-
Leukemia andLymphomaR. Paul Guillerman, MDa,*, Stephan D. Voss,
MD, PhDb,Bruce R. Parker, MDa
into future applications of imaging in the man-agement of
pediatric leukemia and lymphomapatients.
for 80% to 85% of childhood ALL. About 12% ofALL is T-cell
lineage, which is associated with olderage, male gender,
leukocytosis, and a mediastinal
annin Street, Suite 470, Houston, TX
b Department of Radiology, Childrens Hospital Boston, Harvard
Medical School, 300 Longwood Avenue,
KEYWORDS
Lymphoma Leukemia Hodgkin lymphomaleu
iologic.thec
linics
.comRadiol Clin N Am 49 (2011) 767797Boston, MA 02115, USA*
Corresponding author.E-mail address: [email protected]
Department of Pediatric Radiology, Texas Childrens Hospital, 6701
F77030, USAsearch into cancer cooperative group studyprotocols are
also discussed to provide insights
ALL is subtypedby theWorldHealthOrganization(WHO)by
immunophenotypeasB-lymphoblastic orT-lymphoblastic.4 Precursor
B-cell ALL accountsLeukemiaand lymphomaare
themostcommonandthirdmost commonpediatricmalignancies,
respec-tively, and together account for nearly half of allcases of
childhood cancer. Although childhoodleukemia and lymphoma share
similar cell lineageorigins and both are treated with
risk-stratifiedprotocols entailing cytotoxic chemotherapy,
theclinical manifestations and imaging indications forthese
malignancies vary substantially, with someoverlap.Advances in
imaginghaveplayedaparticu-larly important role in improving the
assessment oflymphoma at the time of diagnosis, during treat-ment,
and following therapy. Imaging has alsohelped guide the design of
clinical trials evaluatingnovel treatment strategies.Along with
providing relevant details on current
classification, epidemiology, and treatment, thisarticle reviews
the current roles of imaging in themanagement of pediatric patients
with leukemiaand lymphoma, with attention to diagnosis, stag-ing,
risk stratification, therapy response assess-ment, and surveillance
for disease relapse andadverse effects of therapy. Advances in
functionalimaging and integration of clinical imaging re-
Non-Hodgkin lymphoma Acute lymphoblastic Acute myeloid
leukemiadoi:10.1016/j.rcl.2011.05.0040033-8389/11/$ see front
matter 2011 Elsevier Inc. AllLEUKEMIAClassification and
Epidemiology
Leukemia is the most common childhood malig-nancy, accounting
for one-quarter to one-third ofchildhood malignancy cases. Nearly
all childhoodleukemia cases are the acute form. Acuteleukemia is
classified by the morphology, immuno-phenotype, and cytogenetics of
the leukemic cellsinto acute lymphoblastic leukemia (ALL) and
acutemyeloid leukemia (AML). ALL and AML accountfor three-quarters
and one-fifth of childhood leu-kemia cases, respectively. Chronic
myelogenousleukemia (CML) accounts for less than 5% ofcases of
childhood leukemia, whereas juvenilemyelomonocytic leukemia (JMML),
a myelodys-plastic-myeloproliferative syndrome, accounts forless
than 1% of cases of childhood leukemia.1
There is a sharp peak in ALL incidences amongchildren 2 to 3
years of age, with evidence thatALL initiates in utero2 AML rates
are highest inthe first 2 years of life, decline to a nadir at 6
yearsof age, and slowly increase during the adolescentyears.3
kemiarights reserved. rad
-
dren with leukemia so that those children who
diffuse demineralization. Lytic bone lesions are
Guillerman et al768have a good outcome with modest therapy canbe
spared more intensive and toxic treatment,whereas a more
aggressive, and potentially moretoxic, therapeutic approach can be
provided forpatients who have a lower probability of long-term
survival. The 10-year event-free survival(EFS) rate is 67% to 78%
for standard and higherrisk childhood ALL with risk-adapted
combinationchemotherapy and central nervous system
(CNS)prophylactic therapy (intrathecal chemotherapywith or without
cranial radiation).6 More intensivechemotherapy regimens or
hematopoietic stemcell transplantation (HSCT) may be pursued
forcertain high-risk ALL groups and marrow relapse.Children with
AML have a wide range in outcome
depending on specific biologic factors, with a 5-year EFS rate
of 40% to 58%.7 Infection, severehemorrhage,
hyperleukocytosis-related leukosta-sis, and resistant leukemia lead
to thehighmortality.The mainstay of AML treatment is systemic
combi-nation chemotherapy, with some form of CNS-directed therapy
incorporated into most protocols.Induction of profound bone marrow
aplasia isgenerally necessary to achieve remission, andleukocyte
growth factors such as G-CSF or GM-CSF are often administered to
reduce the durationmass. T-cell lineage ALL may be regarded asa
disseminated form of T-cell lymphoblasticlymphoma in terms of
malignant phenotype,approach to therapy, andpatterns of relapse.
About2% of ALL is mature B-cell and the disseminatedform of Burkitt
or Burkitt-like lymphoma.1 AML hastraditionally been subtyped into
M0 to M7 formsaccording to the French-American-British
(FAB)Cooperative Group morphologic-immunohisto-chemical
classification system. Acute promyelo-cytic leukemia (APL), the M3
subtype of AML, isnotable for bleeding complications related to
severecoagulopathy. A newer classification of AML by theWHO
incorporates cytogenetic abnormalities andspecific gene mutations
and provides more reliableprognostic information.4
An increased risk of leukemia is associated withcertain genetic
disorders, including trisomy 21,monosomy7, andneurofibromatosis
type 1 (partic-ularly JMML), and DNA repair disorders such
asataxia-telangiectasia. Of special interest to theradiologist is
the reported increased risk ofleukemia fromprenatal or postnatal
radiation expo-sure, although the magnitude of the risk is
subjectto considerable uncertainty and debate.5
Treatment
Risk-based treatment assignment is used in chil-of neutropenia,
but have no significant effect onusually metadiaphyseal and
geographic or perme-ative. Subperiosteal resorption of the medial
cortexof the proximal humerus is commonly visible onchest
radiographs at the time of presentation, butis nonspecific and can
also be observed in thesetting of Gaucher disease, sickle cell
disease,mortality. The duration of remission is prolongedby
chemotherapy intensification and/or HSCT,although HSCT may not be
necessary in thosewith complete remission and favorable
prognosticfactors.8,9
Imaging Features
Fever, petechiae, lethargy, and pallor caused bybone marrow
suppression by leukemic cells arecommon at presentation. These
symptoms andsigns often prompt a chest radiograph. Chest
radi-ography may reveal a mediastinal mass (especiallyfrom thymic
infiltration in T-cell ALL), cardiomegalyand pulmonary vascular
plethora (related toanemia), pulmonary air space opacification
(relatedto infection, hemorrhage, or leukostasis),
pleuralthickening (especially in JMML), splenomegaly(present in
75%), or skeletal abnormalities.10
More than a third of children with leukemiapresent with limping,
bone pain, arthralgia, or othercomplaints referable to the
extremities or spine.Approximately 40% of children presenting
withacute leukemia have at least 1 radiographic
skeletalabnormality.11,12 The number of bones involved
onradiographs correlates with bone pain severity,but symptoms
correlate poorly with the location ofskeletal lesions on
radiographs and asymptomaticinvolvement is common, especially in
nonweight-bearing areas.12,13 Findings of leukemia on
skeletalradiographs include transverse lucent metaphysealbands,
diffuse demineralization, subperiostealcortical bone erosion,
periosteal reaction, lyticbone lesions, osteosclerosis, and
pathologic frac-tures. Transverse metaphyseal lucent bands,
alsoknown as leukemic lines, are attributable to distur-bance of
endosteal mineralization resulting inabnormally small trabeculae
adjacent to the zoneof provisional calcification. In preschool-aged
chil-dren, transverse lucent metaphyseal bands aremore specific for
leukemia than for other diseasesand are most conspicuous at sites
of rapid skeletalgrowth such as the distal femur, proximal
tibia,proximal humerus, and distal radius (Fig. 1).12
Diffuse demineralization is common, particularlyafter
therapy,whereasosteosclerosis is uncommonand usually a late
manifestation after therapy. Path-ologic fractures are most
commonly observed asvertebral compression deformities in the
setting ofneuroblastoma, or lymphoma (Fig. 2).14
-
Technetium (Tc)-99m phosphonatebased bonescintigraphy is
abnormal in 75% of patients withALL at diagnosis. The most common
abnormalityis symmetric increased uptake in the metadiaphy-ses of
the lower limbs (Fig. 3). Other patternsinclude diffuse increased
uptake in a superscanpattern with accentuation of the long bone
meta-physes, focal increased uptake at sites of corticalbone
destruction or pathologic fracture, and focaldecreased uptake at
sites of osteonecrosis.15 Theaddition of early phase whole-body
scintigraphymay increase the sensitivity for detection ofabnormal
uptake from leukemia in the long bonemetadiaphyses, spine, and
pelvis compared withthat of delayed-phase whole-body
scintigraphyalone.16 The number of regions with abnormaluptake is
positively correlated with age. There isonly modest correlation
between the sites ofabnormal uptake, radiographic abnormalities,
andclinical signs and symptoms.17
Fig. 1. An ankle radiograph from a 7-year-old girlwith precursor
B-cell ALL shows transverse lucentbands (leukemic lines) along the
distal tibial andfibular metaphyses just proximal to the zones
ofprovisional calcification.
