Pet ct assessment of therapeutic response in extra-nodal non Hodgkin lymphoma presentation

THE ROLE OF PET/CT
IN THE INITIAL STAGING AND
EVALUATION OF THERAPEUTIC
RESPONSE IN ASSESSMENT OF
EXTRANODAL NON-HODGKIN
LYMPHOMA

Introduction
 Lymphoma are tumors of lymphoid tissue, represents
4% of all cancers.
 Lymphoma is generally divided into : Hodgkin’s
disease (HD) and non-Hodgkin’s lymphoma
(NHL).
 NHL is a multifocal disease which often presents
late with disseminated extranodal spread, it
accounts 62.4 % of all lymphomas.

Introduction
 The extra nodal involvements are compromising in
approximately 40% of patients.
 With the introduction PET/CT scanners, a combined
method of metabolic and morphologic imaging is
available.

Aim of Work
 To evaluate the role the PET/CT in initial
diagnosis and staging of lymphoma.
 Assessment of therapeutic response.
 Interim follow up and assessment of
remissions/relapses.
 Highlighting the role of five-point scale
(Deauville criteria) to grade response of
therapy using PET-CT.

Non Hodgkin lymphoma
 NHL's include diffuse large B-cell
(31%), follicular (22%), marginal zone
or MALT (8%), peripheral T-cell (7-
15%), small lymphocyte B-cell (7%),
mantle cell (6%), and others (11%).
 Treatment for NHL is based on several
factors, including tumor grade.

Extranodal NHL
 Non-Hodgkin lymphoma (NHL) may arise
in nodal and extranodal sites.
 Extranodal lymphoma may be:
 Originated in non-nodal tissue (primary ENL)
 Originated in nodal tissue and spread to adjacent
non-nodal tissue,
 Originated in nodal tissue and hematogenous
spread to extranodal sites (secondary ENL).
(Even-Sapir et al,
2007)
o
r

Extranodal NHL
 Most common extranodal sites in Non-
Hodgkin lymphoma (NHL) may arise in:
 Spleen.

Extranodal NHL
 Waldeyer’s ring.

Extranodal NHL
 Lung and & pleura.

Extranodal NHL
 Bone

Extranodal NHL
 GIT.

Extranodal NHL
 Hepatic.

Extranodal NHL
 Orbit.

Extranodal NHL
 Other extranodal sites in Non-Hodgkin
lymphoma (NHL) may arise in:
Skin.

Extranodal NHL
Salivary gland.

Extranodal NHL
The thymus.

Extranodal NHL
 Central nervous system (CNS)

Extranodal NHL
 Peripheral nervous system.

Extranodal NHL
Breast.

Extranodal NHL
Testis.

Extranodal NHL
Genitourinary tract (GUT).

Extranodal NHL
Gall bladder.

Extranodal NHL
Peritoneum

Applicable to any stage:
A No B symptoms.
B Fever, nocturnal sweats, loss of more than 10% of body weight in
previous 6 months.
X Bulky disease: mediastinal widening >1/3 measured at the T5–6
level, or mass >10 cm.
E Involvement of a single extranodal site contiguous or next to the
known lymph node localization.
S Splenic involvement.

Physical Background and
Technical Aspects of PET/CT
PET is a functional imaging technique.
 Radiopharmaceuticals produced by labeling
metabolic markers such as glucose with positron
emitting radionuclides such as fluorine 18.
 Producing 18F-Fluoro-2-deoxy-glucose (FDG).

 Malignant cells show increased glucose
utilization.
 FDG is analogue to glucose , so they elicit high
uptake of FDG.
 FDG is ideal for tumor imaging as it allows
accurate and noninvasive differentiation of
benign from malignant abnormalities.
Physical Background and
Technical Aspects of PET/CT

Hardware of PET-CT Scanner consists of
three main components
CT scanner
PET scanner.
Patient bed

Technique of Whole-Body
PET/CT Imaging with 18F-FDG
Patient Preparation
 Fasting for 6 hours .
 Remove metallic items from the patient.
 Insert I.V. catheter .
 Check the blood glucose level.
 The patient is asked to void activity and
speech before scanning .

