Pediatric Case Management By Richard Lirio,MD 16 th June 2010

1. Pediatric Case Management By Richard Lirio,MD 16th June 2010

2. History • 14 y/o Caucasian Female • h/o seizure disorder, autism, developmental delay • Referred to Hem-Onc clinic for: • Progressively worsening cough • Neck swelling • Abnormal chest x-ray

3. History • Over the past 3 mos • Increasing cough • Initially treated with Abx  improved • Exacerbated by lying supine • Associated with respiratory distress • Axillary lymphadenopathy ~ 2 mos prior • Also treated with Abx  improved • Past few weeks b/l neck swelling • Swelling of face • 5-6 lbs weight loss • No fevers, N/V/D, bone pain, or neuro changes

4. Past Medical History • No prior hospitalizations • No surgical hx • + seizure disorder • Levetiracetam • Clonazepam • Lamotrigine • + autism • + developmental delay

5. Physical Examination • NAD, slightly anxious, slightly thin female, interactive, leaning forward • T = 35.8, RR 22, HR 133, BP 102/69, O2 sats 98% on RA • HEENT - WNL • B/L supraclavicular adenopathy • Large, firm, 5x8cm each, NT

6. Physical Examination • Some swelling noted on anterior chest wall with increased prominence of anterior chest wall veins • No breath sounds on the left; clear on the right • PMI shifted to the midline; no m/r/g • Abdo soft, NT, ND, No HSM

7. Labs 9.4 138 99 12 84 695 15.3 3.7 27 .72 10.5 30.3 Phos 7.7, Mg 2.3 Alb 3.9 , TP 7.7 LDH 686, AP 91 AST 24, ALT 8, TB 0.3 Uric Acid 5.2 6 B, 66 N, 12 L, 10 M ESR 94

11. Differential Diagnosis • Non-Hodgkin lymphoma • Metastatic adenopathy from other primary tumors • Toxoplasmosis • Mycobacterium • EBV • SLE

12. Pathology • Biopsy • Classical Hodgkin Lymphoma • Nodular sclerosis subtype • Bone marrow aspirates • Active tri-lineage haematopoiesis • No evidence of malignancy

13. Objectives • To discuss the epidemiology, presentation, & diagnostic evaluation for Hodgkin’s Lymphoma • To discuss the differential diagnosis for anterior mediastinal masses • To discuss the treatment for Hodgkin’s Lymphoma • To discuss new development regarding prognostic indicators for Hodgkin’s Lymphoma

14. History • Highly curable malignant disease • First cancer to be cured with radiation or with a combination of several chemotherapy agents • Therapeutic success  long-term toxicities • 30-year survivor is more likely to die of therapy-related complications than from HL • current risk-adapted, response-based approach to treatment

15. Pathophysiology • B-cell malignant disorder that affects the reticuloendothelial and lymphatic systems • Can affect other organs and systems, predominantly the lungs, bone, bone marrow, liver parenchyma, and, rarely, the CNS

16. Pathophysiology • Epidemiologic data suggest environmental, genetic, and immunologic factors are involved • Clustering of cases in families or racial groups supports the idea of a genetic predisposition or a common environmental factor • In identical twins of patients with HL, the risk of developing HL is higher than that of other first-degree relatives • Subjects with acquired or congenital immunodeficiency disorders also have an increased risk of developing HL

17. Pathophysiology • Findings from several epidemiologic studies suggest links between HL and certain viral illnesses • The strongest case to date is a relationship to EBV • EBV viral DNA can be found in Hodgkin-Reed-Sternberg (HRS) cells • 25-50% of cases of classical HL in developed countries are EBV +

18. Incidence • Age-adjusted standardized rate (ASR) in North America, western Europe, and Oceania is usually just below 7 cases per million • For children and adolescents younger than 15 years, the incidence is 5.5 cases per million • For individuals aged 15-20 years, the incidence is 12.1 cases per million • Western Asia (from the Mediterranean to northwest India), the ASR is consistently higher than 7 cases per million

19. Incidence • In the US, the incidence among whites and blacks is essentially the same. • However, the ratio is 1.4:1 in children older than 10 years • A significant male-to-female predominance of 3:1 is observed in children younger than 10 years • In older children and adults, the male-to-female ratio is about 1:1

20. Incidence • The incidences by age show a bimodal distribution • In developed nations, the first peak occurs at approximately age 20, and the second peak is observed in patients aged 55 years or older • HL is uncommon before age 5 years. • However, in developing countries, the first peak is shifted into childhood, usually before adolescence

21. History • Persistent painless adenopathy • More than 70% of patients with HL present with cervical lymphadenopathy • Patients with mediastinal adenopathy may present with respiratory symptoms such as shortness of breath, chest pain, or cough • at risk for respiratory failure, especially if they undergo sedation or anesthesia for diagnostic procedures

22. History • Patients with HL may present with symptoms associated with advanced disease & adverse prognosis (B – designation) • Unexplained fever with temperatures above 38°C for 3 consecutive days • Unexplained weight loss of 10% or more in the previous 6 months • Drenching night sweats

