Onc/Rheum/Adolescent Flashcards
Cell cycle
a. G1 (Gap1) = growth and preparation of chromosomes for replication (interphase)
b. S (synthesis) = synthesis of DNA and duplication of genome (interphase)
c. G2 (Gap 2)= preparation of mitosis (interphase)
d. M = mitosis
Tumour suppressor genes
i. Regulators of cellular growth and apoptosis
ii. Inactivation of BOTH alleles required for a tumour suppressor gene
1. Inheritance of one germline mutation can be AD
2. A second mutation at somatic level still required
iii. In inherited mutations, one inactivated allele may be inherited and the other undergoes spontaneous inactivation
iv. Examples: P53 (usually initiates apoptosis) , APC, Rb, BRCA
Proto-onco genes
i. Transcriptional factors, signal transducers, growth factors and growth factor-receptors
ii. Activating mutation in ONE gene results in an oncogene, via:
1. Amplification
2. Point mutations
3. Translocation
iii. These genes interfere with apoptosis, continue to proliferate
iv. Examples
1. Chromosome translocation
a. T(1;19) – pre- B ALL
b. T(14:18) – C Myc in Burkitt’s
c. T(9:22) – Philadelphia chromosome in ALL, CML
2. Gene amplification = N myc in neuroblastoma (poor prognosis)
3. Point mutation
a. 1p in AML – NRAS signal transducer, point mutation
b. 10q in MEN2
DNA repair genes
i. Function to repair damaged DNA
ii. Mutations result in replication of damaged DNA
iii. Examples
1. Fanconi anaemia (AR leukaemia)
2. Bloom’s syndrome (AR leukemia and lymphomas)
3. Ataxia-telangiectasia (AR lymphoreticular cancers)
4. Dysplastic nevus syndrome (AD melanoma)
Genes encoding telomeres
i. Telomeres – structures that cap ends of chromosomes protect the ends from degradation, rearrangement and fusion with other chromosomes
ii. With each cell division , a portion of the telomere is eroded so it eventually becomes nonfunctional cell should then undergo apoptosis
iii. Telomerase in the GIT/stem cells/BM is an enzyme that maintains and stabilizes telomeres, but it is usually absent from mature cells
iv. Expressed in 95% cancer cells
v. Examples
1. Congenital dyskeratosis (XR/AR leukaemia, H+N SCC)
Leukostasis
Onc emergency
a. High white blood cell (total leukaemia WBC > 50-100x 10^9)
b. Most common in AML ( > ALL, CLL, CML) (up to 20% at diagnosis)
c. Pathophysiology
i. White cell plugs seen in microvasculature, leading to respiratory / neurological distress
ii. Other pathophysiological factors:
1. Increased blood viscosity
2. Cytokine production
3. Hypoxia
d. Clinical features
i. Alteration of consciousness, headache , dizziness, tinnitus, gait instability
ii. Dyspnoea, hypoxia
iii. Haemorrhage (due to release of fibrinolytic proteases released from blasts + consumption of coagulation factors) MAJOR RISK
e. Treatment
i. Cytoreduction – hydroxyurea
ii. Leukapharesis
iii. Aggressive hydration
iv. Start induction chemotherapy
v. WH red blood cell transfusions if possible
f. Prognosis
i. Mortality 20-40%
Tumour lysis syndrome
Onc emergency - high K/PO4/urate, low Ca, acidosis, AKI
Risk of TLS highest in
i. Patients who have rapidly proliferating cancers
1. Acute leukamias with WCC > 100
2. Lymphoma – especially T cell and B cell lymphoma (Burkitt’s lymphoma)
3. Some large tumours – especially abdominal tumours
ii. Patients with preexisting renal disease
b. Other risk factors
i. Large tumour burden
ii. Pretreatment hyperuricaemia ( > 7.5 mg/dL)/ hyperphosphatemia
iii. Preexisting nephropathy
iv. Dehydration
v. Initiation of chemotherapy/radiotherapy/steroids
c. Timing
i. Electrolyte imbalances may (rarely) occur within 6 hours of treatment, but generally within 24-48 hours
ii. Acute TLS generally resolves within 4-7 days after chemotherapy has been initiated
d. Physiology
i. Occurs due to cell breakdown
1. Following commencement of chemotherapy
2. Rarely before chemotherapy started
ii. Cell membrane ruptures
1. Potassium and phosphorous = released directly into the blood
2. Nucleic acids are released from cells = converted to uric acid by the liver
3. Hypocalcaemia = occurs as a result of the inverse relationship between phosphorous and calcium (ie. elevation of phosphorous causes a decrease in calcium
e. Consequences
i. Hyperuricaemia
1. Precipitation of uric acid in the renal tubules
2. Renal vasoconstriction
3. Inflammation
4. Promotes calcium phosphate deposition in the kidneys
5. All lead to acute oliguric renal failure
ii. Hyperphosphataemia
1. Promotes calcium deposition in the kidneys as calcium phosphate
2. Promotes uric acid deposition in the kidneys
iii. Key consequence = results in acidosis + renal impairment
1. Urate crystals may precipitate within and cause obstruction of the renal tubules uric acid nephropathy
2. Phosphate can also precipitate in renal tubules
f. Clinical manifestations
i. Nausea, vomiting
ii. Diarrhoea, anorexia
iii. Lethargy, haematuria
g. Complications
i. Acute kidney injury
ii. Cardiac dysrhythmias, sudden death
iii. Seizures
iv. Muscle cramps, tetany, syncope
h. Treatment
i. Monitoring: UEC, Uric acid
ii. Hyperhydration
iii. Low risk = allopurinol 10 mg/kg/day (TDS dosing)
1. Allopurinol blocks catabolism of hypoxanthine and xanthine ( ↓ uric acid, ↑ hypo/xanthine) by inhibiting xanthine oxidase
2. Xanthine more soluble than uric acid – BUT can still precipitate if very high levels
3. Note – avoid with mercaptopurines (azathioprine) as it promotes formation of active thioguanine nucleotides
4. If very large TLS, xanthine can also precipitate in the kidneys
iv. High risk = rasburicase
1. Rasburicase = degrades uric acid to water soluble allantoin
2. Should not be given fluids containing bicarbonate, increases risk of precipitation
v. Hyperhydration: 125 mL/ m2/ hour
Mediastinal compression (oncology)
a. Occurs in : T cell ALL (two thirds) + lymphoma
b. Pathophysiology:
i. Vena caval compression and bronchotracheal compression
ii. facial oedema, dyspnoea and orthopnoea
c. Clinical features
i. Prominent neck veins
ii. Facial oedema
iii. Wheezing/stridor/cough
iv. SOB/orthopnoea/lethargy
v. Chest pain
d. Management
i. Always look for pericardial effusion (AP + lateral XR)
ii. AVOID GA
iii. May need steroids and local irradiation
Coagulopathy (onc emergency)
a. Occurs in: APML (acute promyelocytic leukaemia)
b. 30% patients die before 14 days, often before starting treatment
c. Investigations (similar picture to DIC)
i. Low fibrinogen very suggestive
ii. Elevated D-dimer
iii. Reduced platelets
iv. PT/ APTT can be normal
d. Treatment
i. Aim to get platelets > 30-50, fibrinogen > 1
Spinal cord compression (oncology)
a. Cause
i. 5% of children with solid tumour:
1. Rhabdo
2. Osteosarcoma
3. Ewing’s
4. Neuroblatsoma
5. Metastases
b. Clinical features:
i. Back pain, ↑ on vertebral percussion
ii. Scoliosis, tenderness
iii. Incontinence/retention of urine
iv. Changes in sensation
c. Investigations: needs URGENT imaging
d. Management
i. Dexamethasone
ii. Chemotherapy
Febrile neutropenia - high risk treatment protocols
- AML treatment
- ALL induction, ALL delayed intensification, infant ALL
- Lymphoma induction
- Allogeneic transplant (day -14 to day +356)
- Autologous transplant (day -7 to day +30)
- Re-induction chemotherapy for any relapse
Febrile neutropenia - general
a. Overview
i. One of the common complications of cancer treatment
ii. Risk of serious bacterial infection is related to the degree and duration of neutropenia
iii. Bacteraemia is diagnosed in up to 1/3 of children with FN (GPC > GNB)
b. Key points
i. Fever and suspected or confirmed FN is a medical emergency
ii. Children with FN and signs of sepsis require urgent treatment
iii. Antibiotics must be administered within 30 minutes if there are signs of sepsis and within 60 minutes if there are no signs of sepsis
c. Definitions
i. Fever = single temperature >38.5 or sustained temp >38 over 1 hour
ii. Neutropenia = absolute neutrophil count < 500/mm3 or <1000/mm3 with predicted decline to <500/mm3 over the next 48 hours
iii. Suspected neutropenia = neutropenia should be suspected in any oncology patient that has received chemotherapy (oral or IV) within the last 14 days, and other children with recurrent neutropenia
e. Antibiotics
i. Piperacillin-tazobactam (OR flucloxacillin + ceftazadime)
ii. Depending on context add: amikacin, vanc (MRSA), or metro (GIT)
f. Ongoing management
i. Modifying antibiotics after 24-48 hours = Patient is clinically unstable OR a resistant organism has been identified add amikacin or vancomycin
ii. Prolonged (>72 hours) or recurrent fevers
1. Evaluate and consider treatment of invasive fungal infection (IFI)
iii. Treatment of suspected IFI
1. Empiric antifungal agent amphotericin (or caspofungin or voriconazole if contraindicated)
Patients high risk for invasive fungal infection
a. Relapsed acute leukaemia
b. AML
c. GVHD
d. Allogeneic HSCT
e. Sever aplastic anaemia
f. Prolonged corticosteroid use
g. Prolonged ICU admission
Chemotherapy - general adverse effects
o Antiproliferative effects Marrow suppression • RBC have 120 days, less frequently affected (and take longer to recover) • WC and platelets recover rapidly Infertility Teratogenicity Ulceration of GIT (esp cyclophosphamide) Cystitis Hair loss Impaired wound healing Mucositis
o Infections
o Late complications
lymphomas, skin tumours
Gonadal failure
Teratogenesis
Vincristine associated neuropathy
- Key points
a. Vincristine treatment is limited by a progressive sensorimotor peripheral neuropathy
b. Exact mechanism not known
c. Experienced by nearly all children who have vincristine treatment - Timing
a. Can occur within a week of initiating vincristine and continue to worsen even after dosing and frequency is reduced
b. Can remain unchanged for up to 12 months following dose reduction
c. Can persist for years beyond treatment completion
d. Often gradual improvement following cessation - Manifestations
a. In most cases VIPN progresses distally to proximal - signs and symptoms often first appear in the toes and feet
b. Earliest feature = paraesthesia of fingertips and feet +/- muscle cramps
c. Types of neuropathy
i. Sensory neuropathy - Numbness, tingling and neuropathic pain
- Bilateral
- Upper and lower extremities
ii. Motor - Foot drop
- Reduced power
- Focal mononeuropathies – most commonly occumulotor nerve
iii. Autonomic neuropathy - Constipation
- Urinary retention
- Orthostatic hypotension
- Examination
a. Reduced light touch, pinprick vibration and temperature sensation
b. Hyporeflexia, loss or reduction in deep tendon reflexes
i. Hyporeflexia is the most common and severe VIPN manifestation - Risk factors
a. Treatment related
i. Higher dose
ii. Higher drug concentration
iii. Concomitant azole antifungals
iv. Pre-eexisting neurological condition such as Charcot-Marie Tooth
b. Patient related
i. Race – higher in Caucasians
ii. Age – higher occurrence in older children and adults
Lung toxicity with chemotherapy (agents and types)
Many agents cause lung toxicity (prev question bleomycin)
Methotrexate
- inflammatory and fibrotic lung disease
- pneumonia (PJP most common)
- pulmonary lymphoproliferative disease
Cyclophosphamide
- rare<1%
Bleomycin
- Major limitation to the use of this drug is the potential for life limiting pulmonary fibrosis (fibrosing alveolitis) which occurs in up to 10% of patients receiving the drug
- Onset of symptoms usually 1-6 months after bleomycin treatment, but may occur > 6 months following administration of bleomycin
- Injury can occur at any dose (but dose relationship)
- Associated with four main types of pulmonary toxicity
o Subacute progressive pulmonary fibrosis
o Hypersensitivity pneumonitis
o Organising pneumonia
o Acute chest pain syndrome during rapid infusion
- Treat with pred
Radiation therapy - acute side effects
- Acute side effects = <3 months after therapy begins
a. Fatigue
b. Nausea and vomiting
c. Radiation dermatitis + alopecia
i. Usually localized to site of radiotherapy
ii. May be permanent with high doses
d. Cerebral edema
e. Less commonly:
i. Transient focal neurologic symptoms – headache, memory impairment
ii. Pseudoprogression – on imaging
iii. Somnolence syndrome - extreme sleepiness without raised ICT
Radiation therapy - long term side effects
a. Endocrine
i. Occurs in 80% of adults that receive irradiation to the hypothalamic area > 20 Gy
ii. Hypothyroidism 15-20%
iii. GH > FSH/LH > TSH > ACTH
b. Secondary malignancy (10% after 20 years in CNS radiation)
i. Almost 70% of the second neoplasms are in the field of the original irradiation
ii. Radiation therapy increases the risk of second cancers in a dose-dependent manner for nongenetic neoplasms
iii. Following cranial irradiation increased risk of secondary CNS tumours, such as meningiomas, malignant gliomas, and nerve sheath tumors
iv. Radiation to bone increases risk of osteosarcoma
c. CNS
i. Neurocognitive effects
1. Early-delayed effects: short term learning, memory
2. Long term: cognitive effects
ii. Radiation necrosis necrosis of tissue that can occur up to 10 years after radiation. Causes sx of raised ICP, neurological sx/ cranial neuropathies. Mass enhancing lesion on imaging requires biopsy for diagnosis. May be self-limited/ require trial of treatment with steroids
iii. Cerebrovascular effects:
1. Occlusive vascular disease and strok
2. ICH
3. Cavernous malformations
d. Ophthal
i. Cataracts: develop in 60% of patients who receive 10Gy cranial irradiation
ii. Optic neuropathy
iii. Xeropthalmia (dry eye)
iv. Retinopathy: due to retinal ischaemia
e. Ototoxicity – tinnitus and high frequency hearing loss at > 30Gy (synergistic effect with cisplatin)
f. Fertility
i. Radiation > 15 Gy in prepubertal girls , > 10 Gy in pubertal girls
ii. Any pelvic irradiation in boys 0-> germ cell failure
iii. Gonadal irradiation 20-30 Gy in boys androgen in sufficiency
Cranial irradiation - side effects
a. Cortical atrophy in >50% of patients, some with leukoencephalopathy or calcifications
i. The younger the child > greater atrophy
b. Mineralizing microangiopathy
c. Cerebral necrosis serious complication of radiation-induced vascular disease
i. Clinical= headache, increased ICP, seizures, sensory deficits, and psychotic changes
d. Spinal cord
i. Radiation myelitis (transient or permanent) Lhermitte sign: sensation of little electrical shocks in the arms/legs with movements that stretch the spinal cord (ie neck flexion).
