Pediatric Case ManagementBy

Richard Lirio,MD16th 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 Immunosuppressi

on

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 "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

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 factorSteidl 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 toxicitiesSteidl 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)