Title

18F FDG PET-CT scan in nasopharyngeal carcinoma and nonHodgkin's lymphoma: two common cancers of the Hong
Kongpopulation

Advisor(s)

Khong, PL

Author(s)

Chan, Kit-sum.; .

Citation

Issued Date

URL

Rights

2010

http://hdl.handle.net/10722/131815

The author retains all proprietary rights, (such as patent rights)

and the right to use in future works.

18

F FDG PET-CT SCAN IN

NASOPHARYNGEAL CARCINOMA AND

NON-HODGKINS LYMPHOMA: TWO
COMMON CANCERS OF THE HONG KONG
POPULATION
Submitted by

Chan Kit Sum

BSc in Radiography (The Hong Kong Polytechnic University)

for the degree of Master of Philosophy

at The University of Hong Kong

in September 2010

ABSTRACT OF THESIS ENTITLED

18

F FDG PET-CT SCAN IN

NASOPHARYNGEAL CARCINOMA AND
NON-HODGKINS LYMPHOMA: TWO
COMMON CANCERS OF THE HONG KONG
POPULATION
Submitted by

Chan Kit Sum

For the degree of Master of Philosophy at the University of Hong Kong in September 2010

18

F fluorodeoxyglucose (FDG) positron emission tomography (PET)-computed

tomography (CT) is a sensitive whole-body imaging technique for oncology. It has

been widely used for staging, treatment planning and treatment response monitoring
in various malignancies. Standardized uptake value (SUV), metabolic tumor volume
(TV) and total lesion glycolysis (TLG) provides semi-quantitative information about
the metabolic activity and size of tumors. The objective of the study is to evaluate the
clinical utility of the semi-quantitative parameters of

18

F FDG PET-CT in two

common cancers in Hong Kong.

Nasopharyngeal carcinoma (NPC) has the highest incidence rates in the world
reported in Southern China and it was the 7th most common cancer in Hong Kong in
2007. We evaluated the relationships between maximum SUV (SUVmax), TV and
TLG of primary tumor and tumor-node-metastases (TNM)-classification in NPC
I

patients.

18

F FDG PET-CT scans of 57 consecutive newly-diagnosed NPC patients

(age range 15-80 years) referred to our unit were retrospectively reviewed prior to
treatment. Positive correlations were observed between SUVmax (p<0.001, R=0.516),
TV (p<0.001, R=0.504) and TLG (p<0.001, R=0.620) of primary tumor and T-stage,
and both TV and SUVmax of the primary tumor were independent variables that
significantly affected T-stage (p<0.001,

adjusted R2=0.370). Subsequently,

prognostic impact of SUVmax of the primary tumor (pSUVmax), the highest SUVmax of
cervical lymph nodes (nSUVmax) and TV was evaluated in 49 pre-treatment NPC
patients. pSUVmax 7.5 and nSUVmax 6.5 results in significantly worse disease-free
survival (DFS) (p=0.022 and p=0.036, respectively), loco-regional relapse free
survival (LRFS) (p=0.041 and p<0.001, respectively) and distant relapse-free
survival (DRFS) (p=0.028 and p<0.001, respectively).

In 2007, non-Hodgkins lymphoma (NHL) represented the 9th most common

cancer in Hong Kong and about 6.5% of NHL cases were natural killer (NK)-cell
lymphoma. The spectrum of NHL in Asian/Oriental countries is different from that in
Caucasian populations, with NK-cell lymphoma almost exclusively found only in
Asian countries. We compared the metabolic activity by

18

F FDG uptake across the

various histologic subtypes of NHL in a single center, with particular interest in the
NK-cell lymphoma subtype. We retrospectively evaluated the FDG-avidity of
pre-treatment PET-CT scans of 117 consecutive NHL patients scanned at our unit.
All 16 patients with NK-cell lymphoma had positive PET scans. Although NK-cell
lymphoma was highly FDG-avid, SUVmax of NK-cell lymphoma (9.24.5) was
significantly lower than aggressive B-cell lymphoma (14.16.4) (p=0.013). SUVmax
was similar to aggressive T-cell lymphoma (7.63.9) and significantly higher than
II

that of indolent B-cell lymphoma (5.33.1) (p=0.039). This may reflect the large
amount of coagulative necrosis and inflammatory component of the tumor, and the
relatively slower tumor growth rate compared to aggressive B-cell lymphomas.

The results of this study suggest that semi-quantitative parameters are able to
reflect the metabolic phenotype and useful for providing information of tumor
aggressiveness and prognosis in NPC and NHL patients. Accurate assessment of the
disease status and aggressiveness would enable better treatment planning, such as
modification of drug regimen, to maximally benefit individual patients, and with
greater chance of success.

(Words Count: 496)

Signed:___________________
CHAN Kit Sum

III

DECLARATION

I declare that this thesis represents my own work, except where due
acknowledgement is made, and that it has not been previously included in a thesis,
dissertation or report submitted to this University or to any other institution for a
degree, diploma or other qualifications.

Signed __________________
CHAN Kit Sum

IV

ACKNOWLEDGEMENTS

I wish to take this opportunity to express my deepest gratitude to all the people who
have helped me to complete my MPhil study.