 Dosage Administration
 Inject 18F-FDG into the patient in a dosage of
0.22 mCi/kg “10-20 mCi (370 MBq; approximate dose to patient, 3-
5MBq/Kg) 18F-FDG 45–90 minutes before examination”
 Oral contrast agents are administered 40 to 60
minutes prior to CT scanning (usually mannitoal as
negative oral contrast).
 The patient waits 45-60 minutes after FDG
administration and is instructed to remain quiet
with minimal movement until the completion of
the PET/CT scan.

Advantages of PET/CT
PET demonstrates biological function
before anatomical changes take
place.
CT provides information about the
anatomy and morphology.
PET/CT combines anatomical
information from CT with functional
information from PET.

Applications for FDG-PET/CT in
NHL
 Staging
 Stage before any treatment started; one dose
of chemo may decrease uptake, causing
underestimation of stage
 Assessment for response to therapy and
tumor recurrence
 Differentiate scar from residual tumor
mass.
 Predict outcome.

Applications for FDG-PET/CT in
NHL
 FDG-PET/CT findings can result in
:
• Change in patient staging up to 44%
of patients (either up-stage or down-stage).
sensitive and specific than CT
imaging alone for staging and
restaging lymphoma
• Change in patient management in up
to 62%.

 Image interpretation:
Interpretation of the PET CT findings was
qualitative and semi-quantitative.
 The qualitative evaluation (visual) included
the description of all the hypermetabolic
lesions (activity > liver or blood pool).
 The semi-quantitative evaluation or SUV
bases evaluation was performed using the
maximum standardized uptake value
(SUVmax) in a region of interest located over
the hypermetabolic lesion.
Therapy Response Evaluation

 Evaluating response to therapy either
early assessment, after one to three
cycles of treatment, interim or after end of
treatment of the overall response.
 Usually performed approximately one
month after cessation of chemotherapy.

Patients and Methods
 Patients with pathologically proven NHL
were included.
 Patients performed one or more of the
following:
Initial PET/CT for staging
Interim PET/CT
End of treatment PET/CT
Follow up PET/CT exams to detect relapse.
 Study population 50 patients.

We classified the patients in our study into 4 groups;
Group I included 10 patients came for initial
staging by PET/CT exams.
Group II included 8 patients came for pre-
treatment staging, continued interim follow
up and end treatment assessment by
PET/CT exams.
Group III included only 22 patients whom
underwent interim PET/CT for response
assessment after mid treatment.
Group IV included 10 interim patients that ended
treatment and were seen in our institution
for end of treatment PET/CT for
relapse/response assessment.
Patients and Methods

 Most common therapeutic response
evaluation guideline in lymphoma was done
according to:International Workshop Criteria IWC (1999)
guidelines
Revised response criteria by international
harmonization project (IHP) (Cheson. et al,
2007)
Modified Deauville Criteria
‘‘PERCIST’’ — Positron Emission
tomography Response Criteria In Solid
Tumors.
The EORTC PET

CRITERION CR PR SD PD
IHP
• Any size/no
, if no
FDG
•Variable/un
known FDG,
LN must
regressed
to <= 1.5 cm
• Size  50%
SPD*
• No  LN/L/S
• PET+, variable
or regression
in previous
site
• Fails to
attain
CR,PR or
PD
•50% SPD*
•50% LN§
• New lesions >
1.5 cm
*Sum product of diameters, § Lymph
node
 Patients in our study were assessed using IHP
(Cheson, et al 2007) and correlated by modified
Deauville criteria.
I- Revised response criteria by international
harmonization project (IHP) (Cheson. et al,
2007).

II- Modified Deauville criteria.
Scor
e
PET/CT Scan Result
1 No uptake above background
2 Uptake at an initial site that is ≤ to mediastinum
3 Uptake at an initial site that is > mediastinum but ≤ to liver
4
Uptake at an initial site moderately > the liver at any site.
“Uptake > the maximum SUV in a large region of normal liver (Barrington. et al,
2014)”
5a Uptake at an initial site that is markedly > the liver
5b
Uptake at any new site that is markedly > the liver that is
possibly related to lymphoma
“uptake is 2 X to 3 X > the maximum SUV in the liver (Barrington. et al, 2014)”.
X New areas of uptake unlikely related to lymphoma

Assessment of treatment response by modified Deauville
criteria.
 Complete response (CR): scores 1, 2 or 3 together with
absence of FDG-avid bone marrow lesion(s) are
interpreted as complete metabolic response (CR),
irrespective of a persistent mass on CT
 Partial response (PR): a Deauville score of 4 or 5,
provided:
 Uptake is decreased compared with baseline and
 Absence of structural progression development on CT
 Stable disease (SD): also called no metabolic response: a
Deauville score of 4 or 5 without significant change in
FDG uptake from baseline.
 Progressive disease (PD): a Deauville score of 4 to 5
with increasing intensity compared to baseline or any
interim scan and/or any new FDG-avid focus consistent

