Wilms Tumor

							   Pediatric Oncology


  Jeffrey S. Dome, MD, PhD
      Chief, Division of Oncology
  Children’s National Medical Center
        Professor of Pediatrics
    George Washington University
School of Medicine and Health Sciences
Outline
 Epidemiology of pediatric cancer

 Common pediatric malignancies

 Chemotherapy

 Oncologic emergencies
Childhood Cancer: Statistics

 Ages 0-15 yr        9000 cases/yr
 Ages 15-19 yr       3700 cases/yr
 Ages 19-21 yr       1500 cases/yr
 Total               14,200 cases/yr

Childhood Cancer Deaths: 2,500-2,800/yr
Cancer is leading cause of disease-related
death in children in United States     SEER
Annual USA Cancer Mortality Rate
Children <15 Years

                        8
                                             Survival rate for
                                             pediatric cancer
Mortality per 100,000




                        6
                                             is now 75-80%!
   Age Adjusted




                        4


                        2




                        1950   1960   1970   1980     1990       2000
Top Pediatric Cancers
(age 0-14)
Histology                 Incidence per million
ALL                             38.7
Astrocytoma/gliomas             18.5
Neuroblastoma                   9.8
AML                             7.9
Wilms tumor                     7.1
Embryonal CNS tumors            6.7
Other CNS/spinal tumors         6.6
NHL                             6.2
Hodgkin lymphoma                5.3
Rhabdo                          5.2     SEER website
Question
Which of the following statements is TRUE about
  pediatric cancer:

A. The overall cure rate is about 50%
B. After HIV infections, it is the second leading
   cause of disease-related death in children in
   the United States
C. Acute myeloid leukemia is the most common
   pediatric cancer
D. All of the above
E. None of the above
Overview of Common
 Pediatric Cancers
Leukemia
ALL                         AML
75-80% of pediatric         20% of pediatric leukemia
  leukemia
                            Peak: 0-2, adolescence
Peak: 2-5 years
                             Treatment:
Treatment:                     -4-6 months duration:
  -2.5-3.5 years duration:     -often includes
  -induction, consolidation,   allogeneic BMT, CNS
  maintenance, CNS             prophylaxis
  prophylaxis
Leukemia

SYMPTOMS AND PHYSICAL FINDINGS
Fever
Bleeding (e.g., petechiae or pupura)
Bone pain
Lymphadenopathy
Hepatosplenomegaly
Testicular enlargement
Leukemia Syndromes
Down Syndrome                   ALL, AML, TMD*
Ataxia telangiectasia           ALL
Wiscott-Aldrich                 AML
Bloom Syndrome                  ALL, AML
Fanconi Anemia                  AML
Neurofibromatosis               AML, JMML


 *TMD-Transient myeloproliferative disease-occurs in 10%
 of Down Syndrome individuals—usually self-resolves
Work-up for Leukemia
•   CBC, differential & platelet count
•   Bone marrow aspiration
         Cytogenetics
         Immunophenotyping
•   Chest x-ray
    • T-cell ALL can have mediastinal mass

•   Metabolic (uric acid, Creatinine, K+, PO4)
    • Monitor for tumor lysis syndrome

•   PT/PTT, fibrinogen, D-dimers
    • AML (particularly APML) can present with DIC
Acute Lymphoblastic Leukemia
                  COG ALL Study Series


100                                                  1996-2000
                                                     (n=3421)
                                                     1989-1995
80                                                   (n=5121)
                                                     1983-1988
                                                     (n=3711)
60                                                   1978-1983
                                                     (n=2984)
                                                     1975-1977
40                                                   (n=1313)
                                                     1972-1975
                                                     (n=936)
20                                                   1970-1972
                                                     (n=499)
                                                     1968-1970
 0                                                   (n=402)
      0   2   4     6   8   10   12   14   16   18

                  Years From Study Entry
Rubnitz et al, Ped Clin North America, 2008
Pediatric Brain Tumors

