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Childhood Cancer

Wendy Woods-Swafford MD, MPHPediatric Hematology Oncology

Blank Children’s Hospital

Housekeeping

• I have no financial disclosures

Goals and ObjectivesUpon completion of the program,

participants will be able to:• Recognize the most common

cancers of childhood• Be familiar with the clinical

presentation and initial evaluation of childhood cancers

• Recognize current treatment options and prognosis

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Cancer

“Cancer” is not one disease, but over a

hundred different diseases

Childhood cancers are different in many ways from adult cancers

Facts

• Each Year:• 1.5 Million people are diagnosed with cancer

• 0.5 million people die from cancer

• 5 year survival rates:• 65% for adults

• 80% for children

First Take Home point

• Childhood Cancer is a rare disease…

New Cases of Cancer in the U.S. in 2003

105,000125,000130,000

12,500

0

20000

40000

60000

80000

100000

120000

140000

Breast Lung Prostate ChildhoodCancers

Cancer Type

Nu

mb

er

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Impact

• One in every 330 Americans develops cancer before age 20

• ~ 46 U.S. children & adolescents are diagnosed with each day

• We will see >450 cancer patients each year; more than 50 will have a new cancer diagnosis

Mortality

• Over 3,000 children die from cancer yearly in the U.S.

• > than deaths from AIDS, asthma, diabetes, and cystic fibrosis combined

Long Term Impact

• 1:750 20-year-olds alive in the U.S. today is a survivor of childhood cancer

• 3 out of every 5 children diagnosed with cancer suffer from long-term or late onset side effects

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Common Childhood Cancers Birth – 14SEER Data 2012

Estimated New Cases of Childhood and Adolescent

Cancers in the US

Journal of Clinical Cancer Research 2014

Incidence Trends By Site1975-2010

Source: SEER 9

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Trends in Mortality RatesAge 0-19;1975-2010

How Do We Treat …

• State of the Art Care, offered to every patient, every time

• Cooperative Group Studies• Children’s Oncology Group

• The World’s Cancer Experts

Causes of Childhood Cancers

• The causes of childhood cancers are largely unknown• Specific chromosomal/genetic abnormalities,

and ionizing radiation exposures explain only a small percentage of cases

• Environmental causes of childhood cancer have long been suspected by many scientists but have been difficult to pin down

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Known Causes

• Familial/genetic diseases associated with increased cancer risk

• Neurofibromatosis• Familial polyposis• Li-Fraumeni syndrome

• Major categories of diseases linked with an increased cancer risk include

• Immune deficiencies• Metabolic disorders• Disorders of chromosome stability

General Points

• Signs and symptoms of cancer are relatively non-specific and mimic a variety of more common childhood problems

• For an oncologist the index of suspicion for cancer is high

• For a primary care providers the opposite is true

• You have to think about the possibility of cancer before you can make the diagnosis

Disease Presentation

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CNS Malignancies

• Brain tumors comprise 20% of the malignancies in childhood

• Brain tumors are the most common solid tumor of childhood

Signs and Symptoms

• Headache, even vague

• Nausea and vomiting• Abnormal behavior• Eye changes• Head tilt• Nuchal rigidity• Seizures

• Ataxia • Anorexia• Developmental Delay• Loss of milestones• Macrocephaly• Sunset sign• Diencephalic

syndrome

Diagnostic Evaluation

• Detailed H&P, including neurological exam

• Diagnostic imaging

• CT, MRI, MRA MRS

• Tissue Diagnosis

• Surgical biopsy or resection

• CSF cytology

• Metastatic evaluation (when indicated)