I would like to express my heartfelt thanks to Professor Pek-Lan Khong, my research

supervisor, for her unfailing support and guidance in my study during the past three
years.

My great thanks also go to Dr. Henry Mak and Professor David Yeung for their
invaluable advice and guidance during my study. I would like to thank my colleagues
in the Department: Mr. Stephen Kwok, Mr. Ken Liu, Mr. Chris Ho, Ms. Carol Lam,
Mr. Thomas Iong, Miss Carol Leung, Mr. Bingsheng Huang, Dr. Deqiang Qiu, Ms.
Irene Leung and Miss Alice Lau.

Last but not least, I would like to thank my family for their continuous love and
understanding for me.

TABLE OF CONTENTS

TABLE OF CONTENTS

ABSTRACT of thesis entitled ...................................................................................... I

DECLARATION ........................................................................................................ IV
ACKNOWLEDGEMENTS ........................................................................................ V
TABLE OF CONTENTS ........................................................................................... VI
LIST OF ABBREVIATIONS .................................................................................. VIII
Chapter 1 Positron Emission Tomography-Computed Tomography (PET-CT) ....... 1
1.1 Basic Principles of Whole-body 18F-FDG PET-CT Scan ............................................... 1
1.2 Calculation of Standardized Uptake Value (SUV) ......................................................... 5

Chapter 2
2.1
2.2
2.3
2.4

Oncological Applications of Whole-body PET-CT .................................. 8

Overview ........................................................................................................................ 8
SUV Application in Oncology .................................................................................. 11
Metabolic Tumor Volume (TV) .................................................................................... 13
Total Lesion Glycolysis (TLG) .................................................................................... 16

Chapter 3 Background and Hypotheses .................................................................. 17

3.1 Nasopharyngeal Carcinoma (NPC) .............................................................................. 17
3.1.1 Staging and Treatment ....................................................................................... 17
3.1.2 Imaging Methods............................................................................................... 20
3.2 Non-Hodgkins Lymphoma (NHL) .............................................................................. 23
3.2.1 Histological Subtypes and Geographical Disease Spectrum ............................. 23
3.2.2 Diagnosis and Staging ....................................................................................... 27
3.2.3 Treatment and Prognosis ................................................................................... 30
3.2.4 Imaging Methods............................................................................................... 31
3.3 Research Objectives ..................................................................................................... 33
3.4 Hypotheses ................................................................................................................... 33
3.5 Significance and Value ................................................................................................. 34

Chapter 4 PET-CT Protocol .................................................................................... 35

4.1 Patient Preparation ....................................................................................................... 35
4.2 Scanning Protocol ........................................................................................................ 36
4.3 Image Analysis ............................................................................................................. 37

Chapter 5

Nasopharyngeal carcinoma: Relationship between 18F FDG PET-CT

Maximum Standardized Uptake Value, Metabolic Tumor Volume and
Total Lesion Glycolysis with TNM-Classification ................................ 38

5.1 Introduction .................................................................................................................. 38

5.2 Materials and Methods ................................................................................................. 39
5.2.1 Patient Cohort.................................................................................................... 39
5.2.2 PET-CT Protocol ............................................................................................... 39
5.2.3 Image Analysis .................................................................................................. 40
5.2.4 Statistical Analysis ............................................................................................ 40
5.3 Results .......................................................................................................................... 40
5.4 Discussion .................................................................................................................... 41
5.5 Conclusion.................................................................................................................... 43
Figures ......................................................................................................................... 44
Tables ......................................................................................................................... 47

Chapter 6 Prognostic Stratification Using Standardized Uptake Value of 18F FDG

PET-CT in Nasopharyngeal Carcinoma ................................................. 51
6.1
6.2

Introduction .................................................................................................................. 51
Materials and Methods ................................................................................................. 52
6.2.1 Patient Population ............................................................................................. 52

VI

TABLE OF CONTENTS

6.2.2 PET-CT Protocol ............................................................................................. 53

6.2.3 Image Analysis ................................................................................................ 53
6.2.3 Treatment ........................................................................................................ 53
6.2.4 Study Design and Statistical Analysis ............................................................. 54
6.3 Results .......................................................................................................................... 55
6.3.1 Univariate Analysis ......................................................................................... 56
6.3.2 Multivariate Analysis ...................................................................................... 56
6.3.3 Spearmans Test .............................................................................................. 57
6.3 Discussion .................................................................................................................... 57
Figures ......................................................................................................................... 61
Table ......................................................................................................................... 63

Chapter 7

Metabolic Activity Measured by PET in NK-cell Lymphoma Compared

to Aggressive B- And T-cell Lymphomas .............................................. 64

7.1 Introduction .................................................................................................................. 64

7.2 Materials and Methods ................................................................................................. 65
7.2.1 Patient Population ............................................................................................. 65
7.2.2 PET-CT Protocol ............................................................................................... 65
7.2.3 Statistical Analysis ............................................................................................ 65
7.3 Results .......................................................................................................................... 66
7.4 Discussion .................................................................................................................... 67
7.5 Conclusion.................................................................................................................... 68
Figures ......................................................................................................................... 70
Tables ......................................................................................................................... 73

Chapter 8 Conclusion Summary and Future studies ............................................... 76

