Haematology II: *1

• Leukaemias are malignant neoplasms of haemopoietic stem cells, leading to the diffuse replacement of bone marrow and normal blood precursor cells by neoplastic cells.
• Bone marrow failure in leukaemia causes anaemia, neutropenia, and thrombocytopenia.
• Leukaemic cells can spill over into the blood and infiltrate organs.
• Leukaemias are classified into two cell lines: myeloid and lymphoid.
• Myeloid leukaemias result in basophils, neutrophils, eosinophils, monocytes, and macrophages.
• Lymphoid leukaemias result in B cells, T cells, and plasma cells.
• Leukaemias are classified into two types of maturity: acute and chronic.
• Acute leukaemias have >50% myeloblasts or lymphoblasts in bone marrow at clinical presentation.
• Chronic leukaemias have more differentiated cells.
• Diagnosis of leukaemia involves analysing blood film and bone marrow.
• Blood film and bone marrow analyses are important prognostic indicators, revealing leukaemia type, cell phenotype, and chromosomal abnormalities.

Aetiology of Leukaemia

• Ionising radiation
• Chemicals like 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

Marrow Infiltration Effects

• Neoplastic cells cause this
• Pallor
• Malaise
• Fever and infections due to immune system effects
• Bleeding due to effects on coagulation
• Bruising/petechiae

Tissue Infiltration Effects

• Neoplastic cells spill out of the bone marrow into the blood and tissues
• Lymphadenopathy
• Hepatosplenomegaly
• Central nervous system involvement
• Bone and joint pain (acute lymphoblastic leukaemia ALL)
• Testicular involvement (ALL)
• Gingival hypertrophy (acute myeloid leukaemia AML)

Types of Leukaemia

• AML- Acute Myeloid Leukaemia
• ALL- Acute Lymphoblastic leukaemia
• CML- Chronic Myeloid Leukaemia
• CLL- Chronic Lymphoblastic Leukaemia

Acute Lymphoblastic Leukaemia (ALL)

• Peak incidence in children aged 4-5 years
• Remission induced with non-myelosuppressive chemotherapy.
• This has a cure rate of over 60% for 2-12 year olds.
• The cure rate in adults is 20% with chemotherapy.
• Combination chemotherapy is used to induce remission.
• CNS treatment is performed prophylactically.
• Maintenance therapy for up to 2 years increases disease-free survival.

Acute Myeloid Leukaemia (AML)

• It it the most common leukaemia in adults
• Incidence increases with age.
• 400x higher incidence in children with Down’s syndrome.
• Intensive chemotherapy has a cure rate higher than 80% in young patients.
• 15% of patients have a disease resistant to chemo. They require 4-5 courses of intensive chemo each lasting 5-10 days.
• Typically maintenance therapy is not required.
• Autologous and allogenic stem cell transplant are used if chemo fails.

Chronic Lymphoblastic Leukaemia (CLL)

• Peak incidence in the elderly (over 60s)
• 25% of leukaemias are CLL.
• M:F ratio is 2:1.
• Asymptomatic patients do not require treatment.
• 30% of patients with early-stage disease die of unrelated causes.
• Chemotherapy is typically effective.
• Median survival is 10-12 years.
• Mortality usually stems from infection or bone marrow failure.
• Bone marrow transplantation is occasionally attempted in younger patients with poor prognostic disease.

Chronic Myeloid Leukaemia (CML)

• Median age is 40-50 years for onset.
• Less than 20% of all leukaemias.
• Slight male predominance.
• Chronic phase lasts for years with no treatment necessary.
• Treatment is required during accelerated phase and blast crisis phases.

CML Clinical Features

• Bone marrow failure (anaemia, thrombocytopenia)
• Hypermetabolism (anorexia, weight loss, night sweats)
• Splenomegaly
• Leucostasis (visual disturbances, priapism)
• Hyperuricaemia (gout, renal failure)

Philadelphia Chromosome

• Over 90% of CML patients have it.
• Balanced translocation between chromosome 9 and 22.
• Results in an oncogene with tyrosine kinase activity, leading to imatinib (tyrosine kinase inhibitor) as the first targeted therapy.

Dental Symptom of Leukaemia

• Gingival overgrowth due to large production of abnormal white blood cells.
• Abnormal white blood cells cannot fight infection which impairs the ability of the bone marrow to create red blood cells and platelets.
• Bleeding is a frequently encountered symptom which can affect the gums.

Differences Between Hodgkin's and Non-Hodgkin's Lymphoma

• Hodgkin's involves the lymph nodes, Non-Hodgkin's does not.
• Hodgkin's spreads contiguously, Non-Hodgkin's does not.
• Hodgkin's has a good outcome, Non-Hodgkin's has a variable outcome.
• Hodgkin's is not associated with immunodeficiency, Non-Hodgkin's is.

Hodgkin’s Peak Incidence

• In the 3rd decade.

Aetiology of Hodgkin’s

• Unknown, but EBV (infectious mononucleosis) is suggested.

Clinical Features of Hodgkin’s

• Lymphadenopathy in cervical and contiguous areas.
• Lymphadenopathy is painless, non-tender, and rubbery.
• Alcohol induced pain.
• Additional constitutional 'B' symptoms: Anorexia, fatigue, Fever, Night sweats, and Weight loss >10% in 6/12.
• Pruritus and erythematous rash may occur.
• Mediastinal involvement with hilar lymphadenopathy, causing bronchial compression and SVC obstruction.
• Hepatosplenomegaly is common.