Fig. 2. Anteroposterior (A) and lateral (B) chest
radiograpsubperiosteal resorption of the medial cortex and
subtlehumeri, as well as diffuse demineralization of the
vertebr
Leukemia and Lymphoma 769On magnetic resonance (MR) imaging,
malig-nant infiltration of the bone marrow by leukemiatypically
manifests as increased signal intensityon fat-suppressed
T2-weighted and short-tauinversion recovery (STIR) sequences and
de-creased signal intensity on T1-weighted images.18
Prolongation of the T1 relaxation time correlateswith the
proportion of blast cells in the marrow.19
The infiltration is usually diffuse, including involve-ment of
the epiphyses (Fig. 4). The findings areless conspicuous in
hematopoietic marrow thanin fatty marrow and consequently are more
difficultto appreciate in younger children before the phys-iologic
conversion of hematopoietic to fattymarrow.20 ALL and AML cannot be
reliably
hs of a 7-year-old boy with precursor B-cell ALL
revealtransverse lucent metaphyseal bands of the proximal
al bodies.
-
Leukemic involvement of the solid viscera,especially the spleen
and thymus, is common,and manifests as organomegaly from diffuse
infil-tration or as focal masses. Diffuse infiltration ofthe thymus
is characteristic of T-cell ALL (Fig. 5).Splenomegaly and a
mediastinal mass fromthymic infiltration at presentation of
childhoodALL are independent predictors of tumor lysissyndrome.22
The constellation of splenomegaly,hepatomegaly, lymphadenopathy,
and skin rashis characteristic of JMML.23 Nephromegaly
atpresentation is usually caused by leukemic cellinfiltration, but
can also be caused by renal veinthrombosis from intravascular
leukostasis.24 Focalrenal leukemic masses at presentation are
usuallymultifocal, bilateral, low attenuation on computedtomography
(CT), and hypoechoic on ultrasound,and must be differentiated from
lymphoma,nephroblastomatosis, and infection. Renal infiltra-tion is
most frequent with T-cell ALL and the M4and M5 subtypes of AML, and
is often accom-panied by extramedullary involvement at other
Fig. 3. A delayed-phase Tc-99m methylene diphosph-onate bone
scintigraphy image of the lower extremi-ties of a child with
precursor B-cell ALL depictssymmetric increased radiopharmaceutical
uptake inthe long bone metadiaphyses.
Guillerman et al770distinguished from MR imaging or MR
spectros-copy. The MR imaging appearance associatedwith marrow
infiltration by acute leukemia is notspecific and can also be seen
in settings of hema-
topoietic marrow hyperplasia and infiltrativemetastases from
solid tumors such as neuroblas-toma, rhabdomyosarcoma, and Ewing
sarcoma.21
Fig. 4. An MR imaging examination of the lower extremitishows
diffuse abnormal low signal intensity of the bonabnormal high
intensity of the bone marrow on a STIR (B-cell ALL.sites.25
Leukemic infiltration of the kidneys israrely associated with acute
renal failure or renaltubular dysfunction at presentation.26,27
Pancre-atic enlargement from leukemic infiltration isunusual.28
Brain atrophy, at least borderline in degree andof unclear
cause, can be seen by CT in 40% ofchildren with ALL at diagnosis.29
Even in the pres-ence of neurologic symptoms, CNS imaging find-ings
other than atrophy are uncommon. Head CTor MR imaging can reveal
hemorrhage or infarction
es performed on a 3-year-old boy with refusal to walke marrow on
a T1-weighted image (A) and diffuseB) image caused by marrow
infiltration by precursor
-
associated with AML and is rare, occurring as anisolated finding
in less than 1% of cases of AMLand in 11% of cases along with
marrow diseaseat the time of diagnosis.36
A definitive diagnosis of leukemia is usually es-
imaging examination in an 11-year-old girl withAML shows a soft
tissue mass of the right maxillarysinus, zygoma, and inferior orbit
that is isointense tothe marrow of the diploe of the skull,
consistentwith a chloroma.
Leukemia and Lymphoma 771caused by intravascular leukostasis or
throm-bocytopenia.30 Cerebral hemorrhage is morecommon than
subdural or subarachnoid hemor-rhage. Abnormal enhancement of the
meningesor nerve roots in a child with leukemia
suggestsleptomeningeal involvement, even if CSF cytologicstudies
are negative. As many as half of all casesof acute leukemia involve
ocular manifestations,and the most frequent finding is retinal
hemor-rhage. Retinal hemorrhages related to leukemiaare usually
bilateral and located in the posteriorpole.31
A potential diagnostic pitfall is aleukemic or sub-leukemic
leukemia. From one-quarter to one-thirdof cases of leukemia present
with anemia andthrombocytopenia but no leukocytosis or leukemic
Fig. 5. A coronal chest CT image of 13-year-oldpatient with
T-cell ALL shows a characteristic medias-tinal mass from diffuse
leukemic infiltration of thethymus.blasts on peripheral blood
smear.11,32,33 Many ofthese patients have bone or joint pain that
canmasquerade clinically as osteomyelitis or arthritisfor several
months and prompt referral for muscu-loskeletal MR imaging
examinations. Appropriaterecognition of bone marrow infiltration on
MRimaging can suggest the correct diagnosis ofleukemia before
leukocytosis or blasts in theperipheral blood are noted.34
Extramedullary leukemia (EML), also known asgranulocytic sarcoma
or chloroma, describesa mass of leukemic cells outside the bone
marrow.EML is more common in infants than in older chil-dren and
can precede the blast phase by up to 4years.35 The skin, orbits,
CNS, and spine are themost common sites, and symptoms relate tomass
effect. On CT, EML masses show variableenhancement and can be
confused with otherneoplasms, hematoma, or abscess. On MR ima-ging,
EMLmasses show isointensity to hypercellu-lar bone marrow (Fig. 6).
EML is most commonlyFig. 6. A coronal T1-weighted image from an
MRtablished by bone marrow aspiration or biopsyrevealing malignant
cells of myeloid or lymphoidlineage. Definitive diagnosis can also
be estab-lished by biopsy of an extramedullary mass ofleukemic
cells.
Staging and Risk Stratification
Leukemia is conceptualized as a disseminatedmalignancy of the
hematopoietic system and thereis no role for traditional staging
based on imagingfindings as for lymphoma and solid tumors, evenfor
children with isolated EML whomust be treatedas if there is
systemic disease. ALL is classified aslow risk, standard risk, high
risk, and very high riskfrom clinical and biologic features and
early treat-ment response. Higher risk ALL groups includeinfants,
adolescents, those with high leukocytecounts, those with CNS
disease, those with initialinduction failure or high levels of
end-inductionminimal residual disease (MRD), and those with
-
Nephromegaly at the time of presentation is
several weeks before relapse is detected by iliac
Guillerman et al772reportedly an adverse prognostic factor
forALL.41 Nephromegaly in childhood ALL is alsocorrelated with
subsequent renal damage detect-able by renal MAG-3 or
dimercaptosuccinic acid(DMSA) scintigraphy.42 Overt testicular
involve-ment at diagnosis has been considered anadverse prognostic
factor for ALL, but this mayno longer be the case with aggressive
initialtherapy. Neither the presence of a mediastinalmass at the
time of diagnosis nor an incompleteresponse with a residual
mediastinal mass onchest radiograph at day 35 or 70 of
therapypredicts a worse prognosis in T-cell ALL.43
Therapy Response Evaluation
Imaging is not currently relied on to evaluateresponse to
therapy for childhood leukemia.However, some trends may be observed
onskeletal radiographs. The transverse metaphyseallucent bands
usually resolve quickly with treat-ment, whereas periostitis,
cortical erosion, andlytic bone lesions resolve more slowly, and
osteo-penia may worsen, related to steroids. Bone scle-rosis and
osteonecrosis may also develop aftertherapy.The high sensitivity of
MR imaging for bone
marrow abnormalities has led to investigation ofMR imaging as a
method for therapy responseevaluation. During chemotherapy for
leukemia,the bone marrow becomes hypocellular and ede-matous.
