Malignancy in a child

Question 1

What is the most common malignancy affecting children?

Answer 1

ALL (acute lymphoblastic leukaemia) also accounts for 80% of childhood leukaemia

Leukaemia accounts for 31% of all childhood cancers - is the most common childhood cancer

Question 2

When is the peak incidence of ALL? Which sex is more affected?

Answer 2

2-5 years

Boys slightly more affected

Question 3

What are the signs showing bone marrow failure in ALL?

Answer 3

• anaemia: lethargy and pallor
• neutropaenia: frequent or severe infections
• thrombocytopenia: easy bruising, petechiae

Question 4

Which of these will be high in ALL?

1. Hb
2. Neutrophils
3. Platelets
4. Potassium
5. Phosphate
6. Uric acid
7. Calcium
8. LDS

Answer 4

Potassium, phosphate, uric acid and LDH will be high - these are due to high number of cells undergoing lysis.

Bone marrow fails to produce normal cells such as Hb, neutrophils or platelets so these are low.

Question 5

What are the non-bone marrow failure features of ALL?

Answer 5

Other features

• bone pain (secondary to bone marrow infiltration)
• splenomegaly
• hepatomegaly
• fever is present in up to 50% of new cases (representing infection or constitutional symptom)
• testicular swelling

Question 6

What are the three types of ALL?

Answer 6

• common ALL (75%), CD10 present, pre-B phenotype
• T-cell ALL (20%)
• B-cell ALL (5%)

Question 7

What features of ALL are poor prognostic factors?

Answer 7

Poor prognostic factors

• age < 2 years or > 10 years
• WBC > 20 * 109/l at diagnosis
• T or B cell surface markers
• non-Caucasian
• male sex

Question 8

What is a complication of ALL with high WCC that should be avoided? How do you treat infection in these patients?

Answer 8

Tumour lysis sundrome and subsequent renal failure - this can occur due to high cell breakdwon. Manage with hyperhydration and allopurinol.

Risk of gram negative sepsis, since there is neutropenia - so use broad spectrum antibiotics like piptazobactam/gentamycin.

Question 9

A 3-year-old girl is brought in by her mother. Her mother reports that she has been eating less and refusing food for the past few weeks. Despite this her mother has noticed that her abdomen is distended and she has developed a ‘beer belly’. For the past year she has opened her bowels around once every other day, passing a stool of ‘normal’ consistency. There are no urinary symptoms. On examination she is on the 50th centile for height and weight. Her abdomen is soft but slightly distended and a non-tender ballotable mass can be felt on the left side.

What is the diagnosis?

Answer 9

Wilm’s nephroblastoma

Question 10

What age group is most affected by Wilm’s nephroblastoma?

Answer 10

It typically presents in children <5 years , with a median age of 3 years old.

Question 11

What are the genetic associations with Wilm’s nephroblastoma?

Answer 11

Most occur in healthy children but 10% occur in children with malformations e.g.

• Overgrowth syndromes (excess somatic growth causing macroglossia, nephromegaly and hemihypertrophy) e.g. Beckwith-Wiedemann syndrome or isolated hemihypertrophy
• No ‘overgrowth’ - e.g. trisomy 18 (Edwards syndrome), WAGR syndrome (Wilm’s with Aniridia, Genitourinary malformations, mental Retardation)

1-2% - Familial Wilms’ tumour - autosominal dominant transmission, associated with mutation in the WT1 gene (WAGR) or WT2 gene (BW) on chr11, or WT3 on chr16

Question 12

What are the presenting features of Wilm’s nephroblastoma?

Answer 12

• abdominal mass (most common presenting feature) - unilateral in 95%
• painless haematuria
• UTI
• flank pain
• other features: anorexia, fever, respiratory symptoms if metastasised

Question 13

How often is Wilm’s nephroblastoma unilateral? How common are metastases?

Answer 13

• unilateral in 95% of cases
• metastases are found in 20% of patients (most commonly lung)

Question 14

What investigations are useful in diagnosing Wilms’ tumour?

Answer 14

Bloods: FBC, U&E, creatinine

Imaging: US/renal angiography - may show distorsion of renal pelvis/hydronephrosis

Staging: CT/MRI including chest for metastases

Question 15

How quickly should children with suspected Wilm’s tumour be seen?

Answer 15

Refer to a paediatrician to be seen within 48 hours.

Question 16

What is the prognosis with Wilm’s tumour?

Answer 16

Prognosis - good, 80% cure rate

Management - nephrectomy, chemotherapy, radiotherapy if advanced disease

Question 17

What is the aetiology of childhood leukaemia?