ii. Delayed myelopathy: sensory disassociation followed by spastic and flaccid paralysis
e. Endocrine
i. Any degree of hypopituitarism ranged from 37-77%
ii. Most common least common
1. Reduced growth hormone production/release (50%)
a. Due to compromised function of the pituitary-hypothalamic axis
b. Occurs at low dose (>18Gy)
2. Gonadotrophin deficiency or precocious puberty, females mostly (25%)
3. Hyperprolactinemia
4. ACTH deficiency
5. Central hypothyroidism
Radiation recall dermatitis
• Radiation recall dermatitis = inflammatory skin reaction that develops in an area of previously irradiated skin AFTER administration of certain promoting agents
o May be a long interval between administration of the causative agent and RRD
o Particularly associated with anthracyclines and anthra-cycline like drugs
o Other example drugs = bleomycin, doxorubicin, mercaptopurine, MTX
Radiation enhancement
• Radiation enhancement = enhancement of the dermatological toxicity of radiation therapy
o Occurs if radiosensitizing chemotherapy administered within one week of radiation therapy
o Results in painful erythema, edema, superficial desquamation and if severe erosions
o Eruption usually localises to the irradiated field, but there may be local extension
o Particularly associated with 5FU (flurouracil) as it is given at the same time as radiation therapy for GIT tumour
o Example drugs = bleomycin, cyclophosphamide, methotrexate
Hodkin lymphoma - secondary malignancies
• Secondary malignancies among survivors of Hodgkin’s lymphoma and soft-tissue sarcomas higher than that of any other childhood cancers
• 18.5 fold increase in risk of secondary cancer following treatment for Hodgkin lymphoma
o 10 years following treatment – 10% develop secondary malignancy
o 30 years following treatment – 26% develop secondary malignancy
• Secondary malignancies
o Breast cancer = directly related to dose of radiation given
o Thyroid cancer
o AML = associated with use of alkylating agents, anthracycline and etoposide
o Soft tissue malignancy
• Latency of 3 years for AML
• Latency of 14 years for solid tumour
ALL - secondary malignancies
• ALL
o 2-3% of ALL survivors develop secondary malignancy
o Risk greatest among those who receive cranial radiation or intensive therapy for relapse
o Most frequent secondary malignancies Brain cancer MDS/AML o Chemotherapies associated with risk Cyclophosphamide – biggest risk Doxorubicin
Endocrine complications of oncology treatment
- Highest risk
a. CNS tumours
b. Orbital/ facial sarcomas
c. Hodgkin lymphoma
d. HSCT - Common endocrinopathies
a. Hypothalamus + pituitary
i. Linear growth and/or metabolic disturbance due to GH deficiency - Brain tumours located near the hypothalamus/pituitary result in most risk
- GH deficiency is most common endocrinopathy following cranial irradiation
ii. Pubertal disorders - Precocious puberty
- Delayed puberty
- Pubertal arrest
iii. Central hypothyroidism
iv. ACTH deficiency
v. Diabetes insipidus = usually due to surgical intervention
b. Thyroid = hypothyroidism due to direct damage
c. Gonads = delayed puberty and infertility
Bone problems in childhood cancer patients
Avascular necrosis
a. Complication that can destroy the bone underlying the articular surface of joints – especially in weight-bearing joints of lower extremities
b. Associated with high-dose glucocorticoid treatment and bone marrow transplantation
e. Investigations
i. Crescent sign of avascular necrosis is seen on conventional radiographs
ii. It indicates imminent articular collapse.
f. Treatment
i. Conservative therapy – restriction of weight bearing
ii. Decrease or modification of glucocorticoid dose if possible
iii. Hip or knee often require surgical intervention – core decompression or joint replacement
Altered epiphyseal growth
a. Epiphyseal growth is altered temporarily during chemotherapy
b. Children with ALL display marked deceleration in growth velocity but generally catch up following chemotherapy completion
c. Agents that directly alter bone growth include
i. Glucocorticoids
ii. Doxorubicin
iii. Actinomycin D
iv. Methotrexate
v. Cisplatin
d. Direct irradiation can also retard bone growth
Reduced bone mineral density
a. MANY treatments reduce bone mineral density in oncology patients
i. Cranial irradiation
ii. HSCT
iii. Glucocorticoids
iv. High dose MTX
v. Alkylating agents
b. Other factors
i. GH deficiency – cerebral irradiation
ii. Hypogonadism
iii. Hyperthyroidism – irradiation
iv. Illness itself – deconditioning
Bone marrow aspirate - contraindications
Absolute contraindications
• Severe haemophilia
• Severe DIC
• Other related bleeding disorder
NOTE:
• Thrombocytopenia (regardless of severity) is not a contraindication – some centres give platelets if <20
• Most haematologists do not consider therapeutic anticoagulation to be an important risk factor for bleeding following bone marrow biopsy – practice varies
Bone marrow aspirate versus trephine
Bone marrow aspirate A needle is passed through the skin and into the iliac crest and a small amount of liquid bone marrow will be withdrawn into a syringe Info: Cellular morphology and cell count Cytogenetics Culture Flow cytometry Immunohistochemistry
Bone marrow trephine Is done immediately after the aspiration In some cases a second needle will be inserted into the same site after removal of the aspiration needle Alternatively the first needle may be left in place and used to take the trephine biopsy Info: Marrow’s overall cellularity Detection of focal lesions Extent of infiltration
Stem cell transplantation - indications
a. Malignancy
i. ALL
1. Any child with high risk disease: hypodiploid ALL , MLL rearrangements, induction failure, T cell ALL (IR + HR)
ii. AML
1. High risk disease: FLT3 +ve , monosomy 7, monosomy 5, 5q deletion, 3q deletion , complex karyotype ( 3 or more abnormalities)
2. Tx in first CR
3. NOT for favourable risk disease: 8:21 inv 16
iii. CML
b. Immunodeficiencies
i. Cellular – SCID/ DiGeorge, Wiskott-Aldrich, Hyper IgM
ii. Neutrophil – CGD/ LAD
c. Bone marrow failure
i. Severe aplastic anaemia – Fanconi, Blackfan Diamond, Congenital dyskeratosis, reticular dysgenesis
ii. Congenital neutropenias
iii. Congenital amegakaryocytic thrombocytopenia
iv. Anaemias – thalassemia, sickle cell disease
v. HLH, X linked lymphoproliferative disease
d. Storage disease
i. Leukodystrophies
1. Adrenoleukodystrophy (pre neurological deterioration)
2. Metachromatic leukodystrophy – 12 months before onset of sx
3. Does not reverse neuronal death
ii. Globoid cell leukodystrophy (Krabbe)
iii. MPS
1. Hurlers, Maroteaux- Lamy, Sly syndrome
2. NOT indicated: Hunters, Sanfilippo, Morquio
Stem cell transplant - cell sources
a. Bone marrow
- pros
• Moderately brisk engraftment
• Moderate risk of GVHD
• DLI available
- cons
• Increased risks of collection – GA, bleeding, pain
• Contains all marrow cells including RBC
b. Peripheral blood – needs increased dose
- pros
• Rapid engraftment
• Low risk during collection
• Only CD34+ stem cells collected
• Availability of donor lymphocyte infusion
- cons
• Increased rates of GVHD especially chronic GVHD
• Not practical procedure on small patient
c. Cord blood – lower cell dose
- pros
• Risk free collection
• Less requirement for HLA matching (accept 4/6, normally minimum 5/6)
• Low risk of transmitting infection
• Low incidence of GVHD (immune immaturity)
• Rapid availability
- cons
• Relatively low does available
• Slow engraftment (longer period neutropenia)
• No possibility of donor lymphocyte infusion (DLI)
Stem cell transplant - phases
- Phases of BMT
a. Conditioning
b. BMT infusion
c. Aplasia
d. Engraftment
e. GVHD acute
f. GVHD chronic - Summary of phases
a. Pre-engraftment = from transplantation to neutrophil recovery (day 20-30)
b. Early post-engraftment = from engraftment to day 100
c. Late post-engraftment = after day 100
HLA matching testing
HLA genes chromosome 6
i. Based on HLA typing
ii. Tested in 2 ways:
1. Serologic testing: uses antibody based assays for HLA antigens (does not ensure same genes)
2. Molecular typing: looks at underlying alleles on chromosome more specific if testing unmatched donors
Ideal donor is a matched sibling
i. 6/6 (used for related donors) : HLA A, B, DRB1
ii. 8/8 (for matched unrelated donors): HLA A, B, C, DRB1
iii. Mismatches described as graft vs host direction (patient possesses an allele not possessed by the donor, so you would get a graft vs host response) or host vs. graft (donor possesses one or more alleles not present in the patient, which would cause a host response towards the graft)
ii. HLA B and C sit very close together on chromosome 6, so C not specifically typed
iii. Mismatches at HLA-B and C better tolerated than A and DR
Stem cell transplant - complications - overview
a. Febrile neutropenia
b. Sinusoidal obstruction syndrome
i. Most serious complications after myeloablative transplant
ii. Incidence 10-60%
iii. Risk factors
1. Older age (ie adults)
2. Poor performance status
3. Prior abdominal irradiation
4. Elevated busulphan
5. Recent gemtuzuab, ozagmicin (myeloarg), pembrolzumb (Keytruda)
iv. Clinical triad
1. Weight gain
2. Painful hepatomegaly
3. Jaunice
v. Onset within 30 days of transplant
vi. Platelet refractoriness = key feature (but could also represent platelet alloimmunisation or thrombotic microangiopathy)
c. GVHD
d. Graft failure
i. Rare complication of HSCT
ii. More common with CBT – rates of 10-15%
iii. May result in iatrogenic aplastic anaemia or autologous reconstitution
Acute graft versus host disease - pathogenesis
i. Phase 1 = damage to host tissues by inflammation from the preparative chemo and/or radiotherapy regimen
ii. Phase 2 = T cell activation phase
1. Recipient and donor antigen presenting cells as well as inflammatory cytokines trigger activation of donor derived T cells which expand and differentiate
2. Minor MHC play a central role particularly in the setting of matched transplants
3. Initial inflammatory cascade is thought to begin in the gastrointestinal tract and patients with higher volumes of diarrhoea at the time of preparative regimen have a higher likelihood of acute diarrhoea
iii. Phase 3 = effector phase
1. T cells mediated cytotoxicity against target host cells
2. Additional production of cytokines – particularly TNF-alpha
a. Induces apoptosis of target tissues through TNF-alpha receptor
b. Activates macrophages, neutrophils, eosinophils, B and T cells
c. Stimulates production of other inflammatory cytokines
d. Increases expression of HLA antigens and facilitates T cell lysis
iv. SUMMARY
1. Competent cells in the graft
2. Recipient expresses antigens NOT present in the donor
3. Recipient incapable of mounting effective response to eliminate implanted cells
4. Donor T cells respond to recipient tissue antigen
a. Class I (A, B, C) present on all nucleated cells
b. Class II (DR/ DQ/ DP) present on hematopoietic cells but expression can be induced following injury
