Childhood Hodgkin and Non-Hodgkin

Lymphomas
Brigid G. Leventhal, MD*, and Gregory J. Kato, MDt

bined immune deficiency syndrome,

The questions below should help X-Iinked lymphoprolifenative syn-
EDUCATIONAL OBJECTIVES
focus the reading of this article. drome, and Bloom syndrome, and
1. What changes have taken place in they are found in patients receiving E. The pediatrician should have a
the prognoses of Hodgkin lymphoma immunosuppressive therapy follow- general knowledge of the presen-
(HL) and non-Hodgkin lymphoma ing organ on bone marrow transplant. tation, therapy, and course of non-
(NHL)? Both HLs and NHLs are seen with Hodgkin lymphomas. (Recent Ad-
2. What clinical features distinguish increased incidence in patients with vances, 90/91)
HL from NHL? ataxia-telangiectasia and acquired E. The pediatrician should have a
irnrnunodeficiency syndrome. general knowledge of the current
3. How is the diagnosis of HL or NHL
best confirmed?
Epstein-Barr virus, first strongly im- approach to Hodgkin disease. (Re-
plicated epidemiologically in African cent Advances, 90/91)
4. What are the staging procedures
Bunkitt lymphoma, appears to have a
for HL or NHL?
role in the pathogenesis of at least
5. How does the therapy of HL or NHL 20% of B-cell lymphomas. Evidence
vary with the stage? suggests that Epstein-Barr virus can
lead to a benign lymphoproliferation for NHL, through the course of a few
that may lead to a large pool of B- days or weeks. In the pediatric age
Lymphomas were recognized orig- cells at risk for subsequent malignant group, the incidence of NHL gradually
inally by Virchow as swellings of conversion. Recently, Epstein-Barr increases after 5 years of age,
lymph nodes that were unrelated to virus DNA has been detected in whereas HL is primarily a disease of
tuberculosis or to other recognized Reed-Sternberg cells in HLs, but the adolescents and young adults.
pathology in the drainage area of the significance of this finding is not clear Approximately 30% of patients
lymph node group. Lyrnphomas were at this point. with HL experience symptoms of fe-
not recognized initially as malignan- ver, night sweats, and weight loss,
cies; proof of this came only in this owing to elaboration of cytokines by
CLINICAL PRESENTATION OF HL
century. Hodgkin lymphoma (HL) and the tumor cells. Pruritus aggravated
AND NHL DURING CHILDHOOD
non-Hodgkin lymphoma (NHL), which by ingestion of alcohol is an occa-
together account for approximately The clinical presentations of HL sional presenting symptom. In pa-
12% of childhood cancer, have be- and NHL are compared in Table 1. tients with NHL, weight loss may also
come among the most curable of pe- The most common first clinical mani- be seen; when such loss is unex-
diatric malignancies. Today, the pro- festation of HL or NHL is painless plained, it should always raise the
jected cure rates for children in cer- lymph node enlargement, most often specter of undiagnosed malignancy.
tam categories are as high as 90%. in the cervical on supraclavicular In the case of childhood NHL, pre-
Recent advances in molecular biol- chains. The onset is typically sub- senting symptoms are highly corre-
ogy have permitted immense strides acute and prolonged for HL and rapid lated with histologic subtype. Chil-
in understanding the pathogenesis
and biology of these two diseases.

FACTORS PREDISPOSING TO TABLE 1. Features of Hodgkin and Non-Hodgkin Lymphomas

LYMPHOMAS Presentation Hodgkin Lymphoma Non-Hodgkin Lymphoma

Of individuals with immune defi- Onset of disease Indolent Rapid

ciency or defects of DNA repair func- Most common sites Cervical, mediastinal, Abdominal, mediastinal,
tion, 1 % to 35% develop lymphornas. and supraclavicular and supradavicular
lymph node chains lymph node chains
NHLs are highly associated with Wis- Abdominal pain, ab- Rare Common
kott-Aldrich syndrome, common van- dominal mass, or
able immunodeficiency, severe corn- bowel obstruction
Fever, night sweats, Common Uncommon
“Director of Clinical Research, The Johns Hop- and weight loss
Intussusception Rare Fairly common
kins Oncology Center, Baltimore, Maryland
Painless adenopathy Common Common
21205.
Superior vena cava Rare Common
tSenior Clinical Fellow, Department of Pediat-
rics, The Johns Hopkins University School of syndrome
Medicine, and The Johns Hopkins Oncology Symptomatic airway Rare Common
Center, 600 North Wolfe St, Baltimore, Mary- compression
land 21205.