Following chemotherapy, there is progres-sive regeneration of
normal hematopoietic cellsand fat. Marked increase in the marrow
fat fractionis observed by chemical shift MR imaging in theT-cell
lineage, hypodiploidy or certain chromo-some translocations.37 In
AML, risk category defi-nitions are in evolution. Adolescent and
obesepatients are in a poorer outcome group and leuko-cyte count at
diagnosis is inversely related tosurvival, whereas trisomy 21, APL
subtype, andearly response to therapy are favorable factors.38
The prognostic significance of radiographic andscintigraphic
bone abnormalities is uncertain, relat-ing to conflicting reports
in the literature. It has beenreported that multiple bone
involvement on radio-graphs portends a shorter duration of
remissionand survival39; that there is no correlation of
radio-logical or scintigraphic extent of bone disease andduration
of remission or survival13,17; that childrenwithout radiographic
abnormalities have an aggres-sive form of leukemia, whereas those
with a fewbone lesions have an indolent form40; and that thosewith
radiographic bone lesions represent a subsetwith a better
prognosis.33marrow of patients responding to chemotherapy,bone
marrow aspirate or biopsy, reflecting thepatchy nature of relapsed
leukemia and effectsof sampling bias.50 Unlike the diffuse
marrowabnormality typical of leukemia on MR imaging atpresentation,
early relapsed ALL can manifest aswell-defined nodules of low
signal intensity onT1-weighted sequences and high signal
intensityon T2-weighted and STIR sequences. In thissetting,
directed marrow lesional biopsy may berequired to avoid
false-negative iliac marrowsampling.51 Although time to relapse is
an impor-tant predictor of outcome, evidence that earlydetection of
relapse by frequent surveillanceimproves outcome is lacking.52
Extramedullary involvement is more common atrelapse than at
presentation. Sanctuary sites forleukemic cells during therapy,
where relapse canoccur even in the presence of bone marrow
remis-whereas a low marrow fat fraction persists in thesetting of
unresponsive disease. In children withALL who enter remission,
marrow T1 relaxationtime normalizes, whereas the marrow T1
relaxa-tion time remains prolonged in those who do notenter
remission. However, the specificity of MRimaging is limited by the
difficulty in differentiatingviable neoplasm from effects of
therapy, includinghematopoietic marrow regeneration
(particularlywith G-CSF or GM-CSF therapy), hematopoieticmarrow
reconstitution following stem cell trans-plantation, marrow iron
overload from transfu-sional hemosiderosis, and marrow infarction
andfibrosis.4446 Because of these limitations, MRimaging has not
replaced marrow aspirate orbiopsy for assessment of therapeutic
response inleukemia.47
Surveillance for Relapse
The most common site of ALL relapse is themarrow, followed by
the CNS and testes. Isolatedmarrow involvement occurs in 48% of
cases ofrelapsed ALL in children at a median time of 26months,
whereas the incidence of isolated CNSrelapse is less than 5% and
the incidence of iso-lated testicular relapse is less than 2%.
Outcomeof ALL is poorer with early relapse and with iso-lated bone
marrow relapse than with later relapseand combined marrow and
testicular or CNSrelapse.48 Most AML relapses occur in themarrow,
with CNS relapse being uncommon.Survival is substantially lower in
those with shorterremissions, and relapsed leukemia is still
theprimary cause of death in patients with AML.49
In some instances, relapse of leukemia in thevertebral marrow
can be detected by MR imagingsion, include the CNS, testes, and
kidneys. CNS
-
prophylaxis has greatly reduced the incidence ofCNS relapse, and
surveillance imaging of theCNS is not warranted. A possible
exception isEML, for which relapse is extramedullary in nearly40%
of cases and most often in the CNS.36
Patients with suspected testicular relapse gener-ally go to
biopsy without imaging, but occasionallyultrasound is requested and
may show hypoe-choic, enlarged testicles with or without
focallesions (Fig. 7). Isolated testicular relapse is rareand
testicular biopsy at the end of therapy hasfailed to show a
survival benefit for patients withearly detection of occult
disease,53 arguingagainst a role for surveillance imaging of
thetestes.
incidence begins to equilibrate between thegenders and patients
older than 15 years of age
childhood and adolescent/young adult forms ofHL.54,55
HL is characterized by a variable number of char-acteristic
clonal multinucleated giant cells (Reid-Sternberg [RS] cells) in an
inflammatory milieu.The WHO classification separates the
uncommonnodular lymphocyte-predominant form of HL(NLPHL) from the
common form, designatedclassicHL.WHOsubtypesof
classicHLarenodularsclerosis (NS), lymphocyte rich (LR), mixed
cellu-larity (MC), and lymphocyte depleted (LD).56 TheNS subtype of
HL accounts for greater than 85%ofpediatricHLand is characterizedby
lymphnodesthat have thickened capsules and dense collage-nous bands
that separate the nodes into macro-
-ye
Leukemia and Lymphoma 773have an approximately equal incidence
betweenboys and girls.54 There are some studies suggest-ing an
association between chronic Epstein-Barrvirus (EBV) and HL and this
has led some investi-gators to propose a distinction between
the
Fig. 7. Testicular relapse of precursor B-cell ALL in a
3Surveillance chest radiographs are sometimesobtained to evaluate
for mediastinal relapse inpatients with T-cell ALL with a prior
mediastinalmass. However, a beneficial impact of this prac-tice on
outcome has not been established.
LYMPHOMAClassification and Epidemiology
Pediatric lymphoma, including Hodgkin lymphoma(HL) and
non-Hodgkin lymphoma (NHL), is thethird most common malignant
neoplasm in child-hood and adolescence. HL is unusual in
patientsyounger than 4 years of age, and typically occursin older
children and adolescents.3 In patientsyounger than 10 years of age,
there is a malepredominance of HL; beyond this age the
relativedefined masses on ultrasonography.nodules. The presence of
collagen and fibrousstroma contributes to the presence of
residualmediastinal soft tissue that is commonly seen earlyafter
completion of therapy, even after no viabledisease remains. The MC
subtype accounts for30% of the cases in young children and can
beconfused for NHL.The characteristic RS cell in classic HL is
believed to arise from preapoptotic germinalcenter B-cells that
cannot synthesize immuno-globulin and show constitutive activation
of thenuclear factor k-B pathway, conferring resistanceto apoptotic
stimuli. EBV is associated with 15%to 25% of HL in developed
countries and up to90% in developing countries, most commonly
inyounger patients with MC histology. Despite this,EBV serologic
status does not seem to be a prog-nostic factor in pediatric
patients with HL,57 incontrast with patients with NHL.NHL of
childhood is a heterogeneous collection
of lymphoid neoplasms that are not classified asHL. Although a
large number of forms of NHL arerecognized, the 4 most commonly
occurring inchildren include Burkitt lymphoma (BL), diffuselarge
B-cell lymphoma (DLBCL), anaplastic large
ar-old boy manifests as testicular enlargement by ill-
-
HL, NHL is more common in children younger than
Guillerman et al77410 years of age. There is also a male
predomi-nance, particularly in older patients.58 Age-specific
incidence also varies according to diseaseclassification, with LL
occurring with a fairlyconstant rate across all age groups,
whereasALCL and DLBCL predominate in older adoles-cents. Although
the cause of NHL is uncertain,there is an increased incidence of
lymphomas inimmunosuppressed patients. Other studies haveshown a
role for EBV in the pathogenesis of lym-phoproliferative disease
and NHL. Taken together,these findings suggest that disordered
immuno-regulation, with resultant clonal proliferation ofimmature
cells that have failed to differentiate,contributes to malignant
transformation in NHL.59
Each NHL subtype has characteristic pathologicfeatures, and
recent molecular and translationalinvestigations have led to new
understanding ofthe pathobiology of NHL.54,59 BL and DLBCL
arebelieved to derive from lymph nodegerminal centerregions where
proliferating B-cell lymphoblastsnormally differentiate. The
activation of proto-oncogenes and/or disruption of tumor
suppressorgenes or hypermutation of proto-oncogenes arebelieved to
result in the malignant transformationof these germinal center
lymphoblasts. Consistentwith this interpretation, B-lineage cell
surfaceantigen CD20 shows increased expression onboth BL and DLBCL.
ALCL shows expression ofCD30 and is characterized by overexpression
ofthe anaplastic lymphoma kinase (ALK) tyrosinekinase, which is
believed to play a role in ALCLtumor genesis. LL, in contrast with
the other pedi-atric NHL subtypes, predominantly arises
fromimmature T-cells, corresponding to defined stagesof thymocyte
differentiation. Less than 10%of LL isof B-cell origin.58 When
greater than 25% of thebone marrow is infiltrated with
lymphoblasts, thedisease is termed ALL rather than LL.