Reference list .............................................................................................................. 79
LIST OF FIGURES.................................................................................................... 96
LIST OF TABlES ....................................................................................................... 97
PUBLICATIONS AND PRESENTATIONS RELATED TO THE THESIS ............. 98

VII

LIST OF ABBREVIATIONS

AJCC

American Joint Committee on Cancer

CR

Complete response

CT

Computed tomography

CTV

Clinical target volume

CLL/SLL

Chronic lymphoma leukemia / small lymphocytic lymphoma

DFS

Disease-free survival

DLBCL

Diffuse large B-cell lymphoma

DRFS

Distant relapse-free survival

EBER

In situ hybridization for EBV encoded small RNA

EBV

Epstein-Barr virus

EORTC

The European Organization for Research and Treatment of Cancer

FDG

Fluoro-D-deoxyglucose

FDG-6P

FDG-6-phosphate

GLUT

Glucose transporter

GTV

Gross tumor volume

IMRT

Intensity modulated radiotherapy

IWG

The International Working Group

LRFS

Loco-regional relapse-free survival

MALT

Mucosa-associated lymphoid tissue

MRI

Magnetic resonance imaging

NHL

Non-Hodgkins lymphoma

NK-cell

Natural killer cell

NPC

Nasopharyngeal carcinoma

nSUVmax

Highest SUVmax of cervical lymph node metastases

OS

Overall survival

PET

Positron emission tomography

PERCIST

PET Response Criteria in Solid Tumors

PF

Cisplatin and 5-fluorourcil

PFS

Progression-free survival

pSUVmax

SUVmax of the primary NPC tumor

VIII

PTCL

Peripheral T-cell lymphoma

RECIST

Response Evaluation Criteria in Solid Tumors

ROI

Region of interest

RT

Radiotherapy

SUV

Standardized uptake value

SUVbsa

SUV corrected with body surface area

SUVbw

SUV corrected with body weight

SUVlbm

SUV corrected with lean body mass

SUVmax

Maximum SUV

SUVmean

Mean SUV

SUVpeak

Peak SUV

TLG

Total lesion glycolysis

TLG

Change in TLG

TNM

Tumor-node-metastases

TV

Metabolic tumor volume

UICC

The International Union Against Cancer

WHO

World Health Organization

IX

CHAPTER 1

CHAPTER 1

KS CHAN

POSITRON EMISSION

TOMOGRAPHY-COMPUTED TOMOGRAPHY
(PET-CT)

1.1 Basic Principles of Whole-body 18F-FDG PET-CT Scan

Positron emission tomography (PET) is a functional imaging modality which
images and measures molecular processes in vivo after injection of a radioisotope
such as

18

F Fluoro-D-deoxyglucose (FDG),

11

C Choline etc. The main drawback of

PET is its poor spatial resolution which limits anatomical information. This problem
has been solved by the development of combined PET and computed tomography
(CT) systems.

Another major problem with PET-only machine is long scanning time. The
principle of PET scanning is based on the radioactive decay of radioisotopes such as
11

C, 18F and 67Ga which emit positrons during decay. The emitted positrons undergo

annihilation with electrons and two photons, each with energy of 511 keV, which are
released and go in almost opposite directions (180apart) during the process. The
photons are then detected by coincidence imaging by the scintillation crystals fitted
in the detector ring (Fig 1.1). When the photons pass through the tissues of the body,
attenuation occurs. Photons which emanate from various regions suffer from
different degrees of attenuation. Greater attenuation occurs if the structure is deeper
in the body. In a PET-only scanner, a transmission attenuation map which is obtained
1

CHAPTER 1

KS CHAN

from a rotating positron source (68Ge) is used for correcting the attenuation of the
emission scan and this transmission scan represents 40% of the total scan time
(45min). With the development of PET-CT machines, the transmission scan has been
replaced by a whole-body CT scan which can be performed in 20 seconds for
attenuation correction thus improving patient comfort and increasing patient
throughput. There are various kinds of crystals such as bismuth germinate, lutetium
oxyorthosilicate, or gadolinium silicate and the spatial resolution of image range
from 2-4mm depending on the size of the crystals (Delbeke, 1999; Kapoor et al.,
2004; Poeppel et al., 2009) and data acquisition methods (2-dimensional or
3-dimensional) (Saha, 2010).

Fig 1.1 showing the process of annihilation reaction. Positrons emitted () from the
nucleus of radioisotope interact with electrons (), releasing two photons which are
detected by scintillation crystals (blue triangle). N: neutron; P: proton. (Kapoor et al.,
2004).

CHAPTER 1
18

KS CHAN

F FDG is the most commonly used radiotracer of PET because it has a

practical half-life of

18

F (110 min) and allows investigation of glucose metabolism

(Delbeke, 1999). Due to the sensitive nature of FDG PET in detecting glucose
metabolic changes in early stage of disease, FDG PET has been widely used in
cardiology, neurology, infection and inflammation, as well as oncology imaging.
When 18F FDG is administered intravenously, similar to glucose, it is transported into
cells by glucose transporter (GLUT) proteins and subsequently, phosphorylated by
hexokinase and becomes

18

F FDG-6-Phosphate (FDG-6P). However, contrary to

glucose, 18F FDG-6P cannot be further metabolized through glycolysis in the absence
of an oxygen atom at the C-2-position nor through dephosphorylation by
glucose-6-phosphatase. Since 18F FDG-6P cannot permeate out of the cell, it remains
trapped intracellularly eventually. Therefore, the concentration of 18F-FDG within the
cells is commensurate with the glucose metabolism of the tissue (Fig 1.2) (Abouzied
et al., 2005; Weber et al., 1999).