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Hodgkin disease

dren with lyrnphoblastic lymphoma cells including lymphocytes, plasma nectomy, with liver and multiple
frequently have symptoms of medias- cells, and eosinophils. lyrnph node biopsies, was developed
tinal tumor, with dysphagia, dyspnea, Cases of Hodgkin lymphoma are to maximize the accuracy of identifi-
and pain or swelling of the.face, neck, commonly divided into four histologic cation of the anatomic extent of dis-
and upper extremities as a result of categories based on lymph node ease. The stage assigned after the
superior vena caval obstruction. Pa- morphology: lymphocytic predorni- use of only noninvasive techniques is
tients with small noncleaved cell lym- nance, mixed cellularity, lymphocytic called the clinical stage and that as-
phoma (SNCL) frequently have ab- depletion, and nodular sclerosis (Fig signed after Iaparotorny is called the
dominal masses or pain, and ileocecal 1 B). In all four categories, the lymph
, pathologic stage. Laparotorny will re-
involvement often results in right node architecture is destroyed par- suIt in a change in stage in 20% to
lower quadrant tenderness, intestinal tially or completely. In the case of 30% of patients. The currently used
obstruction, or intussusception. Lym- lymphocytic predominance, the cel- staging system for HL is shown in
phoma is a lead point for intussus- lular proliferation involves benign-ap- Table 2. The steps in a diagnostic
ception in up to 50% of children older pearing lymphocytes and may be workup of a new patient with HL at
than 6 years, and the diagnosis must misinterpreted as reactive hyperpla- our institution are shown in Table 3.
be considered strongly in any patient sia. It is often necessary to examine A careful physical examination of
older than 3 years who has intussus- multiple sections to find and identify all node-bearing areas, including Wal-
ception. Jaw disease due to endemic the diagnostic Reed-Sternberg cell. deyer ring, is essential. Cervical and
Burkitt lymphoma is common in Af- In the case of mixed cellularity, Reed- supraclavicular lymph nodes are in-
rica, but uncommon elsewhere. Pri- Sternberg cells and their variants are volved most commonly and will have
mary lymphoma of the central nerv- usually quite plentiful. The lymph a characteristic “rubbery” quality (ie,
ous system is relatively rare but in- node is usually effaced diffusely, and the consistency of a hard rubber ball
creasing in incidence, particularly in fine interstitial fibrosis may be seen. under the skin). Chest radiography is
association with the acquired immu- Lyrnphocytic depletion is character- required. Masses with a diameter of
nodeficiency syndrome. ized by the presence of principally more than one third of the thoracic
The diagnosis of HL or NHL is abnormal cells, with a relative paucity diameter may have a poor prognosis.
proved only by tissue diagnosis at of lymphocytes. In most cases of The adequacy of the airway must be
lymph node biopsy. Needle aspiration nodular sclerosis, there is a thickened assessed and may be appreciated
is discouraged because of the fre- capsule with a proliferation of orderly only on the lateral film or on a corn-
quent obtainment of inadequate collagenous bands that divide the puted tomography scan of the chest
specimens and the consequent de- lymphoid tissue into circumscribed (Fig 2, A-C). Evidence of involvement
lays in diagnosis and therapy. Due to nodules (Fig 1 B). About two thirds
, of the chest wall or pericardium on
the very rapid growth rate of NHLs, of pediatric patients have nodular the scan also indicates a poor prog-
effective tissue diagnosis is a medical sclerosis, although lymphocytic pre- nosis. Once the adequacy of the air-
emergency. Because specialized re- dominance and mixed cellularity are way is assured, lymph node biopsy
sources are required to perform im- relatively more common in children to establish a histologic diagnosis
munophenotyping of fresh tumor, bi- younger than 10 years of age. Prog- may be performed before proceeding
opsy should be performed at a refer- nosis is correlated generally with the with the remainder of the workup.
ral center that has such capabilities. ratio of lymphocytes to abnormal Lymph node aspiration will not allow
Occasionally, in the case of dissemi- cells. a definitive diagnosis.
nated disease, a bone marrow aspi- The computed tomography scan
rate may be adequate for diagnosis. can be used to assess the extent of
STAGING AND DIAGNOSTIC
Prior to procedures for tissue di- abdominal and pelvic disease, al-
WORKUP OF HODGKIN
agnosis, features of acute tumor lysis though it is not ideal for imaging ret-
LYMPHOMA
syndrome must be sought, with pro- roperitoneal lymph nodes because
phylactic and specific supportive The Ann Arbor staging classifica- enlargement is detected while archi-
therapy initiated. tion for HL at initial presentation has tecture is not well characterized. The
been used for almost two decades. It classic method of evaluating the ex-
forms the basis for selection of treat- tent of retroperitoneal adenopathy is
PATHOLOGY OF HODGKIN
ment and has allowed comparison of lymphangiography. With this tech-
LYMPHOMA
results between investigators. This nique, the nodal architecture can be
The hallmark of Hodgkin lymphoma classification is based on the as- determined and specific nodes iden-
is the Reed-Sternberg cell, a large, sumption that HLs spread contig- tified for biopsy during laparotomy.
typically multinucleate cell (15 to 45 uously along lymphatic pathways and Moreover, because the nodes remain
m or more in diameter) with abun- that the initial portal of entry of dis- opacified for months, they can be
dant cytoplasm (Fig 1, C). It is as yet ease from the thorax to the abdomen monitored by plain abdominal radio-
unclear whether the Reed-Sternberg is the spleen. When radiotherapy was graphs. There are definite drawbacks
cell is derived from lymphocytes or the rnainstay of treatment in the early of the technique, however. The dye
mononuclear phagocytes. In addition, days, it was necessary to localize provokes an inflammatory response
in the lymph node, one sees an ad- disease precisely, and the concept of in the lymph nodes, which invalidates
mixture of apparently normal reactive a staging laparotorny involving sple- the subsequent use of other studies,