c. Minor histocompatibility antigens: autosome + sex chromosomes
5. Process:
a. Tissue damage activation of APC
b. Donor T cell activation
c. Production of cellular and inflammatory effectors
Acute graft versus host disease - manifestations
i. SKIN
1. Erythema, pain , blistering
2. Biopsy: apoptotic bodies in the basal layer of the epithelium
ii. LIVER
1. Jaundice + deranged LFTs
2. DDX – drug toxicity, VOD, infection
3. Biopsy: bile duct destruction with apoptotic bodies
iii. GIT
1. N+V, diarrhoea, abdominal pain, bleeding
2. DDx – infection, drug toxicity (ATB, MMF)
3. Biopsy: apoptotic bodies in the base of crypts
Acute graft versus host disease - treatment/prognosis
c. Treatment
i. Mild cutaneous (grade I)
1. Optimise immunosuppression
a. Push cyclosporine to 250
2. Topical steroids
ii. Grade II or higher= steroids 1-2 mg/kg
1. First line therapy , gold standard
2. Response – D3 for progression, D 5-7 partial response, D28 for complete response
3. Steroid refractory GVHD has dismal prognosis
d. Prognosis (Graded 0-4)
i. Grade III – survival rate 25%
ii. Grade IV – survival rate 5%
Chronic graft versus host disease - general
a. Autoimmune like disorders
b. Can be limited (skin / liver / both) or extensive (other organ involvement)
c. Target organs:
i. Skin – pigment/ moisture/ elasticity
ii. Joints – effusion/ stiffness/ contracture
iii. GIT – malabsorption/ stricture
iv. Liver – chronic change to cirrhosis
v. Conjunctivae – dry, sicca syndrome
vi. Mucosal surfaces – dry, ulcers, lichen planus
vii. Bronchial tree – bronchiolitis obliterans
d. Risk factors
i. HLA mismatch
ii. Pre-existing AGVHD
iii. HSV infection
iv. Age of donor
v. Peripheral blood stem cells
e. Treatment = immunosuppression
i. Prednisolone
ii. Cyclosporin
iii. Mycofenolate
iv. Azathioprine
Acute v chronic GVHD
i. Historically defined by time frame of more / less than 100 days
ii. Now mostly defined by clinical symptoms
Hepatic sinusoidal obstruction syndrome - general
- Key points
a. Hepatic sinusoidal obstruction syndrome (SOS) = previously known hepatic veno-occlusive disease (VOD)
b. Resembles Budd Chiari syndrome clinically – however due to occlusion of the terminal hepatic venules and hepatic sinusoids, rather than hepatic veins and inferior vena cava - Pathogenesis
a. Injury to hepatic venous endothelium
c. Obstruct the sinusoidal blood flow of the liver
d. Venous occlusion necrosis of liver
e. Doppler ultrasound of hepatic vessels shows reversal or decreased flow
f. Develop hepato-renal syndrome
g. May be mild and self-limiting to a rapidly progressing fatal outcome resulting in MSOF - Clinical features
a. Usually occurs 12 days after HSCT (within 3 weeks)
i. Usually PRE-engraftment
ii. Rare after 30 days
b. Sudden weight gain
c. Jaundice
d. Hepatosplenomegaly / hepatic tenderness
e. Peripheral oedema + ascites - Investigations
a. ↑ AST, ALT, hyperbilirubinemia
b. Thrombocytopenia with refractoriness to platelet transfusion
c. USS Dopplers = liver sinusoids may be dilated and congested, reversal of flow - Treatment
a. Defibrotide
b. TIPS - Complications
a. 50% develop renal insufficiency (Hepatorenal syndrome)
b. Multiorgan failure – hepatic encephalopathy and death
Engraftment syndrome - general
- Key points
a. Noninfectious complication that is reported in 7-10% of autologous HCT, but only rarely following allogeneic HCT
b. Develops around 7 to 11 days following HCT during the time of neutrophil recovery
c. The engraftment syndrome usually causes only mild symptoms - Clinical manifestations
a. Cutaneous eruption that mimics acute graft vs host disease
b. Fever without identifiable infectious source
c. Signs of capillary leak syndrome (eg, noncardiogenic pulmonary edema with hypoxia, weight gain) - Peri-engraftment respiratory distress syndrome (PERDS)
a. Pulmonary component of engraftment syndrome
b. Reported in 3-5 percent of autologous HCT
c. Associated with increased capillary permeability that occurs during the neutrophil recovery phase following HCT
d. Characterized by combination of fever, hypoxemia, pulmonary opacities, absence of infection, fluid overload, or cardiac dysfunction, and presentation within five days of neutrophil engraftment
Peri-engraftment respiratory distress syndrome (PERDS) - general
Pulmonary component of engraftment syndrome
b. Reported in 3-5 percent of autologous HCT
c. Associated with increased capillary permeability that occurs during the neutrophil recovery phase following HCT
d. Characterized by combination of fever, hypoxemia, pulmonary opacities, absence of infection, fluid overload, or cardiac dysfunction, and presentation within five days of neutrophil engraftment
Infection following HSCT - timeline
a. Pre-engraftment = from transplantation to neutrophil recovery (day 20-30)
i. Febrile neutropenia
ii. Mucositis = HSV reactivation (prevalent throughout all phases but one of the few early viruses)
iii. Diarrhoea = C diff
iv. Pneumonia = nodular (bacterial or mould), diffuse (non-infectious)
v. Vascath associated cellulitis or blood-stream infection (Gram positive infection with CONS or Staph aureus are the most common, GN and Candida can also occur)
vi. Bacteria: gram neg bacilli, G pos spp, enterococci
vii. Candida an issue
b. Early post-engraftment = from engraftment to day 100
i. Pneumonia = nodular (bacterial), diffuse (PJP), respiratory viruses
ii. CMV becomes more common, HSV an ongoing issue,
iii. Pneumocystis (PJP) becomes a problem (bactrim prophylaxis), Candida ongoing
c. Late post-engraftment = after day 100
i. VZV becomes more prominent, CMV and HSV ongoing issues, EBV PTLD becomes a concern
ii. Encapsulated bacteria predominate
iii. Pneumocystis more prevalent, Candida less prevalent
Post BMT complications - hepatits, DDx/aetiology
Veno-Occlusive disease
A condition resulting from toxic injury to the hepatic sinusoidal capillaries that leads to obstruction of the small hepatic veins
• Classic cause of deranged LFTs during pre-engraftment period
• Occurs by day 21 – average day 12
Acute GVHD
• Most common cause of hepatitis during early post-engraftment period
• Both SOS and acute GVHD can present with abdominal pain and rising bilirubin
• Patients with hepatic dysfunction due to GVHD usually have concurrent involvement of skin and GIT
• Definitive diagnosis can be made by biopsy
Hepatic infections
• Uncommon during pre-engraftment period
• Abnormal liver function tests can be due to hepatic infections eg. CMV, VZV, EBV, HHV6, adenovirus
Drug toxicity
• Many drugs can be associated with cholestasis
Budd Chiari (a condition in which the hepatic veins (veins that drain the liver) are blocked or narrowed by a clot (mass of blood cells))
o Clinical presentation of hepatic SOS is indistinguishable from acute Budd Chiari
o Budd Chiari can be established non-invasively by demonstration of thrombosis of the hepatic veins and/or the intrahepatic or suprahepatic inferior vena cava on imaging
o NOT particularly associated with HSCT
Post BMT complications - diarrhoea, DDx/aetiology
Infectious • C Diff associated • Other enteric pathogens Early Post-Engraftment • CMV colitis • C. difficile • Adenovirus, Enteric pathogens such as Coxackie, rotavirus, norovirus
Non-Infectious
Pre-Engraftment
• Mucositis = common following conditioning regimen
• Medications = eg Mg (counteract cyclosporine) result in diarrhoea
• Typhlitis (caecum inflammation) (neutropenic enterocolitis) = occurs while neutropenic in engraftment phase
Early Post-Engraftment
• GVHD = most important and frequent cause of diarrhoea in the early post-engraftment period; usually occurs with other manifestations of GVHD particularly rash
• Medications
Post BMT complications - pneumonia, DDx/aetiology
Nodular Lesions
Pre-Engraftment
• Usually infectious etiologies during the pre-engraftment and engraftment period
Early Post-Engraftment
• Invasive aspergillosis is a more frequent cause of nodular infiltrates (40-50%) during early post-engraftment period – risk factors GVHD and CMV
• Other less common fungal infections can also occur in early post-engraftment period eg. mucurmycosis (5-10%), Fusarium spp, Scedosporium
Late Post-Engraftment
• Bacterial or fungal
Diffuse Lesions
Pre-Engraftment
• Usually non-infectious etiologies during to the pre-engraftment period
o Examples = pulmonary edema, lung damage due to conditioning regimen
o Haemorrhagic alveolitis or cytokine-driven inflammatory process (engraftment syndrome) can result in bilateral infiltrates around the time of engraftment
Early Post-Engraftment
• Infectious causes MUCH more likely in early post-engraftment period – CMV, respiratory viruses, PJP
• Non-infectious causes such as toxicity from conditioning regimen can also occur in post-engraftment period
Late Post-Engraftment
• Non-infectious = bronchiolitis obliterans/ bronchiolitis obliterans syndrome and cryptogenic organising pneumonia (BOP)
• Infections = CMV, respiratory viruses, PCP
Post BMT complications - encephalitis, DDx/aetiology
Infectious
• Most common in early post-engraftment period • Causes o HHV6 – reactivation occurs in 30-50% of patients o HSV o VZV o CMV o EBV o JC polyomavirus o Adenovirus o Toxoplasmosis
Post BMT complications - haemorrhagic cystitis, DDx/aetiology
Chemotherapy
• Most common cause of haemorrhagic cystitis during pre-engraftment period is due to toxicity from conditioning (cyclophosphamide, ifosfamide, busulfan, TBI)
Viral infection • Viral infections most common in early pre-engraftment period • BK polyomavirus most common • Adenovirus second most common • Less frequent - CMV, JV polyomavirus
Haematological causes
• Thrombocytopenia
• GVHD – rare
Most common cancer childhood
Leukaemia
- ALL is commonest malignancy of childhood
a. Leukaemia accounts for 30% of all malignant disease in children
i. 23% ALL
ii. 5% AML
Acute lymphoblastic leukaemia - background
- Epidemiology
a. Incidence – 30 per million
b. Commonest malignancy of childhood
c. Peak presentation 2-5 years
d. Slightly more common in boys - Risk factors
a. Down syndrome
b. NF1
c. Bloom syndrome
d. Ataxia telangiectasia - Pathophysiology
a. Lymphoid progenitor cell becomes genetically altered and undergoes dysregulated proliferation and clonal expansion
b. Leukaemic blasts thought to arise in bone marrow, but may be systemic by presentation
c. Cause unknown
Acute lymphoblastic leukaemia - classification
a. Morphology
i. 85% B cell in origin (most pre-B ALL)
1. CD10(-) = Pro-B
2. CD10 = Precursor B
3. Pre B
4. Mature B (Burkitt) – has different treatment approach
ii. 15% are T cell ALL
1. CD2/ 3/4/5/7/ 8
2. 10% of T cell ALL is ‘early T cell precursor phenotype (ETP ALL) high rate of remission failure and poor overall survival
b. Chromosomal abnormalities – see below
Acute lymphoblastic leukaemia - presentation
a. Bone marrow infiltration/failure
i. Signs of marrow failure
1. Anaemia fatigue and pallor
2. Thrombocytopenia petechiae and bleeding
3. Neutropenia recurrent fever