I- Organ based analysis and
demographic features of all
studied groups

RESULTS
Characteristics
Patients group
(n= 50)
Age (yrs)
Range 20-78
Mean ± SD 51.47 ± 14.70
Gender
Female 16 (32%)
Male 34 (68%)
I- Organ based analysis and demographic
features of all studied groups

At time of presentation of patients in each group we found that
6 % presented stage II-S, 8% presented II-E, 10%
presented stage III-S, 26% presented III-E, 12% presented
III-SE and 38% presented stage IV.
Staging
Group Tot
al
no.
%
I II III IV
I-E 1 0 1 0 2 4%
II-S 1 0 2 0 3 6%
II-E 2 0 0 2 4 8%
III-S 0 0 3 2 5 10%
III-E 2 3 6 2 11 22%
III-
SE
1 2 1 2 6 12%

The different organ involvement
reported was:
Sites of extra-nodal disease Total number of patients Percent %
spleen 17 34
Bone marrow & osseous 15 30
liver 9 18
Pulmonary nodules 12 24
Renal 2 4
muscular 4 8
pleural 3 6
GIT 4 8
cutaneous 4 8
nasopharyngeal 4 8
salivary Gland 1 2
Tonsils 2 4
adrenal 2 4
thyroid 1 2
breast 1 2

High PET-CT
sensitivity 100%
with significant
P-value 0.0001.
Comparison between detection of lymph
nodes involvement by CT and PET CT
showed that :
100
0
100
0
0
20
40
60
80
100
120
Percent
CT positive CT negative
PET CT positive PET CT negative
All patients in this study had PET-CT evidence of
metabolically active one or more lymph node groups,
while 42 patients had enlarged lymph nodes by CT.
PET/CT depicted avid sub-centimetric lymph nodes in
eight out of the 50 patients, that were normal sized LN in

high sensitivity of
PET-CT of about
100% with
high specificity of
about 82.5% and
significant P-
value 0.001
Comparison between detection of splenic
involvement by CT and PET CT showed
that :
100
0
20
82.5
0
10
20
30
40
50
60
70
80
90
100
Percent
Out of the 50 patients in our study groups, 17 patients had
evidence of splenic involvement (increased metabolic activity
of the spleen &/or splenic lesions) and 33 patients had no
splenic affection detected by PET-CT; while 10 patients only
showed splenic involvement by CT and 40 patients show no
splenic involvement by CT

Comparison between detection of bone
marrow involvement by CT and PET CT
showed that :
high sensitivity
of PET CT of
100%
with specificity of
74.5% and high
significant P-
value 0.006.
100
0
25.5
74.5
0
20
40
60
80
100
120
Percent
Out of the 50 patients, 15 patients had evidence of
increased metabolic activity of the bone marrow &/or
osseous lesions detected by PET-CT while only three
patients showed osseous lesions by CT.

high sensitivity of
PET CT of 76.9%
with specificity of
56.8% and high
significant P-
value 0.037.
Comparison between detection of other
extranodal involvement by CT and PET CT
showed that :
76.9
23.1
43.2
56.8
0
10
20
30
40
50
60
70
80
90
100
Percent
Out of the 50 patients, 26 patients had evidence of
increased metabolic activity of other extranodal organs
detected by PET-CT while only 13 patients out of those
showed affection by CT.

100 100 100 100
25
82.5
74.5
64.9
87
58.8
20
50
50
97 100 100
84 86
76 74
0
20
40
60
80
100
120
Percent
Sensitivity Specificity PPV NPV Accuracy
Lymph node Spleen Bone marrow Other organs
• PET⁄CT is a useful tool for staging of extranodal lymphoma with
high sensitivity.
• Specificity of PET-CT seems to be related to the sites of
involvement
• Highest specificity in detection of splenic and bone marrow
involvement respectively.
• PPV is higher in lymph node detection
• NPV highest in the bone marrow and other extra nodal affection
by PET CT.
• The highest accuracy is that in splenic involvement detection by