CHAPTER 1

Fig 1.2 showing the process of

KS CHAN
18

F Fluoro-D-deoxyglucose (FDG) uptake. FDG-6P:

FDG-6-phosphate; Glut: Glucose transporter. (Kapoor et al., 2004)

Malignant tumors frequently demonstrate a higher glucose metabolism than

normal tissue. It is due to the increased numbers of GLUT proteins, e.g. hexokinase
and phosphofructokinase, which raise the transport capacity of cellular membrane,
and increase the level of glycolytic enzymes within cells, that boost glycolysis
(Delbeke, 1999; Weber et al., 1999). Thus, tumor cells, compared to normal tissue,
usually have a higher uptake of

18

F FDG and appear as hot spots on PET images.

Highly differentiated tumors and certain malignancies, though, show very low

18

FDG accumulation including prostate and renal cancer (Schder and Larson, 2004)
and low-grade lymphomas (Kwee et al., 2008), because of the limited hexokinase
activities and may lead to false negative results.

Physiological uptake is seen in various organs including brain, salivary glands,

CHAPTER 1

KS CHAN

myocardium, liver, bowels and urinary tract (Wang et al., 2007b). Both female
(endometrium and ovaries) (Lerman et al., 2004) and male (testes) (Kitajuma et al.,
2007) reproductive organs may also have physiological uptake.

18

F FDG uptake is

not tumor-specific; many studies have shown that infection and inflammation
triggers high uptake of

18

F FDG. Examples are chronic osteomyelitits,

post-surgical/radiotherapy (RT) induced inflammation, acquired immunodeficiency

syndrome and tuberculosis (Bakheet et al., 1998; Bleeker-Rovers et al., 2005; Love
et al., 2005).

1.2 Calculation of Standardized Uptake Value (SUV)

Interpretation of PET images is usually carried out both visually (qualitative
analysis) and semi-quantitatively. First, the reader visually analyses the images for
any area with increased FDG uptake besides the organs with known physiological
uptake. If there are any suspicious hot spots on images, semi-quantitative
measurement can be employed to provide a more objective way of analysis.

SUV is a widely-used semi-quantitative measure of the intensity of

18

F FDG

uptake in neoplasms (Ramos et al., 2001). It is calculated as the concentration of

injected radiotracer in the tissue (mCi/mL) divided by the administered dose (mCi)
divided by the body weight (g) (Lindholm et al., 1993).

It has been reported by Zasadny et al. (1993) that there is a strong correlation
5

CHAPTER 1

KS CHAN

between body weight and SUV corrected with body weight (SUVbw) and Kim et al.
(1994) found that SUV in larger patients was approximately 70% higher than that in
slender patients. Bodies of heavy people have relatively more fat than those of
slender people and in fasting state, FDG uptake of fat, which contributes to body
weight, is very low. Therefore, overestimation of SUVbw in heavy patients may occur
due to the higher proportion of total body fat than light people (Zasadny et al., 1993).
In order to eliminate the effect of body weight on the SUV measurement, several
investigators recommended correcting SUV with lean body mass (SUVlbm) and body
surface area (SUVbsa). Both SUVlbm and SUVbsa were found to be independent of
body weight (Kim et al., 1994; Schomburg et al., 1996; Sugawara et al., 1999;
Zasadny et al., 1993) and age; though SUVlbm was found to significantly correlate
with body height and lean body mass (Schomburg et al, 1996).

Clinically, maximum SUV (SUVmax) and mean SUV (SUVmean) are the most
commonly used approaches for defining the region of interest (ROI) for SUV.
SUVmax is a measurement of a single pixel with the highest radiotracer concentration
within the ROI. It is often used since it is more reproducible and operator
independent. SUVmean, which is calculated as the mean SUV of a volume of interest
using semiautomatic or automatic thresholding algorithms, is highly dependent on
the shape and size of ROI (Menda et al., 2001). Several less commonly used methods
are peak SUV (SUVpeak) and SUV measured within an automatically-defined volume
and tumor-to-background ratios (Benz et al., 2008).

Patz et al. (1993) evaluated 51 patients with focal pulmonary abnormalities and
found that SUV cutoff value at 2.5 yielded 100% specificity in discriminating benign

CHAPTER 1

KS CHAN

and malignant lesions and suggested any lesion with SUV >2.5 should be considered
malignant. The controversy over this cutoff value is that SUV can be influenced by
many factors which include blood glucose levels, body weight, the uptake time
between the injection of FDG and the start of scan, partial volume effect and the
reconstruction method (Keyes, 1995). The uptake of 18F FDG has been shown to be
decreased significantly when there is an elevation of blood glucose levels (Delbeke,
1999). There are also reports showing that long-term or high dose corticosteroid use
before PET scan can lead to reduction of FDG accumulation (Brepoels et al., 2007).
Although with the advances in technology and improved intrinsic spatial resolution
of PET scanners to 4mm, some neoplasms which are less metabolic may still be
missed because of very little

18

F FDG uptake (Blodgett et al., 2007), such as

follicular lymphoma (Kazama et al., 2005). Moreover, when structures two-time

smaller or more than the spatial resolution are imaged, the tracer uptake may be
underestimated due to partial volume effect (Berkowitz et al., 2008).

