1. Clinical Assessment and Differential Diagnosis of a Child with Suspected Cancer Pediatric Resident Education Series

2. 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 physician the opposite is true You have to think about the possibility of cancer before you can make the diagnosis

3. General Points Nothing replaces a thorough medical history, family history and physical exam 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 Environmental exposures Previous diagnosis of cancer/cancer therapy

4. Common things are not always common… Symptoms and Signs of cancer mimicking normal childhood illnesses for which an initial evaluation for cancer is usually Not warranted include: Generalized malaise, fever, adenopathy Headache, rhinorrhea, epistaxis, febrile seizure, rhinitis, pharyngitis, earache Nausea, vomiting, diarrhea, Hepatomegaly, splenomegaly Hematuria, trouble voiding, vaginitis Masses (bony or soft tissue), pain/swelling

5. Symptoms and Signs of Cancer Mimicking Normal Childhood Illnesses: Initial Evaluation for Cancer Usually Not Warranted

6. Symptom / Sign Generalized malaise, fever, adenopathy Head & Neck Headache, nausea, vomiting Febrile Seizure Earache Rhinitis Epistaxis Pharyngitis Adenopathy Possible Malignancy Lymphoma, leukemia, Ewings (EWS), neuroblastoma (NBL) Brain tumor, leukemia Brain tumor Soft Tissue Sarcoma (STS) STS Leukemia STS NBL, thyroid tumor, STS, leukemia, lymphoma,

7. Symptom / Sign Thorax Extrathoracic Soft tissue mass Bony mass Intrathoracic Adenopathy Abdomen External: soft tissue Internal: diarrhea, vomiting, hepatomegaly and/or splenomegaly Possible Malignancy STS, PNET EWS, NBL Lymphoma, leukemia STS, PNET NBL, lymphoma, hepatic tumor, leukemia

8. Symptom / Sign Genitourinary Hematuria Trouble voiding Vaginitis Paratesticular mass Musculoskeletal Soft tissue mass(es) Bony mass/pain Possible Malignancy Wilms’, STS Prostatic or bladder STS STS RMS, other STS, PNET Osteosarcoma, EWS, Non-Hodgkin’s lymphoma (NHL), NBL, Leukemia

9. Signs and Symptoms in the Child with Cancer If the signs and symptoms listed in previous table do not subside within a reasonable period, a consult with an oncologist is warranted Exception to this rule – soft tissue mass in a child without a explanatory traumatic event warrants an early evaluation

10. DiagnosisnMeanMedian25 th %75 th % Brain1942119338237 Ewing’s8218212779255 Hodgkin’s14322313649270 Leukemia9081095220129 NHL1841176225141 NBL2371205815164 OS671279840191 RMS1261275525161 Wilms’223101319120 Distribution of Lag Time in Days by Diagnosis of Common Childhood Cancers Table 7-1. Pizzo & Poplack, 4 th ed.

11. Common things are not always common… (part 2) Unusual Symptoms and Signs that warrant an immediate laboratory and/or imaging studies and consultation include: Hypertension, unexplained weight loss Focal neurologic abnormalities Masses Petechiae, pallor Adenopathy not responding to antibiotics Early morning vomiting Pain waking from sleep, not responsive to acetaminophen or NSAIDs

13. Symptoms/SignsLaboratory, imaging studies, & consultations Major associated tumors HypertensionCXR, Abd USRenal or abdominal tumor, NBL Weight loss, sudden onsetAbd USAny malignancy PetechiaeCBC, manual diffLeukemia, NBL Adenopathy unresponsive to ABs Surgical consultation, CXR, CBC, manual diff Leukemia, Lymphoma Endocrine abnormalities Growth 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 Brain Headache, 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

14. Symptoms/SignsLaboratory, imaging studies, & consultations Major associated tumors Eyes White Spot, proptosis, blindness Wandering Eye Intraorbital hemorrhage Ophthalmologic consultationRetinoblastoma, metastatic neuroblastoma, rhabdomyosarcoma (RMS), or other STS Ears Bulging mass external canal Mastoid tenderness, swelling CBC, diff, Imaging studies LCH, RMS Puffy face & neckCBC, diff, imaging studiesMediastinal tumors Pharyngeal massCBC, diff, imaging studiesRSM, lymphoma, naso- pharyngeal carcinoma Periodontal mass, loose teeth Dental consultation, imaging studies LCH, Burkitt’s lymphoma, neuroblastoma, osteosarcoma Thorax Extrathoracic: mass Intrathoracic: coughing, SOB without fever or no history of asthma, allergies CBC, diff, imaging studies Soft tissue tumors, mediastinal tumors, metastatic tumors