RESULTS
II- Therapeutic response analysis and
response designations according to the
IHP and Deauville criteria classifications
of groups II & III of the study:

Concordance of response designations
between (IHP) and Deauville after early interim
in groups II & III
 Our study showed that 24 out of 30 patients had
concordant designations (91.7%, 83.3%, 70%, and
33.3%) and six patients had discordant
designations.
91.7
0
8.3
16.7
83.3
0
10 10
70
0 0
50
0
20
40
60
80
100
120
Percent
CR IHP PD IHP PR IHP ST IHP
CR deauville PD deauville
PR deauville ST deauville

between (IHP) and Deauville after late interim in
groups II & III
concordant designations (100%, 100%, 80%, and
50%) and two patients had discordant
designations.
100
0 0
0
0
100
0 0
9
66.7
16.7 16.7
0
50
25 25
0
20
40
60
80
100
120
Percent
CR deauville PD deauville
PR deauville ST deauville

between (IHP) and Deauville after end of
treatment in groups II & III
concordant designations (100%, 100% and 71.4%)
and only one patient has discordant designations.
100
0 0 0
100
0 0
28.6
71.4
0
100
0
0
20
40
60
80
100
120
Percent
CR deauville PD deauville PR deauville

Case I:
43 years old male patient with recently
diagnosed lymphoma for pre-treatment
staging.
Then he received 3 cycles chemotherapy for
early interim therapeutic response,
Received additional 2 cycles for late interim
therapeutic response,
Then came for end treatment response.

Case I
In the pretreatment evaluation:
• There’s metabolically active disease involving
multiple lymph nodes above and below the
diaphragm.
• Extranodal involvement of liver, spleen and
bone marrow with soft tissue intermuscular
nodules.
STAGE
IV-S
Deauville criteria
Score 5

Case I
Deauville criteria
Score 4
After 3 cycles chemotherapy (early interim
response),
• There’s complete metabolic response of
the nodal, hepatic and splenic disease and
• Partial metabolic response of the bone
marrow lesions.

Case I
The patient came for late interim
therapeutic response after 2 more
additional chemotherapy cycles,
showed:
• No FDG-avid lesions distinctive for
active lymphoma.
Deauville criteria
Score 2

Case I
Deauville criteria
Score 1
After end of treatment, the patient
underwent PET-CT for relapse/recurrent
assessment showed:
• Still no FDG-avid lesions distinctive for
active lymphoma with no
relapse/recurrent disease.
Overall response by Deauville criteria
showed concordance with IHP .

Case II:
67-year-old female patient with history of large
cell lymphoma, underwent surgical excision of
large left axillary nodal mass followed by 8
cycles of chemotherapy & ended radiotherapy
thereafter, for interim and end treatment
response.

Case II
STAGE
IV-S
Deauvill
e criteria
Score
5
In the baseline study evaluation:
•There’s wide spread
metabolically active nodal
“largest at the Lt. axillary
apex” as well as splenic
lesions.

Case II
Deauville
criteria
Score
3
Interim therapeutic response
after 8 cycles chemotherapy,
showed:
•Two newly observed
hypermetabolic lymph nodes in
the apex of the left axilla,
suggestive of metabolically
active disease.
•Complete metabolic and
morphologic resolution of

Case II
Deauville
criteria
Score
5
After end of treatment, assessment showed:
• Metabolic and morphological progression of the lymph nodes
above and below the diaphragm.
• Marked disease progression regarding the extranodal disease
• Newly depicted splenic, right lung, left kidney, left adrenal and
multiple soft tissue nodules "cutaneous, muscular and inter-
muscular",
Overall response by Deauville
criteria showed concordance with
IHP .

Case III:
A 55 years old male patient with pathologically
proved gastric Lymphoma; for pre-therapy
assessment, the patient received 6 cycles
chemotherapy and underwent 2 sets of
radiotherapy, and came for interim follow up
and end treatment assessment.

Case
III
STAGE
II-E
Deauvill
e criteria
Score
5
In the baseline study
evaluation:
• Metabolically active lymphoma
localized to the gastric pyloric
canal with no extra-gastric
active disease
• There’s few metabolically
active infra-diaphragmatic

Case
III
•In the interim response after
6 cycles of chemotherapy
there’s Complete metabolic
and morphologic response of
the nodal and extranodal
disease with no current
metabolically active gastric
Deauvill
e criteria
Score
2

Case
III
After end of treatment,
showed no evidence of
metabolically active nodal or
extranodal disease,
Deauville
criteria
Score
1
Deauville criteria showed discordance in
interim therapeutic response while
concordance in end of treatment
therapeutic response with IHP

Case IV:
42-year-old male patient with biopsy from
cervical lymph node (pathology details not
available), came for initial staging.

