Table 21CANCER IN CHILDREN AND YOUNG PEOPLE: signs and symptoms, including risk factors

AuthorSettingDescriptionNo.InclusionExclusionResultsGold StdQuality
Abramson et al 1998Hospital. USARetrospective study to describe the presenting signs of retinoblastoma1265 childrenChildren with a diagnosis of retinoblastomaThirty-two distinct presenting signs of retinoblastoma were identified, the most common of which were leukocoria (56.2%), strabismus (23.6%), poor vision (7.7%) and family history (6.8%).
Leukocoria, the most common presenting sign, was associated with more advanced disease (p<0.005). Strabismus correlated strongly (p<0.005) with macular involvement. All eyes with strabismus proved to have either tumour in the macula or a retinal detachment at the macula. No statistically significant correlation was found between laterality, sex or race and any presenting sign or between survival and any intraocular presenting sign.
Retrospective. Very large study.
D0H, Referral guidelines for suspected cancer 2000National guidelines based on expert opinions and consensus, after consideration of the limited evidence availableLeukaemia:
Often present with relatively short history (weeks) with pallor, fatigue, irritability, fever, bone pain and bruising/petechiae. 70% have hepatosplenomegaly; >50% have lymphadenopathy.
Brain::
headache (65–70%), vomiting (65–70%), changes in mood/personality (45–50%), squint (20–25%), deterioration in school performance (20–25%), growth failure (20%), or in infants, rapidly increasing head circumference Lymphomas:
Hodgkin’s disease: usually presents with non-tender cervical/supraclavicular lymphadenopathy. Natural history is long (months). Only minority have systemic symptoms.
Non-Hodgkin’s lymphoma: lymphadenopathy and/or disease in mediastinum or abdomen. Rapid progression of symptoms.
Neuroblastoma:
Majority have symptoms of metastatic disease. Infants <1yr may have localised abdominal or thoracic masses; very young infants (< 6 months) may have rapidly progressive intra-abdominal disease. Wilms’ tumour (nephroblastoma)
Unilateral abdominal mass +/− pain.
Haematuria (rare)
Soft tissue sarcoma
Mass at almost any site
Bone tumours
Limbs are most common sites. Persistent localised bone pain.
Retinoblastoma
Family history (in approximately 15% cases). White pupillary reflex. Squint Gonadal tumours
Testicular/paratesticular masses can be difficult to differentiate – any non transilluminable mass associated with the testis is significant. Ovarian tumours can be associated with precocious puberty. abnormal blood count If reported as requiring urgent further investigation.
Petechiae/purpura.
Fatigue in a previously healthy child when combined with either of the following: generalised lymphadenopathy, hepatosplenomegaly.
Bone pain especially if it is: diffuse or involves the back, persistently localised at any site, requiring analgesia, limiting activity.
Lymphadenopathy: non tender, firm/hard and >3 cms in maximum diameter progressively enlarging associated with other signs of general ill health, fever and/or weight loss involves axillary nodes (in the absence of any local infection or dermatitis)or supraclavicular nodes seen as a mediastinal or hilar mass on chest x-ray (particularly if no evidence of previous local infection)
Headache of recent origin with one or more of the following features increasing in severity or frequency noted to be worse in the mornings or causing early wakening associated with vomiting associated with neurological signs (e.g. squint, ataxia) associated with behavioural change or deterioration in school performance.
Soft tissue mass: any mass which occurs in an unusual location particularly if associated with one or more of these: shows rapid or progressive growth -size > 3 cms in maximum diameter fixed or deep to fascia associated with regional lymph node enlargement
Nationally recognised guidelines, but no explicit link between the limited evidence base and the consensus recommendations
Dobrovoljac et al 2002Childrens’ hospital. SwitzerlandRetrospective study to identify factors related to delays in diagnosis252 childrenChildren admitted with primary brain tumoursIntiial symptoms were (in decreasing order of frequency) headache, nausea/vomiting, seizures, behavioural changes, ataxia, squint/diplopia, lethargy, hemiparesis/quadriparesis, head tilt, anorexia, growth failure, sleep disturbance, polyuria/polydipsia, visual loss, weight loss, facial nerve palsy, enlargement of the head, cranial neuropathies other than III, IV, VI, VII, gaze depression/separation of cranial sutures/bulging fontanelle, dizziness, nystagmus, papilloedema, amenorrhoea, proptosis. Symptoms and frequencies changed when analysed by age of the childRetrospective. Large study. Symptoms at initial presentation described.
