Review Article

Current status of PET/CT in the diagnosis and follow up of lymphomas

Carlos Alberto Buchpiguel Lymphomas are a heterogeneous group of malignancies that have a distinct biological behavior
according to the subtype and degree of differentiation. Adequate staging, which has a direct impact on
prognosis, is essential to properly plan therapy. Structural cross-sectional imaging, such as computed
Centro de Medicina Nuclear,
Instituto de Radiologia, Hospital das
tomography, has been the standard imaging tool to stage and monitor patients with lymphoma.
Clínicas, Faculdade de Medicina, However, molecular imaging such as positron emission tomography has shown complementary
Universidade de São Paulo – USP, diagnostic and prognostic values. This review discusses the current value of positron emission
São Paulo, SP, Brazil tomography imaging using 2-[fluorine-18]fluoro-2-deoxy-d-glucose in staging, restaging, monitoring
Instituto do Câncer do Estado de and detecting relapse in Hodgkin's and non-Hodgkin lymphoma.
São Paulo – ICESP – Grupo Fleury,
São Paulo, SP, Brazil
Keywords: Lymph Nodes/radionuclide imaging; Lymphoma/radionuclide imaging; Positron-emission
tomography; Fluorodeoxyglucose F18/diagnostic use; Lymphoma, Hodgkin’s disease; Lymphoma,
non-Hodgkin

Introduction
Lymphomas consist of a heterogeneous group of malignancies that bear distinct
biological behavior according to the subtype and the degree of differentiation. They are
mainly characterized by enlargement of lymph nodes (nodal disease) although any organ in
the body can be involved in different settings of the disease (extranodal disease). They
account for approximately 5% of all cancers in the United States and for a US$ 4.6 billion
annual healthcare cost.(1)
Lymphomas can be divided into two main groups: Hodgkin's (HL) and non-Hodgkin
(NHL). The most common type is NHL which represents approximately 85% of all
lymphomas. According to the biological behavior and consequently the prognosis, they
can be grouped as indolent (low grade) and aggressive (intermediate or high grade)
tumors.(2) The presence of extranodal disease has also prognostic implications as this
may define a more advanced staging status (III or IV). However, patients with primary
extranodal disease can still be categorized as stage I or II according to Ann Arbor system
with the incorporation of the classification of bulky disease of the Cotswold consensus
meeting held in 1989.(3)
The diagnosis of primary versus secondary lymphoma remains a challenge despite
the great development in diagnostic tools. Part of this difficulty is related to the subtle
changes frequently missed by conventional cross-sectional structural imaging. The
limitations of computed tomography (CT) imaging in restaging, monitoring treatment and
detecting relapse of lymphoma, especially with indolent lymphomas, are already well
recognized.(4) Most of the limitations reside in the criterion of size, that is when to classify
an enlarged lymph node as abnormal. It is not rare that normal-sized lymph nodes, according
Conflict-of-interest disclosure:
The authors declare no competing to the criteria, are involved by a tumor and enlarged lymph nodes are not infiltrated by
financial interest lymphoma cells. Enlargement of lymph nodes can be seen in many non-malignant conditions
Submitted: 2/13/2011 such as inflammatory disorders.
Accepted: 4/4/2011 The sensitivity to detect lung nodules has increased with current multi-detector CT
Corresponding author:
scanners (MDCT) although the specificity is not that high.(5) The detection of gastric or
Carlos Alberto Buchpiguel small/large bowel involvement requires special techniques and much expertise in CT
Instituto de Radiologia, Hospital das Clínicas imaging.(6)
Av. Dr. Enéas de Carvalho Aguiar, 255 –
Cerqueira César Therapeutic strategies for the management of lymphoma are constantly being refined
05403-000 – São Paulo, SP, Brazil to improve long-term survival with the lowest possible risk of toxicity to the patient. However,
Phone: 55 11 3082-1015
[email protected] therapy planning is directly dependent on proper staging with definite prognostic
implications in the various categories of lymphoma.
www.rbhh.org or www.scielo.br/rbhh
Positron emission tomography (PET) using 2-[fluorine-18]fluoro-2-deoxy-d-glucose
DOI: 10.5581/1516-8484.20110035 (FDG) has already been validated to assess patients with different types of malignant