Hodgkin’s Staging

• Based on the Ann Arbor system:
  • Stage I: Single lymph node region
  • Stage II: Two lymph node regions on the same side of the diaphragm
  • Stage III: Groups on both sides of the diaphragm
  • Stage IV: Widespread disease outside lymphatic sites, e.g., lung.

Hodgkin’s Investigation

• FBC (normochromic normocytic anaemia)
• Elevated ESR
• LFTs/U&Es/bone profile/LDH
• CXR/CT
• Lymph node biopsy (Reed-Sternberg cells)
• Rarely bone marrow examination

Hodgkin’s Treatment

• Early-stage disease (IA/IIA): Chemotherapy + radiotherapy
• Advanced-stage disease: Combination chemo
• Complete remission is 60-90%
• Prognosis is relative to stage of disease
• Stage I has a 90% 5-year survival rate
• B symptoms (weight loss, night sweats, unexplained fever) indicate a poorer prognosis

Non-Hodgkin’s Peak Incidence

• Increases with age.
• Rare for under 40s to have it.

Aetiology of Non-Hodgkin’s

• Immunodeficiency
• Infections
• Ionising radiation
• Carcinogenic chemicals
• Inherited disorders affecting DNA damage and repair

Non-Hodgkin’s Clinical Features

• Generalised lymphadenopathy
• Oropharyngeal involvement (Waldeyer’s ring)
• Bone marrow infiltration causing anaemia, recurrent infections, and haemorrhage

Non-Hodgkin’s Management

• Low grade disease; asymptomatic patients may require no treatment, otherwise intermittent oral chemo is used.
• High grade disease; Combination chemotherapy is used (30% cure).

Multiple Myeloma

• Arises from malignant transformation of terminally differentiated B cells (plasma cell).
• Malignant transformation is described as monoclonal expansion; results in secretion of Ig or light chains (paraproteins).
• Peak incidence between 40-80 years old.

Multiple Myeloma Clinical Features

• Long asymptomatic phase known as MGUS (monoclonal gammopathy of undetermined significance). MGUS can last for many years.
• Bone destruction due to myeloma cells stimulating osteoclasts, resulting in well-defined osteolytic lesions and raised serum Ca2+.
• Bone marrow failure caused by marrow infiltration, leading to anaemia, thrombocytopenia, neutropenia, and recurrent infections.
• Renal failure due to deposition and accumulation of paraproteins.
• Hyperviscosity syndrome that causes headache and dizziness.
• Amyloidosis caused by development of abnormal protein cells depositing in parts of the body.

Multiple Myeloma Investigations

• FBC to detect bone marrow failure
• Raised ESR and Ca2+.
• U&Es demonstrate renal damage
• Protein electrophoresis demonstrates monoclonal paraprotein
• Bence-Jones proteins in urine

Multiple Myeloma Management

• Only treated if there is evidence of organ damage.
• Chemotherapy used if there is evidence of bone marrow failure or bone lesions.
• Most patients respond to chemotherapy, but relapse is common.
• Radiotherapy is useful if there is bone pain.

Secondary Oral Manifestations of Leukaemias and Lymphomas

• Manifestations of anaemia
• Haemorrhagic tendency
• Increased susceptibility to infection
• Neutropenic ulceration

Leukaemic Infiltration into Oral Tissues

• Tissue infiltration
• Typically in the gingiva, but bone infiltration also occurs
• Friable and haemorrhagic
• Increased tooth mobility
• Most common in AML

Intraoral Lymphomas

• In Non-Hodgkin lymphomas (NHL) associated with HIV
• Commonly affect fauces and gingivae
• Managed with chemotherapy and radiotherapy

Common Oral Complications with Treatment of Leukaemias

• Mucositis
• Infections including candidosis and viral (HSV, VZV)
• Mucosal bleeding
• Xerostomia

Mucositis

• Associated with chemotherapy agents and radiotherapy: 5-fluorouracil, Methotrexate, Bleomycin, Daunorubicin, Doxorubicin

Clinical Features of Chemo-Induced Mucositis

• Rapid onset and good recovery following cessation of chemotherapy
• Severity related to white cell depletion
• Increases the risk of infection and may limit chemotherapy

Complications of Radiotherapy

• Mucositis
• Xerostomia
• Caries
• Candidosis
• Loss of taste
• Trismus
• Osteoradionecrosis and osteomyelitis

Oral Care Advice Prior to Radiotherapy

• Dental disease assessment.
• Oral hygiene and preventative care provided.
• Minimum 2 week interval between extracting and commencing radiotherapy (no bone should be left exposed).

Oral Care Advice Following Radiotherapy

• Reinforcement of oral hygiene and preventative dental care
• Palliation for dry mouth
• Dental extractions: Minimal trauma with careful suturing and Prophylactic antibiotics

Haematopoietic Stem Cell Transplant (HSCT)

• Suggested when chemotherapy/radiotherapy fails.
• Autologous (own cells used)
• Allogenic (cells used from other human that match)

Graft vs Host Disease (GvHD)

• Complication of HSCT
• Allogenic HSCT causes it
• Clinical features are lichenoid inflammation on the tongue and buccal mucosa. Salivary glands may get hypofunction (on major glands) and recurrent mucoceles (on minor glands) which causes Xerostomia
• Lichenoid treated with topical steroids.
• Pilocarpine (Salagen) or cevimeline (Evoxac) can treat xerostomia to stimulate saliva production.