2. Lymphoma
• The third most common cancer among children
• It is the most common cancer in adolescents
–>25% of newly diagnosed cancers in persons 15-
19 yr old.
• 2 category
–Hodgkin lymphoma (HL)
–Non-Hodgkin lymphoma (NHL),
4. EPIDEMIOLOGY
• Bimodal age distribution
–1ST peak: 15-35 yr of age
–2nd peak: > 50 yr.
• A male predominance is found among young children, but
lessens with age.
6. CLINICAL MANIFESTATIONS
• Lymphadenopathy
– Painless, non tender, firm, rubbery
– Common site: cervical or supraclavicular
• Usually some degree of mediastinal involvement
• Symptoms and signs of airway obstruction
• HSM
– Rarely encountered
• Involvement below the diaphragm is rare and occurs in approximately
3% of all cases.
7. • Metastatic effect
– Pleural or pericardial effusion
– BM infiltration
– Hepatocellular dysfunction
• Systemic symptoms (B symptoms)
– Important in staging
– Unexplained fever >38°C (100.4°F),
– Weight loss >10% total body weight over 6 mo
– Drenching night Sweats.
8. Lab
• Complete blood cell count
• Erythrocyte sedimentation rate
• Measurement of serum ferritin
• Excisional biopsy: diagnostic
• Reed-Sternberg cells are pathognomonic
• Bone marrow aspiration
13. Radiation therapy
• Prolonged remission and cure
rates
• Used in low-stage HL.
• Causes significant long-term
morbidity
• including growth retardation,
thyroid dysfunction, and
cardiac and pulmonary
toxicity.
Combination chemotherapy
– Complete response rate of
70-80%
– Cure rate of 40-50% in
patients with advanced-
stage disease.
14. • The combination chemotherapy regimens includes
–COPP: Cyclophosphamide, vincristine [Oncovin],
procarbazine, and prednisone or
–ABVD: doxorubicin [Adriamycin], bleomycin,
vinblastine, and dacarbazine
–ABVE-PC
–BAVD : Brentuximab , doxorubicin [Adriamycin],
vincristine, dacarbazine
15. • A complete response is defined as
–Complete resolution of disease on clinical examination
and imaging studies or
–At least 70-80% reduction of disease and a change
from initial positivity to negativity on PET scanning.
16. RELAPSE and Prognosis
• Most occur within the 1st 3 yr after diagnosis
• Can occur late as 10 yr.
• Poor prognostic factors
–Tumor bulk
–Stage at diagnosis
–Extralymphatic disease
–Presence of B symp
17. • Early stage disease
–Even free survival (EFS) of 85-90%
–Overall survival (OS) at 5 yr of >95%.
• Advanced stage disease
–EFS :80-85%
–OS : 90%)
19. • Results from malignant proliferation of cells of lymphocytic
Lineage.
• Generally restricted to lymphoid tissue such as lymph
nodes, Peyer’s patches and spleen
• Bone marrow involvement in children.
• Bone and primary CNS lymphomas are rare presentations.
20. EPIDEMIOLOGY
• 8–10% of all malignancies in children between 5–19 years
of age.
• 60% of all lymphomas in children and adolescents.
• Male : Female : 2.5:1 overall and over 3:1 in ages 5–14.
• Similar across all ages, but peaks at ages 15–19 years,
23. Cont…
Cell origin Common site
of involvement
Incidence Genome alteration
LBL Immature
B(10%) and T
cell(90%)
Mediastinum 19% t(5;14) translocation
(20%)
BL Mature B cell Abdomen ,
Head and Neck
21% t(8;14) (90%)
t(8;22) translocation
(10%).
DLBCL Mature B cell Abdomen 37% t(8;14) translocation
(30%) often have a
complex (80%)
karyotype
Atypical large B
cell lymphoma
Mature T(70%)
Mature B cell(
10%)
17% t(2;5) translocation
(90%)
24.