Answer 17

• De novo mutations (most common)
• Genetic syndromes may predispose
• Chromosomal and genetic abnormalities:
  
  • Translocation to TCR loci in ALL
  • TF mutations regulating B cell development and maturation in ALL
  • Aberrational disruption of genes coding for TFs and coactivators in AML
  • BCR-ABL1 fusion and activation of multiple kinases in CML

Question 18

What age is ALL/AML/CML most common?

Answer 18

• ALL - 2-3 years
• AML - <2 years
• CML - <1 year and young adolescents

Question 19

What are the risk factors for leukaemia?

Answer 19

• Boys>girls
• Caucasian
• Cytogenetic abnormalities
• Down’s syndrome (x10-20 fold risk), Faconi’s anaemia, ataxia telangiectasia and Bloom’s syndrome
• Exposure to ionising radiation/maternal XR exposure during pregnancy

Question 20

What are the presenting features of leukaemia?

Answer 20

• Anaemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy
• Malaise, fatigue, lethargy
• Prolonged fever
• Growth restriction/failure to thrive
• SOB/dizziness/palpitations
• Bone/joint pain
• Constipation
• Headache
• Nausea and vomiting (CNS infiltration)
• Repeated/severe common childhood infections

Signs:

• Pallor
• Petechiae/purpura/bruising
• Expiratory wheeze
• CN lesions
• Testicular enlargement

Question 21

What investigations would you do for lymphoma?

Answer 21

• FBC with differential and blood film - pancytopenia due to bone marrow infiltration; WCC elevated due to blasts despite neutropenia
• BM aspiration and biopsy
• Imaging
• Immunophenotyping and cytogenic analysis (e.g. FISH) for risk stratification
• Lumbar puncture (if suspected CNS infiltration)

Question 22

Summarise the management of ALL/AML/CML.

Answer 22

ALL - high intensity chemotherapy through Hickman lines or myeloablation with allogeneic BM transplantation in disease refractory to chemotherapy

AML - intensive chemotherapy to destroy leukaemic population ASAP

CML - imatinic anti-tyrosine kinase therapy being investigated; myeloablative HSCT mainstay therapy for now

Colony stimulating factors given to promote haematopoiesis following chemotherapy.

Question 23

Which two electrolyte abnormalities are common in leukaemia?

Answer 23

hyperkalaemia and hyperphosphataemia (due to blast crisis)

Question 24

What is the prognosis of childhood leukaemia?

Answer 24

• Five year survival is 79% and cure rates are 68%
• ALL cure rate is 80% and best in those ages 1-10 years
• Average time to cure in ALL is 19 years (due to relapse, secondary malignancy and toxicity)
• AML 5 year survival is 66%

Question 25

What is lymphoma? What are the types?

Answer 25

Malignancy of the lymphatic system which includes lymph nodes, the spleen, the thymus and the bone marrow. Two main types: Hodgkin's and non-Hodgkin's lymphoma

Question 26

What is the difference between lymphoblastic lymphomas and lymphoblastic leukaemias?

Answer 26

Degree of bone marrow infiltration lymphoma = \<25% bone marrow involvement leukaemia = \>25% bone marrow involvement

Question 27

How common is lymphoma?

Answer 27

Accounts for 10% of cancer cases in children 3rd most common cancer in children * NHL - affects about 80 children per year in UK* * HL - affect about 60 children per year in UK*

Question 28

Which type of lymphoma is more common in boys?

Answer 28

Non-Hodgkin's lymphoma HL is equal in males:females

Question 29

What is the aetiology of lymphoma?

Answer 29

* Abnormal proliferation of lymphocytes * The malignant cells are MATURE lymphocytes which arise OUTSIDE of the bone marrow e.g. lymph nodes (unlike in leukaemia where blasts come from bone marrow) * Usually unknown underlying cause or chromosomal abnormalities _Exceptions_: rarely lymphoblastic lymphomas come from immature precursor lymphoblasts.

Question 30

What are the risk factors for lymphoma?

Answer 30

1. **Immunodeficiency**: * post-solid organ transplant (post-transplant lymphoproliferative disorders), * ataxia telangiectasia, * Nijmegan-Breakage syndrome, * HIV, * and immunosuppressant drugs 2. **EBV infection**

Question 31

What are the types of Hodgkin's lymphoma?

Answer 31

NB: no difference in the prognosis or management of the different subtypes of classical Hodgkin's lymphoma

Question 32

What is the characteristic finding in Hodgkin's lymphoma?

Answer 32

Reed-Sternberg cells (giant multinucleated cells) with associated smaller mononuclear cells, which arise from B lymphocytes \

Question 33

What are the types of non-Hodgkin's lymphomas?

Answer 33

Question 34

What is the pathophysiology of most non-Hodgkin's lymphomas? Name the most common type of NHL.