With cautious control of the variable factors, SUV can still be a useful tool in
quantitative assessment of cancer. For example, blood glucose level should be
measured before injection of 18F FDG and patients should be instructed to fast for at
least 6-8 hours before scan. The uptake time should be standardized, 60-90 minutes.
For treatment response assessment, uptake time and dosage of FDG injected should
be comparable between pre- and post-treatment scans and if possible, same scanner
should be used (Wahl et al, 2009). The addition of CT to the PET system may also
help to reduce the false-positive or false-negative findings by correlating the images
with detailed anatomical information (Blodgett et al., 2007).

CHAPTER 2

CHAPTER 2

KS CHAN

ONCOLOGICAL APPLICATIONS

OF WHOLE-BODY PET-CT

2.1

Overview
Cancer is a significant health problem and a leading cause of death in Hong

Kong. In 2007, there were 24342 new cases and 12316 cancer deaths. In the past 25
years, the number of new cases has increased with a rate of 2% each year. A change
in the trend of various cancer types has been observed. For example, a decrease in
number of cases has been observed in nasopharyngeal, oesophageal, gastric, lung and
cervical cancers, whilst an increase has been noted in female breast, corpus, ovarian,
prostate and male colorectal cancers. This may be due to the changes in lifestyle and
socio-economic conditions of the Hong Kong population, improvement in diagnostic
procedures and coding practices and the launch of cancer screening campaign (Hong
Kong Cancer Registry, 2009) such as introduction of cervical cancer screening in
2004.

CHAPTER 2

KS CHAN

Table 2.1 shows the main cancer sites of Hong Kong in 2007 (Hong Kong Cancer
Registry, 2009).

10 Most Common Cancers

Rank
1
2
3
4
5
6
7
8
9
10
1
2
3
4
5
6
7
8
9
10
1
2
3
4
5
6
7
8
9
10

10 Major Causes of Cancer Deaths

Site

Rank
Male
Lung
1
Colorectum
2
Liver
3
Prostate
4
Nasopharynx
5
Stomach
6
Non-melanoma skin
7
Bladder
8
Non-Hodgkins Lymphoma
9
Oesophagus
10
Female
Breast
1
Colorectum
2
Lung
3
Corpus Uteri
4
Ovary etc.
5
Thyroid
6
Cervix
7
Liver
8
Non-melanoma skin
9
Stomach
10
Both Sexes
Lung
1
Colorectum
2
Breast
3
Liver
4
Prostate
5
Stomach
6
Nasopharynx
7
Non-melanoma skin
8
Non-Hodgkins Lymphoma
9
Corpus Uteri
10

Site
Lung
Liver
Colorectum
Stomach
Prostate
Oesophagus
Nasopharynx
Pancreas
Non-Hodgkins Lymphoma
Leukaemia
Lung
Colorectum
Breast
Liver
Stomach
Pancreas
Ovary etc.
Cervix
Leukaemia
Non-Hodgkins Lymphoma
Lung
Colorectum
Liver
Stomach
Breast
Pancreas
Oesophagus
Nasopharynx
Non-Hodgkins Lymphoma
Prostate

It is well known that proper staging of malignancies is essential for efficacious

treatment planning and thus survival. Currently, CT and conventional magnetic
resonance imaging (MRI) are routinely used for cancer diagnosis and treatment
assessment. They provide detailed morphological information on lesion localization
and disease response to treatment. However, morphological imaging largely depends
9

CHAPTER 2

KS CHAN

on the lesion size and contrast-enhancement pattern which may not always reflect the
actual disease extent and tumor viability.

Since the introduction of PET and PET-CT scanners in 1980 and 2001
respectively, this imaging procedure has established an important role in clinical
oncology and replaced some conventional procedures for staging, restaging and
treatment response assessment of cancer patients. PET-CT provides both anatomical
and functional information of malignant lesions and results in great benefits and
impact on cancer patient management. A lot of studies have been done and validated
the results with creditable reference criteria (e.g. pathology, imaging, tumor markers
and other clinical follow-up procedures) on the application of PET-CT in different
types of malignancies, including lung, breast, colorectal, lymphoma, cervix, head and
neck and so on. Antoch et al. (2004) retrospectively evaluated the PET-CT images for
staging of various tumor types in 260 patients and reported an accuracy of 84% in
assessment of tumor-node-metastasis (TNM) system using PET-CT and PET-CT was
more accurate than either PET or CT alone or side-by-side viewing. Shim et al. (2006)
reported on a prospective study in 106 patients with non-small cell lung cancer and
compared PET-CT with CT for pre-surgical staging: the accuracy of PET-CT in
staging primary tumor was 89%, compared to 79% with CT alone. The accuracy,
sensitivity and specificity in detecting nodal metastasis of PET-CT was 85%, 84%
and 84%, respectively, compared to 70%, 69% and 69% with CT alone. In 30
patients with cervical carcinoma, Mittra and colleagues (2009) retrospectively
reviewed the post-treatment PET-CT scans. The sensitivity, specificity, accuracy,
positive and negative predictive values of PET-CT in detecting local recurrence and
distance failure was 93%, 93%, 93%, 86%, 96% and 96%, 95%, 95%, 96%, 95%,

10

CHAPTER 2

KS CHAN

respectively and the PET-CT findings altered the therapy management in all 30
patients.

