Childhood Cancer. Housekeeping. Goals and Objectives 4/27/2016. I have no financial disclosures

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1 Childhood Cancer Wendy Woods-Swafford MD, MPH Pediatric Hematology Oncology Blank Children s Hospital Housekeeping I have no financial disclosures Goals and Objectives Upon 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 1

2 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 Number , , ,000 12,500 Breast Lung Prostate Childhood Cancers Cancer Type 2

3 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: 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 3

4 Common Childhood Cancers Birth 14 SEER Data 2012 Estimated New Cases of Childhood and Adolescent Cancers in the US Journal of Clinical Cancer Research 2014 Incidence Trends By Site Source: SEER 9 4

5 Trends in Mortality Rates Age 0-19; 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 5

6 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 6

7 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 7

8 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 8

9 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 9

10 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 10

11 Complications of Surgery The Little Brain - Constitutes only 10% of the total Oculomotor dysfunction volume of the brain but contains more than 50% of Motor paralysis neurons -Motor Face Planning -Coordination Arm/Legof Movements -Motor Swallowing Learning (repitition) Dysfunction -Attention Dysmetria -Language Truncal ataxia -Memory Gait ataxia -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 11

12 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 12

13 Work Up CT: 65-95% sensitivity to detect brain tumors MRI: with and without contrast CSF examination Biopsy or preferred excision biopsy/resection Astrocytomas Low 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 13

14 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 14

15 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. 15

16 CT Scan concerning for Wilms Tumor 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 16

17 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 17

18 Staging of Wilms Tumors I II III IV V Limited to kidney; complete resection Extent beyond kidney, but complete R Residual tumor, confined to abdomen Hematogenous mets (lung, liver, bone, brain) or lymph nodes outside abdomen Bilateral renal involvement at diagnosis Evaluation: CBC, CMP CT Abdomen (Assess of renal function prior to giving contrast) Chest Xray and CT chest Abdominal Ultrasound Tumor spill at time of surgery considered stage III 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 Stage II, III and IV diffuse anaplasia Nephrectomy Nephrectomy Vincristine Dactinomycin Doxorubicin Vincristine Dactinomycin Doxorubicin Etoposide Stage II,III,IV RTK Nephrectomy Cytoxan Etoposide Carboplatin Yes Yes Yes Prognosis 80-90% survival with current multi-modal therapy When bilateral tumor 70-80% survival if synchronous 18

19 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 19

20 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 20

21 Neuroblastoma Take Home Most common extracranial 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 Clinical microscopic Evaluation: nodes 2B Urine Unilateral, Catecholamines: positive ipsilateral HVA, nodes; VMA negative Imaging contralateral Studies: CT, bone scan, MIBG 3scan Across midline, or contralateral nodes 4 Dissemination: Bone Marrow bone Biopsies marrow, liver, skin, bones Lymph Node evaluation 4S <1y: local stage 1-2, with mets to BM, liver, skin 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 21

22 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 symptoms depend on age and site Signs and Symptoms Head and neck Orbit Proptosis Periorbital swelling Parameningeal Cranial nerve palsies Hearing loss Chronic aural or sinus drainage 22

23 Signs and Symptoms Genitourinary Bladder and prostate Hematuria Urinary obstruction Paratesticular Painless mass - testicle Vagina and uterus Abdominal mass Vaginal mass Vaginal bleeding or discharge 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 23

24 Ewing s Sarcoma Peaks in ages 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 24

25 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) Osteogenic Sarcoma Metaphyses of long bones: Distal femur Proximal tibia Proximal humerus Pelvis Ewing Sarcoma All bones: Long: diaphyses Flat Pelvis Skull Ribs 25

26 Presentation of Bone Tumors Plain X-Rays are usually abnormal Ewing: Moth-eaten lytic lesion Osteosarcoma: Sunburst pattern Periosteal reaction Soft 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 26

27 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 27

28 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) 28

29 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 29

30 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, 2 nd malignancies, endocrinopathies, etc Distribution of Lag Time in Days by Diagnosis of Common Childhood Cancers Diagnosis n Mean Median 25 th % 75 th % Brain Ewing s Hodgkin s Leukemia NHL NBL OS RMS Wilms Table 7-1. Pizzo & Poplack, 4 th 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 Endocrine abnormalities Growth failure Electrolyte disturbances Sexual abnormalities Cushing s syndrome Brain Headache, early AM vomiting Cranial nerve palsy, ataxia Dilated pupil, papilledema Afebrile seizures Hallucinations, aphasia Unilateral weakness, paralysis Surgical consultation, CXR, CBC, manual diff Hormonal assays CT hypothalamic area Abdominal CT Endocrine consult Neurology and/or Neuro- Surgery Consultation followed by Imaging Studies Leukemia, Lymphoma Pituitary tumors Hypothalamic tumors Gonadal tumors Adrenal tumors Brain Tumor 30

31 Symptoms/Signs Eyes White Spot, proptosis, blindness Wandering Eye Intraorbital hemorrhage Ears Bulging mass external canal Mastoid tenderness, swelling Laboratory, imaging studies, & consultations Ophthalmologic consultation CBC, diff, Imaging studies Major associated tumors Retinoblastoma, metastatic neuroblastoma, rhabdomyosarcoma (RMS), or other STS LCH, RMS Puffy face & neck CBC, diff, imaging studies Mediastinal tumors Pharyngeal mass CBC, diff, imaging studies RSM, lymphoma, nasopharyngeal carcinoma Periodontal mass, loose teeth Thorax Extrathoracic: mass Intrathoracic: coughing, SOB without fever or no history of asthma, allergies Dental consultation, imaging studies CBC, diff, imaging studies LCH, Burkitt s lymphoma, neuroblastoma, osteosarcoma Soft tissue tumors, mediastinal tumors, metastatic tumors Symptoms/Signs Abdomen/Pelvis Intra-abdominal mass Genitourinary Testes, vaginal mass Masculinization / feminization Musculoskeletal Soft tissue, bone marrow, and/or pain Laboratory, imaging studies, & consultations Abd US; CBC, diff UA, CBC, diff US of abdomen/pelvis CBC, diff Imaging studies Major associated tumors Wilms tumor, soft tissue sarcoma, neuroblastoma, hepatoblastoma, hepatocellular carcinoma Germ cell tumor, RMS, adrenal tumor 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 Other tables taken from Gurney JG & Bondy ML, Epidemiology of Childhood Cancer, in Principles and Practice of Pediatric Oncology, 5 th ed, Pizzo PA and Poplack DA, eds, LWW, Childhood and Adolescent Cancer Statistics, 2014 Journal of Clinical Cancer ACS 31