• CSF evaluation

• Bone scan

• Bone marrow aspirates

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Symptoms

• Directly related to location of tumor

• Rate of growth

• Compression or infiltration of normal tissue

Increased Intracranial Pressure

• Secondary to obstruction of the ventricular system

• Classic triad• AM headaches

• Lethargy

• Nausea and vomiting

• 80% of midline tumors are associated with hydrocephalus

Anatomy Review

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Brain Tumor Locations

• Supratentorial• 30-50%

• Infratentorial• 50-60% of pediatric brain tumors are located

in the posterior fossa

• Midline• 10-15%

Supratentorial Tumors

• Anaplastic astrocytomas• Optic pathway gliomas• Hypothalamic tumors• Craniopharyngiomas• Glioblastoma multiforme

Presentation of Supratentorial Tumors

• Headache is the most common symptom

• Seizures (35-40%) • Generalized tonic clonic

• More common in LG glial tumors

• Focal motor or sensory deficits• Hemi paresis, Hyperreflexia

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Seizures

• 20-45% of patients with newly diagnosed brain tumor patients develop seizures

Infratentorial Tumors

• Medulloblastomas (33%)

• Astrocytomas (25%)

• Ependymomas (15%)

• Brain stem gliomas (25%)Brain Stem 25%

Cerebellum 60%

Fourth Ventricle 15%

Presentation of Infratentorial Tumors

• Cerebellar (think balance)• Truncal ataxia (midline)

• Appendicular ataxia (hemispheres)

• Brain Stem = Cranial nerve deficits• III, V, VI, VII, and IX

• Pupillary light reflex, EOM, facial muscles, facial sensation, tongue, palate, and gag

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Complications of Surgery

• Oculomotor dysfunction

• Motor paralysis

• Face

• Arm/Leg

• Swallowing Dysfunction

• Dysmetria

• Truncal ataxia

• Gait ataxia

The “Little Brain” - Constitutes only 10% of the total volume of the brain but contains more than 50% of neurons-Motor Planning-Coordination of Movements-Motor Learning (repitition)-Attention-Language-Memory-Spatial Ability-Executive Fuctioning

Midline Tumors

• Hypothalamus, thalamus, pituitary, and pineal gland

• Low and high grade astrocytomas

• Germ cell tumors

• Craniopharyngiomas

Presentation of Midline Tumors

• Associated with endocrinopathies• DI

• Excessive weight gain

• FTT

• Premature puberty

• Short stature/Giantism

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Spinal Cord Tumors

• Primary vs. Metastatic

• LG and HG glial tumors

• Ependymomas

• Medulloblastoma/PNET

• ATRT

Presentation of spinal tumors

• Pain

• Extremity weakness

• Loss of bowel or bladder

• Scoliosis

Posterior Fossa & Brainstem Clinical Features

Posterior Fossa primary

• Ataxia

• Tremors

• Dysarthria

• Stiff neck

• Papilledema

Brainstem primary

• Extremity weakness

• Cranial nerve signs• double vision

• facial weakness

• swallowing dysfunction

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Work Up

• CT: 65-95% sensitivity to detect brain tumors

• MRI: with and without contrast

• CSF examination

• Biopsy or preferred excision biopsy/resection

AstrocytomasLow Grade Gliomas

• Astrocytoma is the most common brain tumor

• Grade 1 – “JPA”• Seen in association with

neurofibromatosis, malignant by location

Treatment - Surgery

• In general, needed for diagnosis

- exceptions: GCT, BSG

• Gross total resection

Balance prognosis vs. morbidity

• Debulking, shunts, reservoirs

- for symptom/ICP reduction, therapy

• Greatest impact on outcome

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Treatment – Radiation Therapy

• Potential for use in all brain tumors• exceptions: choroid plexus tumors

• Neuro-axis prophylaxis (cranio-spinal rx)• if tumor disseminates via CSF

• Concerns for long term effects• neuro-cognitive• hearing• secondary cancers• endocrine• skeletal growth

Therapy - Chemotherapy

• Adjunct therapy in most cases• particularly in GCT, medulloblastoma

• Of interest in young children • (avoid or prolong XRT)