Farwell at al 1984Community – regional tumour registry. USARetrospective study of CNS tumours in adolescents compared with younger children144 adolescentsChildren aged 13 to 19 yrs with diagnosis of CNS tumour (intracranial or intraspinal)Presenting symptoms included those that resulted from increased intracranial pressure as well as those that were local effects of tumours. The most common symptoms were headache (N=65), nausea or vomiting (N=53) and diplopia (30). Visual disturbances such as blurred vision (N=18), dim vision or field deficits were next in frequency followed by ataxia (N=15) and then mental status change (N=8) or longstanding retardation. Less common symptoms included paresis (N=7) and vertigo (N=7). At the time of diagnosis, papilloedema was present in 41 patients.Retrospective. Population based.
Farwell et al 1978Community – regional tumour registry. USARetrospective study of intracranial neoplasms, including presenting symptoms54 infantsInfants ≤18 months at diagnosis of intracranial neoplasmnfants presented at diagnosis with vomiting (47%), increasing head size (32%), lethargy (19%), convulsions (13%), paresis (9%), cranial nerve palsies (9%) and ataxia (6%). The physical findings at diagnosis indicated that 20 patients had an increased head circumference. A bulging fontanelle was reported in 12 cases (27%). Eleven infants (25%) had cranial nerve palsies. Papilloedema (16%) and nuchal rigidity (16%) were each seen in seven instances. Two patients (4%) were comatose and another five (16%) had a diminished level of consciousness. Other findings included ataxia (7%), nystagmus (11%), hemiparesis (9%), hyperreflexia (16%), hypertonia (9%), irritability (6%), hyptonia (11%), extracranial masses (4%) and hyperalertness (6%). Vomiting was the only symptom, besides enlargement of the head that occurred in more than six children. The loss of a previously acquired skill such as rolling over, sitting or crawling was a symptom observed in seven patients, and in two of these, it was the only symptom in addition to abnormal growth of the head. The physical findings were more varied than the symptoms. Nearly half of the children had an increased head circumference, often accompanied by a bulging fotanelle or prominent veins over the scalp. Papilloedema was noted in two children. Cranial nerve palsies occurred in infants with tumours in all locations. However, nystagmus occurred in cerebral hemisphere or brain stem tumours only and was not found in cerebellar tumours.Retrospective. Population based.
Flores et al 1986University hospital;. USARetrospective study to compare time to diagnosis in children with primary brain tumours, Wilms’ tumour, or leukaemia79 childrenChildren diagnosed with primary brain tumoursCommon presenting symptoms and signs in children with brain tumours were ataxia and abnormalities in gait observed in the zero to five year old patients. Headaches were described more frequently in the six to 20 year old age group. Seizures were observed in the six to 20 year old group, while none were recorded among children 0 to 5 years of age. Nausea and vomiting frequently occurred in all groups.Retrospective
Golden and Feusner 2002Children’s hospital. USARetrospective study to give guidance on evaluation and diagnosis of malignant abdominal masses in children150 childrenChildren diagnosed with malignancy of the abdomenOf children either younger than one year or older than ten years, 26% (11/43) had normal abdominal examinations at diagnosis, compared with only 9% (7/78) of all the remaining children. The authors investigated how these masses were characterised on physical examination. Not all children had every aspect of their masses described fully, but patterns could be identified: 70% (49/70) were distinguished as nontender, 79% (11/14) were recorded as being nonmobile, and at least 87% (61/70) were firm. Not all malignant masses were defined as nontender.Retrospective.
Hasle 2001Narrative review of malignancies in children with Down’s syndromeOverall risk of cancer was not significantly increased in individuals Down’s syndrome. However, the distribution of tumour types in Down’s syndrome differed from the pattern in non-Down’s children. Leukaemia constituted 95% of cases of cancer in children with Down’s but only 34% of non-Down’s children.Narrative review.
Honig and Charney 1982Children’s hospital. USARetrospective stuffy to establish practice guidelines105 childrenChildren with a final diagnosis of brain tumourHeadaches were occipital in location in 16 children (28%), unilateral in 13 (22%) and diffuse in 29 (50%). 32 children (67%) were either awakened from sleep by the pain or were in pain on arising. Eight of 61 children had unusually severe or prolonged headaches and 19 (31%) had changes in headache frequency or severity. Vomiting was described as intermittent in 26 of 72 (36%), daily in eight of 72 (11%) and pernicious in two of 72 (3%). The vomiting was described as intermittent in 26 of 72 (36%), daily in eight of 72 (11%) and pernicious in two of 72 (3%). The vomiting increased in frequency (four patients) or first began (11 patients) following the onset of the headaches in 15 of 72 children (21%). In nine of these 15, the change coincided with increased frequency or severity of the existing headache pattern. Five patients were vomiting prior to the onset of their headaches.