Posttrans-plant lymphoproliferative disease (PTLD) is seenin the
setting of both solid organ and bone marrowtransplantation, and
results directly from hostimmunosuppression.60,61 PTLD, which is
usuallyEBV-related, is not initially classified as
amalignantlymphoma and frequently responds to reduction
inimmunosuppression. However, the lymphoproli-ferative disease may
progress to an aggressiveB-cell lymphoma, resulting in widespread
malig-nant disease.62
Treatment
With current treatment approaches, the 5-yearcell lymphoma
(ALCL), and precursor T-cell and B-cell lymphoblastic lymphoma
(LL). In contrast withsurvival rate for children and
adolescentsdiagnosed with HL is around 95%.7 This highcure rate has
led to renewed interest in the rolethat treatment-related
toxicities and long-termconsequences of therapy play in overall
morbidityand mortality.63,64 The risk of death caused bydisease at
20 years from diagnosis almost equalsthe risk of death from other
causes, includingtreatment-related effects.63
In the 1960s and 1970s, extended field radiationtherapy improved
disease-free and overall survivalrates amongst patients with HL.55
However, thisso-called mantle radiation resulted in significantlate
effects in the irradiated tissues. Subsequentdevelopment of a
combination of chemotherapyregimens showed that disease-free
survival couldbe improved with lower dose radiation
therapyregimens, and, in certain patients with HL, elimina-tion of
radiation therapy altogether. In patients withlow-stage HL, overall
survival was no different forpatients whose initial therapy was
chemotherapyalone, because of effective salvage regimens.65,66
In patients with advanced-stage HL, EFS washigher for those who
received initial chemotherapyand radiation therapy compared with
those withchemotherapy alone.54,67 As with current
standardregimens, these early treatment regimens wererisk adapted:
those with favorable-risk disease,defined by low stage and low bulk
disease,typically receive 2 to 4 cycles of multiagent che-motherapy
with either low-dose involved field radi-ation or no radiation,
whereas those patients withhigher risk disease are stratified to
receive moreintensive chemotherapy before involved
fieldradiotherapy.55
These risk-adapted approaches do not take intoaccount initial
disease response, in contrast withresponse-adapted approaches, in
which the over-all treatment intensity is modulated during
thecourse of therapy based on initial response. Thislatter approach
is emerging as a potential meansof further reducing therapy and
potentially reduc-ing late effects for those patients with HL
inwhom cure is likely, while maintaining high curerates and
aggressive treatment of those patientsat higher risk of
relapse.64,67
Patients with NHL have lower overall survivalrates compared with
HL. With current treatmentapproaches, more than 85% of children and
75%of adolescents with NHL survive at least 5 years.7
Treatment of childhood NHL depends on localizedversus
disseminated disease. Localized disease istypically defined as
stage I or II disease, whereasstage III or IV disease is generally
considered tobe disseminated. In most children, NHL is
widelydisseminated from the outset, and systemic treat-ment with
aggressive combination chemotherapy
is usually recommended for most patients.54,58
-
Children with refractory or relapsed NHL havea worse outcome
than newly diagnosed patients,and thus aggressive up-front therapy
and earlyremission remain the goal of new treatmentregimens.68
The outcome for LL is excellent, with longer leu-kemialike
therapy consisting of induction, consoli-dation, and maintenance
therapy. In contrast,nonlymphoblastic NHL has superior outcomewith
short, intensive pulse therapy. For recurrentor refractory
B-lineage NHL or LL, survival is low(10%20%), emphasizing the
importance ofachieving cure during the initial therapy. For
recur-rent or refractory ALCL, as many as 60% ofpatients can
ultimately be salvaged and achievelong-term survival.69 PTLD can
involve multipleorgans and systems, and responds variably
toconventional lymphoma therapies.6062
Radiation therapy plays little role in the routinemanagement of
pediatric NHL, in contrast withHL.58 Mediastinal radiation is not
commonly used
Leukemia and Lymphoma 775for patients with mediastinal masses,
except in theemergent treatment of symptomatic superior venacava
obstruction or airway obstruction. Even inthis instance, low-dose
radiation is usually used.
Imaging Features
In HL, chest radiographs obtained for upper respi-ratory
symptoms and/or vague constitutionalsymptoms, such as fever or
night sweats, oftenprompt the initial diagnosis. At the time of
diag-nosis, a mediastinal mass is present in more thantwo-thirds of
patients with HL (Figs. 8 and 9).70
Fig. 8. An 18-year-old patient with HL. On the
uprightposteroanterior (PA) chest radiograph, the transversewidth
of the mediastinal mass exceeds one-third ofthe thoracic diameter,
meeting the criterion for bulk
disease.The diagnostic evaluation should always includeimaging
of the chest and neck up to the level ofthe Waldeyer ring. Large
neck and mediastinalmasses may compress the airway and
centralvascular structures. Care must therefore be takenin sedating
these patients before imaging.71 Aftera careful physiologic and
radiographic evaluationof the patient has been performed, the least
inva-sive procedure should be used to establish thediagnosis. If
possible, peripheral lymph nodebiopsy is preferable. Aspiration
cytology is notsufficient because of the absence of stromaltissue,
and core needle biopsies are necessary.Surgical staging has been
largely replaced byimaging; however, mediastinoscopy or
thoraco-scopy may be needed when other modalities failto establish
the diagnosis or if questionable areasof involvement result in
upstaging the patient andhistologic confirmation is required.Lung
involvement is seen in less than 5% of chil-
dren younger than 10 years of age and 15% ofadolescents with
HL.70,72 Nodules greater than 1cm are the most common pulmonary
finding duringstagingof patientswithHL, althoughdiffuse
intersti-tial thickening and lobar or segmental consolidationare
other pulmonary manifestations of disease. Thepresence of pulmonary
disease usually occurs inassociation with ipsilateral hilar or
mediastinallymphadenopathy (Fig. 10). The most commonmechanisms of
disease spreading into the lungsare hematogenous and lymphangitic
spread, andless frequent, direct invasion. Pleural
andpericardialeffusions are infrequent findings in HL and
usuallyresult from lymphatic obstruction.70 Pleural effu-sions are
typically transudative and usually negativefor malignant cells.
Pericardial effusion, whenpresent,maysuggest tumor involvement of
theperi-cardium fromdirect extension of the adjacentmedi-astinal
mass. Where pericardial involvement issuspected, MR imaging may be
superior to CT,particularly with the advent of respiratory
andcardiac gated MR imaging.Liver involvement by HL is almost
always
associated with splenic involvement, and splenicinvolvement
without associated para-aortic lym-phadenopathy is unusual (Fig.
11). Splenic in-volvement occurs in 30% to 40% of Hodgkindisease
(HD). Splenic size is unreliable for predict-ing splenic HD
involvement.73
At diagnosis, bone marrow involvement isunusual in HL. MR
imaging and [18F]fluorodeoxy-glucose (FDG)positron emission
tomography(PET) are more sensitive than conventional CT
fordetecting bone marrow involvement.72 Corticalbone involvement is
similarly rare in HL. Whenpresent, lesions are typically lytic and
may have
accompanying periosteal reaction.70
-
Historically, gallium (67Ga) scintigraphy was themainstay of
functional imaging in lymphoma buthas now usually been replaced by
FDG-PET.FDG-PET has been shown to be more sensitivethan gallium
scintigraphy for determining lung,bone, and nodal involvement and
has amuch lowerradiation dose than gallium scintigraphy.7476
Gallium has prolonged retention in the bowel,further limiting
its usefulness in evaluating intra-abdominal disease. Although
gallium scintigraphyapproaches the sensitivity of FDG-PET for
diag-nosis and staging of neck and mediastinal/chest
Fig. 9. Chest CT images of an 18-year-old girl (see
chesconglomerate lobular mediastinal lymphadenopathy.
Guillerman et al776nodal disease in pediatric HL, nearly all
institutionsFig. 10. A 14-year-old girl with HL. CT images
showpulmonary,mediastinal, andbilateralhilar involvement.have
access to FDG-PET scanning and there iscurrently little
justification for gallium scanning.FDG-PET has been studied
extensively in adult
lymphoma77 and, to a lesser extent, in
pediatricpopulations.72,78 The overall consensus frommultiple
studies is that FDG-PET is more sensitivethan CT for involvement of
normal-sized lymph no-des and extranodal disease, including the
spleen,liver, and bone marrow (see Fig. 11; Fig. 12).7984
Combined FDG-PET/CT imaging retains the highsensitivity of
FDG-PET for detecting disease, butimproves the specificity, with
coregistered fusedimages resulting in the highest sensitivity
andspecificity at detecting disease and correlatingsites of
abnormal FDG uptake with specificanatomic regions.80,82,85,86
False-positive FDG uptake is well recognizedand can result from
rebound thymic hyperplasia,hypermetabolic brown fat, muscle,
hyperplastic/recovering marrow and/or spleen, gonadal andbreast
cyclic hormonal stimulation, and sites ofrecent surgery or
infection (Fig. 13).87,88 The char-acteristic patterns of
nonspecific uptake are wellrecognized by experienced radiologists
and nu-clear medicine physicians and the use of coregis-tered
FDG-PET/CT has proved invaluable for
t radiograph in Fig. 8) with HL depict characteristicidentifying
and eliminating areas of false-positiveuptake from the diagnostic
evaluation.88 In someinstances, background uptake can be
reduced.For example, brown fat uptake can be largely elim-inated by
warming the patient, and, in challengingcases, premedicating the
patient with fentanyland/or benzodiazepines.89
Among pediatric NHL, BL most commonlypresents with
intra-abdominal visceral disease,and widespread extranodal
involvement is oftenpresent. The initial imaging evaluation is
usuallydirected at assessment of symptoms referable toabdominal
involvement. Involvement of the perito-neum, solid abdominal
organs, and bowel withcomplicating intussusception can be seen
(Figs.14 and 15).