140 Rev Bras Hematol Hemoter. 2011;33(2):140-147

 Current status of PET/CT in the diagnosis and follow up of lymphomas

tumors, including lymphomas. The principle of the imaging show faint or very low glucose concentrations. The level of
test is based on metabolic changes that reflect fundamental FDG uptake can be evaluated semiquantitatively using the
differences in the central metabolic pathways in malignant standardized uptake value (SUV). The SUV is the activity in
tissue. Most cancer cells exhibit elevated levels of glycolysis the lesion measured as µCi/mL corrected for the patient's
and this metabolic pathway seems to be related to a higher weight and the dose of FDG administered. Aggressive NHL
glucose uptake. Because of those changes, tumor cells lymphomas such as DLBCL and grade III follicular lymphoma
produce lactate at higher levels compared to non-malignant (FL) have mean SUVs as high as 17.1 and 16.0, respectively.
tissue, even in the presence of oxygen, a phenomenon termed On the other hand, indolent lymphomas such as marginal
"aerobic glycolysis" or the "Warburg effect".(7) FDG-PET zone lymphoma (MZL) and grade I/II FL can have SUVs as
relies on this principle to detect foci of tumor proliferation. low as 9.0 and 7.0, respectively.(8) The sensitivity of PET in
This review comments on the value of adding molecular detecting the degree of FL may be as high as 98% but it
imaging information, as provided by FDG-PET, to the staging drops to the 50% range when detecting MZL, peripheral T-
and monitoring of therapy of patients with HL and NHL. cell lymphoma and small-cell lymphocytic lymphoma.(9)
However, even though controversies still arise regarding the
Staging value of PET/CT in staging low-grade lymphomas, in special
cases it seems to provide very reliable and important
FDG-PET has been widely used to stage and restage information for decisions on clinical management.(4) For
HL and NHL. Staging HL and NHL with FDG-PET is directly example the limitations of PET/CT are well recognized in MZL
dependent on many different factors including biological and of the mucosa-associated lymphoid tissue (MALT) subtype,
technical aspects of the lymphoma. since it has a tropism for gastrointestinal organs that usually
One of the most important factors is the histology. show physiological FDG activity (Figure 2).
Normally, the most common subtypes of HL and the most
aggressive NHL, such as diffuse large B cell lymphoma
(DLBCL), show high levels of cell proliferation that reflect in
a higher aerobic glycolysis rate (Figure 1).
Therefore, higher FDG uptake values are seen in
aggressive tumors compared to more indolent ones that usually

Figure 2 – Non-Hodgkin lymphoma MALT type involving the stomach.

Note how difficult is to confirm and detect disease based only on the
CT images

However, in the nodal subtype, FDG-PET can be as

valuable as in intermediate/high grade NHL for staging
purposes. So, it is very important to know the histological
subtype before performing the PET/CT study, in order to
understand the limitations and to apply the correct technique
for adequate staging. A lower level of evidence is seen
regarding the accuracy of PET/CT on staging the different
histological subtypes of HL. However higher SUV values are
Figure 1 – High grade Hodgkin's lymphoma on PET/CT. First row commonly seen with the nodular sclerosis subtype and lower
shows the CT, second row shows the PET images and the third row
SUV values with the lymphocytic subtype. It has been shown
shows the fused PET/CT images. Note the intense uptake do 2-[fluorine-
18]fluoro-2-deoxy-d-glucose in the bulky mass and enlarged lymph that SUV may be correlated with cell proliferation as measured
nodes in the mediastinum using the Ki-67 proliferative index, which may suggest that