Answer 34

Most are high-grade lymphomas of B-cell origin Burkitt's (most common) then large B cell, lymphoblastic, anaplastic

Question 35

How does B cell vs T cell NHL usually present?

Answer 35

B-cell NHL mostly affects lymph nodes in abdomen/GI tract but also in head and neck - **usually localised lymph node disease** T cell NHL usually affects lymph nodes in the chest --\> **mediastinal mass with varying degree of BM infiltration**

Question 36

What complications may arise from T cell NHL?

Answer 36

T cell NHL --\> mediastinal mass --\> **_SVC obstruction_** may cause dyspnoea, facial swelling, flushing and venous distension in neck as well as chest and arms

Question 37

What complications may arise from B cell NHL?

Answer 37

**B cell NHL** --\> abdominal/head/neck localised lymph node disease --\> in abdomen can present with pain from intestinal obstruction, palpable mass or intussusception in some cases with involvement of ileum

Question 38

What are common presenting features of lymphoma?

Answer 38

* **Painless progressive lymphadenopathy** (weeks to months) * Mediastinal involvement: * Cough * Dyspnoea * Facial oedema * Pruritus * B symptoms: * Fatigue * Weight loss (\>10% in 6 months) * Drenching night sweats * Fever * Loss of appetite Extranodal involvement is more common in NHL: * BM: anaemia, infections, bruising * Abdominal: bloating satiety, pain, constipation, vomiting * Retroperitoneal lymphadenopathy: urinary retention * Skin: new lesions like mycosis fungoides, jaundice * Testicular swelling * CNS: behavioural change, headache, confusion, N&V, seizures, weakness, sensory change, raised ICP

Question 39

What investigations are used to diagnose paediatric lymphoma?

Answer 39

**Bedside**: swabs for infection, urine dip **Bloods**: * FBC - ancytopenia or differentiates leukaemia (anaemia, thombocytopenia and raised WCC) * U&E - important for baseline treatent, in TLS electrolytes raised * LDH - raised if high cell turnover * LFTs - important basline for treatment, low albumin means poor prognosis * Hep B/HIV/G6PD - complications of treatment may occur in these groups **Imaging**: CXR, CT/MRI/PET for staging, US liver and spleen. **Invasive**: biopsy for staging of lymph node +/- bone marrow

Question 40

Which staging classifications are used for lymphoma?

Answer 40

Ann Arbor - HL St Jude - NHL as more extranodal involvement

Question 41

Summarise the staging for lymphoma.

Answer 41

Given a number I-IV + a letter (A [none] , B [systemic symptoms] and E [extranodal] in HL)

Question 42

List the B symptoms.

Answer 42

* weight loss * fever * night sweats NOT lymphadenopathy or fatigue

Question 43

What is the general management of HL?

Answer 43

**Chemotherapy** is mainly used Other: * Radiotherapy if chemotherapy is not effective * Lymphocyte-predominant HL usually has surgery or low-dose chemotherapy alone as it is slower growing

Question 44

What is the general management of NHL?

Answer 44

Chemotherapy is mainly used - regimen depends on the type but generally: * B-cell NHL has 4-6 courses of ***intensive** therapy* * T-cell NHL has ***less intensive** therapy* but lasting 2-3 years*.* Other: * Biologics - e.g. rituximab is anti-CD20, used for high-risk B cell NHL * BM tranplant - if relapsed * Lymphoblastic lymphoma is treated like ALL * Radiotherapy rarely used

Question 45

What are the condition-related (long and short-term) complications of lymphomas?

Answer 45

Short term: * SVC obtruction * Bowel obstruction/perforation * Pain from invasion * Pericardial/pleural effusion * Cytopenias * Tumour lysis syndrome Long term: * Few

Question 46

What are the treatment-related (long and short-term) complications of lymphomas?

Answer 46

Short-term: * Alopecia * Mucositis, diarrhoea * Neutropenic sepsis * TLS * N&V * Anorexia and weight loss Long-term: * Secondary cancers * Growth impairment * Infertility * Cardiotoxicity/pulmonary toxicity/renal impairment

Question 47

What is the prognosis of paediatric lymphomas?

Answer 47

90% of those with HL and \>90% of those with NHL achieve remission. But long term effects of treatment can be significant and require long-term follow up.

Question 48

Summarise TLS.

Answer 48

* AKI * Arrhythmias * N&V * Seizures ...may occur as a result of TLS which is most common in highly proliferative tumours and causes electrolyte disturbance: * hyper-phosphataemia * hyper-uricaemia * hyper-kalaemia * hypo-calcaemia **Tx**: allopurinol (prevents uric acid production) and hyperhydration [+/- rasbiricase if WCC \>50 to break down uric acid]

Question 49

A 14-year-old girl complained of a cough for 2 weeks which was non-productive and worse at night. She had seen her general practitioner and her chest was clear. She returned 2 weeks later, as she had noticed a swelling in her neck. On examination, she had a large anterior cervical lymph node which was non-tender. On referral to hospital, she had a chest X-ray, which showed a large mediastinal mass (Fig. 22.10). What is the differential diagnosis?