24. Diagnostic Evaluation • In addition to stage and male sex, certain laboratory findings suggest poor prognostic factors • Hemoglobin < 10.5 g/dL • WBC count of 15,000/μL or less • Absolute lymphocyte count < 800/μL • Albumin level < 4 g/dL • ESR > 50

25. Imaging • Chest XR – AP and lateral • Mediastinal mass with a thoracic ratio of 33% or greater is of prognostic importance • CT or MRI of neck, chest, abdomen, and/or pelvis • to assess sites of disease (nodal and extranodal) as well as to assess liver and spleen involvement • PET scans • to identify the extent of disease at diagnosis and for follow up

26. Staging • The most widely used staging system is the Ann Arbor staging system. • Stage I - Single lymph node region or single extranodal site • Stage II - Two or more lymph node regions on the same side of the diaphragm • Stage III - Lymph node regions on both sides of the diaphragm • Stage IV - Diffuse or disseminated involvement of one or more extralymphatic organs (liver, bone marrow, lung) or tissues with or without associated lymph node involvement (The spleen is considered a nodal site.) • A vs B

27. Treatment • Hodgkin lymphoma can be cured with radiation therapy, chemotherapy, or a combination of both. • Acute and late toxicities vary depending on treatment • Balance between reducing late effects of therapy vs. maintaining cure rates

28. Treatment based on Stage • Standard treatment regimens for pediatric Hodgkin lymphoma are as follows: • Early or favorable disease (stage IA or IIA with <3 nodal sites) • 2-4 chemotherapy cycles without alkylators (VAMP; etoposide, bleomycin, vinblastine, and prednisone [EBVP]; OEPA; or ABVE) plus low-dose, involved-field radiation of 15-30 Gy or 6 chemotherapy cycles (alternating COPP and ABVD or derivatives of these regimens) and no irradiation. The use of very limited doses of chemotherapy (2-3 cycles) should be administered only as part of a clinical trial. • Intermediate-risk disease (stage IA, IIA, or IIA bulky disease with extension or >3 nodal sites): • 4-6 chemotherapy cycles (OPPA and COPP, Stanford V) plus low-dose, involved-field radiation of 15-30 Gy or 6 chemotherapy cycles (alternating COPP and ABVD or their derivatives) or a dose-intense, hybrid regimen (eg, Stanford V, ABVE-PC, or BEACOPP) and no irradiation. • Advanced or unfavorable disease (stages IIB, IIIB, or IV): • 6-8 chemotherapy cycles (OPPA and/or COPP, ABVE-PC, BEACOPP) plus low-dose involved-field radiation of  15-30 Gy or 6-8 chemotherapy cycles (alternating COPP and ABVD or their derivatives) or a dose-intense, hybrid regimen (ABVE-PC or BEACOPP) and no irradiation.

29. Radiation Erythema +/- hyperpigmentation Transient hair thinning GI sx Dry mouth or altered taste Chemotherapy N/V Alopecia Myelosuppression Immunosuppression Acute Effects of Treatment

30. Late Complications • Impaired growth of soft tissue and bones • Thyroid dysfunction • Gonadal dysfunction • Cardiopulmonary toxicity • Second malignancies • Functional impairment and reduced overall general health

31. Steidl et al. • New England Journal of Medicine • About 20% of HL patients cannot be cured • About 20% of HL patients are over-treated • "An increased number of tumor-associated macrophages was strongly associated with shortened survival in patients with classic Hodgkin's lymphoma, and provides a new biomarker for risk stratification" • The tumor-associated macrophages were identified by a single marker of CD68+ cells Steidl et al. Tumor-Associated Macrophages and Survival in Classic Hodgkin’s Lymphoma. N Engl J Med. 2010; Vol 362, No 10:875-85

32. Tumor-Associated Macrophages • Previously, thought that macrophages were a manifestation of an immune response against the tumor • Currently, Lewis et al (2006) link the presence of tumor-associated macrophages with a poor prognosis • Possibly by increasing blood-vessel formation through the secretion of vascular endothelial growth factor Steidl et al.. N Engl J Med. 2010; Vol 362, No 10:875-85

33. Implications of CD68 marker • Identify the subgroup of patients with HL who have a poor prognosis and prescribe aggressive treatment with both radiotherapy and combination chemotherapy • Would spare majority of the patients from over treatment and associated toxicities Steidl et al.. N Engl J Med. 2010; Vol 362, No 10:875-85

34. References • Jemal et al. Cancer statistics, 2009. CA Cancer J Clin 2009;59:225 • Alexander et al. Risk factors for Hodgkin’s disease by EBV antibodies – a prospective study. Br J Cancer 2000; 82:1117 • Steidl et al. Tumor-Associated Macrophages and Survival in Classic Hodgkin’s Lymphoma. N Engl J Med. 2010;Vol 362; No 10: 875-85 • Lewis et al. Distinct role of macrophages in different tumor microenvironments. Cancer Res 2006;66:605-12 • Pollard et al. Trophic macrophages in development and disease. Nat Rev Immuno 2009;9:259-70 • Montovani et al. The origin and function of tumor-associated macrophages. Immunol Today 1992;13:265-70 • DeVita et al. A selective history of the therapy of Hodgkin’s disese. Br J Haematol 2003;122:718-27 • www.instantanatomy.net (figure)