2.2 SUV Application in Oncology

FDG uptake, measured as SUV, is associated with glucose metabolic rate and the
concentration of tumor cells, as well as tumor aggressiveness and grading. Lapele et
al. (1995) reported on a retrospective study in twenty-two patients with untreated
non-Hodgkins lymphoma (NHL) and high FDG uptake was significantly correlated
with high metabolic rate and histological grading. A study in 20 head and neck
cancer patients evaluating the role of pre- and post-treatment SUV in predicting
disease aggressiveness and treatment response was published by Kitagawa and
colleagues (2003). FDG uptake was revealed to be closely associated with tumor
cellularity and size and tumors with pre-treatment SUV >7 was more resistant to
treatment whilst post-treatment SUV=4.0 may act as a threshold for differentiating
the presence or absence of viable tumor cells after treatment. Patients with tumor
post-treatment SUV < 4 were considered as complete remission and those with
SUV> 4 underwent reduced conservative surgery and the 5-year overall survival (OS)
was 90%. SUV of primary tumor may also predict the chance of metastasis. In
sixty-six patients with known lung cancer, Nambu et al. (2009) found that there was
significant difference in FDG uptake of primary lung mass between patients with
lymph node metastasis and those without and the frequency of lymph node
metastasis increases as FDG uptake increases.

Metabolic changes of tumor often precede structural changes after treatment and

11

CHAPTER 2

KS CHAN

tumor size may remain the same even after successful treatment due to development
of necrosis and/or fibrosis (Spaepen et al., 2002). Allal et al. (2002) evaluated the
contribution of FDG uptake to prognostication in 63 patients with head and neck
cancer treated with radiotherapy and with or without chemotherapy. PET-CT scans
before treatment were prospectively analyzed. High SUV ( 5.5) was found to be a
significant adverse factor to 3-year disease-free survival (DFS) and local control rate
(55% and 42% respectively). Javeri and colleagues (2009) evaluated 151 patients
with gastroesophageal cancer who were treated with chemo-radiotherapy and surgery
found that a decrease in SUV by more than 52% in the post-treatment PET-CT
compared to pre-treatment scan correlated positively with longer OS, and the
percentage decrease of SUV was the sole prognostic indicator of OS. Cazaentre et al.
(2010) retrospectively assessed the prognostic value of SUVmax in 35 consecutive
NHL patients who were treated with radioimmunotherapy, and found high
pre-treatment SUV (>15-20) to be predictive of poor treatment outcome.

Impressive findings regarding the use of mid-treatment SUV in assessing

treatment efficacy have also been published. Lin and colleagues (2007) assessed the
prognostic value of the change of SUV before and after 2-cycle of chemotherapy in a
study of 92 diffuse large B-cell lymphoma (DLBCL) patients. Reduction of SUV by
more than 65.7% was found to be a favorable factor to better 2-year
event-free-survival (79% vs. 21%). The authors also suggested compared to visual
assessment, the use of SUV helps to better differentiate patients with favorable
outcome from those with poor outcome by reducing false-positive results after
treatment. Further study by the same group of investigators (Itti et al., 2009) was
carried out to evaluate the reduction of SUV before and after 4-cycle chemotherapy

12

CHAPTER 2

KS CHAN

in eighty patients from the previous study and > 72.9% reduction in SUV predicts
significantly better 2-year event-free survival (79% vs. 32%).

Based on the extensive evidence in literature concerning the usefulness of PET

in assessing treatment outcome, recommendations of incorporating PET into
response assessment criteria have been proposed, including the guidelines of the
International Working Group (IWG)+PET criteria for lymphoma (Cheson et al.,
2007) and the European Organization for Research and Treatment of Cancer
(EORTC) criteria (Young et al., 1999). Wahl et al. (2009) recently proposed a new
set of criteria using PET for tumor response assessment - PET Response Criteria in
Solid Tumors (PERCIST) to complement the WHO response criteria, the Response
Evaluation Criteria in Solid Tumors (RECIST), and RECIST 1.1 which use only
anatomic imaging for assessment, have limitations in evaluating the efficacy of the
newer cancer therapies. In PERCIST, a minimum reduction of 30% in SUVpeak
(corrected for lean body mass) and an absolute drop of 0.8 SUVpea is considered as
partial response to treatment. Since it is unlikely to have a 100% reduction in SUV
even if patients are in complete remission, the authors suggested it would be essential
to use visual assessment for the presence or absence of tumor along with the
semi-quantitative measurement. As for progressive disease, a >30% increase in
SUVpeak, a >75% increase in total lesion glycolysis (TLG) or presence of new
FDG-avid lesions were recommended as indication of disease progression.