68 children (94%) with headaches had neurologic and/or ocular signs at the time of diagnosis. In 60 of these, signs developed following the onset of their headaches. Thirty-three of 60 (55%) had findings within two weeks and 51 (85%) had an abnormality on physical examination within two months of the onset of their headaches. Within four months, 53 of 60 (88%) had neurological and/or ocular signs. The numbers of patients with ocular signs and symptoms were papilloedema (42), diplopia (11), decreased acuity (8), squint (9), nystagmus (5), optic atrophy (4), blurred vision (3), blindness (2), failure of upward gaze (2), anisocoria (1), optic atrophy on side of tumour and papilloedema of the opposite disc (1).
Retrospective.
Jonsson et al 1990Children’s medical centre. USARetrospective study to assess relationship between bone pain and haematological findings at diagnosis of acute lymphoblastic leukaemia (ALL)296 childrenChildren diagnosed with ALLHaematologic indices were relatively normal in patients presenting with musculoskeletal signs and symptoms as prominent presenting manifestation. Patients with prominent bone pain could experience diagnostic delay because haematological values appeared normal. Haemoglobin and platelets were higher, blast cell and leucocyte counts lower among children with severe bone pain. Statistically significant differences found between groups for haemoglobin concentration (p<0.001), leukocyte count (p=0.014), absolute neutrophil count (p=0.001), percentage circulating blast cells (p=0.009) and platelet count (p<0.001).Retrospective. Not primary care population based. Large study.
Jooma et al 1984Children’s hospital. UKRetrospective study to analyse cases of children with intracranial tumours100 infants aged under 1 yrInfants admitted with intracranial tumours.Infants with posterior fossa dermoid tumours, and orbital tumoursMost common symptoms reported by parents were vomiting and alteration of psychomotor development. In 7 patients a febrile illness preceded more specific symptoms of raised intracracranial pressure, whereas in 6 a head injury had recently occurred. A head tilt was noted in 7 infants with infratentorial tumours and in 2 each of the infants with hemispheric and axial lesions. Macrocrania and signs of raised intracranial pressure were recognised in a majority of the children. 10 patients with suprasellar tumours had rotary nystagmus or bizarre eye movements. Behavioural disturbances with irritability, somnolence and indifference to surroundings were commonly reported and were important if combined with loss of a previously acquired motor skill or arrest of development. The following signs were observed in infants: papilloedema (n=36), optic atrophy (n =10), nystagmus or abnormal eye movements (n =22), sixth nerve palsy (n =17), seventh nerve palsy (n =13), altered limb tone (n =35), hemiparesis (n =16), truncal ataxia (n =10), abnormal neck posture (n =20), neck stiffness (n =9).Retrospective.
Keene et al 1999Children’s hospital. CanadaRetrospective study to describe the clinical patterns associated with childhood brain tumours200 childrenChildren aged under 18 years at diagnosis with primary intracranial neoplasm, and lined within the study catchment areaHemispheric tumours occurred in 52 patients. The presenting signs were seizures 60%, headache 37%, vomiting 23%, changes in behaviour or personality 11%, facial asymmetry 9% and visual difficulties 6%. Initial findings on examination included one or more of the following: no abnormalities (51%), hemiplegia 34%, signs of increased intracranial pressure 23%, cranial nerve dysfunction 3% and macrocrania 3%. Supratentorial axial or midline tumours occurred in 50 patients. The presenting signs for tumours arising from axial structures included one or more of the following: non-specific headache 60%, polyuria 35%, non-specific malaise 10%, short stature 10% and visual difficulties 5%. Initial examination at the time of diagnosis included signs of increased intracranial pressure 30%, visual field disturbances 25%, optic atrophy 15% and Parinaud’s sign 15%.
Cerebellar tumours were present in 74 patients. The presenting symptoms included vomiting, headache 62%, and incoordination 55%. The frequency of clinical signs included ataxia 69%, increased intracranial pressure 57%, nystagmus 31%, head tilt 14%, cranial nerve palsies 28% and macrocrania 10%. Brainstem tumours affected 19 children. Patients experienced gait difficulties 83%, squint 50%, headaches 25%, vomiting 25% and swallowing difficulties 8%. The initial examination included findings of cranial nerve VI dysfunction 67%, ataxia 50%, cranial nerve VII dysfunction 42%, nystagmus 33%, hemiplegia 33% and head tilt 33%.