15. Symptoms/SignsLaboratory, imaging studies, & consultations Major associated tumors Abdomen/Pelvis Intra-abdominal mass Abd US; CBC, diffWilms’ 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

16. CNS Symptoms Concerning for Brain Tumors Masses can be suspected on the basis of a symptom complex that reflects the site of the tumor (seizures, weakness, difficulties with coordination) Pediatric tumors are often situated such that they interfere with CSF circulation resulting in increased intracranial pressure Headaches and vomiting are common presenting signs in these cases

17. Symptoms and/or Signs concerning for Leukemia Unexplained fever > 101 o F for more than a week Petechiae Unexplained anemia / pallor Generalized lymphadenopathy Hepatosplenomegaly Bone or joint pain (30%) not relieved with pain medications or that wakes from sleep

18. Conditions Suggesting the Need for Radiographic Evaluation in Children with Headaches Presence of neurologic abnormality Ocular findings, papilledema Vomiting that is persistent, increasing or preceded by recurrent headaches Changing character of the headache Recurrent morning headaches or headaches that awaken or incapacitate the child Short stature or deceleration of linear growth Diagnosis of Neurofibromatosis Previous history of leukemia or CNS radiation

19. Lymphadenopathy Diagnosis Lymph Node is considered large if > 10 mm; exceptions: Epitrochlear nodes > 5 mm Inguinal node > 15 mm Most enlarged lymph nodes in children are related to infections Bacterial – Staph and Strep Atypical mycobacterium Cat scratch disease Viral – EBV and other herpes viruses

20. Lymphadenopathy Regional or generalized? Generalized more likely malignant (except EBV) Regional adenopathy not involving the head and neck more likely malignant Characteristics of the enlarged node(s) Hard/rubbery, non-tender, matted (fixed, non-mobile) node is more likely malignant Location of the adenopathy Adenopathy in the posterior auricular, epitrochlear or supraclavicular areas is abnormal Mediastinal adenopathy is frequently malignant

21. Need for Lymph Node Biopsy is Suggested by the Following Signs and Symptoms Enlarging nodes after 2-3 weeks of antibiotic therapy Nodes that are not enlarging but have not diminished in 6-8 weeks Nodes associated with any abnormal chest X-ray Adenopathy with associated weight loss, hepatosplenomegaly, unexplained fevers, and/or drenching night sweats Adenopathy in the posterior auricular, epitrochlear or supraclavicular areas

22. Masses Abdominal, Thoracic and Soft Tissue Masses (without a traumatic explanation) All require evaluation

23. Bone and Joint Pain Most pain associated with cancer is caused by bone, nerve or visceral involvement or encroachment Bone pain is usually not an early symptom of cancer except for malignancies involving bone Ewing’s sarcoma, osteosarcoma Come and go early on disappearing for weeks or months Bone or joint pain is a presenting symptom in about 30% of patients with ALL Can be confused with rheumatic diseases

24. Bone and Joint Pain Evaluation should be performed when Bone/joint pain is persistent associated with swelling or mass Limited mobility or joint motion Consistently wakes from sleep at night Not relieved by NSAIDs

26. Another way to think of things….. What is it? Where is it? Where can it go? The answer to any one of the above can help answer the other two

27. Work-up: Two Components Staging – find out where the tumor is (and isn’t) X-ray of 1 o site CT body; CXR baseline, bone scan Specialty tests Gallium, MIBG Tumor markers (HCG, HVA/VMA, …. Bone marrow Evaluate for Complications of the tumor CBC w/manual differential, TPN panel Other studies DIC screen, UA, …

28. Approach to the diagnosis…. Tissue diagnosis Incisional biopsy Excisional biopsy Special cases… Calicified suprarenal mass + bone scan – in the absence of any desire for biologic studies, might consider getting diagnosis from bone marrow FNA vs. excisional biopsy Bias towards excisional -> sufficient sample to be representative and to send for special research studies (histology, chromosomes, special studies, research studies)

29. Summary Presenting signs and symptoms of childhood cancer are common to many childhood illnesses Early diagnosis of cancer may improve outcome If the possibility of cancer is not considered, delayed diagnosis is the result Although the incidence of childhood cancer is low, the impact of cancer makes it imperative that all professionals have a high index of suspicion of cancer

31. Credits Tables from: Principles and Practice of Pediatric Oncology, 4 th edition, Pizzo PA & Poplack DG eds., Lippicott Williams & Wilkins, Philadelphia, 2002 Bruce Camitta MD Michael Kelly MH PhD Kelly Maloney MD Anne Warwick MD MPH