b. Extramedullary disease
i. Lymphadenopathy + hepatosplenomegaly
ii. Bone pain +++ – particularly lower extremities, can be severe and wake patient at night
iii. T cell disease mediastinal adenopathy causing major airway compression with stridor and/or superior vena cava obstruction
iv. Signs of CNS involvement are INFREQUENT at diagnosis:
1. Headache, nausea and vomiting
2. Irritability, nuchal rigidity and papilledema
3. Cranial nerve involvement – most frequently involving CNVII, CNIII, CNIV, CNVI
v. Rarely, leukaemia evolves as an intracranial or spinal mass, with symptoms relating to nerve compression
vi. Testicular involvement at diagnosis is rare – appears as painless testicular enlargement and is usually unilateral
c. Generalised signs and symptoms = weight loss, bone pain, lethargy, joint swelling + fever
d. Signs on examination
i. Pallor, listlessness, purpuric and petechial skin lesions, mucous membrane haemorrhage
ii. Lymphadenopathy, splenomegaly, (less common hepatomegaly)
iii. Bone and joint tenderness, swelling or effusion
iv. Signs of raised ICP: papilledema, retinal hemorrhages, cranial nerve palsies (as above)
v. Respiratory distress related to anaemia OR obstructive airway problems
Acute lymphoblastic leukaemia - risk stratification: high risk
i. Age = <1 or >10 years
ii. Presentation
1. WCC > 50 at diagnosis
2. CSF involvement
3. Testicular involvement
iii. Additional cytogenetic + molecular features
1. Hypodiploidy (chromosome number reduced <44)
2. KMT2A/MLL genetic rearrangements - translocations of 11q23 (eg. t4;11)
a. Found in most infant ALL
3. iAMP21 amplification
4. Philadelphia chromosome t(9;22) BCR-ABL fusion protein – very poor prognosis
a. Characteristic of CML
5. Abnormal 17p, Loss of 13q
iv. Response = failure to achieve remission by end of induction (D29)
1. If minimal residual disease (>0.01%) detectable at the end of induction prognosis worse unless treatment intensified
Acute lymphoblastic leukaemia - favourable cytogenetics
- Hyperdiploidy (chromosome number increased >50)
- Trisomies 4, 10
- ETV-RUNX protein (t12;21) (previously known as TEL-AML protein)
Acute lymphoblastic leukaemia - treatment (general)
a. Risk-directed therapy = age at diagnosis, initial WCC, immnophenotypic and cytogenetic characteristics of blast populations, rapidity of early treatment response, and assessment of MRD at end of induction
b. Standard treatment involves chemotherapy for 2-3 years
c. General
i. Correct thrombocytopenia + anaemia (if indicated)
ii. Treat infection
iii. Anticipate and prevent tumour lysis – monitor regularly
iv. Prophylaxis for PJP
d. Stratified based on risk
i. Specific treatment protocols for treatment of infant and T-cell ALL
ii. ‘Standard’ and ‘high’ pre-B ALL also treated as separate entities
iii. All children > 10 years and WCC >50 are automatically categorized as high risk
e. SUMMARY
i. Backbone of treatment
1. Induction (achieve remission)
- Vincristine + corticosteroid + PEG asparaginase
2. CNS prophylaxis
a. Radiation plus IT MTX
b. Progressive replacement of radiation by HD MTX
3. Post-induction
iii. Interim maintenance = a less intensive ‘rest’ block to allow bone marrow recovery
iv. Delayed intensification = final burst of intensive chemo to eradicate any blasts prior to maintenance
4. Maintenance
- mainly oral medication at home with monthly visits for IV vincristine and quarterly LP/intrathecal therapy - lasts ~3 years depending on protocol
ii. Chemotherapeutics
1. 3 drugs = vincristine, steroid, asparaginase
2. 4 drugs = anthracycline for T cell and high risk
Acute lymphoblastic leukaemia - prognosis
a. 5 year survival = 85% (standard), 75% (high risk)
i. 90% overall cure rates
ii. 92% for standard risk
iii. 99% for double/triple trisomies or ETV6-RUNX1
b. T ALL = higher risk group than pre-B ALL
i. Overall 90% survival
ii. Presentation WCC not prognostic in T ALL
c. Philadelphia + ALL
i. Addition of TKI (imatinib/ dasatinib) improved outcome
ii. Current 7 year relapse free survival >70%
d. Relapse
i. Late (>18 months off therapy) isolated extramedullary relapse 70% with chemotherapy alone (with early achievement of MRD negative status)
ii. T cell <30%
iii. Early (>18 months since diagnosis and <6 months off therapy) relapse 50% (with transplant)
iv. Very early (<18 months since diagnosis) 20-30% with transplant
Acute myeloid leukaemia - general
- Epidemiology
a. 2nd most common leukaemia
b. 11% of childhood leukaemia
c. Relative frequency of AML increases in adolescence
d. Acute promyelocytic leukaemia (APML) = more common in certain regions of the world - Clinical presentation
a. Bone marrow failure
b. Blastic infiltration
c. Specific to AML
i. Subcutaneous nodules – ‘blueberry muffin’ lesions (especially in infants)
ii. Infiltration of gingiva (especially in monocytic subtypes)
iii. Signs and symptoms of DIC (especially indicative of APML)
iv. Discrete masses – chloromas, granulocytic sarcomas – can occur in the absence of apparent bone marrow involvement; typically seen with t(8;21) translocation - Can be seen in the orbit and epidural space
- Diagnosis
a. Bone marrow - >20% of bone marrow homogenous population of blast cells
i. Features that characterize early differentiation states of the myeloid-monocyte-megakaryocyte series
ii. Aurer rod characteristic of AML - Treatment
a. Aggressive chemotherapy successful in achieving remission in 85-90% of patients
b. Matched-sibling bone marrow or SCT after remission achieves long-term disease free survival in 2/3 of patients
c. Chemotherapy alone curative in 1/2 of patients
e. APML
i. Characterised by gene rearrangement t15;17 = PML-RARA responsive to all-trans-retinoic acid (ATRA, tretinoin) – combined with anthracyclines and cytarabine
ii. Marrow transplantation in first remission unnecessary
iii. Very good prognosis if survive induction
- Supportive care
a. Increased supportive care because of intensive therapy resulting in prolonged bone marrow suppression
b. High incidence of serious fungal and bacterial infections – especially streptococcal viridans - Prognosis
a. Current survival rate 60-70%
Acute myeloid leukaemia - favourable cytogenetics
i. Favourable prognosis
1. t(8;21), t(15;17), inv(16)
2. NPM1 – favourable risk factor if present by itself
3. CEBPA
ii. FLT3-ITD – adverse risk factor predicts relapse
Leukaemia and Down Syndrome
- Acute Leukamias
a. Acute leukaemia occurs 15-20x more frequently in children with DS
b. Ratio of ALL: AML same as general population
i. EXCEPT during first 3 years of life AML more common
c. Outcome of ALL poorer in children with DS
i. Partially explained by lack of good prognostic characteristics (eg. ETV6-RUN1) and trisomies
ii. Genetic abnormalities associated with inferior prognosis (eg. IKZF1)
iii. Remarkable sensitivity of MTX and metabolites – can develop toxicity if standard doses given
d. Outcome of AML better in children with DS
i. >80% long term survival
ii. After induction therapy children receive therapy that is less intensive - Myeloproliferative disorder
a. 10% of neonates with Down syndrome develop transient leukaemia or myeloproliferative disorder
b. Key features
i. High leukocyte counts
ii. Blast cells in peripheral blood
iii. Associated anaemia, thrombocytopenia and hepatosplenomegaly
c. Features usually resolve within the first 3 months of life
d. Neonates can require temporary transfusion support – however do not require chemotherapy unless life-threatening complications
e. Require close follow-up 20-30% develop typical leukaemia
i. Often acute megakaryotic leukaemia
ii. Usually by 3 years of life (mean onset 16 months)
iii. GATA1 mutation are present in blasts from patients with DS who have transient myeloproliferation disease and also in those with leukaemia
iv. Transient myeloproliferative disease can also occur in patients who do not have phenotypic features of DS
v. Blasts from these patients might have trisomy 21, suggesting a mosaic state
Chronic myelogeneous leukaemia - general
- Overview
a. Accounts for 2-3% of childhood leukaemia
b. 99% due to Philadelphia chromosome – t(9;22) (q34;q11) BCR-ABLE fusion protein - Clinical manifestations
a. Non-specific – fever, fatigue, weight loss and anorexia
b. Splenomegaly – can cause upper abdominal pain - Diagnosis
a. Peripheral blood = high WCC with myeloid cells at all different stages
b. Bone marrow = myeloid cells at different stages, Philadelphia chromosome on cytogenetics - Natural history
a. Initial chronic phase in which the malignant clone produces an elevated leukocyte count with a predominance of mature forms but with increased number of immature granulocytes
i. Also results in mild anaemia and thrombocytosis
b. Typically the chronic phase terminates 3-4 years after onset accelerated or ‘blast crisis’ phase
i. Blood counts rise dramatically and clinical picture indistinguishable from acute leukaemia
ii. Additional manifestations can occur from hyperleukocytosis including CNS manifestations - Treatment
a. Imatinib (first generation); dasatinib (second generation)
i. Inhibits BCR-ABL tyrosine kinase used in adults and children
ii. Major cytogenetic response in >70% of patients
iii. Second generation TK inhibitors improved remission rates
b. While waiting for response to TK inhibitor, disabling or life-threatening signs and symptoms of CML can be controlled during the chronic phase with hydroxyurea (gradually returns the WCC to normal)
c. Prolonged morphological and cytogenetic responses are expected
d. HLA-matched family donor allogeneic SCT 80% cure in children
Juvenile myelomonocytic leukaemia - general
- Overview
a. Rare, aggressive disorder of infancy
b. Usually affects children < 2 years
c. Rare <1% of childhood leukemia
d. Do NOT have Philadelphia chromosome characteristic of CML
e. Most patients have mutations in the RAS/MAP kinase pathway - oncogene mutations including NF1, PTPN11, KRAS, NRAS - Risk factors
a. NF type 1
b. Noonan syndrome
i. Half have mutation in PTPN11
ii. Others have mutations in NRAS, KRAS - Clinical manifestations
a. 1/3rd present with an URTI with hepatosplenomegaly and a rash
b. Remainder may have a slower course – pallor, fever, bleeding, infection, cough, malaise - Investigations
a. FBE
i. Monocytosis
ii. Thrombocytopenia
iii. Anaemia
iv. Elevated foetal Hb
b. BM hypercellular myeloid cells, < 20% myeloblasts
c. Karyotype/FISH
d. Molecular analysis for above mutations - Treatment
a. Little evidence
b. SCT offers best opportunity to cure – much less success than for CML
Infant leukaemia - general
- Overview
a. 2% of childhood leukaemia in children < 1 years
b. Ratio of ALL to AML is 2:1
c. Leukaemic clones have been noted in cord blood at birth before symptoms appear
d. Chromosome translocations can also occur in utero during fetal haematopoeisis malignant clone formation
e. >80% of cases have rearrangements in MLL gene (11q23 band translocation; majority t(14;11))
i. Subset of patients have VERY high relapse rate