25. CLINICAL FEATURES
• The clinical manifestations of childhood NHL depend primarily on
– Pathological subtype
– Sites of involvement.
• Tumors which grow rapidly can cause symptoms based on size
and location.
• Approximately 70% of children present with advanced-stage
disease including involvement of GI, bone marrow and central
CNS.
26. Abdomen
• BL and DLBCL commonly have primary tumors in the abdomen.
• Is the primary site in 35% of childhood NHL.
• Common site
–The ileocecal region
–Appendix
–Ascending colon
–Some combination of these sites.
27. Abdomen
• Present with:
– Abdominal pain and distention
– Nausea, vomiting and bowel changes
– Palpable masses
– Intussusception
• Lymphoma is the most frequent cause of intussusception in children over 6years of age
– HSM, obstructive jaundice, ascites, or peritonitis.
– Bleeding and perforation of the intestine, although rare, may occur.
28. Head and Neck (13%)
• Present with:
–Enlargement of the cervical node(s) and parotid gland,
–jaw swelling
–Unilateral tonsillar hypertrophy.
• The endemic form of BL has a much higher incidence of
facial involvement, with around 50–60% at presentation
29. Mediastinum(26%)
• Patients with large mediastinal masses may have superior
mediastinal syndrome
• SMS present with
–Distended neck veins
–Edema of the neck and face
–Marked dyspnea, orthopnea
–Dizziness, headache, dysphagia, epistaxis, altered
mental status and syncope
30. • Mediastinal tumors may lead to pleural effusion through
–Direct pleural involvement or
–Compression of lymphatics by the mediastinal mass.
• The presence of significant pericardial effusion may cause
cardiac tamponade.
31. • Lymphoblastic lymphoma (LL) commonly presents with an
intrathoracic or mediastinal mass along with spread to other
sites, e.g., bone marrow, meninges and gonads.
• BL and anaplastic large cell lymphoma (ALCL) involve the
mediastinum less commonly.
32. Bone Marrow
• BL and LL have a predilection for spreading to the bone
marrow.
• Rarely, ALCL and DLBCL will present with bone marrow
involvement.
• Bone marrow involvement is consistent with acute leukemia
in 25%
34. Other Primary Sites(11%)
• Skin and subcutaneous tissue
• Orbit
• Thyroid
• Bone (with or without hypercalcemia)
• Kidney
• Epidural space, breast and gonads.
35. Constitutional Symptoms
• Fever and weight loss are relatively uncommon except in
ALCL.
• Weight loss may also occur secondary to mechanical bowel
obstruction.
39. • Chemotherapy
• Radiation Therapy
– only indicated for acute life-threatening complications refractory
to initial chemotherapy
• Surgical Therapy
– The role in NHL treatment is limited.
– It should be performed on patients that total resection can be
achieved
40. PROGNOSIS
• Excellent for most forms
• Patients with localized disease have a 90-100% chance of
survival
• With advanced disease have a 70-95% chance of survival.
It is the most common cancer seen in adolescents and young adults, and the third most common in children younger than the age of 15 yr.
The role of EBV is supported by prospective serologic studies. EBV antigens have been demonstrated in HL tissues, particu-larly type II latent membrane proteins 1 and 2, although EBV status is not thought to be prognostic of outcome
The Reed-Sternberg (RS) cell,a pathognomonic feature of HL, is a
large cell (15-45 µm in diameter) with multiple or multilobulated
nuclei. This cell type is considered the hallmark of HL, although similar
cells are seen in infectious mononucleosis, NHL, and other conditions.
The RS cell is clonal in origin and arises from the germinal center B
cells but typically has lost most B-cell gene expression and function.
There is no single simple genetic aberration that leads to malignant
transformation of the RS cell, but rather a combination of somatic
mutations, chromosomal instability, and complex chromosomal rear-rangements have been reported with no particular pattern or frequency.
This typically leads to cell regulation defects such as constitutive
activation of the nuclear factor-κB pathway or abnormal regulation of
the Bcl-2 family of proteins.