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 HEMATOLOGY/ONCOLOGY

p
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Fig 1. A, normal lymph node showing normal architecture with germinal centers; B, lymph node in Hodgkin disease showing fibrotic bands of
nodular sclerosis histology; C, Reed-Sternberg cells characteristic of Hodgkin disease (high power view); 0, lymph node of Burkitt lymphoma
showing ‘starry sky” appearance of macrophages.

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Hodgkin disease

less generally in the practice of mod-

TABLE 2. Ann Arbor Staging System for Hodgkin Lymphoma em pediatrics.
Because HL is a disease of the
Stage Definition
reticuloendothelial system, measure-
I Involvement of a single lymph node region (I) or of a single extralym- ments of acute phase reactants such
phatic organ or site (IE) as the erythrocyte sedimentation rate
II Involvement of two or more lymph node regions on the same side of
and serum ferritin and serum copper
the diaphragm (II) or localized involvement of an extralymphatic
levels will often be abnormal in pa-
organ or site and one or more lymph node regions on the same
side of the diaphragm (lIE) tients with active disease. These non-
III Involvement of lymph node regions on both sides of the diaphragm specific tests are useful during follow-
(Ill), which may be accompanied by involvement of the spleen up, but they must be interpreted with
(IllS) or by localized involvement of an extralymphatic organ or caution.
site (IIIE), or both (IIIE) At the moment, the only way to
IV Diffuse or disseminated involvement of one or more extralymphatic evaluate the spleen fully is by surgical
organs or tissues, with or without associated lymph node in- resection at the time of laparotomy.
volvement Involvement of the spleen may be
The absence or the presence of fever, night sweats, or unexplained loss of 10% patchy. Computed tomography
or more of body weight in the 6 months preceding diagnosis is to be denoted scans have not been useful in detect-
in all cases by the suffix letters A or B, respectively. ing involvement; magnetic resonance
imaging is currently being evaluated
for this purpose. Splenectomy
causes a secondary immunodefi-
ciency, however, with a 5% to 10%
TABLE 3. Elements of the Evaluation of a Patient Newly Diagnosed with
likelihood of sepsis with encapsulated
Lymphoma
organisms, such as pneumococcus
Hodgkin Non-Hodgkin or Haemophllus influenzae, and pos-
Lymphoma Lymphoma
sibly a 5% to 1 0% mortality, even
Physical examination with measurement of + + with modern antibiotics. If the plan is
enlarged nodal areas to use only chemotherapy in the man-
Chest radiograph (anteroposterior and lat- + +
agement of the patient, splenectomy
eral) may be avoided.
Complete blood count + +
Computed tomography scan of abdomen + +
and pelvis TREATMENT OF HODGKIN
Computed tomography scan of chest + +
LYMPHOMA
Erythrocyte sedimentation rate and meas- +
urement of serum levels of copper and Because HL is curable, patients
femtin should be referred for evaluation and
Examination of bone marrow aspirate +
therapy to a center that has an active
Bone marrow biopsy + +
pediatric oncology program. The mi-
Cerebrospinal fluid examination (induding +
cytology) tial management decisions about a
Gallium scan + new patient must be made collabo-
Human immunodeficiency virus serology ± + ratively by the radiation oncologist,
Liver and renal chemistries + + pediatric oncologist, and pediatric
Lymphangiography* ± surgeon. It is imperative that patients
Measurement of serum lactate dehydrogen- ± + who will be treated with radiotherapy
ase and uric acid levels
alone undergo a staging laparotomy.
Nuclear bone scan + +
Staging Iaparotomy* including splenectomy, +
node sample, liver biopsy, and oopho- Stages I and IIA Disease
ropexy
Radiation therapy alone was used
Thyroid function studies (baseline) +
early in the treatment of HL. With
* text for discussion of controversy
See regarding the use of lymphangiography radiation alone to an extended field,
and laparotomy. about 50% of patients with early
stage disease will be cured. Many
others have recurrent disease and
such as gallium scanning. In addition, anatomic localization of disease is be- can be saved with chemotherapy, so
a lipoid pneurnonitis may develop coming less critical with increasing that the overall survival rate is around
after exit of dye from the thoracic use of chemotherapy and because 95%. In most pediatric centers these
duct, so the study should not be per- there is often not an experienced days, three to six courses of chemo-
formed in patients with respiratory team to perform this procedure, therapy are added to radiotherapy.
compromise. Because the precise lymphangiography is becoming used This allows patients to be cured with

