Pediatric Case Management - June 2010
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Pediatric Case Management - June 2010

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  • Differential Diagnosis
  • Malignant, infectious, inflammatory Thymoma, thyroid dz or cancer, teratoma, rhabdomyosarcoma, germ cell tumor or T cell lymphoblastic lymphoma
  • 17-40% of children with HL have a mediastinal mass on CXR at initial presentation; can initially c/o dysphagia, dyspnea, cough, stridor, or SVC syndrome
  • Fewer than 20% of children with HL have the classic fever and night sweats seen in adults. Pts can also present with pruritis, urticaria, fatigue postulated to be secondary to cytokine release from HRS cells
  • Most children and adolescents with HL have EXCELLENT prognosis with current therapy regimens. Overall 5 year survival rate for early disease >90%. The overall 5 year survival rate in patients with advanced stage disease treated with chemo + radiation ~93%
  • A majority of these late complications are dose and volume related to the amount of chemo +/- radiation received
  • Using gene-expression profiling – analyzed 130 frozen samples obtained from patients with classic HL during diagnostic LN bx to determine which cellular signatures were correlated with treatment outcome. Then they confirmed these findings in an independent cohort of 166 patients using immunohistochemical analysis for CD68 markers on macrophages – which per the study can be done by all pathology departments
  • Along with Lewis et al - Pollard et al 2009; Mantovani et al 1992 Possibly, the number of tumor associated macrophages leads to a poor response to treatment because their increased number signals a deregulation of apoptosis in Reed-Sternberg cells that inhibits cell death in response to cytotoxic agents????
  • FUTURE = Catering therapy!!!

Pediatric Case Management - June 2010 Pediatric Case Management - June 2010 Presentation Transcript

  • Pediatric Case Management By Richard Lirio,MD 16 th June 2010
  • 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
  • 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
  • Past Medical History
    • No prior hospitalizations
    • No surgical hx
    • + seizure disorder
      • Levetiracetam
      • Clonazepam
      • Lamotrigine
    • + autism
    • + developmental delay
  • 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
  • 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
  • Labs 15.3 9.4 30.3 695 6 B, 66 N, 12 L, 10 M ESR 94 3.7 99 27 12 .72 138 84 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
  •  
  •  
  •  
  • Differential Diagnosis
    • Non-Hodgkin lymphoma
    • Metastatic adenopathy from other primary tumors
    • Toxoplasmosis
    • Mycobacterium
    • EBV
    • SLE
  • Pathology
    • Biopsy
      • Classical Hodgkin Lymphoma
        • Nodular sclerosis subtype
    • Bone marrow aspirates
      • Active tri-lineage haematopoiesis
      • No evidence of malignancy
  • 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
  • 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
  • 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
  • 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
  • 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 +
  • 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
  • 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
  • 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
  • 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
  • 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
  •  
  • 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
  • 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
  • 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
  • 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
  • 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.
  • Acute Effects of Treatment
    • Radiation
      • Erythema +/- hyperpigmentation
      • Transient hair thinning
      • GI sx
      • Dry mouth or altered taste
    • Chemotherapy
      • N/V
      • Alopecia
      • Myelosuppression
      • Immunosuppression
  • Late Complications
    • Impaired growth of soft tissue and bones
    • Thyroid dysfunction
    • Gonadal dysfunction
    • Cardiopulmonary toxicity
    • Second malignancies
    • Functional impairment and reduced overall general health
  • Steidl et al.
    • New England Journal of Medicine
      • About 20% of HL patients cannot be cured
      • About 20% of HL patients are over-treated
      • &quot;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&quot;
        • 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
  • 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
  • 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
  • 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)