Rev Bras Hematol Hemoter. 2011;33(2):140-147 141

Buchpiguel CA

this kind of measurement might have a prognostic value in

staging lymphoma.(10)
The molecular mechanisms involved in particular tumor
micro-environments might also affect the performance of
molecular imaging tools since a down-regulation or even a
lack of expression of glucose transporter (GLUT) receptors
(the proteins responsible to transport glucose from
extracellular to intracellular moiety) on a tumor membrane
would promote no FDG uptake by the tumor. However, the
GLUT receptor is not the only mechanism that might increase
the sensitivity of PET, since higher expressions of
hexokinase-II (HK-II) have markedly increased FDG uptake,
in particular in DLBCL.(11)
Benign tumors may show low FDG uptake and therefore
this may reduce the specificity of FDG-PET. However, the
integration of CT into the PET gantry, providing simultaneous
structural and functional data, improves the interpretation
and consequently the specificity of PET.
Another aspect that might impair specificity is the
possibility that inflammatory cells trap glucose at a similar
level to indolent or low-grade lymphomas. Hence, accurate Figure 3 – Patient with nasopharyngeal non-Hodgkin lymphoma
showing marked asymmetrical 2-[fluorine-18]fluoro-2-deoxy-d-glucose
correlation with CT findings and even with laboratory and uptake in the right pharyngeal tonsil
clinical features may help improve the overall accuracy of
the test.
A relatively recent meta-analysis evaluating the
accuracy of FDG-PET on staging lymphoma showed a
sensitivity of 90% and a specificity of 91%. The false-positive
rate was 10.3% with a maximum accuracy of 88%.(12) Another
systematic review showed very high sensitivity (97%) and
specificity (100%) for staging HL and NHL.(13)
FDG-PET has also proved to be superior to a CT-alone
strategy for staging. Upstaging can be up to 32% in HL(14)
and 31% in NHL.(15) Figure 4 – Series of transverse slices of CT, PET and PET/CT in a
PET/CT can detect any form of extranodal disease, patient with Hodgkin's lymphoma. Study performed after 8 weeks of
including brain, head and neck, liver, spleen, muscle and skin ABVD therapy showing 2-[fluorine-18]fluoro-2-deoxy-d-glucose
uptake in lymph nodes in the mediastinum and right pleural effusion.
involvement. However, in some locations special care in Biopsy confirmed the diagnosis of sarcoidosis
interpretation is recommended since physiological activity
or inflammation after therapy can preclude an accurate staging
or restaging. Physiological and symmetrical activity is moderate diffuse FDG uptake, mainly after therapy, probably
commonly seen in the lymphatic structures of the head and represents thymus hyperplasia (Figure 5).
neck however lymphoma involvement presents asymmetric However, distinction from a low grade thymoma can be
activity and a more intense degree of FDG uptake that is challenging. Leptomeningeal metastasis can also be more
often easily recognized (Figure 3).(16) difficult to detect by PET compared to MRI due to its spatial
Staging lung involvement is feasible when the size of resolution limitations.
nodules is within the spatial resolution range of the modern Detecting bone marrow involvement is also very
PET/CT equipment (> 7-8 mm). However, specificity can be important for a proper disease staging. Recent papers have
impaired due to the higher frequency of chemotherapy- shown a complimentary role of PET/CT on detecting bone
associated pneumonitis, pneumonia and radiation-induced marrow infiltration. PET/CT has higher sensitivity and
changes. Inflammatory processes such as sarcoidosis are comparable specificity in relation to bone marrow biopsy as
one of the most common causes of false-positive results in it can detect disease in locations not usually covered by
evaluations of the mediastinum and lungs (Figure 4).(17) marrow biopsies (iliac crest or sternum) (Figure 6).(19)
Another area where interpretation requires special In a systematic review and meta-analysis comparing PET,
attention is the thymus, although thymus involvement does PET/CT and magnetic resonance imaging (MRI), PET/CT
not change the staging in HL as it is considered a "nodal showed the highest pooled sensitivity (91.6%) and pooled
organ".(18) Enlargement of the thymus associated to mild/ specificity (90.3%) compared to PET alone or MRI.(20)

142 Rev Bras Hematol Hemoter. 2011;33(2):140-147

 Current status of PET/CT in the diagnosis and follow up of lymphomas

However, after chemotherapy, especially after using colony-

stimulating factors, a diffuse bone marrow activity can
normally be seen on PET/CT, which reflects bone marrow
hyperplasia rather than infiltration. In contrast, a
heterogeneous and irregular pattern of bone marrow FDG
uptake suggests infiltration by the disease rather than a
physiological reaction.
Another area that can be considered quite challenging
for staging and restaging disease is the gastrointestinal tract.
High gastric to large bowel activity is commonly observed
since excretion and even lymphoid bowel elements might
promote physiological concentrations of FDG without
representing foci of disease activity. However, gastric and
bowel involvement usually shows typical findings on CT
with irregular or diffuse wall thickening when the proper
diagnostic technique is applied. Therefore, the joint
interpretation of PET together with CT helps to differentiate
physiological uptake from pathological uptake in the
gastrointestinal tract.
Another issue that has been widely discussed with the
implementation of PET/CT is whether or not the use of iodine
Figure 5 – FDG-PET showing increased uptake of 2-[fluorine-18]fluoro- contrast in CT makes much difference in staging lymphomas.
2-deoxy-d-glucose in an enlarged thymus after therapy representing
thymic hyperplasia A recent paper showed that staging was almost similar using
unenhanced low-dose PET/CT compared to enhanced full-
dose PET/CT, although fewer indeterminate findings were
seen with the enhanced technique and more extranodal
lesions were detected.(21) Another recent study showed that
a diagnostic CT did not have any incremental value on staging
lymphoma when carried out concurrently with PET/CT.(22)
Therefore the decision to use iodine contrast in CT depends
on the imaging professional who is evaluating the patient, as
this decision may change according to the PET findings, the
availability of a recent enhanced MDCT exam and the
probability of extranodal involvement among other things.