Retrospective. Large study.
Linet et al 2003Review of risk factors for sarcomas, brain and haematological cancersSee tables in full guidelineNarrative review, linked with evidence base
Mag et al 1999University hospital. MalaysiaRetrospective study to describe presenting features and prognostic significance78 childrenChildren ≤12 yrs admitted with new diagnosis of neuroblastomaThe main presenting signs and symptoms in decreasing order were pallor, fever, abdominal mass, weight loss and bone/joint pain. Weight loss was reported in 36% and bone or joint pain in 33% of patients. Other presenting symptoms or signs were bleeding, infection or sepsis, seventh nerve palsy and bilateral leg swelling.Retrospective.
Mehta et al 2002Paediatric neurosurgical centres. CanadaRetrospective and prospective study to determine the tiem required for diagnosis and important associated factors104 childrenChildren ≤17 yrs diagnosed with brain tumour, and lived in the study areaChildren referred from outside the region. Neoplastis lesions that involved the spinal cord/leptomeninges. Children with Neurofibromatosis Type I, and only an optic pathway tumour that did not need treatment9 children (66%) exhibited vomiting or nausea as a presenting symptom. Nine of those children did not experience associated headaches. Five of these nine patients experienced vomiting for more than one month. 66 of the children (63%) complained of headaches or exhibited behaviour that indicated its presence (such as clutching the head). 37% (seven of 19) children less than four years of age exhibited behaviour that could be positively confirmed as indicating headaches. Among older children, 76% (28 of 37 children) and 67% (31 of 46 children) of those four to eight and nine to 17 years of age respectively had complaints of headaches as one of their presenting symptoms. Among the 66 children with histories of headaches, 85% (56 of 66 children) exhibited evidence of either nausea or vomiting at some point during their histories.
Many did not experience headaches that increased in intensity, duration or frequency. 23 patients (22%) did not exhibit evidence of headaches, nausea or vomiting. Among these 23 cases, 18 presented with either a seizure or a focal neurological deficit. The most common neurological findings were focal weakness and cranial nerve dysfunction.
Behavioural changes, failure to reach certain milestones and incidental imaging findings were responsible for identification in the remaining five cases. Of the 104 children, 52 exhibited behavioural changes, which were most often described as changes in temperament.
Some prospective element.
Soule and Pritchard 1977Selected review of cases from literature and personal practice (clinic based). USARetrospective study to describe clinicopathologic results in children with fibrosarcoma110 childrenChildren with a diagnosis of fibrosarcoma with histological resultsChildren with revised histological diagnosis. Lesion located in the orbit, dura, or base of the skullThe primary symptom of most patients was that of a mass or swelling in the soft tissues. Most of the lesions were enlarging, and with the exception of the congenital tumours were known to have been present from a few weeks to four years. Four patients first complained of discomfort or pain before a tumour was apparent. In some the skin had become tense, shiny and red. One congenital lesion became ulcerated and exhibited partial destruction of the adjacent tibia and fibula by the 13th day of life.Retrospective. Selected cases from literature.
Stiller 2002Narrative review of the epidemiology of cancer in adolescentsThe risk of both acute lymphoblastic leukaemia and acute non-lymphocytic leukaemia throughout the age range 5–29 years among people with Down’s syndrome is approximately 10 times that in the non-Down population. Down’s syndrome also appears to be associated with an increased risk of germ cell tumours of the testis and brain and possibly of other sites but the risk of most other solid tumours is lower than in the general population. Neurofibromatosis carries an increased risk for central nervous system tumours and soft tissue sarcomas.
The considerable variation in the incidence of Ewing sarcoma, with its extreme rarity among black and east Asian populations suggesting a strong genetic component to its aetiology. The risk of Hodgkin’s disease in adolescents and young adults who have an affected sibling is approximately seven times that in the general population. Epstein-Barr virus has a role in the development of some cases, though its relations with histologic subtype, age and ethnic group are complex. Hodgkin’s disease is more common among adolescents in populations of higher socio-economic status.
The thyroid gland is especially sensitive to the carcinogenic effects of ionising radiation, with the highest risk for young age at exposure; the excess risk of thyroid cancer persists for at least 40 years after irradiation.