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 HEMATOLOGY/ONCOLOGY

radiotherapy be given as well? The

first chemotherapeutic regimen to be
tested was the combination known
as MOPP (nitrogen mustard [me-
chlorethamine hydrochloride], vincris-
tine sulfate, prednisone, and procar-
bozine hydrochloride). With 6 to 12
courses of this therapy, there will be
a 50% to 70% 5-year failure-free sur-
vival rate in patients with advanced
disease. A newer combination, ABVD
(Adriamycin, bleomycin, vinblastine,
and dacarbazine), has been used in
adults and in a randomized study.
ABVD, either alone or alternating with
MOPP, appears to provide better dis-
ease control than MOPP alone. This
chemotherapy is being studied exten-
sively in childhood HL and appears to
be effective. Results of therapy are
summarized in Table 4.

THERAPY OF RELAPSED
HODGKIN LYMPHOMA
There is a significant salvage rate
in patients who relapse after initial
therapy. The response rate will be
highest in those patients who re-
ceived the least amount of initial ther-
apy. If radiotherapy alone was given,
then about 90% of the patients will
respond to later chemotherapy. If
chemotherapy alone was given, then
around 70% will respond to a differ-
ent, effective chemotherapy. If pa-
tients have already received alterna-
ting MOPP and ABVD and radiation,
then the response rate may be low.

PATHOLOGY OF CHILDHOOD
NON-HODGKIN LYMPHOMA

Fig 2. Radiographs and computed tomography scan of chest on a single patient at the time of In contrast to adult lymphomas, pe-
diagnosis: A, anteroposterior chest radiograph with large mediastinal mass and apparently diatric non-Hodgkin lymphomas all
adequate airway; B, lateral chest film showing some airway compression; C, computed tomog- show diffuse destruction of lymph
raphy scan at level of carina showing distal airway compression from mediastinal mass. node architecture and may be divided
simply into three main categories on
their first course of treatment and ours), these patients receive chemo- the basis of histopathology: lympho-
allows a lower dose of radiation to be therapy as well. Overall survival rate blastic lymphoma, about 33% of
given, avoiding the deleterious ef- is approximately 90%. cases; small noncleaved cell lym-
fects radiation therapy has on phoma, including Burkitt and non-
growth. Burkitt type, about 50% of cases, and
large cell lymphoma, about 15%. The
Stage IIIB or IV Disease
Stage lIB and Favorable lIlA remainder of NHLs are miscellaneous
Disease
There is general agreement that or unclassified. The development of
patients who have stage IIIB or IV immunocytochemical staining and tu-
In some centers, patients who disease should receive chemother- mor karyotyping has added valuable
have stage IIB and favorable lIlA dis- apy as their primary treatment. The tools for the specific pathologic di-
ease may be treated with radiation questions are: Which type of chemo- agnosis of the lymphomas.
alone but, in most centers (including therapy and for how long? Should Lymphoblastic lymphoma may be