2.3 Metabolic Tumor Volume (TV)

FDG PET-CT has been used increasingly in RT treatment planning for the

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assessment of metabolic tumor volume (TV) due to its ability to provide more
accurate assessment of tumor volume delineation (Paulino et al., 2003). Daisne et al.
(2004) compared the gross tumor volumes delineated by PET, CT and MRI in 29
patients with pharyngolaryngeal squamous cell carcinoma and PET-derived TV were
the smallest among the three. Nine patients underwent total laryngectomy and the
authors verified the tumor volumes delineated by imaging with surgical specimen
and PET-derived TV were found to be the most accurate when compared to volumes
derived by CT or MRI. A recent report in patients with non-small cell lung cancer
comparing the accuracy of PET-CT, PET alone and CT alone in delineating tumor
volume by verifying with surgical specimen was published by Yu and co-authors
(2009) and PET-CT was proved to be the best tool for defining tumor volume. Benz
and colleagues (2008) suggested that in pretreatment tumors, due to their
homogeneity, PET-derived TV is practical and reproducible. However, after
treatment, especially RT, the physiology and anatomy around the tumor may be
altered. Edema and inflammation is commonly found around the post-irradiated area.
For these reasons, the difference of FDG uptake between the tumor and the
surrounding tissue is usually low which leads to difficulty in accurately delineating
the volume of lesion.

Various methods (manual contour, fixed SUV cutoffs, fixed thresholds of

40%-50% of maximum signal intensity, adaptive thresholds for signal-to-background
ratio, gradient find and region growing) using PET or PET-CT for delineation of
tumor volume have been developed in the recent years (Bradley et al., 2004; Heron
et al., 2004; Nestle et al. 2005; Paulino et al., 2005, Vees et al., 2009). There is
controversy over the accuracy of these methods. Manual contouring is the most

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commonly used. However, it is highly operator-dependent and so results in large

inter-observer variations. Burri et al. (2008) compared TV obtained by various
methods with pathologic and CT-derived volumes and suggested that PET is superior
to CT and the method using threshold 40% or greater of SUVmax has the best
correlation with pathologic and radiographic volume of head and neck malignancy.
Opposite conclusions were suggested in the report of Zhong et al. (2009) who
addressed the issue that a fixed threshold of SUVmax does not properly delineate the
volumes of tumors and operators should modify the threshold according to the lesion
size and SUVmax for each individual tumor. Another issue in the fixed threshold
method is that it is highly dependent on signal-to-background ratio. The perfect
threshold was found to vary according to signal-to-background ratio using a series of
phantom studies (Black et al., 2004).

Although currently the best contouring method of tumor volume using PET is
not yet determined, the prognostic values of TV delineated by PET have been
recognized. Roedl et al. (2008) evaluated 51 patients with esophageal tumor who
were treated with neoadjuvant radiochemotherapy and underwent PET-CT before and
after treatment. Histopathologic response was predicted with a sensitivity of 91% and
specificity 90%, by a threshold of 63% decrease of TV and this was found to be the
best predictor of DFS and OS. In a recent study of La et al. (2009), usefulness of
SUVmax and TV in prediction of prognosis in patients with head and neck cancer was
analysed. The authors concluded that other than the Karnofsky performance status,
TV is the only independent predictor of disease recurrence and death of head and
neck cancer patients.

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2.4 Total Lesion Glycolysis (TLG)

TLG was introduced by Larson and colleagues in 1999 for measuring the
glycolysis changes in tumor before and after treatment. The authors studied the preand post-chemotherapy PET scans in 41 patients with esophageal, rectal, gastric or
lung cancer and showed that the mean changes of TLG was 59.7% which was higher
than that of SUVmax (46.9%). TLG is a parameter combining SUVmean and tumor
volume (TLG = SUVmean tumor volume).Whilst SUVmax presents a lone pixel with
the highest FDG uptake in a tumor, TLG takes into account the whole tumor which
provides a more complete picture on the metabolic activity of the tumor.

Impressive findings have been demonstrated regarding the use of TLG in

assessment of treatment response and prediction of patient outcome though studies
are still limited. Roedl et al. (2008) demonstrated a further improvement in the
specificity (93%) in assessment of treatment response of patients with esophageal
adenocarcinoma with the use of TLG as compared to tumor volume (91%) alone. In
a recent study of 31 patients with osteosarcoma, the change in TLG (TLG) was
shown to be a powerful predictor of progression-free survival (PFS) and a high TLG
predicts poor OS (Costelloe et al., 2009). Nevertheless, it was noted that the value of
TLG may be limited by the minimal change of tumor volume before and after
treatment (Tateishi et al., 2008). In a study by Xie and coauthors (2010b), the preand post-radiotherapy TLG of 41 NPC patients were retrospectively evaluated and
the authors found that TLG positively correlated with DFS and OS, and patients with
recurrence or distant metastasis were found to have higher TLG.