Therapy response evaluation

An important and valid application of PET/CT is to

detect viable tumor in residual lesions after the treatment of
patients with HL and NHL. A residual mass at the end of
therapy is not a rare finding and is considered a clinical
challenge in HL and intermediate/high grade NHL restaging.
FDG-PET has proved to be much more accurate in
distinguishing fibrosis from viable tumor, since fibrosis
does not show high metabolic activity in contrast to viable
residual tumor. The PET result also has prognostic
implications, as a higher relapse rate is usually associated
with positive PET results after treatment. Jerusalem et al.
showed that patients with residual mass after therapy,
including in HL and NHL, and who present with positive PET
results had a 100% relapse rate in contrast to patients who
Figure 6 – Patient with non-Hodgkin lymphoma showing multiple showed no activity of the residual mass with a relapse rate of
bone lesions seen only on PET/CT. A bone marrow biopsy of the
only 26%.(23) The 1-year progression-free survival (PFS) was
iliac crest was negative. After reviewing the PET findings, a repeated
marrow biopsy in the right femur confirmed bone marrow 0% for the PET positive group compared to 86% for the PET
involvement negative group (p-value < 0.0001) and the 1-year overall

Rev Bras Hematol Hemoter. 2011;33(2):140-147 143

Buchpiguel CA

survival (OS) was 50% for PET positive versus 92% for PET
negative. A meta-analysis of FDG-PET in restaging HL and
NHL included 20 studies and 854 subjects and showed a
median sensitivity of 90.3% and a median specificity of
91.1%.(12)
A systematic review of 15 studies involving 705 patients
with residual mass after therapy of HL and aggressive NHL
showed that the pooled sensitivity and specificity for the
detection of residual disease of HL by PET were 84% (95%
CI: 71-92%) and 90% (95% CI: 84-94%), respectively. For
NHL, the pooled sensitivity and specificity were 72% (95%:
CI 61-82%) and 100% (95%: CI 97-100%), respectively.(24)
There are well known pretreatment prognostic factors
that help to precisely predict the OS and the clinical stage
status of patients with HL and NHL.(25,26) However, the tumor
response is, in itself, an important prognostic factor that might
not only tailor the therapy strategy, but also help to
understand and apply the risk-adapted therapy strategy.
Structural imaging cannot always conclude whether
therapy was successful in eliminating the tumor since residual
Figure 7 – Therapy monitoring with PET/CT. An example of complete
masses are not rare after therapy, and might take time to shrink response. Note that the multiple foci of 2-[fluorine-18]fluoro-2-deoxy-
completely. It is difficult by CT to differentiate post-treatment d-glucose uptake in abdominal lymph nodes seen on pre-therapy scan
fibrosis from active viable tumor in residual lesions seen in (left) show no more activity in the post-therapy study (right)
structural imaging. Even using standard criteria to quantify
the size reduction on CT, limitations still exist in distinguishing
active tumor from fibrosis.(27)
Molecular imaging such as PET/CT can be more
effective in this task as it is more accurate at defining comple-
te remission after therapy compared to the state of the art
structural imaging. The concept of its use is based on the
fact that viable tumor cells still require glucose to maintain
cell proliferation as opposed to fibrotic tissue where a very
low level of activity or no activity at all is seen in the residual
lesions after completing treatment. It is important to
understand that PET/CT cannot be used, however, to identify
microscopic malignant changes far below its threshold of
spatial resolution.
PET/CT can be used to evaluate treatment in two distinct
situations with specific clinical purposes. The most common
is to evaluate response after completion of therapy in order
to verify incomplete remission that would require further
therapy (Figures 7 & 8).
The early PET monitoring of lymphoma therapy (interim- Figure 8 – Therapy control of a patient with non-Hodgkin lymphoma.
A partial response is observed after therapy however, persistent activity
PET) can be used to predict the relapse rate (prognosis) and is seen in the axillary and left cervical regions
in future may be used to tailor drug regimens and other
treatment alternatives for refractory patients. There are groups
that suggest that a negative interim-PET result might permit PET/CT performed after 2 cycles of ABVD showed a 2-year
a reduced number of therapy cycles as this situation predicts PFS of only 0-6% in the positive interim-PET group of patients
a better outcome after treatment compared to a positive compared to 94% for the negative interim-PET group of
interim-PET result (Figure 9). patients.(28) By increasing the number of cases of advanced
However, more prospective trials are required to prove HL, the authors even showed that interim-PET overshadows
that outcomes, including OS, are not impaired using that the role of the current standard criteria to establish the
strategy. prognosis, the International Prognostic Score (IPS). However,
In HL, the PFS directly reflects the PET/CT results. interim-PET results can be changed according to the drug
Retrospective and prospective studies have shown that regimen used since the BEACOPPesc protocol promotes a