-
Leukemia and Lymphoma 777Asmany as 75% of patients with LL
present witha mediastinal mass and dyspnea, wheezing,stridor, or
dysphagia.58 The mediastinal enlarge-ment in LL is attributable to
diffuse thymic involve-ment and does not show the typical
nodularheterogeneous appearance more characteristicof HL and other
forms of NHL (Fig. 16). Thesetumors grow rapidly and patients with
LL maydeteriorate quickly because of airway compres-sion and
impairment of venous return, particularlywhen patients are placed
supine or sedated. In thispopulation of patients, diagnostic
imaging may notbe possible because of the tenuous clinical statusof
the patient, and pleural fluid and/or bonemarrow aspiration may be
the only means of accu-rately diagnosing these patients.ALCL is
often associated with systemic symp-
toms and signs such as fever and weight loss,and a prolonged
waxing and waning course beforediagnosis. A mediastinal mass may be
seen in upto 40% of patients with ALCL, and, when present,is often
accompanied by large pleural and pericar-dial effusions. ALCL can
also involve lung, skin,
Fig. 11. Axial and coronal contrast-enhanced CT images
omediastinal mass with accompanying diffuse splenic invothis
patient with HL. The accompanying FDG-PET imageboth the chest and
abdomen.and bone,54 and often presents with extensivemultifocal
disease (Figs. 17 and 18).DLBCL has a less characteristic clinical
pattern
compared with other NHL subtypes. Most patientswith DLBCL
present with localized disease. Anteriormediastinal and/or bulky
cervical/supraclavicularlymphadenopathyaremorecharacteristicofDLBCLthan
of the other NHL subtypes. Up to 70%of thesepatients have a
mediastinal mass, which mayproduce airway obstruction and superior
venacava syndrome (Fig. 19).54,72 In general, thesetumors are more
aggressive than HL and malignantpericardial effusions resulting
fromdirect pericardialinvasion, malignant pleural effusions, and
pulmo-nary involvement may be seen (Fig. 20). Patientswith DLBCL
with disease localized to the medias-tinum may be difficult to
distinguish from HL basedon imaging (see Fig. 19).54 The presence
of meta-chronous peripheral lymphadenopathy or boneinvolvement
makes DLBCL the more likely diag-nosis. About 20% of pediatric
patients with DLBCLpresent with primary mediastinal disease
(primarymediastinal B-cell lymphoma).90 This presentation
f the chest and abdomen, respectively, show a largelvement and
mesenteric lymph node enlargement inshows diffuse FDG uptake
throughout the mass in
-
Guillerman et al778is more common in older children and
adolescents.These tumors are more aggressive and are associ-ated
with a worse outcome compared with otherpediatric large B-cell
lymphomas. Growth into adja-cent structures is common and there is
a character-istic tendency for focal involvement of the kidneys(see
Fig. 20).PTLD can involve multiple organs or have focal
involvement. The use of FDG-PET to stage theextent of disease
and assess response to therapyin PTLD is increasingly advocated
(Fig. 21).62,91
Staging and Risk Stratification
The Ann Arbor system for staging of HL was devel-oped to
classify anatomic sites of disease basedon a combination of
clinical, surgical, and imagingfindings. The Cotswold modifications
of the AnnArbor staging system incorporated the
prognosticimplications of tumor bulkiness and number ofdisease
sites into the staging system.92 The revisedAnn Arbor staging
system is shown in Box 1.Staging is largely based on identifying
diseaseabove or below the diaphragm and at identifyingnoncontiguous
involvement of extralymphatic sites
Fig. 12. Axial CT, coronal FDG-PET, and fused axial PET/CTnode
involvement was shown by FDG-PET and PET/CT fusiohave been
interpreted as unopacified bowel. This patient ihad extensive
pulmonary nodules, confirmed as FDG-avidof disease that indicate
hematogenous spread.Unique to HL is the designation of
extralymphaticdisease that results from direct extension of
aninvolved lymph node region, which can be chal-lenging at the time
of staging. For example, contig-uous involvement of lung adjacent
to a largemediastinal mass may be considered stage IIErather
thanstage IVdisease.However, thepresenceof a malignant pleural
effusion that is cytologicallypositive for HL would be considered
stage IV. Forareas of questionable noncontiguous extralym-phatic
involvement, pathologic confirmation maybe requiredbeforeassignment
tostage IV.Thepres-ence of B symptoms (fever, night sweats,
weightloss) is included in the staging of the patient,
andinfluences whether the patient is assigned to a lowor
intermediate/high-risk treatment regimen.The posteroanterior (PA)
upright chest radio-
graph is still used for determining the presence ofbulk disease
(mediastinal mass > one-third of themaximal transthoracic
diameter) (see Fig. 8).55
However, the Cotswolds modification of the AnnArbor
classification also defines lymph nodesgreater than 10 cm in
maximal dimension on CTimaging as bulky. Despite various attempts,
the
show extensive FDG-avid HL. Retroperitoneal lymphn, whereas the
same site shown on the CT alone coulds the same 14 year old who is
shown in Fig. 9, who alsosites of disease.
-
Fig. 13. A 15-year-old patient with stage IV HL. Baseline
FDG-PETand CT show extensive disease, including pulmo-nary lesions.
At the end of therapy, FDG uptake has resolved, except for presumed
background brown fat uptakein the neck. Residual CT abnormalities
were interpreted as scar tissue in view of the negative FDG-PET
scan. By 4months after completion of therapy the patients pulmonary
relapse was obvious by CT and confirmed by FDG-PET. Rx,
treatment.
Fig. 14. Sporadic BL has a proclivity for widespread extranodal
involvement, as illustrated by the presence ofmasses in the
pancreas and right kidney on an abdominal CT image (A), proximal
right tibial bone marrow onan T1-weighted MR image (B), and
lumbosacral epidural space on a sagittal STIR MR image (C) in this
8-year-old boy.
Leukemia and Lymphoma 779
-
Guillerman et al780current definitions of bulky disease are not
stan-dardized and frequently depend on the clinical trialprotocol
and the cooperative group from whichthe protocol derives. For
example, bulky disease,
Fig. 15. An 8-year-old girl with BL. Coronal CT
reconstruc(arrows). Two days later, the patient presented with
abdintussusception. A contrast enema confirmed the
intussuintussusception recurred, she was taken to the operating
Fig. 16. Diffuse infiltration of the thymus resulting ina
smoothly marginated homogeneous anterior medias-tinal mass that
compresses the airway and occludes theleft brachiocephalic vein or
superior vena cava isa common presentation of T-cell lymphoblastic
lym-phoma, as shown in this chest CT image.as defined by PA chest
radiograph and CT of nodaldisease, is still recognized in the risk
stratification ofpatients enrolled in Childrens Oncology
Grouptrials and St Jude Consortium trials. However,results from the
German-Austrian Pediatric Multi-center trial suggest that bulk
disease alone is nota prognostic factor for outcome with a
risk-adapted treatment strategy.93 Contrast-enhancedCT and FDG-PET
imaging complete the contribu-tion of imaging to staging and risk
stratification.There is currently no role for bone scintigraphy
inthe routine staging evaluation.94 Increasingly,particularly in
Europe, the use of MR imaging,including diffusion-weighted imaging,
is beingadvocated to reduce radiation exposure in theseheavily
imaged and treated patients.95,96
Combined FDG-PET/CT imaging provides themost sensitive and
specific means of accuratelystaging patients with HL (see Figs.
1113). Forexample, in one study of children and adolescentswith HL,
FDG-PET changed the staging in 15% ofthe patients, most of whom
were upstaged. Mostof the false negatives not detected by
FDG-PET
tion shows thickening of the distal ileum and cecumominal pain.
An ultrasound examination showed ansception, which was successfully
reduced. When theroom where the diagnosis of BL was
established.
-
ang a
Leukemia and Lymphoma 781Fig. 17. An 11-year-old patient with
paraspinal ALCL. CTtion and invasion of the spinal canal. An MR
imaginhad tiny pulmonary nodules shown by chest CT.97
Most discordance between CT and FDG-PEToccurs at extranodal
sites, such as the lung, inwhich CT is superior for tiny nodules,
and thespleen and bone marrow, in which FDG-PET issuperior.98 The
highest diagnostic accuracy istherefore achieved using a
combination of FDG-PET and CT.Despite these advances in functional
imaging,
staging with conventional imaging modalities (CTand/or MR
imaging) alone as the standard initialstaging procedure for risk
and treatment stratifica-tion has historically been sufficient to
achieve curerates greater than 90% in pediatric HL. Therefore,the
ultimate impact of additional whole-bodyimaging with either MR
imaging or FDG-PET,although promising, may be modest in terms
ofchanging overall cure rates of pediatric HL.However, the
incorporation of FDG-PET/CT find-ings into radiation treatment
planningmaybe signif-icant in treatment-related toxicity, by
guidingtreatment dose and target treatment volume.55,63,99
Onestudy found that involved field radiation therapy(IFRT)
volumes needed to be adjusted from FDG-PET findings in 70%of
pediatric patients with HL.98
The St Jude (Murphy) classification is used forthe staging of
pediatric NHL (Box 2). This system
therapy showed a decrease in size of the mass. Althougthe
presence of FDG uptake after completion of consolidaRx,
treatment.dMR images show paraspinal mass with bone destruc-nd
FDG-PET scan obtained while the patient was onis based on tumor
burden, and has served clini-cians well for many years. In the
past, even withless effective chemotherapy, the St Jude
systemprovided a sound basis for treatment stratification.Children
with NHL, in contrast with HL, frequentlypresent with disseminated
disease. As with HL,CT scanning is most commonly used for the
initialstaging of NHL. For specific sites of bone or CNSdisease, MR
imaging is used. FDG-PET detectsadditional disease in a small
proportion of pedi-atric patients with NHL (see Figs. 17, 18 and
20;Figs. 22 and 23), but it has not been shown todetect additional
sites of disease that would resultin frequent alterations of
patient stage, nor has itbeen generally shown to result in any
modificationof treatment.100 High cure rates result from
risk-adapted intensive chemotherapy without radiationtherapy, and
it has not been necessary to mapprecisely every small site of nodal
disease, be-cause patients are being treated intensively
andsystemically.58 As a result, in contrast with theadult
situation, FDG-PET is not routinely includedin the diagnostic
staging of childhood NHL.101
However, NHL is often disseminated at the timeof initial disease
presentation and, in this setting,early response assessment may be
more usefulin predicting ultimate patient outcome rather than
h the patient did not have a baseline FDG-PET scan,tion
chemotherapy suggested residual active disease.