• Blood brain barrier may be limiting• Newer studies suggest this may not be so

• Local delivery via pumps/reservoir/IT

• Vaccine Therapy

Prognosis• Astrocytoma

• Low grade: 50-80% EFS

• High grade: OS 0-30%

• Medulloblastoma

• Standard risk 70-80% 5 yr survival

• High risk 50%

• Ependymoma

• Near to gross total resection 50-75%

• Less than NTR 0-30%

• Brain Stem Gliomas

• <9 months, 90% by 2 years

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Brain Tumors

• Leading cause of morbidity and mortality in pediatric cancers

• Survivorship does not come without significant cost

Case WT

• 4 year old child is brought in because he has become “constipated” as per mother

• Mother noticed that his belly is hard and seems larger than usual

• On exam, you find a asymptomatic, healthy appearing child with a very large distended abdomen. His abdomen is tender to palpation and you note his blood pressure was elevated at check in.

History

• Hypertension, gross hematuria, and fever in 5-30% of the patients.

• A small number of patients who have hemorrhaged into their tumor may present with signs of hypotension, anemia, and fever.

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CT Scan concerning for WilmsTumor

Differential Diagnosis

• Kidney tumors: Wilms, clear cell sarcoma • Kidney diseases: polycystic kidney disease,

dysplastic kidney, renal thrombosis, hydronephrosis

• Neuroblastoma• Rhabdomyosarcoma• Liver tumors such as sarcoma or

hepatoblastoma• Lymphoma

Wilms’ Tumor

• 2nd most common abdominal malignancy in children

• WT1 is a tumor suppressor gene that is critical for normal renal development; Mutations in WT1 predispose to embryonal tumor formation

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Incidence and Etiology

• Renal tumors represent 5-6% of pediatric cancer; • 460 new US cases/yr

• Higher in AA, lower in Asians• Peak age at 2-3; rare in kids >5

Wilms Tumor Associations

• Anomalies & Syndromes • Hemihypertrophy

• Aniridia

• Denys-Drash Syndrome• GU anomalies and renal failure

• Beckwith-Wiedemann Syndrome

Physical Exam

• Large palpable abdominal mass• Examination

• abdominal exam should be performed carefully

• palpating a mass too vigorously could lead to rupture of a large tumor

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Staging of Wilms Tumors

I Limited to kidney; complete resection

II Extent beyond kidney, but complete R

III Residual tumor, confined to abdomen

IV Hematogenous mets (lung, liver, bone, brain) or lymph nodes outside abdomen

V Bilateral renal involvement at diagnosis

Tumor spill at time of surgery – considered stage III

Evaluation:CBC, CMPCT Abdomen (Assess of renal function prior to giving contrast)Chest Xray and CT chestAbdominal Ultrasound

Treatment

Stage, Histology Surgery Chemotherapy Radiotx

Stage I,II with FH

Stage I with anaplasia

Nephrectomy Vincristine

Dactinomycin

None

Stage III or IV with FH

Stage II,III or IV with anaplasia

Nephrectomy Vincristine

Dactinomycin

Doxorubicin

Yes

Stage II, III and IV diffuse anaplasia

Nephrectomy Vincristine

Dactinomycin

Doxorubicin

Etoposide

Yes

Stage II,III,IV RTK Nephrectomy Cytoxan

Etoposide

Carboplatin

Yes

Prognosis

• 80-90% survival with current multi-modal therapy

• When bilateral tumor 70-80% survival if synchronous

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Case RB

• You are seeing a 6 month old female at her well child exam and notice her right pupil appears white

• Referral to an ophthomologist reveals loss of vision and increased intracranial pressure

• She has …

Retinoblastoma• 1% of all childhood cancers

• 80% occur in children <3

• 30% are bilateral

• Loss of both alleles of the RB gene

• 60% spontaneous, 40% hereditary

• Tx: radiation, chemotherapy, enucleation

• 85% long term survival

Case NB

• 11 month old male presents with distended abdomen and juandice

• Laboratory evaluation reveals normal CBC, but elevated LFT’s, amylase and lipase and total bilirubin >40