ii. Without this rearrangement – prognosis similar to older children with ALL
f. Leukaemic cell morphology – large irregular lymphoblasts, with a phenotype negative for CD10 (common ALL antigen) marker (pro-B) unlike most older children with B-ALL who are CD10+ - Clinical manifestations
a. Patients with MLL gene rearrangements
i. Hyperleukocytosis
ii. Extensive tissue infiltration organomegaly, CNS disease
iii. Subcutaneous nodules (leukaemia cutis)
iv. Diffuse pulmonary infiltrates tachypnoea; more often in infants than older children - Treatment
a. Intensive chemotherapy programs, usually including SCT in those with MLL gene rearrangements
b. Infants with AML often present with CNS or skin involvement and have a subtype known as acute myelomonocytic leukaemia – treatment same as older children with AML with similar outcome
Haemophagocytic Lymphohistiocytosis - background
- Key points
a. Aggressive and life-threatening syndrome of excess immune activation
b. Most frequently affects infants from birth to 18 months of age
c. NOT a malignancy
d. Syndrome of uncontrolled haemophagocytosis + activation of inflammatory cytokines - Pathophysiology
a. Syndrome of excessive inflammation and tissue destruction due to abnormal immune activation and excessive inflammation
b. Excessive inflammation due to lack of normal down-regulation of activated macrophages and lymphocytes
c. NK cells and/or CTLs fail to eliminate activated macrophages – results in excessive macrophage activity and highly elevated levels of IFN-g and other cytokines
d. Haemophagocytosis characterised by presence of RBC, platelets or WBC within the cytoplasm of macrophages
e. Cytokines found in high levels include IFN-g, TNF, IL-6, IL-10 and IL-12, soluble IL-2 receptor (CD25)
Haemophagocytic Lymphohistiocytosis - classification
- Classification
a. Primary/ familial HLH = caused by gene mutation
i. Overview - Most AR
- Genes may involve perforin mutations (↓ CMI), hypertriglyceridemia, Munc 13-4 mutations (↓ monocyte killing)
- Decreased/ absent cytotoxicity: perforin granules unable to migrate and fuse with plasma membrane activation of T cells and macrophages, reduces threshold for developing HLH
b. Secondary/ sporadic/ acquired HLH = without known familial HLH
i. Infection-associated HLH
1. Viral = EBV, CMV, parvovirus, HSV, VZV, measles, HHV8, H1N1
2. Less commonly due to bacteria (eg. Brucella, GN bacteria, TB), parasites (eg. Leishmaniasis, malaria), and fungi
ii. Malignancy-associated HLH
1. Most commonly lymphoid cancers – T, NK and anaplastic large cell lymphomas and leukamias
c. Macrophage activation syndrome
i. Form of HLH that occurs primarily in patients with JIA or other rheumatological disease
Haemophagocytic Lymphohistiocytosis - familial mutations
ii. HLH familial mutations
1. PRF1/perforin
2. UNC14D/Muc-13-4
3. STX11/Syntaxin 11
4. STXBP2/Munc18-2
Haemophagocytic Lymphohistiocytosis - manifestations and diagnosis
- Clinical manifestations
a. Fever (90-100%)
b. Maculopapular and/or petechiae (30%)
c. Hepatosplenomegaly (70-100%)
d. Lymphadenopathy (20-50%)
e. Respiratory distress (40-50%)
f. Symptoms of CNS involvement (50%) – aseptic meningitis, ADEM - Diagnostic criteria
a. A molecular diagnosis consistent with HLH (eg. PRF mutation, SAP mutation)
OR
b. Having 5/8 of the following
i. Fever
ii. Splenomegaly
iii. Cytopenia = affecting >=2 cell lineages (Hb <9 g/dl, platelets <100,000/uL, neutrophils <1,000/uL)
iv. Hypertriglyceridaemia and/or hypofibrinogenaemia
v. Haemophagocytosis in the bone marrow, spleen or LN without evidence of malignancy
vi. Low or absent NK cell cytotoxicity = NK cell cytotoxicity, intracellular perforin expression, CD107a expression
vii. Hyperferritinaemia (>500 ng/ml)
viii. Elevated soluble CD25 (IL-2R alpha chain >= 2500 U/ml)
Haemophagocytic Lymphohistiocytosis - management
a. Overview
i. Variable treatment protocols
ii. Steroids +/- chemotherapeutic agents
iii. BM transplantation
b. Familial
i. Etoposide, corticosteroids and intrathecal MTX (not contraindicated by pancytopenia)
ii. ATG and cyclosporin for maintenance
iii. Stem cell transplant required for cure
c. Secondary
i. Prognosis may be good if infection treatment
ii. If infection unable to be treated, prognosis may be as poor as familial disease, CTx require
iii. Theory = cytotoxic effect on macrophages interrupts cytokine production
Lymphoma - general background
- Key points
a. Solid tumours of lymphoid origin – lymph nodes or extranodal lymphoid tissues (bone marrow, thymus, tonsils, spleen, GIT, liver or skin)
b. They differ from leukaemias only in that they do not originate from the bone marrow and are not characterised first by their presence in the circulation.
c. Lymphomas can develop in lymph nodes in almost any part of the body and spread
d. NHL cells can also spread into the CSF and/or bone marrow
e. Third most common paediatric malignancy, comprising 15% of all paediatric cancers. - Two major categories
a. Hodgkin’s Disease (HD)
b. Non-Hodgkin’s Lymphoma (NHL) - Clinical presentation
a. Lymphomas more often present with regional lymphadenopathy
b. Constitutional symptoms and signs include: fevers, anorexia, body aches and pains, weight loss and night sweats
c. Only 1/3 of children with Hodgkin’s Lymphoma and 10% with NHL display constitutional symptoms/signs (less common compared with leukaemias)
d. “B symptoms” – Fevers, night sweats and weight loss
i. Their presence or absence has prognostic significance in HL
Concerning features with lymphadenopathy
i. Size > 1-2 cm
ii. Increasing size over 2-4 weeks
iii. Matted, firm, rubbery consistency or fixed to underlying tissues
iv. No associated tenderness, erythema, warmth or fluctuance
v. Supraclavicular, or low cervical location of LN
vi. Regional lymphadenopathy that predominates in non-cervical areas
vii. Fevers > 38.5 C for 2-4 weeks
viii. Constitutional symptoms
ix. Hepatosplenomegaly
Lymphoma - general investigations
Biopsy
c. Laboratory
i. FBC and film
ii. Biochemistry including EUC, CMP, LFT, LDH, Uric Acid, Ferritin, CRP
iii. Baseline immunologic profile (Immunoglobulins, T- and B-Cells)
iv. Viral serology – EBV, Hepatitis A, B, C, HIV, CMV, HSV, VZV, Varicella
d. Radiology
i. USS – Of lymphadenopathy, Abdominal
ii. CXR
iii. CT Scan – Neck, chest, abdomen, pelvis
iv. PET Scan
v. MRI of bones, CT/MRI of spine, bone scan
e. Disease specific tests
i. ESR for HD
ii. CSF for NHL
iii. Peritoneal, pericardial or pleural fluid aspirates (if clinically indicated)
Most common malignancy in adolescents and young adults
Hodgking lymphoma
Hodgking lymphoma - background
- Key points
a. A malignancy of the germinal centre B-Cells that affects the reticuloendothelial and lymphatic systems
b. Characterised by the presence of Reed-Sternberg cells (histopathologically)
c. Spread: slow, predictable, with extension to contiguous lymph nodes
d. Haematogenous spread also occurs (LESS COMMON) liver, spleen, bone, bone marrow or brain
e. Infiltration to non-lymphoid organs is rare
f. Highly sensitive to chemotherapy and irradiation
g. HL appears to arise in lymphoid tissue and spread to adjacent lymph node areas in an orderly fashion - Epidemiology
a. 6% of childhood cancers
b. Accounts for 40% of childhood lymphomas
c. Bimodal peaks of incidence, at 15-35 yo and > 50 yo
i. Incidence is rare under 5 yo
d. M:F ratio 3:1.
e. Most common malignancy in adolescents and young adults - Pathogenesis
a. Reed-Sternberg (RS) cell = pathognomonic of HL (but also seen in EBV)
i. Large cell with multiple or multilobated nuclei
ii. Clonal in origin; arise from the germinal B cells but typically has lost most B cell gene expression and function
iii. No single simple genetic aberration
b. Characterised by variable number of RS cells surrounded by inflammatory infiltrate of lymphocytes, plasma cells and eosinophils of different proportions depending on HL histological subtype
c. Reactive infiltration of eosinophils and CD68+ macrophages, and increased concentration of cytokines (eg. IL11, IL-6, TNF) associate with unfavourable prognosis including:
i. Presence of ‘’B” symptoms
ii. Decreased response to therapy
iii. Advanced stage
iv. Reduced survival
Hodgkin lymphoma - presentation and diagnosis
- Clinical manifestations
a. Painless, non-tender, firm, rubbery cervical or supraclavicular lymphadenopathy present in 90%
i. Usually some degree of mediastinal involvement
ii. Persists despite antibiotic therapy
b. Clinically detectable hepatosplenomegaly rare (25%)
c. Mediastinal mass (60%)
d. Depending on extent of disease
i. Symptoms and signs of airway obstruction = dyspnoea, hypoxia, cough
ii. Pleural or pericardial effusion
iii. Hepatocellular dysfunction
iv. Bone marrow infiltration = anaemia, neutrophilia, thrombocytopenia (5%)
e. Disease manifesting below the diaphragm is rare (3% of cases)
f. B symptoms (30%) important in staging = unexplained fever, weight loss >10% over 6 months, night sweats
g. Less common (and not of prognostic significance) = pruritis, lethargy, anorexia, pain worsens after alcohol - Diagnosis
a. CXR = identify presence or absence of large mediastinal mass; size is important in prognostication
b. Biopsy = excisional biopsy preferred
c. Bone marrow aspiration = to rule out advanced disease
d. Staging = CT neck, chest, abdomen, pelvis + PET scan
e. Bloods = FBE, ESR, serum ferritin (prognostication)
Hodgkin lymphoma - staging
- Staging = Ann Arbor
a. A = asymptomatic
b. B = B symptoms present
e. X = bulky nodal disease, nodal mass >1/3 of intra-thoracic diameter or 10cm in dimension
Stage I Involvement of single LN (I)
Involvement of single extralymphatic organ or site (IE)
Stage II Involvement of 2 or more LN regions on the same side of the diaphragm (II)
Localise involvement of extralymphatic organ or site and 1 more LN regions on the same side of the diaphragm (IIE)
Stage III Involvement of LN regions on both sides of the diaphragm (III)
May be complicated by involvement of the spleen (IIIS)
Or by localised involvement of extralymphatic organ or site (IIIE) or both (IIISE)
Stage IV Diffuse or disseminated involvement of 1 or more extralymphatic organs or tissues with or without associated LN involvement
Hodgkin lymphoma - treatment and prognosis
- Treatment
a. Treatment determined largely by disease stage, presence or absence of B symptoms, and the presence of bulky nodal disease
b. Treatment includes chemotherapy and/or radiotherapy
c. Radiation therapy alone can lead to prolonged remission and high cure rates, however growth retardation, thyroid dysfunction, cardiac and pulmonary toxicity
d. Multi-agent combination chemotherapy resulted complete response 70-80%, cure rate 40-50% in those with advanced disease, however acute and long-term toxicity - Prognosis
a. 5-year OS for HD of all stages is > 80%
b. Favourable Prognostic Indicators
i. <10 yo, female, favourable subtypes (LP and NS) and Stage I non-bulky disease.