-
Guillerman et al782extent of disease and overall tumor burden
atdiagnosis (see Fig. 23). For these patients, diag-nostic FDG-PET
imaging is obtained to providea baseline for subsequent response
assessment.ALCL is an example of disease distribution not
fitting well into the St Jude NHL staging system
Fig. 18. A 12-year-old boy with ALCL. He initially
presenenlargement. Ultrasonography (not shown) revealed
hetetesticular biopsy was negative for malignancy. The CT scpain,
reveals diffuse mesenteric and retroperitoneal lympobliteration of
the left renal vein likely accounted for theuptake in the primary
mass, as well as a left supraclavicul
Fig. 19. Primary mediastinal large B-cell lymphomaoften assumes
a lobular morphology like HL and tendsto occlude the superior vena
cava, as shown on thischest CT image.(see Figs. 17 and 18). Sites
of involvement that areunusual in childhood lymphoma, such as
skin,lung, and bone, are common in ALCL. LL is anotherexample of
the limitations of the NHL stagingsystem. Most patients are stage
III, with few pre-senting with either stage I or stage II
disease.Furthermore, the outcome of patients with stageIV disease
(usually the result of bone marrowinvolvement), differs little from
those with stage IIIdisease. Because of the overall excellent
responseof these patients, features such as tumor bulk,pleural
effusion, and respiratory obstruction donot ultimately influence
overall outcome.54,58 Aswith LL, BL responds rapidly to aggressive
che-motherapy.58 Patients with localized disease haveanexcellent
outcomeaftera short courseofaggres-sive chemotherapy, and, with
improvements intreatment, even patients with advanced-stagedisease
at diagnosis have an excellent overalloutcome.
AlthoughFDG-PETscanningmaybeper-formed during staging of patients
with BL, given thespeed with which these tumors grow and
enlarge,there is little evidence that functional imagingaffects
staging or outcome in this population ofpatients.101
ted with testicular pain, swelling, and left testicularrogeneous
testicular echogenicity, but no focal mass;an shown here, obtained
for subsequent abdominalhadenopathy. Occlusion of the inferior vena
cava andinitial left testicular complaints. FDG-PET scan shows
ar site. No uptake was present in the scrotum.
-
Leukemia and Lymphoma 783Therapy Response Evaluation
Initial efforts to develop objective measurementcriteria for
assessing solid tumors were putforward by the WHO and used
bidirectionalmeasurement techniques.102 These measurementtechniques
focused primarily on disease staging
Fig. 20. (A) Axial CT images in a patient with mediastinal
Dbrachiocephalic vein, tracheal narrowing, pulmonary metuptake in
the mediastinal mass, pulmonary lesions, and rof disease in the
pancreas that are difficult to resolve byand determining initial
disease bulk in an effort tostratify patients into treatment
groups. Earlycriteria for response were also developed, andled to
categories ranging from complete response(CR) to progressive
disease, and included stable/no change or partial response (PR) in
the classifi-cation scheme, depending on the estimates of
LBCL, showing mediastinal mass, near occlusion of theastases,
and bilateral renal lesions. (B) FDG-PET showsenal lesions. In
addition, FDG-PET clearly shows 2 fociCT.
-
eveulatoapy
Guillerman et al784change in tumor size. The WHO criteria
presentedmany challenges, particularly for tumors such as
Fig. 21. A 12-year-old heart transplant recipient with fnode
enlargement in the retroperitoneum, supraclavicment, consistent
with PTLD. Disease did not respondextensive FDG-avid PTLD. One
month after chemotherHL, which frequently leave measurable
residualposttreatment scar tissue. Minimum lesion sizeand numbers
of lesions to be recorded were notspecified and, depending on the
location of tumor,size measurements of lymph nodes may havebeen
based on physical examination estimates.In addition, these methods
were devised beforethe advent of the multiplanar
cross-sectionalimaging techniques that are in common use today(CT
and MR imaging), and underestimates ofdisease burden and the choice
of measurementtechnique often led to errors in establishingdisease
progression or response.Developing objective measures of
treatment
response is essential to having evaluable prospec-tive end
points in early phase clinical trials anddetermining whether new
agents warrant furthertesting. The challenge is developing
surrogateend points that accurately reflect the diseaseprocess and
response to therapy at a time whenother indicators of response (eg,
change in clinicalstatus) may not reflect treatment response.
Forexample, a brisk response to chemotherapy is anindirect
determinant of biologic homogeneitywithin the tumor, which, in
turn, translates intomore uniform chemosensitivity across the
entiretumor volume. As a result, changes in FDG uptakethat occur
soon after the initiation of therapy serveas an in vivo
chemosensitivity test, even whensignificant changes in tumor volume
or complete
r and increased EBV titers. CT showed extensive lymphr regions,
and mediastinum, as well as splenic involve-reduction in
immunosuppression. FDG-PET confirmedthere is no residual
disease.resolution of the tumor mass are not yet seen onmorphologic
imaging (Fig. 24). Studies showingthat significant reductions in
tumor volume andFDG-PET negativity are associated with
favorableoutcome in both pediatric HL and NHL suggestthat rapid and
homogeneous cytotoxic chemo-therapy responsiveness may lead to
improveddisease-free survival.103
Several studies of FDG-PET for response as-sessment in pediatric
lymphoma have beenreported.86,104107 The use of FDG-PET in
assess-ing response during therapy for tumors that areFDGavidat the
timeof staging isbeing investigated.In one study of pediatric and
young adult patientswith HL or NHL, the negative predictive value
ofFDG-PET during therapy was 96%, whereas thepositive predictive
value was 100%.86 This obser-vation, substantiated by other
studies, suggeststhat interim FDG-PET scanning during therapy isan
excellent prognostic indicator for predicting clin-ical outcome.An
ongoing major European study in childhood
and adolescent HL is evaluating the role of interimFDG-PET in
determining the need for involved fieldradiotherapy in patients who
have a good earlyresponse to induction chemotherapy (ie,
thosepatients who are in complete remission or in partialremission
based on CT, but FDG-PET negative).100
-
Leukemia and Lymphoma 785Box 1Modified Ann Arbor staging system
forchildhood HL
Stage I: involvement of single lymph node region (I) orlocalized
involvement of a single extralymphaticorgan or site (IE)
Stage II: involvement of 2 or more lymph node regionson the same
side of the diaphragm (II) or localizedcontiguous involvement of a
single extralymphaticorgan or site and its regional lymph node(s)
withinvolvement of 1 or more lymph node regions onthe same side of
the diaphragm (IIE)
Stage III: involvement of lymph node regions on bothsides of the
diaphragm (III), which may also beaccompanied by localized
contiguous involvement ofan extralymphatic organ or site (IIIE), by
involvementof the spleen (IIIS), or both (IIIE1S)This represents an
early effort to incorporate aresponse-based treatment algorithm
into ongoingclinical trials of pediatric lymphoma patients. Mostof
the data have been obtained after 2 cycles ofchemotherapy, although
there is no evidence tosuggest that a response evaluation after 2
or 3cycles is either superior or inferior to that performedafter 1
cycle. A very early response to therapy after 1cycle may be more
predictive than responsesmeasured after more prolonged therapy.As
noted earlier, the use of two-dimensional
measurement techniques does not account forfunctional and
metabolic changes in the tumor.The International Harmonization
Project (IHP)was convened to address this issue in adultlymphoma
and issued revised criteria in 2007 forcomplete remission, partial
remission, progressivedisease, and stable disease (SD) both for HL
and
Stage IV: disseminated (multifocal) involvement of 1or more
extralymphatic organs or tissues, with orwithout associated lymph
node involvement, orisolated extralymphatic organ involvement
withdistant (nonregional) nodal involvement
Anatomic lymph node regions for the purpose of HLstaging are
Waldeyer ring, cervical/supraclavicular/occipital/preauricular,
infraclavicular, axillary/pectoral,epitrochlear/brachial,
mediastinal, hilar, splenic/splenichilar, mesenteric,
para-aortic/celiac/periportal/retro-crural,iliac, inguinal/femoral,
and popliteal.