   Posterior fossa
       • Cerebellar astrocytoma
       • Medulloblastoma
       • Brainstem glioma
       • Ependymoma
       • Atypical teratoid rhaboid

   Suprasellar/pineal gland
       • Germ cell
       • Craniopharyngioma
       • Optic pathway glioma

   Cerebral cortex
       • Gliomas (low or high-grade)
Posterior Fossa Tumor
Supratentorial Tumor
Brain tumors: Signs and Symptoms
 Posterior fossa
      Increased intracranial pressure
      Early morning headaches
      Vomiting (morning)
      Nausea
      Ataxia
      Cranial nerve findings
 Suprasellar/pineal gland
     Hormonal problems
     Changes in visual acuity
     Behavioral problems/school difficulty
 Cerebral Cortex
     Headaches
     Seizures
     Loss of motor function
     Personality changes
Brain Tumor Syndromes

•   Neurofibromatosis Type I (optic pathway
    gliomas)

•   Tuberous sclerosis (giant cell astrocytomas)

•   Li-Fraumeni (gliomas)

•   Gorlin Syndrome (medulloblastoma)
    • Nevoid basal cell carcinoma

•   Turcot Syndrome (medulloblastoma)
    • Familial adenomatous polyposis
Diagnostic Studies

  •   CT (usual first line)

  •   Magnetic resonance (MR)
  •   Biopsy (if possible)
  •   Spine MRI
  •   CSF (look for tumor cells)
Pediatric Brain Tumors: Treatment

•   Treatment varies according to tumor type, typically:

    • Surgery
    • Radiation Therapy
    • Chemotherapy
    • Children <3 years old—special considerations
           due to desire to limit radiation therapy
Pediatric Brain Tumors: Outcomes

•   Medulloblastoma-65-85% survival

•   Cerebellar astrocytoma- 90-100% survival

•   Brainstem glioma- 10% survival

•   Ependymoma- 75% survival

•   Atypical teratoid/rhabdoid- 20% survival
Lymphoma
                 Hodgkin           Non-Hodgkin
Onset of Disease Indolent          Rapid
Age Peak           Adolescence     3-6 & adolescence
Common/site        Cervical LN     Abdomen, mediastinum
Intussusception Rare               Fairly common
Constitutional Sxs Common          Uncommon
Stage              65% localized   33% localized
Med. emergency Unlikely            Likely-tumor lysis
Treatment          XRT ± CT        Combined modality
Hodgkin Lymphoma

  •   Painless enlargement of lymph nodes
      • Cervical 80%, mediastinal 60%

  •   Early nodal spread - late to organ
  •   Rare in child <5 y.o.
  •   Peak : 15 - 30 y.o.; >50 y.o.
  •   Fever, weight loss, night sweats
  •   Biopsy: Reed Sternberg Cells
  •   5-year survival >90%
Hodgkin Lymphoma: Late
Effects
 Second malignant neoplasms- 20% at 20 years
         AML: (4%) within first 10 years of
         diagnosis, chemotherapy, poor
         survival
         Solid tumors (16%): breast cancer,
         bone sarcomas, thyroid carcinoma,
         soft tissue sarcomas

 Fertility

 Cardiopulmonary
Non-Hodgkin Lymphoma

•   Classification
     Lymphoblastic 30%
     Small non-cleaved (Burkitt) 50%
     Large cell, immunoblastic 20%
•   Can arise anywhere
    Abdomen (35%)
    Mediastinum (25%)
    Head and neck (13%)
    Peripheral nodes (14%)
    Other sites

•   5-year survival: 75%
Soft Tissue Sarcomas

• Rhabdomyosarcoma (pre-school/school
  age)
• Non-rhabdomyosarcoma (adolescence)
  • Synovial cell sarcoma
  • Malignant peripheral nerve sheath tumor
  • Fibrosarcoma
  • Liposarcoma
  • Desmoplastic small round cell tumor
Rhabdomyosarcoma
•   Can occur anywhere
    •   Orbit
    •   Paratesticular
    •   Extremity
    •   Pelvis
    •   Vagina
    •   Prostate
    •   Bladder