c. Unfavourable Prognostic Indicators
i. Persistently elevated ESR, LD histopathology, Stage IV/bulky disease (largest dimension > 10 cm), hypoalbuminaemia, B symptoms, male, poor response to chemotherapy - Relapse
a. Most relapses occur within the first 3 years after diagnosis; however up to 10 years have been reported
b. Relapse CANNOT be predicted accurately with this disease
c. Prognosis depends on: the time from completion of treatment to recurrence; the site of relapse (nodal vs extranodal); the presence of B-symptoms at relapse
Hodgkin lymphoma - complications of treatment
- Complications of treatment
a. Second Malignant Neoplasms
b. Infertility – Azospermia (males), amenorrhoea (females)
c. Pulmonary damage
d. Cardiac damage
e. Spinal cord damage
f. Radiation nephritis
g. Hypothyroidism
Non-Hodgkin Lymphoma - background
- Epidemiology
a. Accounts for 60% of lymphomas in children
b. 2nd most commonly malignancy in those 15-35 years old
c. Burkitt lymphoma most common in children 0-14 years
d. DLBCL most common in adolescents/young adults - Key points
a. Malignant solid tumour characterised by undifferentiated lymphoid cells
b. Spread: aggressive, diffuse, unpredictable
c. Involves lymphoid tissue and can infiltrate the BM and CNS
d. Characterised by a high growth fraction and doubling time
e. Early diagnosis and treatment is critical
f. Rapid chemotherapy response can occur, therefore there is a higher risk for tumour lysis
Non-Hodgkin lymphoma - classification
a. Classification
i. Lymphoblastic lymphoma (LBL)
1. Immature
2. If >25% BM involvement classified as ALL
3. 90% T cell origin, 10% B cell origin
ii. Burkitt lymphoma (BL)
1. Mature
2. Mostly B cell origin
iii. Diffuse large B cell lymphoma (DLBCL) – further divided into sub-types
1. Mature
2. Most are B cell origin
3. Germinal centre B-cell like favourable prognosis and accounts for majority of paediatric cases of DLBCL
4. Activated B-cell like and primary mediastinal B cell type poorer prognosis
iv. Anaplastic large cell lymphoma (ALCL)
1. Mature
2. 70% T cell origin, 20% null cell origin, 10% B cell origin
b. Summary:
i. BL and DLBCL = mainly B cell origin
ii. LBL = 90% T cell origin
iii. ALCL = 70% T cell origin
Non-Hodgkin lymphoma - staging
- Murphy staging
a. Stage I: Involvement of single tumour or single anatomic area excluding the mediastinum or abdomen
b. Stage II: Two or more lymph node regions on the same side of the diaphragm or resectable primary abdominal
c. Stage III: Involvement of lymph node regions on both sides of the diaphragm; all primary mediastinal, paraspinal or extensive intra-abdominal disease
d. Stage IV: Any of the above and initial involvement of the CNS, BM or both
Non-Hodgkin lymphoma - manifestations and diagnosis
- Clinical manifestations
a. 70% of children present with advanced stage disease (stage III or IV) – including extranodal disease with bone marrow and CNS involvement
b. B symptoms can be seen (fever, weight loss, night sweats) uncommon except ALCL – but NOT prognostic
c. Capillary leak syndrome seen in ALK + ALLs
d. Site specific manifestations (some oncological emergencies)
i. Rapid lymph node enlargement
ii. Abdominal primary (ileocaecal area, appendix or colon) (35%) - Present with pain, distension, jaundice, GI issues, abdominal mass
- Ascites, increased abdominal girth or intestinal obstruction
iii. Mediastinal primary (26%) - Cough or dyspnoea with thoracic involvement
- Superior mediastinal syndrome – can occur as a consequence of large mediastinal mass causing obstruction of blood flow or airways
iv. Head and neck primary (13%) - Present with lymphadenopathy, mandibular swelling, single enlarged tonsil, nasal obstruction, rhinorrhea, cranial nerve palsies
v. CNS (rare) – Present with headaches, vomiting, irritability, signs of raised ICP (papilloedema)
vi. Constitutional symptoms (fevers, malaise, night sweats and weight loss) uncommon except in ALCL
vii. Localised bone pain
viii. Spinal cord tumours – cord compression and acute paraplegias emergent radiotherapy
ix. Tumour lysis syndrome – especially common in BL and LBL - Investigations
a. Basic bloods including LFTs and LDH
b. Bone marrow aspiration + biopsy
c. LP + CSF cytospin
d. CT neck, abdomen, pelvis (head if suspicious of CNS disease)
e. Pet scan
f. Tumour tissue – tested on flow cytometry for immnophenotypic origin (T, B or null) and cytogenetics (karyotype)
g. Additional tests – FISH, PCR. Microarray
Non-Hodgkin lymphoma - treatment and prognosis
- Treatment
a. Treatment of potential life-threatening complications of NHL:
i. SVC syndrome in lymphoblastic lymphoma
ii. TLS in Burkitt’s or Burkitt’s-like NHL
b. Surgery = for diagnostic biopsy and/or excision
c. Radiation Therapy = emergency airway obstruction or CNS complications, may be used for local control or residual mass (e.g. advanced stage lymphoblastic lymphoma).
d. Chemotherapy = combination chemotherapy is usual, with overall cure rates of > 60-80%
i. Low stage NHLs: Treated with CHOP (It includes the drugs cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin), and prednisone) - (+/- Rituximab – Anti-CD20)
ii. Higher-stage lymphoblastic lymphomas are treated on leukaemia protocols
iii. Higher-stage non-lymphoblastic NHLs require extremely aggressive chemotherapy with significant infection risks, but still have generally good remission rates
e. Relapse of disease = reinduction chemotherapy, followed by HSCT - Relapse
a. Minimal residual disease (MRD) – prognostic in ALCL and LBL
b. Patients who have progressive or relapsed disease re-induction chemotherapy + allogeneic or autologous stem cell transplantation - Prognosis
a. Localised disease = 90-100% chance of survival
b. Advanced disease = 70-95% chance of survival
Non-Hodgkin lymphoma - late effects
a. Long-term complications
i. Solid tumours
ii. Leukaemia
iii. Cardiac disease
iv. Pulmonary complications
v. Thyroid disease
vi. Infertility
Burkitt lymphoma - general
Subtype Non-Hodgkin lymphoma
- Key points
a. M:F ratio 2-3:1
b. Mean age 11 years (non-endemic form)
c. Most common primary site = intra-abdominal (sporadic type) or jaw (endemic type)
d. Extremely rapidly-growing, therefore high risk for tumour lysis with initiation of treatment - Classification
a. Endemic type
African
Peak age: 7 yo
Jaw, orbit, paraspinal, abdomen, ovary
CNS involvement > BMA
Breakpoints upstream of c-myc
b. Sporadic type
Worldwide
Peak age: 11 yo
Abdomen, BM, nasopharynx, ovary
BMA involvement > CNS
Within c-myc - Cytogenetics
a. 90% have t (8;14) - c-myc gene on chromosome 8; chromosome 14 – heavy chains - Treatment
a. Paediatric BL and DLBCL are treated with similar chemotherapy regimens
i. If localised disease – chemotherapy for 6 weeks to 6 months excellent prognosis
ii. If advanced disease – multi-agent chemotherapy for 4 to 6 months
b. Primary mediastinal B cell lymphoma (PMBCL) – note inferior outcome when treated with the standard protocols
c. Rituximab
i. Monoclonal Ab directed at CD20 improves outcomes in adults with B-NHL
ii. No good studies on paediatric efficacy - Prognosis
a. Localised disease >90%
b. Disseminated (but not B-ALL) 80-90% on newer protocols
Lymphoblastic lymphoma - general
Subtype Non-Hodgkin lymphoma
- Key points
a. Comprise 30-35% of paediatric NHLs
i. 90-95% are derived from immature T-Cells (very similar to T-Cell ALL)
ii. Remainder pre-B Cell phenotype (as in ALL)
b. Cytologically, these tumours are indistinguishable from ALL and when greater than 25% of BM involvement exists, they are classified as ALL - Clinical presentation
a. 50-70% manifest as anterior mediastinal mass.
b. Patients present with respiratory distress and signs and symptoms associated with SVC syndrome
c. May also present as painless, non-tender masses in the head and neck region, or with supraclavicular or axillary lymphadenopathy
d. Abdominal involvement is rare, but a classic presentation is an older child with intussusception.
e. Spread to the CNS and BM may occur, but uncommon - Treatment
a. Requires 12-24 months of therapy including chemotherapy, intrathecal chemotherapy and cranial radiation in some cases
b. Similar protocol to those used for acute leukaemia
Large cell lymphoma - general
Subtype Non-Hodgkin lymphoma
- Key points
a. Heterogeneous group of tumours
b. Phenotypically includes B-Cell, T-Cell and indeterminate neoplasms
c. Comprises 15-20% of paediatric NHLs. The 3 phenotypes occur with equal frequency - Classification
a. Diffuse Large B-Cell Lymphoma (DLBCL)
i. Predilection for mediastinum and abdomen
ii. Rarely involve the CNS or bone marrow
iii. More like Hodgkin’s Lymphoma than the other NHLs
b. Anaplastic Lymphoma
i. Express CD30 (Ki-1); ALK fusion protein.
ii. Also manifest in mediastinum, as well as involving skin, lymph nodes, testes and bone
iii. Majority of patients require multivalent chemotherapy
iv. CNS prophylaxis (intrathecal chemotherapy) may be required
v. CNS disease treated with intrathecal chemotherapy + radiotherapy
c. Peripheral T-Cell Lymphoma
i. Often involves the skin, CNS, lymph nodes, lung, testes, muscles and GIT
Post-Transplant Lymphoproliferative Disorder - general
- Key points
a. Lymphoid and/or plasmacytic proliferations occurring post solid organ transplantation or HSCT
b. Results from immunosuppression
c. One of the most serious and potentially fatal complications of transplantation
d. In most patients B cell proliferation results from infection with EBV in the setting of immunosuppression and decreased T cell immune surveillance - Epidemiology
a. Overall incidence 1% in transplant population
b. Most common malignancy complicating solid organ transplantation – accounting for 20% of cancers
i. Lower risk for HSCT, renal and liver transplants
ii. Higher among heart and lung transplants
iii. Highest following multi-organ transplant
c. PTLD accounts for a minority of secondary cancers following HSCT
d. Majority (>80%) occur in the first year post transplant - Risk factors
a. EBV serostatus of the recipient
i. Increased risk among EBV-negative recipients of EBV-positive donor organs
b. T cell immunosuppression - Clinical manifestations
a. Highly variable
b. Non-specific constitutional symptoms
c. Lymphadenopathy
d. >50% present with extra-nodal mass (GIT, lungs, skin, liver, CNS) - Treatment
a. Immunosuppression
b. Immunotherapy with CD20 Mab rituximab
c. Chemotherapy
d. Radiation therapy
e. EBV specific cytotoxic T cells – persistent disease - Prevention
a. Limiting immunosuppression
b. Aggressive withdrawal and tapering of agents required for graft acceptance
c. Anti-viral prophylaxis - Prognosis
a. Survival rate of 25-35%
Most common malignancy complicating solid organ transplantation
Post transplant lymphoproliferative disorder
Neuroblastoma - background
- Key points
a. Heterogenous clinical presentation and course
b. Tumours that undergo spontaneous regression to very aggressive tumours unresponsive to very intensive multimodal therapy - Primary site + metastases
a. Site
i. Develop at ANY site of sympathetic nervous system - 50% adrenal gland
- 50% paraspinal and sympathetic ganglia
ii. Abdomen (70%), thorax (15%), pelvic/sacral (5%), neck (4%)
b. Metastases = more common in children >1 years at diagnosis
i. Occurs via local invasion or distant haematogenous or lymphatic routes
ii. Most common site regional or distant LN, long bones and skull, bone marrow, liver + skin
iii. Lung and brain metastases rare (3% of cases) - Epidemiology
a. Most common extracranial solid tumour in children
b. Accounts for 8-10% of childhood malignancies and 1/3 of cancer in infants
d. Median age at diagnosis 22 months; 90% of cases are diagnosed by 5 years of age (rare after age 6) - Pathology
a. Embryonal cancer of the peripheral sympathetic nervous system = derived from primordial neural crest cells
i. Undifferentiated small round cells (neuroblastoma)
ii. Tumours of mature and maturing Schwannian stroma with ganglion cells (ganglioneuroblastoma or ganglioneuroma)
Most common extracranial solid tumour in children
Neuroblastoma
Neuroblastoma - risk factors
a. Most cases unknown
b. Familial neuroblastoma = accounts for 1-2% of all cases
i. Mutations in PHOX2B and ALK genes
ii. BARD1 gene also identified as genetic contributor
c. Associated conditions