144 Rev Bras Hematol Hemoter. 2011;33(2):140-147

 Current status of PET/CT in the diagnosis and follow up of lymphomas

conclusions about its value.(34) However, more complex is

the fact that indolent but advanced follicular NHL is quite
different from HL and aggressive NHL. Current therapy is
rarely curative, and the use of autologous stem cell
transplantation (ASCT) or bone marrow transplantation for
non-responding patients is feasible but the optimal timing of
the procedure and its late effects remain questionable. Also,
for indolent tumors it is possible to keep the disease under
control for longer times using various therapy regimes but
without improving the OS.
Adapting therapy according to the early PET response
has been under investigation by many groups(35,36) however,
so far there is not enough evidence to prove that changing
to a more aggressive therapy or even ASCT to treat HL and
NHL non-responders provides better OS and clinical
outcomes.
Many studies have shown the impact of FDG-PET,
performed at the end of therapy in HL and aggressive NHL,
on the PFS and OS. (24,37-43) It is more accurate than
conventional structural imaging, since the information is
Figure 9 – An example of interim PET performed after 3 cycles of dependent on cellular activity rather than on the size of the
chemotherapy. Note a complete metabolic response after the first involved structures. A recent systematic review and meta-
cycles of treatment indicating a low probability of relapse after analysis showed that the negative predictive value of PET in
completion of therapy
evaluating therapy response in HL ranged from 94.3% (95%
CI, 92.8-95.7) to 100% (95% CI, 97.1-100).(44) In aggressive
lower positive predictive value when compared to the ABVD NHL, the result of PET at the end of treatment is also highly
regimen.(29) Another recent paper showed that interim-PET predictive for residual disease or relapse.(45)
performed after 3 cycles of ABVD in HL patients is highly In 2007 a group of experts brought together by the
prognostic, since the 3-year event-free survival (EFS) was International Harmonization Project, developed new
53.4% for the PET-positive group compared to 90.2% for the recommendations for response criteria using FDG-PET to
PET-negative group.(30) monitor aggressive lymphomas during therapy.(46) This was
In NHL, especially with the aggressive subtypes, very important to standardize the way PET is interpreted
interim-PET can also group patients with high and low odds whether by visual or quantitative criteria. Relatively recent
ratio for relapse. PFS ranges from 10-50% in the positive studies confirmed the superiority of the revised
interim-PET group compared to 79-100% in the negative interpretation criteria to evaluate HL and NHL.(47) However,
interim-PET group. In a large retrospective study, which most of the evidence-based literature is related to studies
included a cohort of 121 patients with high-grade NHL and a performed using conventional treatment protocols. Very
median follow-up of 28.5 months, 18F-FDG PET performed little data is available regarding the use of PET in tailoring
after 2 or 3 cycles of treatment strongly predicted PFS and therapy, even by abbreviating chemotherapy in early good-
OS. The estimated 5-year PFS was 89% for a negative interim- responders or by excluding radiotherapy as a complimentary
PET group and 16% for a positive-PET group. Also an therapy option in the end-of-treatment phase when the
association was shown between early-PET results and OS.(31) patient shows complete metabolic response at PET. The
In a prospective study, Haioun et al., performing PET after 2 results of omitting radiotherapy at the end of chemotherapy
cycles of chemotherapy in aggressive NHL patients, showed in patients with residual mass but negative PET is
2-year PFS and OS of 82% and 90%, respectively for a negative- controversial, since there are studies that confirm the high
PET group in contrast to 43% and 60%, respectively for a negative predictive value of PET (95%),(48) in contrast to
positive-PET group. (32) A recent study evaluating the others that show a higher relapse rate in the group of patients
prognostic value of interim-PET during R-CHOP therapy in not randomized to radiotherapy in comparison to the group
aggressive NHL showed no differences in PFS and OS referred to radiotherapy.(49) However, a recent study showed
between the negative interim-PET and positive interim-PET that PET/CT detects occult visceral disease in the liver and
groups. Only the end-therapy scan showed impact on PFS spleen in HL which is not detected by conventional imaging,
and OS.(33) thereby identifying patients requiring consolidation radiation
There is not enough evidence regarding the use of of the spleen. Moreover, the relapse rate was much lower in
interim-PET in indolent low-grade lymphomas. Most data the PET/CT group compared to the conventional imaging
report small cohorts of patients, which precludes any definite staged group.(50)

Rev Bras Hematol Hemoter. 2011;33(2):140-147 145

Buchpiguel CA

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