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Hodgkin disease

regarded as essentially a T-cell rnalig- markers that may suggest T-ceII or such as the serum level of lactate
nancy. Histologically, its cells- are in- B-cell, or even histiocytic, lineage. dehydrogenase, may correspond to
distinguishable from those of acute Histologically, the cells resemble the tumor load, and lactate dehydro-
lymphoblastic leukemia. The cells are SNCL, but the larger cells contain genase levels greater than 1000 lU/L
usually uniform, sometimes with nu- larger quantities of cytoplasm. Some imply a very unfavorable prognosis.
clear convolutions and variable large cell lymphomas are classified Studies of serum chemistries focus
amounts of cytoplasm, but with a furtheras immunoblastic lymphomas, on identification of metabolic disor-
high nucleus-to-cytoplasm ratio. The which are seen more commonly in ders associated with the acute tumor
nuclear chromatin is finely stippled, adults. No characteristic karyotypic lysis syndrome, which is common in
and the multiple nucleoli are subtle. abnormalities have been identified, children who have non-Hodgkin lym-
Immunocytochemical stains reveal despite the fact that the adult form of phomas.
the presence of terminal deoxynu- large cell lymphoma often has a Currently, it is believed that 5% of
cleotidyl transferase and T-ceIl or, ti 4:1 8 translocation. adult cases of NHL may be associ-
rarely, pre-B-ceIl surface antigens. ated with human immunodeficiency
Chromosomal translocations involv- STAGING AND WORKUP OF
virus infection, and preliminary data
ing the T-cell receptor gene on chro- suggests that this figure will be simi-
CHILDHOOD NON-HODGKIN
mosome 14 are common, especially LYMPHOMA
lar in children. Owing to the increas-
ti 1 :14, but others are seen, including ing prevalence of human immunode-
tl:14, t8:14, and tlO:14. Various clinical staging systems ficiency virus infection, human im-
SNCLs have surface 1gM, which have been proposed for pediatric rnunodeficiency virus serology should
identify them as B-cell malignancies. NHL. The most widely used is the now be a mandatory part of the
This category includes both the Burk- Murphy staging system (Table 5). Ex- workup of any patient with a newly
itt and non-Burkitt types, but this dis- pedient staging and commencement diagnosed case of NHL.
tinction appears to be of no clinical of specific therapy is a medical emer-
importance. Histologically, the cells gency, owing to the extremely rapid TREATMENT OF CHILDHOOD
also have a high nucleus-to-cyto- progression of NHL, frequently with NON-HODGKIN LYMPHOMA
plasm ratio (Fig 1 D), although less
, the threat of fulminant airway ob-
than lymphoblastic lymphoma. The struction, acute renal failure, and ab- The treatment of childhood NHL
nucleus is round or oval, with open rupt metabolic decompensation. In begins with immediate assessment
lacy chromatin and multiple obvious cases of cervical or mediastinal and stabilization of the patient’s met-
nucleoli. The cytoplasm is highly ba- masses, the airway should be evalu- abolic status, as soon as the diag-
sophilic, often with lipid-containing ated by chest radiograph, with ante- nosis of NHL is suspected. The acute
vacuoles. The large majority of SNCL nor compression of the trachea tumor lysis syndrome is a result of
bear the t8:1 4 translocation that ac- sometimes being visible only on the rapid lysis of tumor cells, which often
tivates the c-myC oncogene on chro- lateral view. If a paratracheal mass is occurs even before any antineoplas-
mosome 8 by bringing it under the suspected, airway patency is evalu- tic therapy, flooding the bloodstream
regulatory apparatus of the very ac- ated best by a computed tomography with cellular contents. Potassium re-
tive immunoglobulin heavy chain scan of the chest, which is important lease can result in abrupt hyperkale-
gene on chromosome 14. Less com- before any procedure performed un- mia. The metabolism of DNA, RNA,
mon translocations include t2:8, in- der general anesthesia. Appropriate and nucleotides results in hyperuri-
volving the K light chain gene on chro- staging studies at the time of diag- cemia and hyperphosphatemia. Pre-
mosome 2, and t8:22, involving the A nosis, as listed in Table 3, focus on cipitation of uric acid crystals in the
light chain gene on chromosome 22. determining the extent of involvement renal tubules can lead abruptly to un-
These translocations have strongly of lymph nodes, bone, bone marrow, nary obstruction and acute renal fail-
implicated c-myC activation in the and cerebrospinal fluid. Involvement ure, which in turn can result in sudden
pathogenesis of SNCL. of the latter two confers a particularly death due to hypenkalernic cardiac
Large cell lymphomas are a heter- poor prognosis. Tests that represent dysrhythmia. Renal parenchymal lym-
ogenous group with cell surface the extent of cellular proliferation, phornatous involvement and ureteral
compression due to para-aortic ade-
nopathy can contribute to urinary ob-
struction.
TABLE 4. Prognosis of Childhood Hodgkin Lymphoma*
Faure-F7e Survival The patient with suspected NHL
Stage Treatment should receive vigorous hydration
1-IIA RT alonet 50 95 with at least 3000 mL/m2/d of 5%
RT + CT (3-6 courses) 90 95 dextrose in 0.25 isotonic saline, given
IIB-IIIA AT alone 50 90 intravenously, without supplemen-
AT + CT (6 courses) 80 90 tary potassium unless significant hy-
IIIB-IV CT (6-12 courses) 50-70 70-80 pokalemia is present. Sufficient so-
* Values shown are approximate percentages. dium bicarbonate (usually 50 to 100
t AT = radiotherapy; CT = chemotherapy. mEq/L) should be added to maintain
a urine pH of 7 to 7.5 to optimize uric

