Haematology/Oncology: Leukaemia and Lymphoma Flashcards
What is leukaemia?
Leukaemia literally means “white blood”
Neoplastic proliferation of white blood cells
Cancer of the WBCs
Affects both the bone marrow and circulating blood
What is the normal leukocyte count?
4500 - 11000/μL
What is the leukocyte count in infections and what can this also be?
Increase in white blood cell count
Leukocyte count in acute infections is 15000 - 25000/μL
Less often leukocytosis is a sign of primary bone marrow abnormality related to leukaemia.
What kind of cells increase in number with time?
Myeloid or lymphoid cells
What are the forms of leukaemia? What is the difference?
Acute: Rapidly progressive with accumulation of immature non-functional cells in the marrow and the blood.
Chronic: Slower onset and allows for more mature cells to be produced.
What is the aetiology for leukaemia?
Unkown
Increased risk associated with radiation, chemical agents, oncogenic viruses, smoking, and genetic predisposition.
How is leukaemia classified?
Based on primary haematopoietic cell line that is affected (Myeloid or lymphoid)
Based on clinical behaviour (Acute or chronic)
4 most simplistic categories are: AML, ALL, CML, CLL
How is leukaemia diagnosed?
FBC (Peripheral granulocyte count (ANC) increases in chronic leukaemia and increases or decreases in acure leukaemia)
Bone marrow biopsy
Additional techniques including flow cytochemical staining, cytometric immunophenotyping, and genetic analysis
What are the types of myeloid neoplasms?
Acute Myeloid Leukaemia
Myeloproliferative disorders (eg chronic myelogenous leukaemia)
MyeloDysplastic Syndromes
How common is acute myelogenous leukaemia?
1/3 of all leukaemias
What is the aetiology of AML?
De novo
Environmental causes (Tobacco, benzene containing compounds, chemotherapy)
Consequence of myelodysplastic syndrome (30% of MDS progress to AML)
Genetic factors (Translocation and rearrangement of genes, down syndrome, klinefelter syndrome, fanconi anaemia, recklinghausen disease)
What are the clinical signs and symptoms of AML?
Anaemia related symptoms such as shortness of breath, weakness, dyspnea on exertion.
Physical findings: Pallor, bleeding/bruising, hepatomegaly, and/or splenomegaly (<10% of patients), lymphadenopathy (Uncommon)
Unexplained headache or focal neurologic complaints
Pancytopaenia
Accumulation of leukemic forms in peripheral blood, bone marrow, and other tissues.
How is AML diagnosed?
> 20% of BM cellular component is myeloid blasts/precursors
Myeloblasts contain delicate nuclear chromatin, fine azurophilic cytoplasmic granules, and 3 to 5 nucleoli.
Auer rods (Red staining rod-like structures that are numerous in acute promyelocytic leukaemia and are specific to neoplastic myeloblasts)
How is AML treated?
In phases:
Induction therapy: Intensive combination therapy to achieve a CR through reducing number of leukaemia cells and restoring bone marrow function
Post-remission therapy: Includes chemotherapy, targetted therapies, and autologous or allogenic haematopoietic cell transplantation.
What is the goal of AML therapy?
Sustain CR and achieve long-term disease-free survival.
What is CML?
A myeloproliferative neoplasm
Dysregulated production and uncontrolled proliferation of mature and maturing granulocytes with fairly normal differentiation.
What causes CML?
BCR-ABL1 fusion gene:
t(9;22)(q34;q11)
Philadelphia chromosome is formed which produces an enzymatic domain from the normal ABL1 resulting in elevated and constitutive kinase activity.
What percentage of cases of CML are caused by BCR-ABL fusion?
95% of cases are a balanced 9;22 translocation
in 5% of cases it is caused by complex rearrangements.
How is CML diagnosed?
FISH visualization of BCR-ABL
How common is CML?
Accounts for approximately 15 - 20% of adult leukaemias in adults
Annual incidence of 1 to 2 cases per 100000
What age and gender is CML most common in?
Most common in males and median age of 50 years
What are the risk factors for CML?
Only known risk factor is exposure to ionizing radiation.