i. Neural crest disorders –Hirschsprung disease, central hypoventilation syndrome, ROHADD
ii. NF type I
iii. Congenital cardiovascular malformations
iv. Beckwith-Wiedemann syndrome and hemihypertrophy
v. Turner syndrome
d. Environmental factors = maternal and paternal chemical exposures, farming work, electronics
Neuroblastoma - manifestations and investigations
- Clinical manifestations
a. Reflects the tumour site and extent of disease
b. Symptoms can mimic many other disorders delayed diagnosis
c. Localised disease
i. Asymptomatic
ii. Symptoms due to mass effect - Spinal cord compression
a. Anatomic connection between the SNS and the spinal cord accounts for the propensity of the NB to infiltrate the intervertebral foraminae
b. Motor deficits are most common followed by radicular back pain, bladder and bowl dysfunction, and rarely sensory deficits
c. Only 5% have clinical evidence of epidural compression - Bowel obstruction
- Superior vena cava syndrome
- Neck adenopathy, Horner’s syndrome
- Thorax respiratory distress, Horner’s, incidental
- Pelvic/sacral mass, dysuria, constipation
d. Metastatic disease
i. Non-specific symptoms such as fever, pallor, anorexia, bone pain and irritability
ii. Ptosis and periorbital ecchymoses suggests orbital metastases
iii. Infants <1 year can present stage 4s widespread subcutaneous tumour nodules, massive liver involvement, limited bone marrow disease and a small primary tumour without bone involvement or other metastases
e. Systemic symptoms
i. Produce catecholamines sweating, hypertension (NB. hypertension may also be due to renal artery compression)
ii. Tumour lysis syndrome
iii. DIC - Investigations
a. Primary site imaging – CT/MRI
b. Bilateral BMATs
c. Tumour biopsy = histology, molecular
d. MIBG scan
e. Bone scan (if non-MIBG avid) +/- pet
f. Urine catecholamines (HVA/VMA) – 90% sensitivity in children >1 year
i. Homovanillic acid and vanillylmandelic acid
Neuroblastoma - staging
INSS (Surgical)
1: localised, fully excised, lymph nodes negative
2A: localised, incompletely excised, ipsilateral lymph nodes negative
2B: localised, ipsilateral lymph nodes positive, contralateral nodes negative
3: Unresectable unilateral tumour infiltrate across midline OR unilateral tumour with contralateral lymph node involvement OR midline tumour with bilateral extension by infiltration
4: mets to distant lymph nodes/ bone/ bone marrow/ liver/ skin
4S: Stage 4 in infant <1 year
INRG
Stage L1 = localised disease without image-defined risk factors
Stage L2 = localised disease with image-defined risk factors
Stage M = metastatic
Stage MS = metastatic ‘special’ where MS is equivalent to 4s
Neuroblastoma - treatment and prognosis
- Treatment
a. Dependent on age + tumour stage + cytogenetic and molecular profile
b. Low risk (44%) = surgery alone
c. Intermediate risk (20%)
i. Many factors determine the amount of chemo required – age, stage, histo, biology/genetics
ii. Vary from 28 cycles of chemo +/- CRA
iii. Chemotherapy surgery /- radiotherapy
d. High risk (35%)
i. Intensive chemotherapy = cisplatin/etoposide/cyclophosphamide/vincristine/doxorubicin/topotecan
ii. Surgery
iii. High-dose chemotherapy and stem cell rescue - Carboplatin/etoposide/melphalan and cyclo/thiotepa (COG)
- Busulfan/melphalan (SIOP)
iv. Radiation
v. Immunotherapy
e. Stage 4S = very favourable prognosis and many regress spontaneously without therapy
i. Chemotherapy or resection of the primary tumour does NOT improve survival rates
ii. If massive liver involvement and respiratory compromise, low dose cyclophosphamide or hepatic irradiation may alleviate symptoms - Prognostic factors
a. Histological
i. Presence and amount of Schwannian stroma
ii. Degree of tumour cell differentiation
iii. Miosis-karyorrhexis index
b. Pathological
i. Poor prognosis - MYCN (N-myc) proto-oncogene = 25% highly associated with advanced stage + poor outcome
- Outcome + Prognosis
a. Intermediate-risk (including children with stage 3) excellent prognosis with >90% survival
b. High risk poor prognosis 25-35%
c. For children with stage 4S who require treatment to alleviate symptoms survival 81%
d. Management of relapse
i. Low risk = further surgery +/- chemotherapy
ii. Intermediate risk = further surgery +/- chemotherapy
iii. High risk = palliation, MIBG and Radionucleotide therapy, standard chemotherapy, studies, allogeneic SCT
Wilms tumour - background
- Key points
a. Primary malignant renal tumour
b. Can arise in 1 or both kidneys
c. Metastases = lungs, regional LN, liver - Epidemiology
a. Most common primary malignant renal tumour
b. Second most common abdominal tumour in childhood (6-7% of all childhood cancers)
c. 75% of cases occur in children <5 years; peak age 2-3 years
d. Bilateral tumours peak at a younger age - Risk factors
a. Sporadic – in most cases
b. 2% of patients have family history – autosomal dominant (BCR2 or TP53)
c. 10% associated with multiple malformation syndrome
Wilms tumour - genetics
WT1 (gene located on 11p13) encoding transcription factor –15-20% of tumours
Mutations in CTNNB1 encoding beta-catenin regulatory factor – 15% of tumours
Mutations in WTX encoding role in regulation pathway – 20% of tumours
P53 gene – seen in 75% of Wilm’s tumour with anaplastic histology
Wilms tumour - manifestations and investigations
- Clinical manifestations
a. Incidental discovery of asymptomatic abdominal mass – most common presentation
i. At presentation can be very large; as it is retroperitoneal mass can grow large
ii. Usually does NOT cross midline (cf. neuroblastoma)
b. Hypertension – 20% of patients
i. Secondary to increased renin activity
c. Coagulopathy – caused by an acquired von Willebrand syndrome
d. Less common
i. Abdominal pain, haematuria, fever
ii. Rapid enlargement and anaemia result from bleeding – rare presentation
iii. WT thrombus extending into the inferior vena cava (4-10%) and rarely into right atrium - Investigations
a. Basic bloods = microcytic anaemia from iron deficiency or anaemia of chronic disease, polycythaemia, elevated platelet count, and acquired deficiency of vWF or factor VII
b. Imaging
- AXR
- USS
- CT/MRI (claw sign)
c. Biopsy
- discouraged as results in disease upstaging
- only perform if unusual presentation/imaging
d. Histology (from excision)
- histology most important prognostic predictor: presence of anaplasia determines aggressiveness of tumour and response to treatment
Wilms tumour - staging
1: complete resection, tumour limited to kidney, renal sinus not involved
2: complete resection but tumour extends through renal capsule or into renal sinus
3: incomplete resection, LN involved, tumour rupture, previous biopsy
4: haematogenous spread or distal LN
5: bilateral
Wilms tumour - treatment and prognosis
- Treatment
a. Differences around the world = chemo first, nephrectomy first; we do both
b. Surgery = total nephrectomy standard of care in unilateral Wilm’s tumour but small studies showing nephron sparing possible
c. Chemotherapy = most cases require it
i. VCR/AC-d for most
ii. Doxorubicin/cyclophosphamide/etoposide/carbo for HR
d. Radiotherapy = stage 3, +/- lung mets
Bilateral
- chemotherapy first
- nephron sparing surgery aiming to preserve as much kidney as possible
- +/- post op chemo
- prognosis usually favourable
- Outcome + Prognosis
a. Favorable stage I-III have >90% 5 year survival, 90% if stage IV
b. Anaplastic stage II-IV have 50% 5 year survival
c. Bilateral have 70% 5 year survival
Overall 60% 4 year survival, but much better outcomes if not anaplastic
Wilms tumour - long term toxicity of therapy
a. Radiosensitive
i. Doxorubicin/ actinomycin-D
ii. Radiation recall
b. Cardiotoxicity
i. Doxorubicin + radiotherapy
c. Single kidney hyperfiltration
d. Second malignant neoplasm
e. Menopause, infertility – if radiotherapy involves entire abdomen (usually if ruptured)
Wilms tumour - screening indications
BWS/isolated hemihypertrophy
WAGR/WT-1 related mutation
Siblings of familial Wilms, offspring of bilateral Wilms
Mesoblastic nephroma - general
a. Most common solid renal tumour identified in the neonatal period
b. Most frequent benign renal tumour of childhood
c. 3-10% of all paediatric renal tumours
d. Many diagnosed with prenatal USS
e. Can present with polyhydramnios, hydrops and premature delivery
f. Most patients are diagnosed <3 months of age (whereas WT rarely diagnosed before 6 months)
g. Radical nephrectomy treatment of choice
h. Local recurrence uncommon
i. Rare malignant variations – metastases to the lung, liver, heart and brain
Most common solid renal tumour of neonatal period
Mesoblastic nephroma
Most frequent benign renal tumour of childhood
Mesoblastic nephroma
Clear cell carcinoma of kidney - general
a. Uncommon in children – 3% of malignant tumours of the kidney
b. Peak incidence 1-4 years of age; usually presenting as abdominal mass
c. M > F
d. Bone is the most common site of distant metastases, followed by lung, abdomen, retroperitoneum, brain and liver
e. Staging work-up should include bone scan
f. Early stage disease has excellent prognosis (non-metastatic) and use intensive chemotherapy (3-4 drugs)
Rhabdoid tumour of kidney - general
a. Rare but aggressive cancer (2% of kidney tumours)
b. 80% occur in children <2 years
c. Haematuria common presenting feature
d. Both rhabdoid tumour of the kidney and CNS atypical rhabdoid tumours have deletions and mutations in hSNF5/InII gene and are considered to be related
e. Prognosis poor – 5 year survival <30%
f. High metastatic rate
g. 15% have synchronous brain lesions
h. Fever, haematuria and hyperglycaemia can occur
Renal cell carcinoma - general
a. Rare in children; 2-5% of all renal tumours
b. 20% have metastatic disease at diagnosis – lung, liver, bone, brain
c. Older age (10 years)
d. Present with frank haematuria, flank pain and/or palpable mass OR incidental finding
e. May have specific cytogenetic abnormality – ASPL-TFE3 gene fusion)
f. Can be associated with von Hippel-Lindau disease
g. Local LN involvement is not a poor prognostic indicator
h. Nephrectomy alone may be enough for early-stage RCC
i. Survival
i. 90-100% for stage 1
ii. 10% for stage 4
Rhabdomyosarcoma - background
- Epidemiology
a. 4-5% of paediatric malignancies
b. Most common soft tissue sarcoma
c. Accounts for >50% soft tissue sarcomas
d. 2/3 arise <6 years of age
e. Tumour of mesenchymal tissue (connective tissue, bone/fat/cartilage/vascular/haematopoetic) - Risk factors
a. Unknown
b. Li-Fraumeni syndrome - Site
a. Occurs at any site = head and neck (40%), genitourinary tract (20%), extremities (20%), other (20%)
i. Extremity lesions more likely in older children and to have alveolar histology - Pathogenesis
a. Believed to arise from same embryonic mesenchyme as striated skeletal muscle
b. On the basis of light microscopy belongs to the same general category of small round cell tumours
i. Includes Ewing sarcoma, neuroblastoma, NHL
Rhabdomyosarcoma - subtypes
a. Classification based on histology – determines treatment planning and prognosis
b. 2 subtypes
i. Embryonal type = 70-75% (no translocations)
1. Spindle and/or round cell tumour in loose myxoid or dense collagen stroma
2. 2 variants
a. Botryoid type = typically vaginal or nasopharyngeal site
b. Spindle cell = paratesticular
ii. Alveolar type = 20-25% of cases
1. Characterised by
a. T(2;13) or PAX3-FKHR (FOXO1)
b. T(1:13) or PAX-FKHR
2. Grow in nests that often have cleft like spaces resembling alveoli
3. Occurs most often in the trunk and extremities
Worse prognosis
Most common soft tissue sarcoma
Rhabdomyosarcoma
Rhabdomyosarcoma - manifestations and investigations
- Clinical manifestations
a. Mass – may or may not be painful
b. Strongly influenced by site
c. Symptoms caused by displacement or obstruction of normal structures
i. Nasopharynx = nasal congestion, mouth breathing, epistaxis, difficulty swallowing + chewing
ii. Regional extension into cranium = cranial nerve paralysis, blindness, signs of increased ICP with headache and vomiting
iii. Face or cheek = swelling, pain, trismus, and if extension paralysis of cranial nerves
iv. Neck = progressive swelling with neurological symptoms after regional extension
v. Orbital = proptosis, periorbital edema, ptosis, change in visual acuity, local pain