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 HEMATOLOGY/ONCOLOGY

are quite intensive regimens. All in-

TABLE 5. The Murphy Staging System for Childhood Non-Hodgkin dude prophylactic central nervous
Lymphoma system treatment, usually with in-
trathecal methotrexate or cytarabine,
Stage Criteria for Extent of Disease
or both, and hydrocortisone has been
I A single tumor (extranodal) or single anatomic areas (nodal), exclud- included in some protocols. Central
ing mediastinum or abdomen. nervous system radiation therapy is
II A single tumor (extranodal) with regional node involvement. currently used only in the case of
Two or more nodal areas on the same side of the diaphragm.
demonstrable central nervous sys-
Two single (extranodal) tumors with or without regional lymph node
involvement on the same side of the diaphragm. tem disease. The duration of chemo-
A primary gastrointestinal tract tumor (usually in the ileocecal area) therapy has been generally 1 to 2
with or without involvement of associated mesentenc lymph nodes years, but recent data suggest that
only, grossly completely resected. today’s intensive regimens may yield
III Two single tumors (extranodal) on opposite sides of the diaphragm. equivalent results with treatments of
Two or more nodal areas above and below the diaphragm. 6 months or less in selected cate-
All primary intrathoracic tumors (mediastinal, thymic, pleural). gories. Current clinical trials are fo-
All extensive primary intra-abdominal disease, unresectable. cusing on reduction of therapy dura-
All paraspinal or epidural tumors, regardless of other tumor sites. tion for low-stage NHL, on determin-
IV Any of the above with initial central nervous system, bone marrow
involvement, or both. (If the extent of bone marrow involvement is ing the need for maintenance
greater than 25%, the condition is classified as acute lymphoblas- chemotherapy, and on improving the
tic leukemia instead of lymphoma.) prognosis of SNCL with initial bone
marrow or central nervous involve-
ment.
acid solubility in the urine for the first considered strongly for patients with Local radiation therapy has played
24 to 48 hours. Allopuninol should be a high tumor burden, a high lactate an adjunctive role in the past, but it
given orally at a dose of 300 mg/m2/ dehydrogenase value, or metabolic now seems apparent that local radia-
d, divided into two to three doses. disturbances at initial examination. tion therapy adds no clear survival
Serum potassium, CO2, calcium, Antineoplastic therapy should be benefit to the current effective
phosphate, creatinine, and uric acid withheld for 24 to 48 hours if neces- chemotherapy regimens.
levels should be monitored every 4 to sary to establish metabolic stability, Modem intensive chemotherapy
6 hours until stable, with oral potas- but no longer, owing to the very short has demonstrated the curability of
sium binders and phosphate binders doubling time for NHL. It is imperative childhood NHL (Table 6). In its early
administered as indicated. Hypocal- to remember that treatment of an stages, the disease has a prognosis
cemia should not be treated with cal- obstructed airway with corticoster- of 90% long-term survival. The re-
cium unless the patient is sympto- oids or radiotherapy may precipitate suits of clinical trials currently in pro-
matic, owing to the risk of extraos- acute tumor lysis syndrome. gress are likely to indicate a prog-
seus calcium phosphate precipitation, The most recent breakthroughs in nosis of 70% long-term survival in the
especially in the renal tubules. Urine pediatric lymphoma therapy have case of more advanced lymphoblastic
alkalinization should be discontinued come with the proposal that pediatric lymphoma and, of special gratifica-
in the event of hyperphosphatemia, lymphomas are different from adult- tion, a prognosis of 80% long-term
because alkalemia can predispose to hood lymphomas and that lympho-
calcium phosphate precipitation and blastic and SNCLs respond best to
can further depress the serum ion- different chemotherapy regimens. In
ized calcium. general, the chemotherapy of child- TABLE 6. Prognosis of
High tumor burden or high serum hood SNCL relies heavily on cyclo- Childhood Non-Hodgkin
lactate dehydnogenase value may phosphamide and methotrexate, with Lymphoma
suggest higher risk of tumor lysis the best success in treating lympho- Failure-
syndrome, but the only accurate pre- blastic lymphoma coming with a mul- free
Type Stage Survival
dictor of renal failure is a declining tidrug combination of doxorubicin
(approximate
urine output; accordingly, this must (Adniamycin), cyclophosphamide, yin- %)
be monitored fastidiously. Acute cristine, prednisone, cytarabine, and
renal failure should be managed ag- L-asparaginase. The optimal therapy Lympho- I/Il 80-90
blastic lIl/IV 50-60
gressively with hemodialysis, rather for large cell lymphoma is not as Small I/Il 90
than peritoneal dialysis, which is less clear, but it generally responds well noncleaved III 70
effective at clearing uric acid. Addi- to regimens useful in lymphoblastic cell IV 15*
tionally, penitoneal dialysis catheters lymphoma. The rise in cure rates of lymphoma
may pose a high risk of life-threaten- childhood NHL has corresponded di- Large cell 60-70
ing peritonitis during the bone mar- rectly to increases in the intensity of * Preliminary results of current trials
row aplasia due to induction chemo- combination chemotherapy. There suggest an improvement to survival
therapy. Early or prophylactic admis- are several effective protocols for ad- rates of 70% to 80% for this group.
sion to a critical care unit should be ministration of these agents, but all