No known familial disposition with exceptional familial CML involving JAK2 and Ph chromosome.
What are the clincial findings often seen at diagnosis?
It is asymptomatic in 20 - 50% of cases
In the symptomatic patients it produces systemic symptoms such as fever (34%), malaise (3%), weight loss (20%), excessive sweating (15%), abdominal fullness (15%), and bleeding episodes due to platelet dysfunction (21%)
How is CML treated?
Imatinib
Pre-blast phase palliative treatment
Why is imatinib important for dentists?
Imatinib leads to hyperpigmentation of the mouth. Leads to staining of mouth (palate most commonly)
When is CML hardest to treat?
CML exists in 3 phases. If diagnosed in late phase it is hard to treat.
What is methotrexate used for?
It is the first line of therapy for rheumatoid arthritis and lupus as well as part of chemotherapy.
Why is methotrexate relevant for dentists?
It causes mouth ulceration and severe mucositis.
How do lymphomas present?
They show up as enlarged lymph nodes (important to physically examine lymph nodes in extra oral examination).
What condition is ALL similar to?
Overlapping clinical symptoms between ALL and LymphoBlastic Lymphoma
Both pre-B and pre-T cell tumours take on the clinical appearance of ALL during their course.
What cells typically cause LymphoBlastic Lymphoma?
B cell precursors in 85%
T cell precursors in 10 - 15%
Uncommon variants seen in <1% of cases are early T cells and NK cells.
Who most commonly gets B/T-ALL/LBL?
Most common in children (2500 to 3500 new cases in children every year)
Peak incidence at 2 - 5 years of age.
More common in boys.
What risk factors are associated with ALL/LBL?
Unknown cause
Genetic and environmental influences including advanced paternal age and maternal foetal loss, increased birth weight.
Not a familial disease.
How is B/T-ALL/LBL diagnosed?
Characteristic morphology
Diagnostic immunophenotype of cells from the peripheral blood, bone marrow, lymph nodes, and other involved tissue.
Markers
What markers are used for B-lymphoblasts?
CD19
Cytoplasmic CD79a
Cytoplasmic CD22
What markers are used for T-lymphoblasts?
CD3
Which people have bad prognosis when they have B/T-ALL/LBL?
Ages <1 y.o and >10 y.o
Leukocyte count >50000/microL
Race (black or hispanic) due to genomic variations and socioeconomic factors)
Males
How are people with B/T-ALL/LBL treated?
Administration of a multidrug regimen: Induction, Consolidation, and maintenance. (takes 2 - 3 years to complete)
Transfusion support
Treatment of proven or suspected infections
Treatment of proven or suspected infections.
Correction of metabolic imbalances
Rarely leukophoresis
What is the prognosis of treatment?
Induction: 90% of children/adolescents enter complete remission at the end of induction.
What is the induction treatment and how is it done differently for different people?
BCR_ABL1 positive ALL (Rare and treated with TKI)
BCR-ABL1 negative (Weekly vincristine, daily corticosteroids, and asparaginas)
Down-syndrome ALL (Susceptible to adverse events and treatment-related mortality)
What is the purpose of post-remission therapy?
It is started soon after complete remission to prevent leukemic regrowth, reduce residual tumour burden, and to prevent emergence of drug-resistance in remaining leukemic cells.
What drugs are given for consolidation?
Lasts 4 - 8 months:
Cytarabine
Methotrexate
Anthracyclines (Daunorubicin, doxorubicin)
Alkylating agents (Cycllophosphamide, ifosfamide)
Epipodophllotoxins (etoposide, etopophosphamide)
What is more common, Hodgkin’s or non-Hodgkin’s lymphoma?
Non-hodgkins lymphoma is more common than hodgkin’s lymphoma
What are the symptoms of lymphomas?
Night sweats, unexpected weight loss, pallor, bone pain, increased infections, lumps, anaemia, thrombocytopaenia, leukopenia, M protein spike, hypercalcaemia, Bence Jones proteins, Genetic testing , biopsy, and PET-CT.
What is the defining feature of Hodgkin’s lymphoma?
Reed-Sternberg cells
Remember: Owl eyes = Harry potter = Hodgkin’s
What are the WHO classifications of Hodgkin’s lymphoma?