Answer 49

* T cell NHL/acute leukaemia * HL FBC was normal but biopsy confirmed Hodgkin lymphoma.

Question 50

What are the types of Burkitt's lymphoma? What is its pathophysiology and usual presentation?

Answer 50

Burkitt = B cell NHL and there are 3 types: 1. **Endemic** - in malaria endemic regios where coinfection with EBV is common, invovles jaw or facial bones 2. **Sporadic** - EBV-assciated 3. **Immunodeficiency related** - linked to HIV or post-transplant

Question 51

What are are benign vs malignat ... bone tumours called? 1. Bone 2. Cartilage 3. Fibrous tissue 4. Bone marrow 5. Vasculature

Answer 51

Benign (1) and malignant (2) 1. Bone - osteoid osteoma vs **osteosarcoma** 2. Cartilage - chondroma/osteochrondroma vs chondrosarcoma 3. Fibrous tissue - fibroma vs fibrosarcoma 4. Bone marrow - eosinophilic granuloma vs **Ewing's sarcoma**/myeloma 5. Vasculature - heamangioma vs angiosarcoma

Question 52

What is the epidemiology of osteosarcoma?

Answer 52

* Most common primary bone malignancy in childhood * More common in males (1.4 : 1) * Mostly occurs after puberty at ages 10-25 (and \>60 as a complication of Paget's)

Question 53

Which part of the bone does osteosarcoma usually affect?

Answer 53

Sites of rapid bone growth i.e. metaphysis or diaphysis of the distal femur, proximal tibia and proximal humerus. 75% of cases are around the knee

Question 54

What are the presenting features of osteosarcoma?

Answer 54

Progressive pain but often presents painless Pain at night Soft tissue or bony swelling

Question 55

What investigations are done to diagnose osteosarcoma?

Answer 55

_Bedside_: _Bloods_: FBC, U&E, coagulation and CRP to exclude multiple myeloma, osteomyelitis; LDH (exclude secondary tumours), raised ESR, bone profile (ALP raised in osteoblast activity in osteocsarcoma), Ca (high in multiple myeloma and metastatic disease). **_Imaging_**: **plain radiograph** (but cannot exclude), **MRI** for soft tissue extension (GOLD STANDARD), **radionucleotide bone scan** (shows malignant/metastases due to high metabolic activity) + **CT** (CAP for metastases), _Invasive_: biopsy (must refer to bone sarcoma MDT first - only 5 centres in UK).

Question 56

What is seen on XR in osteosarcoma?

Answer 56

'Sunburst' appearance in soft tissue as it calcifies Combination of bone destruction and formation

Question 57

How do you distinguish between malignant and benign bone lesion on plain radiograph?

Answer 57

Question 58

What is the management of osteosarcoma?

Answer 58

Refer to a sarcoma multidisciplinary team (MDT) Principles of treatment: * **Limb sparing surgeries:** local excision and wide excision. * **Radical surgeries:** resection with prosthetic replacement and amputation with prosthetic replacement. * **Adjuvant chemotherapy** (pre and post operative) and **radiotherapy**

Question 59

What are the complications of osteosarcoma (untreated and treated)?

Answer 59

Untreated: * Pain, peripheral nerve and vessel compression * Pathological fractures * Metastasis * Hypercalcaemia Treatment-related (surgical): * Pain, loss of function, neurovascular damage * Blood clots, bleeding, infection * Scarring, swelling, stiffness * Failure of prosthesis

Question 60

Where does osteosarcoma metastasise to?

Answer 60

Lung (rapidly)

Question 61

What is the prognosis with osteosarcoma?

Answer 61

Localised - 70% 5-year survival Metastatic/recurrent - \<20% survival

Question 62

What are poor prognostic factors in osteosarcoma?

Answer 62

* Primary metastases * Axial/proximal involvement * Large tumour volume * Elevated serum ALP * LDH raised * Older age

Question 63

What is Ewing's sarcoma?

Answer 63

Primary neuroectodermal tumour arising from mesenchymal stem cells which mostly occurs in adolescents and has a male predominance. Occurs in bone extramities, pelvis, ribs and vertebrae and presents with mass/swelling. Diagnosed similarly to osteosarcoma but chemotherapy is usually first line treatment (VIDE) +/- radiotherapy +/- surgery. Survival rates similar to osteosarcoma.