•   Treat with surgery/chemo/radiation

•   Survival: 70-75%
Germ Cell Tumors
•   Gonadal (adolescents)
      • Germinoma—testes
      • Dysgerminoma-ovaries
•   Extragonadal
    • Yolk sac tumor- sacrococcygeal
    • CNS tumors
    • Mediastinal
•   Tumor Markers
    • AFP: elevated in yolk sac tumors
    • HCG: elevated in embryonal carcinoma
•   Treatment
    • Mature teratomas: surgery only
    • Malignant elements: surgery/chemotherapy
Neuroblastoma

•   Originates from neural crest cells
    • Adrenal (most common)
    • Paraspinal (sympathetic gangion)

•   Most common extracranial solid tumor
•   Most common neoplasm in first year of life
Neuroblastoma: Signs/Symptoms
 •   Abdominal mass with pain
 •   Respiratory distress, dysphagia,
 •         or cough (thoracic mass)
 •   Cord paralysis - bowel, bladder
 •   Bone Pain (distant spread)
 •   Periorbital Ecchymoses (distant spread)
 •   Opsoclonus/myoclonus
 •   Diarrhea (from catecholamine secretion)
Neuroblastoma: Physical Findings
•   Abdominal mass
•   Neurologic deficits
•   Opsoclonus/myoclonus
•   Raccoon eyes
•   Hepatomegaly
•   Skin nodules
•   Horner’s syndrome (anhidrosis, miosis, ptosis)
Neuroblastoma-Workup

 •   CT, MRI, ultrasound of primary
 •   Bilateral bone marrow aspirates/biopsies
 •   Bone scan, MIBG scan
 •   CXR and Chest CT
 •   Urine catecholamines
 •   Tumor for biology studies: MYCN, DNA ploidy,
     LOH 1p, 11q
Neuroblastoma Treatment/Outcomes

  •     Surgery
  •     Chemotherapy
  •     Radiotherapy
  •     Autologous stem cell transplant
  •     Retinoic Acid
      Low Risk Tumors: Survival >90%
      High Risk Tumors: Survival 40%
Wilms Tumor

 •   6% of all pediatric cancers
 •   500 cases/year in North America
 •   Peak 2-4 years old, 90%  10 years old

 •   Bilateral in 5%

 •   Syndromes or congenital anomalies in 10-15%
Beckwith-Wiedemann

                 Hemihypertrophy
                 Organomegaly
                 High birth weight
                 Omphalocele
                 Neonatal
                  hypoglycemia
                 Wilms tumor,
                  hepatoblastoma (5%)
                 11p15 Loss of
                  imprinting
                 IGF2/H19 genes
WAGR Syndrome
             Wilms tumor
             Aniridia
             GU Malformations
                 Hypospadias
                 Undescended testes
             Mental Retardation
             30% chance of
              Wilms
             11p13 deletions
             WT1 gene
Wilms: Clinical features

  •   Asymptomatic abdominal mass
  •   Hypertension (25%)
  •   Hematuria (25%)
  •   Fever (25%)
Wilms Tumor Work-up

•   Ultrasound of abd and IVC
•   CT of abdomen and chest
•   CBC and UA
Wilms tumor therapy

•     Surgery
•     Chemotherapy
•     Radiotherapy
    Survival Rate:
    Favorable Histology- 90%
    Anaplastic Histology- 60%
                 Neuroblastoma      Wilms
Age Peak         2                  2-4
                 90% < 5 Y.O.       90% < 10 Y.O.
Cong Abn.        Rare               10-15%
Stage            70% disseminated   25% disseminated
Metastatic       Liver, LN, Bone    Lung, Bone, Liver
Sites            BM
Constitutional   Frequent           Rare
Symptoms
Clinical         ill                well
appearance
Bone tumors

