, this is considered an indicator)
• What important prognostic indicators can be ascertained from doing a blood film and bone marrow biopsy?

  Leukaemia type

  Cell phenotype

  Chromosomal abnormalities
• What are the possible causes of leukaemia?

  Ionising radiation

  
  

  Chemicals including benzene and alkylating agents

  
  

  Viruses (e.g.. HTLV - human T-cell leukaemic virus)

  
  

  Genetic factors (e.g.. Down's syndrome)

  
  

  Acquired haematological disorders such as aplastic anaemia
• What does the neoplastic cell infiltration in the bone marrow result in?

  Anaemia, pallor, malaise, fever & infections, bleeding, bruising/petechiae
• What can tissue infiltration of the neoplastic cells look like?

  
• Who does acute lymphoblastic leukaemias (ALL) typically affect?

  Children: peak incidence of 4-5 years old
• How is ALL managed?

  Remission induced with non-myelosuppressivechemotherapy

  2-12 years >60% cure rate with chemotherapy

  Adults 20% cure rate

  Combination chemotherapyto induce remission

  CNS treatment performed prophylactically

  Maintenance therapy for up to 2 years increases disease-free survival
• Who is typically affected by acute myeloid leukaemia (AML)?

  It's the most common leukaemia in adults but the incidence increases with age

  
  

  There are also genetic factors at play: children with Down's syndrome are 400x more likely to develop AML than the general population
• How is AML managed?

  >80% cure rate with intensive chemotherapy in young patients

  
  

  15% resistant disease

  
  

  4-5 courses of intensive chemotherapy (each lasting 5-10 days)

  
  

  No maintenance therapy

  
  

  Autologous and allogenic stem cell transplant if therapy fails
• How common is chronic lymphocytic leukaemia (CLL) and who is typically affected?

  Accounts for 25% of all leukaemias

  
  

  typically more prevalent in elderly population (>60yrs)

  
  

  tends to be more common in men than women, with a 2:1 ratio
• What are the clinical features of CLL?

  Constitutional symptoms

  
  

  Lymphadenopathy (swelling of lymph nodes)

  
  

  Splenomegaly (enlargement of spleen)

  
  

  Recurrent infections

  
  

  Abnormal FBC (anaemia, thrombocytopenia)

  
  

  Hypogammaglobinaemia (low antibody/serum immunoglobulin levels)
• How is CLL treated?

  Asymptomatic patients do not require treatment (monitoring only)

  
  

  30% of patients with early stage disease die of unrelated cause

  
  

  Chemotherapy typically effective

  
  

  Median survival 10-12 years

  
  

  Mortality usually due to infection or bone marrow failure

  
  

  Bone marrow transplantation occasionally attempted in younger patients with poor prognostic disease
• How prevalent is chronic myeloid leukaemia (CML) and who is typically affected by it?

  Accounts for <20% of all leukaemias

  
  

  Median age of onset is 40-50yrs & there is a slight male predominance
• How is CML treated?

  The initial chronic phase may last for years and needs no treatment and simple monitoring

  
  

  It may develop into an accelerated phase before developing a blast crisis at which point treatment is initiated
• What are the clinical features of CML?

  Bone marrow failure (anaemia, thrombocytopenia)

  
  

  Hypermetabolism (anorexia, weight loss, night sweats)

  
  

  Splenomegaly

  
  

  Leucostasis (visual disturbances, priapism)

  
  

  Hyperuricaemia- high levels of Uric acid in the blood (gout, renal failure)
• What is the Philadelphia chromosome and how many people have it?

  -Over 90% of CML patients have the Philadelphia chromosome

  
  

  -It is a 'balanced translocation' between chromosome 9 and 22
• What is the importance of the Philadelphia chromosome?

  The importance of it is the resultant oncogene which is associated with tyrosine kinase activity (an important enzyme within cellular activity)

  
  

  The identification of this chromosome led to the first targeted therapy for leukaemia- imatinib (tyrosine kinase inhibitor)
• How are lymphomas classified?

  Hodgkin's disease:Nodal (lymph nodes)ContiguousGood outcomeNot associated with immunodeficiency

  Non-Hodgkin's disease:ExtranodalNon-contiguousVariable outcomeAssociated with immunodeficiency
• Describe the incidence of Hodgkin's disease.


  Peak incidence in the third decade

  
  

  Annual incidence varies depending on gender: male- 3 per 100,000 whereas female was 1.8 per 100,000

  
  

  There is a possible bimodal age with a second peak potentially developing in adults >60yrs
• What is the aetiology of Hodgkin's disease?