The designation A is for asymptomatic disease and B isfor the
presence of unexplained fever, weight loss, ornight sweats. The
designation E is for minimal extra-lymphatic disease from direct
extension of an involvedlymph node region, originally devised to
indicate ex-tralymphatic disease limited enough to be subjectedto
definitive treatment by radiation therapy. Thedesignation E is not
appropriate for cases of wide-spread or diffuse extralymphatic
disease (eg, a largepleural effusion that is cytologically
positive), whichshould be considered stage IV.NHL.77,108 Although
the focus of this project wasadult lymphoma, the criteria proposed
can, forthe most part, be applied to pediatric lymphomas.A summary
of these criteria is shown in Table 1. Asbefore, measurable
extranodal disease should beassessed in a manner similar to that
for nodaldisease. For HL, the spleen is still considereda site of
nodal disease (see Fig. 11). Disease locithat are assessable but
not measurable (eg,pleural effusions and bone lesions) are
recorded
Box 2St Jude staging system for childhood NHL
Stage I: a single tumor (extranodal) or single anatomicsite
(nodal), excluding mediastinum or abdomen
Stage II: a single tumor (extranodal) with regionalnode
involvement; 2 or more nodal sites on the sameside of the
diaphragm; 2 single (extranodal) tumorswith or without regional
node involvement on thesame side of the diaphragm; a
primarygastrointestinal tract tumor, with or withoutassociated
mesenteric nodes, grossly completelyresected
Stage III: 2 single tumors (extranodal) on oppositesides of the
diaphragm; 2 or more nodal areas aboveand below the diaphragm;
primary intrathoracictumors (mediastinal, pleural, thymic);
extensiveprimary intra-abdominal disease, unresectable;paraspinal
or epidural tumors
Stage IV: any of stages IIII with initial CNS or bonemarrow
involvement (1.5 cm in greatest transverse diameter, ornot more
than 1.0 cm in short axis for lymph nodesless than 1.5 cm in size
at diagnosis). These
-
Guillerman et al786criteria have been developed for adults but
shouldbe applicable for most pediatric patients, althoughsome
clinical judgment is necessary in cases withborderline enlarged
lymph nodes. Splenic and/orliver involvement, either as diffuse
enlargementor focal nodules, should return to normal sizeand
nodules should disappear. However, thedetermination of splenic
involvement may be chal-lenging and multiple imaging modalities may
beused to unequivocally establish the presence orabsence of
residual abdominal visceral disease(see Fig. 24). Bone marrow
involvement, if present,must have cleared based on repeat bone
marrowbiopsy. Residual bone marrow abnormalities byimaging (ie,
FDG-PET or MR imaging) should beconfirmed by biopsy in order for a
patient to beconsidered in CR.PR is defined by the IHP as
regression of
measurable disease with no new sites of disease.There must be at
least a 50% decrease in the sumof the product of the diameters of
up to 6 largestdominant nodes or nodal masses, which shouldbe
clearly measurable in 2 dimensions. Thereshould be no increase in
size of other nodes, liver,
Fig. 22. A 16-year-old patient with DLBCL. Axial CT andmultiple
diaphragmatic lymph nodes. An additional focuwould not have been
detected without the use of FDG-PEand spleen. Splenic/hepatic
nodules must regressby not less than 50% in size. If bone marrow
wasinvolved before therapy and clinical CR was ac-hieved by other
criteria, but there is persistentmarrow involvement, the patient is
still considereda partial responder. For partial responders,
post-treatment FDG-PET should be positive in at least1 previously
involved site. If FDG avidity at base-line is unknown, then the CT
criteria are used.SD is defined by the IHP as failure to attain
either
CR or PR, but not meeting criteria for progressivedisease. For
FDG-avid lymphomas, the FDG-PETscan should be positive at prior
sites of diseasewith no new areas of involvement on the
posttreat-ment CT or FDG-PET. If FDG-PET is not available,there
must be no change in the size of the previouslesions on the
posttreatment CT scan.The appearance of any new lesion at the end
of
therapy should be considered relapsed (after CR)or progressive
disease (after PR or SD) accordingto the IHP unless otherwise
confirmed by histo-logic evaluation. Increased FDG uptake at a
previ-ously unaffected site or at a previously involvedsite that
had responded should also be considered
FDG-PET show uptake in the mediastinal mass ands of disease in a
small aortocaval lymph node (arrow)T.
-
Fig. 23. An 8-year-old patient with hip pain. MR imaging shows
diffuse marrow replacement on T2-weighted andT1-weighted images. CT
shows extensive visceral and intra-abdominal involvement. FDG-PET
confirms diffuseabnormal uptake throughout the abdomen and bone
marrow. Bone marrow aspirate showed greater than25% infiltration of
the marrow by Burkitt cells, indicating Burkitt leukemia.
Fig. 24. This patient with HL received 2 4-week cycles of
therapy. Compared with the baseline examination (seeFig. 11) there
is still residual mediastinal soft tissue abnormality, although
decreased from the baseline examina-tion. The spleen is now normal
in size; however, punctate hypodensities are still present in the
spleen. Despitethese residual CT findings, the accompanying FDG-PET
shows complete resolution of abnormal FDG uptake inthe mediastinal
mass and in the abdomen.
Leukemia and Lymphoma 787
-
Guillerman et al788Table 1Summary of new Harmonization
Projectcriteria for PET and CT in determiningresponse in
lymphomaa
Response Criteriarelapsed or progressive disease (see Fig.
13).Lymph nodes are considered abnormal if theirshort axis is
greater than 1.0 cm. In most patientswith prior pulmonary nodules,
new lung nodulesidentified by CT are typically benign and shouldbe
histologically confirmed to establish relapse/progressive disease.
Sites of relapse or progres-sive disease should be FDG avid unless
the lesion
CR FDG-PET completely negativeResidual lymph nodes/nodalmasses
allowed, if FDGnegative
Bone marrow biopsy negativeSplenic/liver involvement
mustdisappear
No new sites of disease
PR PDG positivity should bepresent in at least 1previously
involved site
Regression of measurabledisease; no new sites ofdisease
50% decrease in SPD of 6dominant LNs/nodal masses
50% reduction in splenic/hepatic nodules, if present
Even if CR by other criteria,positive bone marrowbiopsy is
considered PR
SD Failure to achieve PR, but notmeeting PD criteria
PD/relapse Any lesion increased in size by50% from nadir
Any new lesionPET should be positive in new/progressed lesions
if1.5 cm
Notes: New criteria include PET in definition of CR.
PETconsidered positive if uptake is greater than mediastinalblood
pool (lesions >2 cm), or more than local background(lesions
-
Fig. 25. (A) PET/CT showing increased FDG uptake in the
mediastinal nodal masses of a patient with HL at diag-nosis. The
uptake is clearly greater than in the mediastinal blood pool or
liver. (B) After 2 cycles of therapy, a medi-astinal soft tissue
mass persists. There is low-level FDG uptake in the mass, as great
as in the mediastinal bloodpool but less than in the liver, which
emphasizes the challenge in interpreting residual FDG uptake in
patientscompleting their up-front chemotherapy.
Leukemia and Lymphoma 789
-
unclear whether radiation treatment can be re-duced to initial
involved sites of nodal activity oreliminated entirely for those
patients with HL whohave no residual nodal activity early after
responseto therapy.55 One approach, for example, would
berestricting radiation to sites of residual FDGuptake.The goal
would be to titrate therapy using the prog-nostic value of early
treatment response to reducetreatment intensity in
thosepatientswith rapid earlyresponses and thereby reduce toxicity
while, at thesame time, intensifying treatment of those
withslowearly responses in aneffort to improvedisease
normal tissues compared with involved field radia-
presents as an enlarging thymic mass within 6to 8 months of
completion of chemotherapy(Fig. 26). Rebound thymic hyperplasia can
showavidity for FDG, usually in a pattern of mild, diffuseuptake,
in contrast with the intense, discreteuptake usually associatedwith
lymphoma. If a childor adolescent has imaging findings
compatiblewith rebound thymic hyperplasia, continued sur-veillance
is advised rather than biopsy, especiallyif there is no other
evidence of recurrence or priorneoplastic involvement of the
thymus.112
In a recent pediatric intermediate-stage and
madia
Guillerman et al790tion and, coupledwith functional imaging
responseassessment, could produce significant reductionsin
radiation-related late effects.
Surveillance for Relapse
Relapse occurs in approximately 20% of pediatricpatients with
HL.63 Most of these occur within thefirst 3 years. It has been
suggested that relapsesoccurring beyond 1 year after the completion
oftherapy have a favorable prognosis relative tothose occurring
early after completion of therapyand therefore surveillance imaging
and identifica-tion of relapse has remained an important goal
ofobservation of therapy.Rebound thymic hyperplasia, a potential
mimic
of mediastinal relapse, most characteristically
Fig. 26. A chest CT image (A) obtained in an asymptotherapy for
HL shows enlargement of an anterior mecontrol.These approaches, all
of which require confirma-
tion in clinical trial settings, are intended to
developresponse-adapted therapy to identify patients withfavorable
chemotherapy-sensitive disease whocan be treated with abbreviated
chemotherapyand low-dose IFRT or no radiation therapy at
all.Alternatively, rather than entirely eliminating radia-tion
therapy, radiation therapy volumes may berestricted to lymph node
regions that were initiallyinvolvedwith disease rather than the
entire regionalnodal group.55,99 Such an approach has the
poten-tial to significantly reduce the irradiated volume ofimage
(B) obtained at the end of therapy, representing readvanced-stage
HL study, relapses occurred in10.6%of thepatients,with amedian time
to relapseof 7 months.113 Most of these relapses occurredwithin 18
months after completion of therapy andmost of these relapses were
local, at original sitesof disease. Nearly two-thirds of these
relapsesweredetectedbasedonclinical symptoms, labora-tory tests, or
physical examination findings. Only17% of the patients, all of whom
relapsed morethan 1 year after therapy, were asymptomatic andhad
disease detected solely from surveillanceimaging. A review of the
number of imaging studiesperformed to identify these relapses
revealed thatmore than 400 CT scans were mandated byprotocol to
detect these asymptomatic relapses.Based on this, it has been
suggested that CT, andimaging of any kind, is overused in the
routine post-treatment surveillance of patients with HL,
andmodifications in surveillance protocol are indicatedfor routine
long-term surveillance. A recent reporthas further emphasized the
considerable increasein radiation exposure to these patients
attributableto routine surveillance imaging.114
As has been reported in adult studies, mostrelapses occur in
areas of initial disease and withinthe first year after
completionof therapy,which indi-cates that the frequency of
screening should begreatest in the early posttherapy years. The
role ofFDG-PET as a surveillance tool to detect relapsein
asymptomatic patientshasnot beenestablished.In particular, the
problem of false-positive findings
tic 15-year-old patient 5 months after completion ofstinal soft
tissue structure compared with a chest CT
bound thymic hyperplasia.