vi. Middle ear = pain, hearing loss, chronic otorrhoea, mass in the ear canal; extension can result in cranial nerve paralysis and signs of intracranial mass on involved side
vii. Larynx = unremitting croupy cough
d. Other presenting features
i. Trunk or extremity = usually noticed after trauma and thought to be a haematoma; if swelling does not resolve or increases, malignancy should be suspected
ii. Genitourinary tract = haematuria, obstruction, recurrent UTI, incontinence, mass detectable on abdominal or rectal examination
iii. Paratesticular = painless, rapidly enlarging mass in scrotum
iv. Vaginal = grape-like mass of tumour bulging through the vaginal orifice; sarcoma bulges out of the virginal orifice (sarcoma botryroides) can cause urinary tract or large bowel symptoms - Vaginal bleeding or obstruction of urethra or rectum may occur
e. Tumours of any location may disseminate early and cause symptoms of pain or respiratory distress associated with pulmonary metastases
f. Extensive bone involvement can produce symptomatic hypercalcaemia - Investigations
a. Early diagnosis requires high index of suspicion
b. Imaging
i. CT or MRI to evaluate the primary tumour site include regional LN
ii. CT chest
iii. Bone scan +/- PET
iv. BBMATs
v. CSF (in parameningeal)
c. Biopsy
i. Very important aspect of diagnosis – LN also need to be sampled
ii. Histology = small, round, blue cell tumour
iii. Require Immunohistochemical stains including analysis of PAX/FOXO1 expression
Rhabdomyosarcoma - treatment and prognosis
- Treatment
a. Surgery
i. Aggressive but non-mutilating
ii. Up front best but only if likely clear margins without danger or functional impairment
b. Radiotherapy
c. Chemotherapy
i. Essential (for occult and obvious metastases, and to help with local control)
ii. Vincristine, actinomycin-d, cyclophosphamide (VAC)
iii. Ifosfamide, doxorubicin, topotecan, irinotecan
iv. HDCT not proven, not standard
v. Maintenance chemo – vinorelbine/cyclo
vi. Biologics eg. temsirolimus (mTOR inhibitor) - Prognosis
a. Localised = 70-75% survival
b. Metastatic = 25-30% survival
c. Resectable tumour + favourable histology 80-90% prolonged disease free survival
d. Unresectable tumour
i. Orbit high likelihood of tumour
ii. Other sites 65-70% long-term disease free survival
e. Disseminated disease poor prognosis; 50% achieve remission and only 50% of these are cured
f. Older children have poorer prognosis
Alveolar worse prognosis (a/w translocations 1:13 and 2:13)
“Other” soft tissue sarcomas (non-rhabdomyosarcoma) - general
- Key points
a. Heterogenous group of sarcomas
b. All rare
c. 3% of all childhood malignancies
d. Relatively rare in childhood – most information about natural history and treatment from adult studies
e. Median age of diagnosis 12 years
f. Commonly arise in the trunk or lower extremity - Histological sub-types
a. Synovial sarcoma (42%)
b. Fibrosarcoma (13%)
c. Malignant fibrous histiocytoma (12%)
d. Neurogenic tumours (10%) - Treatment
a. Surgical resection mainstay of therapy
b. Careful evaluation for long or bony metastases
c. Chemotherapy + radiotherapy required for large, high-grade and unresectable tumours
d. Role of chemotherapy for non-rhabdomyosarcoma not as well defined
i. Most have poor response to chemo
ii. Except synovial sarcoma and infantile fibrosarcoma
e. Radiotherapy standard for large/residual
f. Pazopanib (TKI)
g. Patients with unresectable or metastatic disease treated with multi-agent chemotherapy in addition to irradiation and/or surgery
h. Patients with completely resected small (<5cm)) generally treated with surgery alone – generally excellent outcome regardless of whether tumour high or low grade
Most common primary malignant bone tumour in children and adolescents
Osteosarcoma
Second is Ewing sarcoma, but Ewing sarcoma MORE common in patients <10 years old
Both are more likely to occur in second decade of life (10-20)
Osteosarcoma - general
Age: Second decade Race: All Cell: Spindle-cell producing osteoid Predisposition: Retinoblastoma, Li-Fraumeni syndrome, Richmond-Thomas syndrome Site: Metaphysis of long-bone (O is closer to M) - distal femur and proximal tibia most common Presentation: local pain and swelling, history of injury Radiographic: - sclerotic destruction - sunburst pattern - Codman triangle DDx: Ewing, osteomyelitis Mets: Lungs, bone Treatment: - chemotherapy - ablative surgery - NOT radiosensitive Prognosis: - without mets = 70% - with mets = 30%
Ewing sarcoma - general
Age: Second decade
Race: White
Cell: Undifferentiated small round cell, probably of neural origin
Predisposition: None
Site: Diaphysis of long bones (E is closer to D), flat bones
- most commonly pelvis, femur
Presentation: Local pain and swelling, fever
Radiographic:
- lytic lesions
- Multilaminar periosteal reaction (onion skinning)
DDx: Osteomyelitis, eosinophilic granuloma, Lymphoma, Neuroblastoma, Rhabdomyosarcoma
Mets: Lung, bone
Treatment:
- chemotherapy
- radiotherapy, surgery
- VERY radiosensitive
Prognosis:
- without mets 70%
- with mets 30%
Osteosarcoma - background
- Epidemiology
a. Most common primary bone tumour in children/adolescence
b. Peaks 15-19 years - Risk factors
a. Syndromes
i. Hereditary retinoblastoma (RB1 gene)
ii. Li Fraumeni syndrome (p53)
iii. Rothmund-Thomson syndrome
e. Benign conditions with malignant transformation = Paget disease, endochondromatosis, multiple hereditary exostoses, fibrous dysplasia - Pathology
a. A mesenchymal malignancy in which the malignant cells produce osteoid
Osteosarcoma - classification/types
b. Classification
i. Conventional (80-90%)
1. Osteoblastic
2. Chrondroblastic
3. Fibroblastic
ii. Other
c. 4 pathological subtypes = osteoblastic, fibroblastic, chondroblastic and bone [no difference in outcome, although chondroblastic may not respond as well to chemotherapy]
d. Two variants of osteosarcoma = contrasting high-grade osteosarcoma which arise in the Diaphyseal region of long bone and invade the medullary cavity
i. Parosteal osteosarcoma = low-grade, well differentiated tumour that does NOT invade the medullary cavity and most commonly is found in the posterior aspect of the distal femur
1. Surgical resection alone often curative
2. Low potential for metastatic spread
ii. Periosteal osteosarcoma = rare variant that arises on the surface of the bone
1. Higher rate of metastatic spread than paraosteal type and intermediate prognosis
Osteosarcoma - manifestations, investigations
- Clinical manifestations
a. Pain, limp and swelling
b. Initial complaints often attributed to sports injury or sprain
c. Nocturnal pain concerning feature
d. On examination may have reduced ROM, joint effusion, tenderness or warmth - Investigations
a. Bloods = usually normal, may have elevated ALP or LDH
b. X-ray = lesion may be mixed lytic, sclerotic or both in appearance, new bone formation USUALLY visible
i. Classic radiographic appearance sunburst pattern – secondary to ossification in the soft tissues (typical but NOT sensitive or specific)
ii. Periosteal bone formation with lifting of the cortex may lead to the appearance of ‘Codman’s triangle’
c. MRI = evaluate tumour for its proximity to nerves and blood vessels, soft tissue + joint extension, and skip lesions
d. CT chest and Radionucleotide scanning = assess for lung and bony mets
e. Biopsy = diagnosis ALWAYS verified by histology
i. Needs to be done in a manner that it will not compromise the ultimate limb salvage procedure
ii. Histology = highly malignant, pleomorphic, spindle cell neoplasm associated with the formation of osteoid and bone
Osteosarcoma - treatment and prognosis
- Prognostic factors
a. Presence of metastases
b. Axial location
c. Large tumour size
d. Surgical resection
e. Response to chemo - <10% viable tumour (good), >10% viable tumour (bad) - Treatment
a. Surgery
i. Complete surgical removal of primary tumour AND metastases if present
ii. Limb salvage surgery
b. Radiation therapy
i. Restricted to inoperable tumours
ii. Need very high doses of 70Gy+
c. Chemotherapy
i. Pre-operative = cisplatin, doxorubicin, MTX - +/- ifosfamide and etoposide
ii. Side effects = deafness, cardiac and renal dysfunction - Relapse
a. Lung metastases only – cure possible with surgical resection only
b. No chemotherapy known to be curative but may enable complete resection of disease - Prognosis
a. One of the most important prognostic factors = histologic response to chemotherapy
b. Surgical resection alone curative only for patients with paraosteal osteosarcoma
c. Chemotherapy + surgery 5 year disease free survival of non-metastatic extremity osteosarcoma 65-75%
d. Poor prognosis for those with pelvic tumours
e. 20-30% of patients who have limited number of pulmonary metastases can be cured with aggressive chemotherapy and resection
f. Patients with bone metastases and those with widespread lung metastases have extremely poor prognosis
Ewing sarcoma - background
- Key points
a. Undifferentiated sarcoma of bone, but may also arise from soft tissue
i. 10% are extra-osseous
b. Ewing sarcoma family of tumours = refers to a group of small, round cell, undifferentiated tumours thought to be of neural crest origin including Ewing sarcoma of bone and soft tissue, and peripheral primitive neuro-ectodermal tumour
c. Treatment the same irrespective of whether they arise from bone or soft tissue
d. Site of tumour = extremities and central axis (pelvis, spine, and chest wall)
i. Primary tumours arising from the chest wall are referred to as Askin tumours - Epidemiology
a. 2nd most common bone tumour
b. Extremely rare in African or Chinese populations - Pathology
a. All are high grade
b. Need immunohistochemistry to differentiate from other small round cell tumours
i. CD99 + ve in >95%
c. Molecular
i. Rearrangement of EWS gene on Cx 22q12
ii. Mostly occurs with FL-1 gene on 11q24 - T(11;22) in 85%
- T(21;22) in 10%
Ewing sarcoma - manifestations and investigation
- Clinical manifestations
a. Similar to osteosarcoma – pain, swelling, limitation of motion, and tenderness over involved bone/soft tissue
b. Huge chest wall primary tumours respiratory distress
c. Paraspinal or vertebral primary spinal cord compression
d. Often associated with systemic manifestations = fever, weight loss (osteosarcoma less likely to have systemic symptoms) - Diagnosis
a. X-ray = destructive osteolytic lesion of the diaphysis with destruction of the osseous cortex, elevation of the periosteum and infiltration of the surrounding tissue, characteristic onion-skinning
b. Other imaging
- MRI
- CT
c. Bone marrow asps
- to assess for mets
d. Biopsy
i. Immunohistochemical staining assists in the diagnosis of Ewing sarcoma to differentiate it from other small, round, blue cell tumours such as lymphoma, rhabdomyosarcoma and neuroblastoma
ii. Specific chromosomal translocation t(11;22) or variant often present
Ewing sarcoma - treatment and prognosis
- Treatment
a. Local control = Surgery +/- radiotherapy (54Gy)
i. Ewing sarcoma radiosensitive
b. Metastases = whole lung irradiation (16 Gy)
c. Multiagent chemotherapy (usually pre op)
d. High dose chemotherapy with autologous stem cell re-infusion/rescue (high risk disease or relapse) - Prognosis
a. Small, non-metastatic, distally located tumours have best prognosis 75% cure
b. Pelvic tumours have worse outcome
c. Metastatic disease at diagnosis, especially bone or bone marrow have poor prognosis <30% survive long-term - Relapse
a. Late relapse, even as long as 10 years after diagnosis, possible
b. Very poor prognosis
i. Chemotherapy – VTC + gem/doc
ii. HDCT
iii. Surgery/RT
iv. Palliation
c. Note - Secondary malignancy after radiotherapy
Osteochondroma - general
AKA exostosis
a. Most common benign bone cyst
b. Most develop in childhood – arising from the metaphysis of long bone, particularly distal femur and proximal humerus, lesion enlarges with child until skeletal maturity
c. Most discovered at age 5-15 years bony, non-painful mass
d. X-ray = stalks or broad-based projections; marrow space of the involved bone are continuous with lesion
e. Malignant degeneration rare in children, 1% in adults
Multiple hereditary exostoses - general
a. Presence of multiple osteochondromas
b. Severely involved children can have short stature, limb-length inequality, premature partial physeal arrests, deformity of UL and LL
c. Require careful monitoring