Depending on the extent and location of nodal
and extranodal disease, patients may present with symptoms and signs
of airway obstruction (dyspnea, hypoxia, cough), pleural or pericardial
effusion, hepatocellular dysfunction, or bone marrow infiltration
(anemia, neutropenia, or thrombocytopenia).
Less common and not considered of prognostic significance are
symptoms of pruritus, lethargy, anorexia, or pain that worsens after
ingestion of alcohol. Patients also exhibit immune system abnormali-ties that often persist during and after therapy.
DIAGNOSIS
significance and, if abnormal at diagnosis, serves as a baseline to evalu-ate the effects of treatment. A chest radiograph is particularly impor-tant for measuring the size of the mediastinal mass in relation to the
Chest CT more clearly
defines the extent of a mediastinal mass if present and identifies hilar
nodes and pulmonary parenchymal involvement, which may not be
evident on chest radiographs.
maximal diameter of the thorax (Fig. 496-2). This determines “bulk”
disease and becomes prognostically significant. Bone scans are
performed in patients with bone pain and/or elevation of alkaline
phosphatase. Gallium scan can be particularly helpful in identifying
areas of increased uptake, which can then be reevaluated at the end of
treatment. Fluorodeoxyglucose PET imaging has advantages over
gallium scanning, as it is a 1-day procedure with higher resolution,
better dosimetry, less intestinal activity, and the potential to quantify
disease. PET scans are being evaluated as a prognostic tool in HL,
enabling therapy to be reduced in those predicted to have a good
outcome.
Multiple agents allow different mechanisms of action to have non-overlapping toxicities so that full doses can be given to each patient. Chemotherapy and radiation therapy are both effective in the treat-ment of HL. Treatment of HL in pediatric patients is risk adapted and
involves the use of combined chemotherapy with or without low-dose
involved-field radiation therapy based on response. Radiation therapy alone, once
given at higher doses, initially resulted in prolonged remission and
cure rates in patients with low-stage HL.
Causes significant long-term morbidity including growth retardation, thyroid dysfunction, and cardiac and pulmonary toxicity. Combination chemotherapy was a major milestone in the treatment of HL resulting in a
complete response rate of 70-80% and cure rate of 40-50% in patients
with advanced-stage disease. However, this regimen also led to signifi-cant acute and long-term toxicity.
The desire to reduce side effects and morbidity has stimulated attempts to reduce the intensity of chemo-therapy as well as radiation dose and volume. Newer combinations
of chemotherapy have reduced the risk of secondary cancers. Also,
current radiation therapy utilizes lower amounts of overall radiation
in addition to narrowing the radiation treatment field to either
involved-field or even involved-node irradiation. The current Chil-dren’s Oncology Group trials are investigating whether radiation
therapy can be eliminated altogether in patients who have a very good
rapid early response to pre-radiation induction chemotherapy
Chemotherapy agents commonly used to treat children and adoles-cents with HL include cyclophosphamide, procarbazine, vincristine or
vinblastine, prednisone or dexamethasone, doxorubicin, bleomycin,
dacarbazine, etoposide, methotrexate, and cytosine arabinoside. The
combination chemotherapy regimens in current use are based on
COPP(cyclophosphamide, vincristine [Oncovin], procarbazine, and
prednisone) or ABVD(doxorubicin [Adriamycin], bleomycin, vin-blastine, and dacarbazine), with the addition of prednisone, cyclophos-phamide, and etoposide (ABVE-PCand BEACOPP) or BAVD
(brentuximab vedotin, doxorubicin [Adriamycin], vincristine, dacar-bazine) in various combinations for intermediate- and high-risk
groups (Table 496-3). The combination chemotherapy regimens includes
COPP(cyclophosphamide, vincristine [Oncovin], procarbazine, and prednisone) or
ABVD(doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine), with the addition of prednisone, cyclophos-phamide, and etoposide (ABVE-PCand BEACOPP) or BAVD
(brentuximab vedotin, doxorubicin [Adriamycin], vincristine, dacar-bazine) in various combinations for intermediate- and high-risk
groups (Table 496-3).