Nodular lymphocyte predominant Hodgkin lymphoma (distinctive B-cell immunophenotype)
Classic Hodgkin lymphoma:
Nodular sclerosis classic Hodgkin lymphoma
Lymphocyte-rich classic Hodgkin lymphoma
Mixed cellularity classic Hodgkin lymphoma
Lymphocyte-depleted classic Hodgkin lymphoma
What causes Hodgkin lymphoma? (pathogenesis)
Somatic hypermutation and V(D)J recombination of Ig
gene of Reed-Sternberg cells
Establishment of a germinal centre or post-germinal
centre B cell
Activation of NF-kB through
• EBV infection -> LoF mutation of NF-kB gene
Who most commonly gets Hodgkin lymphoma?
Bimodal age distribution:
Economically advantaged countries = 20 years and 65 years
Economically disadvantaged countries = peak in young boys and older adults (low in young adults)
What are the clinical features of Hodgkin lymphoma?
Painless lymphadenopathy
B symptoms (More common in disseminated disease (stage 3 or 4)
How is Hodgkin lymphoma treated?
Early stage:
RT (High dose increases risk of lung cancer, melanoma, and breast cancer)
ABVD (Doxorubicin, bleomycin, vinblastine, dacarbazine)
Advanced stages:
ABVD (longer and more intense)
BEACOPP (Bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone)
What is the prognosis like in Hodgkin lymphoma?
Stage dependent
How are hodgkin and non-hodgkin lymphoma similar?
More often localized to a single axial group of nodes (cervical, mediastinal, and para-aortic) in non-hodgkin its more frequent in peripheral nodes
Orderly spread by contiguity whereas non-contiguous spread in non-hodgkin’s lymphoma
Mesenteric nodes and Waldeyer ring rarely involved whereas they are commonly involved in non-hodgkin lymphoma
Extranodal involvement is uncommon in hodgkin but not common in non-hodgkin
What are the important types of non-hodgkin lymphomas?
Burkitt lymphoma
Multiple myeloma
What is the cause of burkitt lymphoma?
Translocation and deregulation of the MYC gene
What are the clinical forms of burkitt lymphoma?
Endemic (african)
Sporadic (non-endemic)
Immunodeficiency associated
How are BL and Burkitt lymphoma classified in the WHO?
BL and Burkitt leukemia are considered different manifestations of
the same disease in the World Health Organization (WHO)
classification of hematologic malignancies
What is burkitt lymphoma?
Highly aggressive B cell tumour
Where are the types of Burkitt lymphoma seen most often?
Endemic: Equatorial Africa and New Guinea. 30 - 50% of all childhood cancer in equatorial Africa. Peak 4 - 7 years old. Male:female 2:1
Sporadic: US and Western Europe. (30% of paediatric lymphomas and <1% of adult non-hodkin lymphomas) Peak incidence at 11 y.o. Male:Female = 3-4:1
How is burkitt lymphoma treated?
No standard tx:
– Tx is more intensive than other NHL
– Clinical trials
• Aggressive tx with CNS prophylaxis
– Examples of chemotherapy regimens
• CODOX-M plus IVAC (“Magrath regimen”)
– (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate) with
IVAC (ifosfamide, cytarabine, etoposide, and intrathecal methotrexate)
• HyperCVAD
– Cyclophosphamide, vincristine, doxorubicin, and dexamethasone
(HyperCVAD) with or without rituximab alternating with high-dose
methotrexate and cytarabine
What are the signs and symptoms of multiple myeloma?
C - hypercalcaemia
R - Renal obstruction
A - Anaemia
B - Bone lesions “punched out”
What markers are responsible for multiple myeloma?
Cyclin D1 and D3
KRAS+ and FGF+
Bence Jones Proteins
RANK-L induced bone resorption
What are the clinical features of multiple myeloma?
Older age
Aggressive
Monoclonal gammopathy
What are the features of multiple myeloma?
Bone pain
Pathologic fracture
Hypercalcemia
Renal failure
Recurrent infections
Anemia
Amyloidosis
Waldenstroms
Macroglobulinemia