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Hodgkin disease

survival for stage IV SNCL-a re- is neurotoxic and may result in leg who do manage to conceive generally
markable improvement from the 17% weakness, cranial nerve palsies, and have normal offspring.
survival rate documented in previ- constipation. These toxicities are also Patients who have had a splenec-
ously completed trials. These prelim- reversible, and laxatives may be help- tomy are susceptible to life-threaten-
mary data will probably hold up with ful. ing infections with encapsulated or-
time, because relapses of pediatric A number of irreversible toxicities ganisms and should take penicillin
NHL generally occur during the first may also occur. Several agents, most prophylactically for life (250 mg orally,
12 months after diagnosis or not at notably nitrogen mustard, vincristine twice daily). In addition, patients who
all. The ever-improving cure rates sulfate, and doxorubicin may cause have received alkylating agent then-
reinforce the fact that the child with tissue necrosis if they extravasate apy, particularly in combination with
NHL will have the best prognosis if from the veins at the point of admin- radiation therapy, will have an in-
treated on a current research proto- istration. Doxorubicin is also cardi- creased risk of developing a second
col at a pediatric cancer referral cen- otoxic in a dose-related manner, sec- malignancy at a rate of about 0.5%
ten. ondary to myocardial cell death. Pa- per year. The early malignancies that
tients must be followed up with develop are likely to be acute myelog-
TREATMENT OF RELAPSED
echocardiograms, and therapy must enous leukemia; solid tumors can oc-
be stopped if decreases in ejection cur later.
CHILDHOOD NON-HODGKIN
fraction greater than 20% are seen. Despite these serious side effects,
LYMPHOMA
Because bleomycin can cause dose- most patients who are cured of their
Recurrent NHL poses an extremely related pulmonary fibrosis, appropni- lymphomas will lead normal lives.
poor prognosis with conventional ate follow-up studies should be done Current philosophies of therapy are
chemotherapy. Encouraging results when this agent is used. aimed at trying to maintain the excel-
have been obtained with massive Late-appearing toxicities of radio- lent cure rate of these diseases while
chemotherapy, usually with autolo- therapy include local growth failure. decreasing toxicity, either by de-
gous bone marrow rescue, using Following irradiation to an upper tho- creasing the amount of drug or by
agents such as carmustine (also racicfield, patients may develop small giving single modality rather than
known as BCNU), cytarabine, etopo- necks and short clavicles, and breast combined modality therapy. Radio-
side, melphalan, cyclophosphamide, bud development may be impaired. therapy has been all but eliminated
and 6-thioguanine. The long-term Hypothyroidism, manifest initially by from the control of NHL, and current
survival for the patient with isolated an elevated level of thyroid-stimulat- protocols regarding HL are studying
central nervous system relapse, or ing hormone, may occur in patients whether radiotherapy enhances the
relapsed disease which still shows who have received irradiation to the effect of chemotherapy.
some response to conventional neck. Pneumonitis and penicarditis Drug combinations other than
chemotherapy, approaches 50%. with tamponade may occur weeks to those mentioned in this review are in
Thus far, children with recurrent dis- months after treatment in patients use in experimental studies both in
ease unresponsive to conventional who have received full-dose radiation this country and abroad. Future then-
chemotherapy still have a poor prog- therapy. apeutic maneuvers in these patients
nosis of no better than 15% survival. Sterility in males occurs in a dose- may include the use of toxin or radio-
related fashion after alkylating agent actively labeled monoclonal antibod-
therapy. A lifetime dose of 6 g/m2 of ies to cell components such as a T-
TOXICITY AND LONG-TERM
EFFECTS OF THERAPY
cyclophosphamide or six courses of cell antigen, an antibody idiotype, or
MOPP will render all men sterile and ferritin (in HL). Because lymphomas
Most of the drugs used for the some may develop gynecomastia, al- are diseases of the immune system,
treatment of both HL and NHL are though around 50% will retain fertility it may be that immune modulators
toxic to rapidly dividing cells. Acutely, if only three courses of MOPP are (bone marrow transplantation with
the cells lining the intestinal tract will given. In general, since spermato- manipulation of the lymphocyte con-
be affected with consequent possible gonia are more susceptible to dam- tent of the infused marrow) may re-
sore mouth and throat, nausea, vom- age than Sertoli cells, men will de- sult in better control of the disease.
iting, or diarrhea. In addition, reversi- velop normal secondary sexual char- Molecular biologic approaches to
ble myelosuppression may occur with acteristics and will have normal control of cell proliferation may also
thrombocytopenia and anemia that hormonal function; sterility must be become available with better under-
may necessitate transfusions. The determined by sperm count. Women standing of basic cell control mecha-
most dangerous manifestation of will be sterile and amenorrheic if suf- nisms.
myelosuppression is neutropenia ficiently high doses of radiation are
with increased susceptibility to seri- aimed directly at the ovary, and many THE ROLE OF THE GENERAL
ous infection. Patients who are si- women experience premature men-
PEDIATRICIAN
multaneously febnle and neutropenic opause after MOPP chemotherapy.
must be admitted to the hospital for Oophoropexy at the time of laparot- The crucial initial role of the general
broad spectrum intravenous antibi- omy to move the ovaries out of the pediatrician in the diagnosis and care
otic coverage. Temporary hair loss to radiation field can prevent these ef- of the child with cancer is to suspect
varying degrees will occur. Vincristine fects. Those patients, male or female, the diagnosis early and to initiate as