Extralymphatic disease resulting from direct extension of an involved lymph node region is designated by category E.
Patients who achieve an initial chemosensitive response but
relapse or progress less than 12 mo from diagnosis are candidates for
myeloablative chemotherapy and autologous stem cell transplantation
with or without the addition of radiation therapy. Retrospective studies
show a significant decrease in relapse in patients with HL following
allogeneic vs autologous stem cell transplant (18% vs 41%). Although
in earlier studies there was no improvement in overall survival owing
to a high transplantation-related mortality, reduced-intensity condi-tioning or nonmyeloablative regimens are successful at reducing
regimen-related morbidity and mortality associated with myeloabla-tive allogeneic stem cell transplantation while still achieving a strong
graft-versus-HL effect. For more difficult-to-treat refractory cases,
agents such as Zevalin or Bexxar are being trialed, often in combina-tion with stem cell transplantation strategies. Both are monoclonal
anti-CD20 antibodies to which a radioactive isotope is directly linked.
Clinical trials show each to be more effective than rituximab in NHL
patients, and there is some interest in studying their use in the CD20
subpopulation of HL patients
PROGNOSIS
With the use of current therapeutic regimens, patients with favorable
prognostic factors and early-stage disease have an event-free survival
(EFS) of 85-90% and an overall survival (OS) at 5 yr of >95%. Patients
with advanced-stage disease have slightly lower EFS (80-85%) and OS
(90%), respectively, although OS has approached 100% with dose-intense chemotherapy (Table 496-4). Prognosis after relapse depends
Prognosis after relapse depends
on the time from completion of treatment to recurrence, site of relapse
(nodal vs extranodal), and presence of B symptoms at relapse. Patients
whose disease relapses >12 mo after chemotherapy alone or combined-modality therapy have the best prognosis, and their relapses usually
respond to additional standard therapy, resulting in a long-term sur-vival of 60-70%. A myeloablative autologous stem cell transplantation
in patients with refractory disease or relapse within 12 mo of therapy
results in a long-term survival rate of only 40-50%. Allogeneic stem
cell transplantation has shown promise in patients with poor risk fea-tures at relapse/progression
Generally restricted to lymphoid tissue such as lymph nodes, Peyer’s patches and spleen
3. It is the third most common childhood malignancy with an annual incidence of
750–800 cases per year in children,19 years of age in the USA. 4. There has been a stable incidence for children less than 15 years of age over the last
two decades, but in adolescents 15–19 years of age there has been an increase of 50%.
Age: relatively similar across all ages, but peaks at ages 15–19 years, largely because of a
significant increase in the incidence of diffuse large cell lymphoma at this age
Immunological defects (Bruton type of sex-linked agammaglobulinemia,
common variableagammaglobulinemia, severe combined immunodeficiency ataxia-telangiectasia, Bloom syndrome Wiskott–Aldrich syndrome, autoimmune
Drugs: Diphenylhydantoin, Infliximab and other immunosuppressive agents
The disease may present with nasal obstruction, rhinorrhea, hearing difficulty and cranial nerve palsies.
currently classified by the WHO as a distinct sub-type of DLBCL although there are increasing data to suggest that it is a separate entity that shares clinical, morphologic and genetic features with both NHL and Hodgkin lymphoma.
Patients with BL have a significantly worse prognosis if there is bone marrow involvement
this difference in prognosis is not as pronounced in LL.
Involvement of the CNS upstages the risk classifica-tion at diagnosis to advanced-stage lymphoma and confers a worse overall survival, often
requiring intensification of treatment.
As outcomes for pediatric patients with NHL have
improved substantially, the focus has now shifted to minimizing the
long-term toxicity of therapy. Novel targeted agents are desirable as
they have the potential to improve outcomes and decrease the reliance
on toxic conventional chemotherapy