Narrative review,
Thulesius et al 2000Community - regional tumour registry. SwedenRetrospective study to describe the diagnostic process of childhood malignancies, from initial symoptoms until diagnosis and treatment.68 childrenChildren with tumours reported to the regional tumour registryExcluded if tumours could not be classified as malignant, disease was congenital, child diagnosed outside the study area, or incomplete recordsInitial symptoms were for Leukaemia (in decreasing order of frequency) fatigue, upper respiratory tract infection, fever, abdominal pain, joint pain, lympadenopathy, headache, anorexia Brain tumours (in decreasing order of frequency) headache, vomiting, visual problems, convulsions, other neurological symptomsRetrospective. Small sample, But primary care perspective.
Tomita and McLone 1985Children’s hospital. USARetrospective study to decscribe the distribution of brain tumours, their presentation and results of treatment100 infantsInfants diagnosed with intracranial tumours in the first 24 months of lifeApproximately 50% of group 1 with either infratentorial or supratentorial tumours showed macrocephaly beyond the 95th percentile, whereas 25% of group 2 had macrocephaly. Approximately 72% of the anterior fontanelles of the patients harbouring either infratentorial or supratentorial tumours were full, bulging or tense. Hydrocephalus was almost invariably present in association with infratentorial tumours, but its incidence was less in cases with supratentorial tumours (62%). Papilloedema was infrequent despite the high incidence of hydrocephalus and macrocephaly. The incidence of papilloedema was 26.3% in the cases with infratentorial tumours and 18.4% in the cases with supratentorial tumours in group 1, and was 52.6% and 25.0% respectively in group 2.Retrospective
Wdhe and Widhe 2000Community – national cancer registry. SwedenRetrospective study to identify early symptoms of osteosarcoma and Ewing’s sarcoma149 individualsPeople ≤ 30 yrs with diagnosis of osteosarcoma or Ewing;s sarcomaPeople with tumours in the skull or ribsMost patients consulted because of regional pain alone or in combination with a palpable mass. A palpable mass was reported at the first visit in 40 (39%) of the patients with osteosarcoma and 16 (34%) of those with Ewing’s sarcoma. Four patients with osteosarcoma and five with Ewing’s sarcoma did not report pain at the first medical visit and had a palpable mass only. 21 (21%) of the osteosarcomas and nine (19%) of the Ewing’s sarcomas caused pain at night. 87 (85%) of the patients with osteosarcoma and 30 (64%) of those with Ewing’s sarcoma reported pain related to strain. Intermittent pain at rest was reported by 57 (56%) and 27 (57%) patients respectively. 48 (47%) of the patients with osteosarcoma and 12 (26%) of those with Ewing’s sarcoma related the onset of symptoms to trauma occurring at about the time the symptoms began that were of a similar type and magnitude as those experienced regularly in common sports. Tendinitus was the most common initial misdiagnosis for 32 (31%) of the osteosarcomas. Patients with Ewing’s sarcoma often reported relapsing fever and periods of pain that were followed by few or no symptoms, which misled doctors into believing the condition, was resolving spontaneously.Retrospective. Population based
Wilson and Draper 1974Community – national cancer registry.
UK
Retrospective? study to describe the natural history and prognosis for neuroblastoma487 childrenChildren <15yrs with diagnosis of neuroblastoma with histological confirmationThe signs and tumours were varied because they arose in a range of sites. Up to three symptoms were recorded for each case. Abdominal swelling was most commonly a symptom in the youngest age group, its frequency decreasing with increasing age. The same relationship was evident to a lesser extent for the symptoms of breathlessness and stridor. Conversely, pain was a relatively uncommon symptom in very young children. It was more often reported by older children though this was presumably partly due to the greater ease in eliciting this symptom. Those symptoms related to nerve involvement were also more often reported for older children. There was little difference between the two sexes in the type of symptom reported. The figures reflected the infrequent incidence of abdominal tumours (of the adrenal, abdominal sympathetic ganglia and liver) and thoracic tumours in the youngest age groups while those occurring in the spinal canal and brain were more frequent among older children.Retrospective? Some of the analysis did include data on 152 children without histological confirmation

From: Appendix B, Evidence Tables

Cover of Referral Guidelines for Suspected Cancer in Adults and Children
Referral Guidelines for Suspected Cancer in Adults and Children [Internet].
NICE Clinical Guidelines, No. 27.
Clinical Governance Research and Development Unit (CGRDU), Department of Health Sciences, University of Leicester.
Copyright © 2005, National Collaborating Centre for Primary Care.

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