-
in evaluating pediatric lymphoma is becoming
Leukemia and Lymphoma 791TREATMENT-RELATED COMPLICATIONS
Overall survival rates are excellent for ALL,HL, local-ized
low-stage NHL, and even for some advanced-stage NHL and AML. The
goal of reducing toxiceffects of therapy is now a focus of the next
genera-tion of treatment protocols.55,115 Imaging playsan important
role in diagnosing treatment-relatedcomplications of leukemia and
lymphoma. Many ofthe complications associated with leukemia
andlymphoma are shared because of the treatment ofboth with
cytotoxic chemotherapy with associatedmarrow suppression. The
complications can beacute or late in onset, and can involve
virtually anyorgan system. Among the complications amenableto
diagnosis by imaging are opportunistic infecti-ons, cerebral
hemorrhage/infarction, methotrexate-induced leukoencephalopathy,
venous thrombosis,anthracycline-induced cardiomyopathy,
bleomycin-induced pulmonary fibrosis, bronchiolitis
obliterans,radiation pneumonitis, radiation pericarditis,
typhli-tis, asparaginase-associated pancreatitis,
hepaticveno-occlusive disease, graft-versus-host
disease,hemorrhagic cystitis, posttransplant lymphoprolifer-ative
disorder, osteonecrosis, and osteoporosis. Adetailed discussion of
the imaging of these compli-cations is beyond the scope of this
article.Second malignant neoplasms, including AML,remains and
current recommendations do notinclude the use of FDG-PET for
routine surveil-lance.77 However, if sites of disease are
detectedby other imaging modalities or are suspected clini-cally,
there may be a role for FDG-PET imaging inconfirming relapse, but
not as an integral part ofroutine surveillance in either HL or
NHL.100 In onestudy, the use of FDG-PET/CT to identify
recurrentdisease in asymptomatic patients with HL andNHLled to
false-positive results in 63% and 41% ofpatients, respectively, for
a positive predictivevalue of only 53%.106 Although the negative
predic-tive value was greater than 99% in this study, thehigh
frequency of false positives does not allowappropriate treatment
decisions to be confidentlymade based solely on FDG-PET
surveillanceimaging.There will be understandable reluctance to
reducing the intensity of surveillance imaging ata time when
treatment intensity and duration oftherapy are also being reduced.
Nonetheless, allof the available evidence suggests that
aggressivemonitoring early after therapy combined with judi-cious
imaging and close physical examination andlaboratory monitoring
during the surveillanceperiod is the most effective means of
followingthese patients.NHL, and malignancies of breast, lung, and
thyroidfeasible (Fig. 27). Whole-body MR imaging hasshown good
agreement with FDG-PET/CT forboth nodal and extranodal staging of
lymphoma.116
MR imaging false negatives occur with normal-sized involved
lymph nodes and spleen, diseasethat is detectable by FDG-PET. MR
imaging pro-vides an alternative imaging method to CT foranatomic
disease assessment at staging and re-staging without ionizing
radiation exposure. Fur-thermore, surveillance by MR imaging may be
theimaging modality of choice, particularly in patientswith
lymphoma in whom sustained PR or CR hasoccurred.Because of high
tumor cellularity and highwithin radiation fields, are all of
concern.55Historicaltreatment regimens for lymphoma,which used
highradiation doses and intense chemotherapy regi-mens, had
well-established rates of secondarymalignancy.54 The risk of
secondary malignancyafter low-dose radiation is not well
described,because this became the standard treatment ofchildren
only in the mid 1980s and for adolescentsin the early 1990s. With
unknown latency periodsfor developing second malignancies after
low-dose radiation exposure and reduced chemo-therapy, there is
noclear role for routine surveillanceimaging in these patients.
FUTURE DIRECTIONS
With isotropic voxel acquisition of cross-sectionalimaging data,
the ability to generate three-dimensional tumor representations has
improvedand accurate tumor volume calculations are nowfeasible,
although automated measurement tech-niques remain elusive.
Nonetheless, changes in tu-mor volume, particularly with extensive
multifocalsites of bulky lymphoma, may be an important vari-able to
correlate with FDG-PET response. It seemsoverly simplistic to
assume that all patients whobecome FDG negative after 2 cycles of
therapy,even in the presence of large residual masses, willbe
uniformly free of disease progression or relapse.The ability to
provide other criteria for response todevelop a multivariant array
of imaging criteriashould allow us to best identify those patients
trulymanifesting a good response to chemotherapy,without
overlooking those patients in whom moreaggressive treatment is
mandated.In the past, MR imaging of the thoracic and
abdominal cavity has been limited by motion arti-fact and long
examination times. However, withincreasing availability of faster
MR imaging scan-ning techniques and respiratory and cardiac gat-ing
capabilities, a more routine role of MR imagingnuclear/cytoplasm
ratios,most forms of lymphoma
-
entation with cough led to discovery of an anterior
medi-isteiumt a
Guillerman et al792Fig. 27. A 16-year-old boy with stage IIA HL.
Initial presastinal mass, for which a broad differential diagnosis
exPET scan show an FDG-avid mass that abuts the pericard(not shown)
sequences showed that the mass was noexcised, confirming the
diagnosis of HL.that have been studied have high signal
intensity(ie, restricted diffusion) on diffusion-weighted
MRimages.95,96 In one study, diffusion-weighted MRimaging matched
FDG-PET/CT findings in 94% ofthe lymph node regions studied.117
Furthermore,changes in diffusion characteristics may providean
additional means of evaluating residual nodalmasses, because nodal
apparent diffusion coeffi-cient has been shown to increase
followingsuccessful chemotherapy.118 The use of whole-body MR
imaging with diffusion-weighted imagingwith background signal
suppression sequenceshas also been shown to provide better
tissuecontrast in detecting malignant nodal involvementcompared
with conventional MR imaging se-quences.119 As these techniques are
incorporatedinto the evaluation of pediatric lymphoma patients,it
seems likely that changes in tumor characteris-tics as manifested
by changes in diffusion orchanges in enhancement may provide
additionalsurrogates of response to help further developa response
assessment profile. Whole-body MRimaging with diffusion-weighted
imaging mayalso serve as a more sensitive method to rapidlyevaluate
leukemic infiltration of the bone marrowfor therapeutic response to
cytotoxic chemo-therapy.120 However, widespread
interindividualvariation and restricted diffusion as a normald.
Chest CT, T2-weighted chest MR imaging, and FDG-, consistent with
neoplasm. Gated cardiac MR imagingdherent to pericardium. The mass
was subsequentlyfinding in the pelvis and spine of children limit
thespecificity of this technique, raising the risk offalse-positive
interpretations.121
SUMMARY
As the most common childhood malignancy,leukemia is frequently
encountered as an under-lying condition in subjects of pediatric
imagingstudies. The most frequent indication for imagingof
childrenwith leukemia is to evaluate for complica-tions of
treatment. Occasionally, imaging findingssuggest a previously
unsuspected diagnosis ofleukemia, particularly in children with
nonspecificmusculoskeletal complaints or unexplained fever.There is
no current routine role of imaging in riskstratification, therapy
response assessment, or re-lapse surveillance for childhood
leukemia.The use of imaging in guiding diagnostic
procedures, risk stratification, therapy responseassessment, and
relapse surveillance in childhoodlymphoma has evolved in the last
20 to 30 years.From a time when nearly all patients with lym-phoma
were surgically staged to a time whennearly all patients have
multiple imaging studies,each of which provides complimentary
informa-tion, current lymphoma management requires theintegration
of imaging at all phases of treatment.
-
6. GaynonPS,Angiolillo AL,CarrollWL, et al. Long-term
results of theChildrens CancerGroup studies for chi-
ldhood acute lymphoblastic leukemia 19832002:
Leukemia and Lymphoma 793a Childrens Oncology Group Report.
Leukemia
2010;24:28597.
7. Smith MA, Seibel NL, Altekruse SF, et al. Outcomes
for children and adolescents with cancer: chal-
lenges for the twenty-first century. J Clin Oncol
2010;28:262534.
8. Creutzig U, Reinhardt D. Current controversies:
which patients with acute myeloid leukaemia
should receive a bone marrow transplantation?A
European view. Br J Haematol 2002;118:36577.
9. Lange BJ, Smith FO, Feusner J, et al. Outcomes in
CCG2961, a childrens oncology group phase 3
trial for untreated pediatric acute myeloid leukemia:
a report from the childrens oncology group. BloodCurrent
approaches should include a combinationof anatomic and functional
imaging techniques topredict which patients will benefit from less
toxictreatment regimens and which patients will requireaugmented
therapy. Patient-specific and disease-specific imaging biomarkers
to provide specificindicators of disease activity are needed to
guidethe evolution from risk-adapted therapy toresponse-based
therapy. The ongoing challengeis to optimize available imaging
techniques anddevelop a reproducible set of validated biomarkersand
image-processing tools to best accomplishthese goals.
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