  Unknown, although EBV (infectious mononucleosis) has been suggested
• What are the clinical features of Hodgkin's disease?

  Lymphadenopathy (swelling of lymph nodes):-Cervical and contiguous-Painless, non-tender, rubbery-Alcohol induced pain

  Constitutional B symptoms:-Fever-Night sweats-Weight loss >10% in 6/12

  Pruritus and erythematous rash

  Mediastinal involvement-Hilar lymphadenopathy-Bronchial compression-SVC obstruction (superior vena cava)

  Hepatosplenomegaly (enlarged liver and spleen)

  
• How is Hodgkin's disease staged?

  Ann Arbor system

  
  

  Stages 1-4

  
• How is Hodgkin's disease managed?

  Investigations:-FBC-chest x-rays/CTs-Lymph node biopsy-Bone marrow examination (rare)

  Treatment:-Early stages - chemo+radiotherapy-Advanced - Combination chemotherapy

  
  

  Prognosis relative to stage of disease and B symptoms can worsen prognosis

  
• Describe the presentation and incidence of non-Hodgkin's disease.

  Varied presentation because it's essentially a heterogeneous group of disorders

  
  

  Annual incidence of 11 per 100,000

  
  

  Slightly male preponderance

  
  

  Increases with age, it's rare under the age of 40
• What is the suggested aetiology of non-Hodgkin's disease?

  Immunodeficiency

  
  

  Infections

  
  

  Ionising radiation

  
  

  Carcinogenic chemicals

  
  

  Inherited disorders affecting DNA damage and repair
• What are the clinical features of non-Hodgkin's disease?

  Generalised lymphadenopathy

  
  

  Oropharyngeal involvement (Waldeyer's ring)

  
  

  Bone marrow infiltration

  
  

  Anaemia

  
  

  Recurrent infections

  
  

  Haemorrhage
• How is non-Hodgkin's disease managed?

  Management is based on the grade of the disease:

  Low grade disease- may be asymptomatic requiring no treatment or potentially intermittent oral chemotherapy only

  High grade disease- requires combination chemotherapy with only 30% cure on average
• How does a multiple myeloma arise?

  From malignant transformation of terminally differentiated B cell (plasma cell)

  
  

  This monoclonal expansion results in secretion of monoclonal Ig or light chains (paraproteins)

  
  

  There is typically a long asymptomatic phase that can last for many years (MGUS- monoclonal gammopathy of undetermined significance)
• What age group is typically affected by multiple myelomas?

  40-80yr olds
• What are the clinical features of multiple myeloma?

  Bone destruction:-Myeloma cells timulate osteoclasts = bone destruction + osteolytic lesions + raised serum Ca2+

  Bone marrow failure:-Marrow infiltration=anaemia, thrombocytopenia (Low blood platelet count), neutropenia (too few neutrophils) and recurrent infections.

  Renal failure:-Due to deposition and accumulation of paraproteins

  Hyperviscosity syndrome:-Headache and dizziness

  Amyloidosis

  
• How is multiple myeloma managed?

  Investigations:-FBC-Raised ESR (Evidence of inflammation) + Ca2+ (bony destruction.-Renal tests-Protiein electrophoresis-Bence-jones protiens in urine.

  Management:-Only treated if evidence of organ damage.-Chemotherapy if BM failure or bone lesions-Relapse is common-Radiotherapy useful if bone pain

  
• What is the dental relevance of all of this?

  Oral manifestations may result as secondary to the underlying process, including:

  anaemias,haemorrhagic tendency,increased susceptibility to infectionas well asneutropenic ulceration
• How can leukaemic infiltration orally manifest?

  -increased tooth mobility

  -Infiltration is typically gingival but can be bone too.

  -Tissue is friable and haemorrhagic (bleeding)

  
• Can lymphomas develop intra-orally?

  Yes, these are typically non-Hodgkin's lymphomas associated with HIV and the most commonly affected sites are the fauces (back of throat) and gingivae

  
  

  They typically present as rapidly enlarging masses with bone destruction

  
  

  Managed with chemotherapy and radiotherapy

  
• What kinds of oral complications can the treatments of these conditions result in?

  -Mucositis (inflammation+ulceration)

  
  

  -Infections i.e candidiasis

  
  

  -Mucosal bleeding

  
  

  -Xerostomia

  
• What is mucositis associated with?

  A number of chemotherapy agents and radiotherapy:

  
  

  5-fluorouracil

  Methotrexate

  Bleomycin

  Daunorubicin

  Doxorubicin