1. Pediatric Case Management By Richard Lirio,MD 16 th 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 15.3 9.4 30.3 695 6 B, 66 N, 12 L, 10 M ESR 94 3.7 99 27 12.72 13884 10.5 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

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

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)