 •   5% childhood malignancies
 •   Two main types:
     • Osteosarcoma
     • Ewing sarcoma
Osteosarcoma
 •   90% extremities
     • Femur, tibia, humerus
     • Metaphysis

 •   10-20% metastatic disease at diagnosis
 •   Males > females
 •   Pubertal growth spurt
 •   Pain ± swelling
 •   Associated with radiation
Ewing Sarcoma

   •   Can occur in long or short bones
       • diaphysis

   •   Primitive neural tissue
   •   No association with radiation
   •   Rare in Blacks and Asians
   •   Associated with t (11;22) (q24q12)
Evaluation

  •   Plain film of bone

  •   MRI/CT of primary
  •   Chest CT
  •   Bone scan
  •   Bone marrow (Ewing)
  •   Biopsy
Bone Tumors: Treatment

  •   Surgery (limb-sparing)
  •   Radiation (Ewing)
  •   Chemotherapy (Neo-adjuvant)
  •   Survival 70% (localized)
Retinoblastoma
•   70% unilateral/30% bilateral

•   Bilateral associated with hereditary
    predisposition: Rb mutations

•   Presenting feature: leucocoria, eye deviation

•   Treatment
    • Unilateral: enucleation
    • Bilateral: Chemo/laser therapy

•   Survival rate: >95%
Hepatoblastoma
•   Occurs in toddlers/infants

•   Elevated AFP

•   Associated with prematurity, Beckwith-
    Wiedemann Syndrome, Familial
    Adenomatous Polyposis

•   Treatment: surgery, chemotherapy,
    sometimes liver transplant

•   Survival rate: 70-75%
Question 1
11 year old Caucasian boy has had increasing
  pain and swelling over his left thigh over the past
  2 weeks. He is afebrile. His peripheral blood
  count is normal. Radiograph demonstrates a
  lytic lesion in the midshaft of the femur with
  surrounding soft-tissue mass.

  Of the following the most likely diagnosis is:
  A. Leukemia
  B. Aneurysmal bone cyst
  C. Osteosarcoma
  D. Ewings sarcoma
  E. Non-accidental trauma
Question 2
A 4 year old boy presents with bruising, pallor,
    intermittent “achy” pain in the extremities,
    and intermittent low grade fever of 2 weeks’
    duration. Findings on laboratory studies
    include hemoglobin 6.5 gm/dl, WBC
    2,200/cu mm, platelets 30,000.

   Of the following the most likely diagnosis is:
   A. acute lymphoblastic leukemia
   B. transient erythrocytopenia of childhood
   C. infectious mononucleosis
   D. parvovirus infection
   E. ITP
Question 3
A 3-year-old girl is in your office for her annual
   visit. You notice that her blood pressure is
   130/80, pulse is 80 beats/min. A large
   nontender mass is palpated in right upper
   quadrant. Urinalysis is unremarkable except
   for the presence of 7 RBC’s.