• US of abdomen reveals large calcified mass in RUQ

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Neuroblastoma

• Location: any neural crest tissue • Adrenal• Paraspinal sympathetic tissue

• Cervical, Thoracic, Pelvic• Often metastatic at diagnosis

• Bone and/or bone marrow• Lymph nodes• Skin• Liver

Signs and Symptoms

• Signs of metastatic disease• Irritability• Weight loss• Bone pain• Fever

– Proptosis

– Bone lesions

– Periorbital ecchymoses

–“Racoon Eyes”

Clinical Presentation

• Large Abdominal mass• Often crosses midline

• Lower extremity weakness • Spinal cord compression

• Cervical, high thoracic mass• Horner’s syndrome

• Miosis, ptosis, anhydrosis

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Neuroblastoma Take Home

• Most common extra-cranial solid tumor in children

• 75% of children < 4 years of age (Average age 18M)

• Findings of abdominal mass, pallor, weakness, bone pain, fever and weight loss

• Treatment includes chemotherapy, surgery radiation, stem cell transplant

• Poor Prognostic Indicators• Age >18 months

• Myc-N amplification

• Unfavorable Histology

Neuroblastoma Staging

1 Localized tumor; complete excision

2A Unilateral, incomplete gross resection; negative microscopic nodes

2B Unilateral, positive ipsilateral nodes; negative contralateral

3 Across midline, or contralateral nodes

4 Dissemination: bone marrow, liver, skin, bones

4S <1y: local stage 1-2, with mets to BM, liver, skin

Clinical Evaluation:Urine Catecholamines: HVA, VMAImaging Studies: CT, bone scan, MIBG

scanBone Marrow BiopsiesLymph Node evaluation

Survival

• Stage I : 90%

• Stage II : 75%

• Stage III: 40-70%

• Stage IV: 60% if < 1 yr, 30% in ages 1-2, and 20% in those >2 yrs

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Case RMS

• 4 year old female presents with large abdominal mass causing bowel and bladder obstruction

• CT of chest reveals metastatic lung nodules and bone scan reveals several boney metastasis

Presentation of Soft Tissue Sarcomas

• Rhabdomyosarcoma • Age

• Birth to > 20 y/o• 70% < 10 y/o

• Sites• Head and neck – 40%• Genitourinary – 20%• Extremities – 20%• Trunk – 10%• Retroperitoneal – 10%

Signs and symptomsdepend on age and site

Head and neckOrbit

ProptosisPeriorbital swelling

Parameningeal Cranial nerve palsiesHearing lossChronic aural or

sinus drainage

Signs and Symptoms

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• Genitourinary

• Bladder and prostate• Hematuria• Urinary obstruction

• Paratesticular • Painless mass - testicle

• Vagina and uterus • Abdominal mass• Vaginal mass• Vaginal bleeding or discharge

Signs and Symptoms

Botryoid:grape-like

Rhabdomyosarcoma

• 5% of childhood malignancies• Arises from undifferentiated mesencyhmal cells that

differentiate into muscle• Originate anywhere• Incidence peaks between ages 2-6• Multimodal: chemotherapy, resection and local

radiation• Survival

• Stage I (localized w/ complete resection) 74%• Stage II (total resection with regional spread) 65%• Stage III (incomplete resection with gross residual ds) 40%• Stage IV (distant mets) 15%

Case EWS

• 12 year old male fell playing basketball, now has pain and swelling near his hip

• Xray at the local ED showed moth eaten proximal femur lesion

• MRI is obtained

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Ewing’s Sarcoma

• Peaks in ages 11-15• Small round blue cell tumor, PNET• More common in males• Present with pain, swelling, frequently

after a sport related injury• Treat with chemotherapy, surgical

intervention with limb salvage and radiation

• Survival 20-70% depending on stage

Case OG

• 19 year old female dancer noticed swelling and pain in her right leg with recent increase in her training