In the baseline
study evaluation:
• There’s
metabolically
active supra and
infra-
diaphragmatic
nodal disease.
Case
IV

In the baseline study
evaluation:
• Extranodal
involvement of the
following:
Nasopharynx ,
Spleen, Multiple
bilateral pulmonary
nodules, Sub-
cutaneous nodule ,
Diffuse increased
18F-FDG uptake is
noted by the bone
marrow and parotid
glands.
Case
IV
STAGE
IV-S
Deauvill
e criteria
Score
5

Case V:
32 years old male patient with gastric ulcer
proved pathologically to be NHL came for
initial staging.

Case
V
In the baseline study evaluation:
• Intense FDG uptake is noted by extensive gastric wall mural
thickening mainly involving the fundus and extends along the lesser
curvature (white arrow).
• FDG-avid infradiaphragmatic amalgamated nodal soft tissue mass
encasing the aorta, IVC, celiac, mesenteric, and renal vessels. It

• Other multiple FDG-avid discrete supra-
diaphragmatic (cervical, mediastinal )and
infra-diaphragmatic lymph nodes
• FDG-avid omental and peritoneal sheet-
like and nodular masses (yellow arrow).
• Bilateral minimal pleural nodular
thickening (red arrow).
Case
V
STAGE
III-E
Deauville
criteria
Score 5

Discussion
 In our study we found in agreement with
Cronin et al, 2010& Soyka et al, 2008 studies
that:
• PET⁄CT is a useful tool for staging of
extranodal lymphoma with high
sensitivity.
• Specificity of PET-CT seems to be
related to the sites of involvement
• Highest specificity in detection of
splenic and bone marrow involvement
respectively.

Discussion
 Paes et al, 2010 & Soyka JD et al, 2008
agreed that extranodal lymphomatous
involvement may be suspected at PET/CT and
the diagnosis can be confirmed only with
biopsy.
 Early assessment also helps prevent
unnecessary side effects from useless
regimens and reduces cost by discontinuing
expensive therapy in patients who do not
respond to treatment. (Blodgett et al, 2007)

Discussion
 In our study, visual assessment using
(Modified Deauville Criteria) were suited to
assess different degrees of therapeutic
response and has been developed to score
images.
 Recommendations from the international
conference of malignant lymphoma (ICML),
Barrington et al, 2014 and Awan et al, 2013
that Deauville criteria has proved as a useful
tool in evaluating response to treatment.

Discussion
 In concordance with Awan et al, 2013, Evens
& Kostakoglu, 2014 studies, we found that
response assessment according to the
Deauville criteria classification appears to
have good concordance with IHP classification
especially in early interim and after end of
treatment response assessment and intended
to represent a practical framework used for
interim PET CT follow up of NHL.

Discussion
 Hutchings et al, 2006, whose stated that
extranodal disease dissemination is an
indicator of tumor aggressiveness and reflects
in response to treatment and the most
important determinants of outcome in NHL.

Discussion
 During this work, we tried to use maximum
18F-FDG uptake SUVmax of the affected
lymph nodes and that of the extra nodal sites
in an attempt to set a relationship between the
SUVmax and the response, and to set a cut off
value that can be used to predict response,
But the wide variation in the SUVmax and
facing many biologic and technical factors
affecting the SUV in our work showed
statistically non significant levels.

Summary & conclusion
 18F-FDG PET/CT is the best oncologic
imaging modality in initial diagnosis, staging
and management of lymphoma.
 PET/CT has a high prognostic value with early
prediction of the response to therapy.

Summary & conclusion
 Response assessment according to the
Deauville criteria classification appears to
have good concordance with IHP classification
with recommendations from ICML for its use in
reporting.
 Collection of additional data as SUV is
recommended so as to develop a database
suitable for additional information to refine the
response metrics for a given tumor and
therapy and as potential prognosticators with
requirement of further validation with a larger
number of patients.

Pet ct assessment of therapeutic response in extra-nodal non Hodgkin lymphoma presentation

Pet ct assessment of therapeutic response in extra-nodal non Hodgkin lymphoma presentation

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