The most likely diagnosis is:.
A. Hepatoblastoma
B. Neuroblastoma
C. Pheochromocytoma
D. Wilms Tumor
E. Pyelonephritis
Oncologic Emergencies
Tumor Lysis Syndrome
 Associated with leukemia, non-Hodgkin
  lymphoma
 Caused by lysis of tumor cells and
  release of salts and metabolites of
  purines
 Crystallization of uric acid, xanthine,
  hypoxanthine, calcium phosphate in
  kidneys causes renal failure—patients
  may need dialysis
Management of Tumor Lysis
Syndrome
 Monitor K+, Phosphorous, Calcium, uric
  acid, creatinine frequently (q6-q8 hours)
 Give allopurinol—reduces uric acid
 Hydrate-2X maintenance, no potassium
 Alkalinize urine to prevent formation of uric
  acid crystals
   Keep pH 7-8
   If too alkaline, CaPO4, xanthine, hypoxanthine
    crystals precipitate
 Rasburicase (urate oxidase) can be used
  for patients with high uric acid
Spinal Cord Compression
 Associated with neuroblastoma,
  lymphomas, sarcomas
Spinal Cord Compression:
Presentation
 Back Pain: suspect cord compression
  when pain not relieved in supine position
  or back pain has a radicular component
 Weakness, sensory abnormalities, and
  paresis
 Urinary and fecal incontinence if lesion at
  conus medullaris level
 Paraplegia and quadriplegia can occur
  rapidly
Spinal Cord Compression:
Management
  MRI stat
  Dexamethasone
  Consult neurosurgery and neurology:
    Surgery if diagnosis unknown
    Tumor not chemo/radiation sensitive
    Spine unstable
  Radiation or Chemotherapy
Increased intracranial
pressure
Increased ICP: Presentation
 Headache
 Nausea
 Vomiting
 Parinaud’s syndrome: setting-sun sign,
  large pupils, impaired reflex constriction to
  light but not to accommodation, IV nerve
  palsy
 Cranial nerve palsies, nystagmus
 Personality/behavior changes
Increased ICP: Treatment
 CT or MRI scan
 Dexamethasone
 Consult neurosurgery—may need VP
  Shunt or tumor removal
Fever/Neutropenia
 Definitions
   Fever: temperature of 38.3o C (101oF) taken orally
    once or a temperature of 38.0o C (100.4o F) persisting
    for one hour or more

   Neutropenia: absolute neutrophil count less than
    500/ul or less than 1000/ul when counts are falling.
    Patients typically neutropenic 5-10 days after receiving
    chemo

 Associated with life-threatening infections
      Gram negative and positive organisms
Management of Fever
 Get CBC: assess whether patient is
  neutropenic
 Draw blood culture—one from each
  lumen
   1 ml blood for each year of age up to 10 ml
 Immediate antibiotic IV
   ceftazidime if well-appearing
   ceftazidime/vancomycin/gentamicin if ill-
    appearing
 Admit to hospital-ICU if hypotensive
Mediastinal Mass/
Airway Compression
Management
 Airway: alleviation of respiratory distress
    Avoid sedation without anesthesiologist
    least invasive method possible with the least
     anesthesia possible for diagnosis

 Tumor:
    Steroids
    Chemotherapy
    Radiation Therapy
Question
A 4 year old girl who has ALL develops a fever of
  38.5 o C (103.6 o F). Findings include slight
  irritability and clear rhinorrhea. She has a total
  neutrophil count of 100/mm3 following recent
  chemotherapy.

Which is the most appropriate management?
 A. Blood culture, ceftriaxone, follow-up as
     outpatient in 24 hours
 B. Blood culture, ceftazidime, admit for
     observation
 C. Sudafed for rhinorrhea
 D. Ceftazidime first, then blood culture
Chemotherapy
Side effects of treatment
 Chemotherapy preferentially effects rapidly
  growing cells
    Hair
    GI mucosa
    Bone Marrow
       Anemia
       Thrombocytopenia
       Leukopenia
        Neutrophils and Lymphocytes
Side Effects of Specific Drugs
 Cyclophosphamide: hemorrhagic cystitis,
  infertility
 Ifosfamide: hemorrhagic cystitis, infertility,
  Fanconi syndrome (bicarb, protein,
  phosphorous wasting), infertility
 Cisplatin: hearing loss, renal damage,
  magnesium wasting
 Doxorubicin: cardiac damage (CHF)
 Etoposide: secondary leukemia
Side Effects of Specific Drugs
 Methotrexate: renal toxicity, mucositis,
  neurologic toxicity
 ARA-C: fevers, conjunctivitis
 Asparaginase: thrombosis, diabetes,
  allergic reactions, pancreatitis
 Vincristine: peripheral neuropathy,
  constipation
Question
Identify the correct associations:

A. Nephrotoxicity: cisplatin, methotrexate,
    ifosfamide

B. Infertility: Vincristine and doxorubicin

C. Hemorrhagic cystitis: cyclophosphamide and
    cisplatin

D. Hearing loss: doxorubicin and asparaginase
   THE END
(on to Dermatology!)