• Plain Xrays show destruction of her distal femur with formation of new periosteal bone

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Treatment

• Chemotherapy and limb salvage• Methotrexate, Doxorubicin, Cisplatinum

• Investigating Ifosfamide/VP-16 & Interferon

• Not radiosensitive

• Survival 20-70% depending on stage

Bone Tumors in Childhood

• Age – Adolescents > younger children• Signs and symptoms

• Bone pain, palpable mass, pain with motion• Often hx of sports injury (coincidental)

Ewing Sarcoma All bones:Long: diaphysesFlatPelvisSkullRibs

Osteogenic SarcomaMetaphyses of long bones:

Distal femurProximal tibiaProximal humerus Pelvis

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Presentation of Bone Tumors

Plain X-Rays are usually abnormal

Ewing:Moth-eatenlytic lesion

Osteosarcoma:“Sunburst pattern”Periosteal reactionSoft tissue mass + calcium

Conclusions

• Nearly 80% of children diagnosed with cancer will be cured of their disease

• Adult survivors of childhood cancers are growing in number

• Although childhood cancer is “rare”, it will affect your practice of medicine

Acute Lymphoblastic Leukemia (ALL)

• Most common malignancy in childhood• Accounts for 1/3 of all childhood cancers• Peak age 2-5 years• 30 cases per million population• More common in Caucasian than in

African American populations• More frequent in males than in females

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ALL Pathogenesis

• A lymphoid progenitor cell becomes genetically altered and undergoes dysregulated proliferation and clonal expansion

• Altered expression of genes whose products contribute to the normal development of B cells and T cells

ALL

• Thought to arise in the bone marrow, but, at presentation, leukemic blasts may be present anywhere, including the liver, spleen, lymph nodes, testes, CNS.

Leukemia: Signs and Symptoms

• Bone marrow infiltration

• Anemia• Pallor, lethargy• Dyspnea, murmur

• Platelets• Bleeding, petechiae, purpura

• Neutropenia• Fevers and infections

• Bone pain• Limp, walking, irritability

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Leukemia: Signs and Symptoms

• Extrameduallary Disease• Lymphadenopathy

• Hepatosplenomegaly

• Orthopnea, cough • mediastinal mass

• tracheal compression

• Facial nerve palsy

• Testicular enlargement

• Skin lesions

• Gingival hypertrophy

• Fever of Malignancy

Monoblastic leukemia

The Complete Blood Count

• Very helpful in the diagnosis of Acute lymphoblastic leukemia• 50% will have WBC • 80% will have lymphoblasts on the peripheral smear • 95% will have 2 Cytopenias• Only 4% will have 1 cytopenia• Only 1% will have a normal CBC and differential

Is it always leukemia?

NO! COMMON THINGS ARE COMMON!• Mononucleosis (EBV)• Acute anemia• Parvovirus B19• Idiopathic thrombocytopenia (ITP)

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Acute Lymphocytic Leukemia

• The most common cancer diagnosed in children• 23% of cancer diagnoses among children < 15

years

• ~ 2,400 children and adolescents younger than 20 years are diagnosed with ALL each year

• ALL peaks in incidence among children aged 2-3 years

• Incidence of ALL is substantially higher in white children than in black children but it is highest in Hispanic children

ALL continued

• Children with Down syndrome have an increased risk of developing both ALL

• The primary accepted nongenetic risk factors for ALL are prenatal exposure to x-rays and postnatal exposure to high doses of radiation

ALL Outcomes

• More than 95% attain remission • 75% to 85% survive free of leukemia

recurrence at least 5 years from diagnosis

• Late effects of treatment • Osteonecrosis, Osteopenia• Neuropathies• Neuropsychometric concerns• Obesity