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 HEMATOLOGY/ONCOLOGY

early as possible a referral to a pedi- cer patients regarding the etiology of failure at onset of therapy for advanced
atnic oncologist. The subsequent role cancer, the risk to other children, and stage Burkitt lymphoma and B-cell acute
lymphoblastic lymphoma. Pediatrics.
of the general pediatrician in the pa- the delayed effects of cancer treat- 1 988;82:863-869
tient’s care varies according to the ment. Although oncologists often
child, family members, and health provide primary cane to their patients
professionals involved. Unfortu- during chemotherapy, after 6 to 24
nately, family members sometimes months successfully treated patients
Self-Evaluation Quiz
direct their anger at the general pe- will normally return to the primary
diatnician who initially suspected the care of their general pediatricians. 6. The diagnosis of Hodgkin lymphoma
diagnosis of cancer, creating difficul- Although childhood lymphomas are (HL) or non-Hodgkin lymphoma (NHL) in the
ties in the relationship. Some pedia- highly malignant diseases, treatment abdomen is best made:
A. On clinical grounds.
tnicians may feel intimidated at the has become among the most reward-
B. On finding of Epstein-Barr virus DNA in
prospects of participating in cancer ing in the practice of pediatric oncol-
Reed-Stemberg cells.
treatment, and most consulting on- ogy. Lymphomas now serve as C. On biopsy of involved tissues.
cologists will not expect the pediatri- models of curable cancer in child- 0. By lymphangiography.
cian to maintain an active role in the hood. The future undoubtedly holds
cancer therapy, although generally further improvements in cure rates 7. Staging of HL or NHL gives attention to
the pediatrician is welcome to partic- and in management of the medical each of the following except:
A. Cellular type.
ipate if he on she expresses a specific and social consequences of child-
B. Number of sites involved.
desire to do so. hood cancer. C. Whether organs on both sides of the di-
Close consultation with the oncol- aphragm are involved.
SUGGESTED READING
ogist is necessary if the pediatrician 0. Location of a primary tumor.
sees the patient who is receiving Gilchrist GS, Evans RG. Contemporary issues
chemotherapy, because the manifes- in pediatric Hodgkin’s disease. Pediatr Ciln 8. Each of the following is more common
North Am. 1 985;32:721 -734 with NHL than with HL except:
tations of rapidly progressive, life- Graham M. Non-Hodgkin’s lymphomas. Pe- A. Rapid progression.
threatening infection may be subtle in diatr Ann. 1988;17:192-203 B. Superior vena cava syndrome.
neutropenic children. The Red Book Hays D, Temberg J, Chen T, et al. Post-sple-
C. Abdominal mass.
of the American Academy of Pediat- nectomy sepsis and other complications fol-
0. Intussusception.
lowing staging laparotomy for Hodgkin’s dis-
rics provides specific recommenda- E. Night sweats.
ease in childhood. J Pediatr Surg.
tions regarding immunizations in im- 1 986;21 :628-632
9. The tumor lysis syndrome is least likely
munocompromised children and their Leventhal BG, Donaldson SS. Hodgkin’s dis-
to be associated with:
siblings. ease. In: Pizzo PA, Poplack DG, eds. Prin-
A. Hyperphosphatemia.
It is important that the pediatrician ciples and Practice of Pediatric Oncology.
Philadelphia: J. B. Lippincott Company; B. Hyperkalemia.
and oncologist communicate to pro- 1989:457-476 C. Hyperuncemia.
vide compatible answers to common Stapleton FB, Strother OR, Roy S. 3d, wyatt 0. Hypercalcemia.
questions that plague families of can- RJ, Mckay CP, and Murphy SB. Acute renal E. Elevated lactate dehydrogenase activity.

Intracranial Injury

Intracranial Injury After Moderate Head Trauma in Children. Rosenthal BW, Berg-
man I. J Pediatr. 1 989;1 15:346-350.
Records of 459 children who had normal findings on a neurologic examination after
moderate head injury characterized by brief loss of consciousness were evaluated
retrospectively. Skull x-ray examination had been performed in 358 children, and 52
(14%) had fractures. Intracranial complications developed in six children (1.3%); five
had extradural hematomas and one had bifrontal contusions. All six of these children
had skull fractures. Three children required surgical evacuation of hematomas between
24 and 72 hours after injury. On the basis of these results, these researchers conclude
that, in the absence of skull fracture, most alert children without symptoms who have
sustained moderate head injury may be discharged safely from the emergency
department in the care of a competent observer. (R.J.H.)

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 Childhood Hodgkin and Non-Hodgkin Lymphomas
Brigid G. Leventhal and Gregory J. Kato
Pediatrics in Review 1990;12;171
DOI: 10.1542/pir.12-6-171

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 Childhood Hodgkin and Non-Hodgkin Lymphomas
Brigid G. Leventhal and Gregory J. Kato
Pediatrics in Review 1990;12;171
DOI: 10.1542/pir.12-6-171

The online version of this article, along with updated information and services, is located on
the World Wide Web at:
http://pedsinreview.aappublications.org/content/12/6/171

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and
trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove
Village, Illinois, 60007. Copyright © 1990 by the American Academy of Pediatrics. All rights reserved.
Print ISSN: 0191-9601.

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