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Acute Myeloid Leukemias

• Spectrum from AML to JMML/CML and MDS

• Prognostic Indicators

• Age, Race

• Cytogenetics

• Treatment: Cytarabine, Dauno, VP-16 + BMT

• Outcome: EFS remains at approximately 50%

• Late Effects: Cardiac toxicity, 2nd malignancies, endocrinopathies, etc

Distribution of Lag Time in Days by Diagnosis of Common Childhood CancersDiagnosis n Mean Median 25th % 75th %

Brain 194 211 93 38 237

Ewing’s 82 182 127 79 255

Hodgkin’s 143 223 136 49 270

Leukemia 908 109 52 20 129

NHL 184 117 62 25 141

NBL 237 120 58 15 164

OS 67 127 98 40 191

RMS 126 127 55 25 161

Wilms’ 223 101 31 9 120

Table 7-1. Pizzo & Poplack, 4th ed.

Symptoms/Signs Laboratory, imaging studies, & consultations

Major associated tumors

Hypertension CXR, Abd US Renal or abdominal tumor, NBL

Weight loss, sudden onset Abd US Any malignancy

Petechiae CBC, manual diff Leukemia, NBL

Adenopathy unresponsive to ABs

Surgical consultation, CXR, CBC, manual diff

Leukemia, Lymphoma

Endocrine abnormalitiesGrowth failure

Electrolyte disturbances

Sexual abnormalities

Cushing’s syndrome

Hormonal assays

CT hypothalamic area

Abdominal CT

Endocrine consult

Pituitary tumors

Hypothalamic tumors

Gonadal tumors

Adrenal tumors

BrainHeadache, early AM vomiting

Cranial nerve palsy, ataxia

Dilated pupil, papilledema

Afebrile seizures

Hallucinations, aphasia

Unilateral weakness, paralysis

Neurology and/or Neuro-Surgery Consultation followed by Imaging Studies

Brain Tumor

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Symptoms/Signs Laboratory, imaging studies, & consultations

Major associated tumors

EyesWhite Spot, proptosis, blindness

Wandering Eye

Intraorbital hemorrhage

Ophthalmologic consultation Retinoblastoma, metastatic neuroblastoma,rhabdomyosarcoma (RMS), or other STS

EarsBulging mass external canal

Mastoid tenderness, swellingCBC, diff, Imaging studies

LCH, RMS

Puffy face & neck CBC, diff, imaging studies Mediastinal tumors

Pharyngeal mass CBC, diff, imaging studies RSM, lymphoma, naso-pharyngeal carcinoma

Periodontal mass, loose teeth

Dental consultation, imaging studies

LCH, Burkitt’s lymphoma, neuroblastoma, osteosarcoma

ThoraxExtrathoracic: mass

Intrathoracic: coughing, SOB without fever or no history of asthma, allergies

CBC, diff, imaging studiesSoft tissue tumors, mediastinal tumors, metastatic tumors

Symptoms/Signs Laboratory, imaging studies, & consultations

Major associated tumors

Abdomen/Pelvis

Intra-abdominal mass

Abd US; CBC, diff Wilms’ tumor, soft tissue sarcoma, neuroblastoma, hepatoblastoma, hepato-cellular carcinoma

Genitourinary

Testes, vaginal mass

Masculinization / feminization

UA, CBC, diff

US of abdomen/pelvis

Germ cell tumor, RMS, adrenal tumor

Musculoskeletal

Soft tissue, bone marrow, and/or pain

CBC, diff

Imaging studies

Osteosarcoma, Ewings sarcoma, leukemia, neuroblastoma, soft tissue sarcoma

References

• Information and tables, for the most part, taken from the SEER monograph on Childhood Cancer • Cancer Incidence and Survival Among Children and Adolescents:

United States SEER Program http://seer.cancer.gov/publications/childhood/

• Other tables taken from Gurney JG & Bondy ML, “Epidemiology of Childhood Cancer”, in Principles and Practice of Pediatric Oncology, 5th ed, Pizzo PA and Poplack DA, eds, LWW, 2005.

• Childhood and Adolescent Cancer Statistics, 2014 Journal of Clinical Cancer ACS