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CHAPTER 3 BACKGROUND AND

HYPOTHESES

3.1 Nasopharyngeal Carcinoma (NPC)

3.1.1 Staging and Treatment
Nasopharyngeal carcinoma (NPC) is an epithelial malignancy with the highest
incidence rates in the world reported in Southern China, affecting between
10-50/100,000 populations (Luo et al., 2007). Although there has been a downward
trend in NPC, it was still the 7th most common cancer and the 8th leading cause of
cancer death in Hong Kong in 2007 (Hong Kong Cancer Registry, 2009). Accurate
staging is essential for efficacious treatment planning and prognostication. The
American Joint Committee on Cancer (AJCC) and the International Union Against
Cancer (UICC) TNM staging system is the most commonly used classification
system of NPC (Table 3.1 and 3.2) which provides guidelines for treatment
management and prediction of disease prognosis (American Joint Committee on
Cancer, 2002).

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Table 3.1 Nasopharyngeal Carcinoma: AJCC/UICC TNM Classification System, 6th

Edition (American Joint Committee on Cancer, 2002).
T- Primary Tumor
T1
Tumor confined to the nasopharynx
T2
Tumor extends to soft tissues
T2a Tumor extends to the oropharynx and/or nasal cavity without parapharyngeal
extension
T2b Any Tumor with parapharyngeal extension
T3
Tumor Involves bony structures and/or paranasal sinuses
T4
Tumor with intracranial extension and/or involvement of cranial nerves,
infratemporal fossa, hypopharynx, orbit, or masticator space
N Regional Lymph Nodes
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Unilateral metastasis in lymph node(s), 6cm or less in greatest dimension,
above the supraclavicular fossa
N2 Bilateral metastasis in lymph node(s), 6cm or less in greatest dimension,
above the supraclavicular fossa
N3 Metastasis in a lymph node(s) >6cm and/or to supraclavicular fossa
N3a Greater than 6cm in dimension
N3b Extension to supraclavicular fossa
Distance Metastasis
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis

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Table 3.2 Nasopharyngeal Carcinoma: Stage Grouping (American Joint Committee

on Cancer, 2002).
Stage
0
I
IIA
IIB

III

IVA

IVB
IVC

T
Tis
T1
T2a
T1
T2
T2a
T2b
T2b
T1
T2a
T2b
T3
T3
T3
T4
T4
T4
Any T
Any T

N
N0
N0
N0
N1
N1
N1
N0
N1
N2
N2
N2
N0
N1
N2
N1
N1
N2
N3
Any N

M
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M1

Primary treatment of NPC is uniformly radiotherapy (RT) with or without

chemotherapy for all stages of disease without distant metastases. Most stage I and II
diseases are adequately treated with RT alone and 5-year OS of 75-90% are achieved
(Chua et al., 2001). For advanced, stage III-IVB disease, the standard of care is
combined chemo-radiotherapy with the emphasis on concurrent, mainly cisplatinum
based, chemotherapy during RT. OS of 67% to >80% was reported after
chemoradiotherapy (Caponigro et al., 2010; Wei et al., 2010). With modern RT like
intensity modulated radiotherapy (IMRT), loco-regional control rate of >90% is
achieved (Lin et al., 2010; Ng et al., 2010). Distant recurrence is the predominant
cause of treatment failure with a reported 5-year rate of 19% for all stages and 25%
for stage III-IVB subgroups (Lee et al., 2005).

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3.1.2 Imaging Methods

CT and MRI are standard imaging tools for staging and response assessment of
NPC. Compared to CT, MRI is more sensitive to demonstrate tumor invasion in the
intracranial area, parapharyngeal space and skull base due to the high spatial
resolution and intrinsic soft tissue contrast of the MR images (Ng et al., 2009).
However, sometimes the conventional imaging which depends greatly on size of
lymph nodes and patterns of contrast enhancement, fails to reveal the true staging.

In recent years, FDG PET and PET-CT has been increasingly used for staging,
treatment planning and detecting local recurrence of NPC. Prior studies, mainly from
countries with a predominant southern Chinese population, including Taiwan (Chan
et al., 2009; Ng et al., 2009), Guangzhou (Wang et al., 2007a; Zheng et al., 2006) and
Hong Kong (King et al., 2008; Ma et al., 2008a) have reported the use of FDG PET
or PET-CT for staging and therapy monitoring of NPC, and a few have evaluated the
utility of semi-quantitative parameters of PET such as SUV, TV and TLG. In a series
of 85 patients with primary NPC and 10 with recurrent tumor, Chang et al. (2005)
showed that FDG PET is more accurate and sensitive than conventional workup for
detecting nodal and distant metastasis with sensitivity, specificity and accuracy 100%,
90.1% and 90.6%, respectively. Gordin and coworkers (2007) assessed the value of
FDG PET-CT vs. FDG PET and conventional imaging in the diagnosis and impact
on clinical management of NPC in a study of 45 patients. FDG PET-CT provided
additional information leading to an improvement of accuracy in defining anatomical
borders of FDG-avid foci and in distinguishing physiologic or benign lesions from
metastatic FDG-avid tumors. The sensitivity, specificity, accuracy, positive and
negative predictive values of PET-CT for diagnosis of the disease were 92%, 90%,
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91%, 90% and 90%, respectively. FDG PET-CT changed the management of
nineteen patients (57%) by obviating the need of other diagnostic procedures (eleven
patients), by changing the pre-planned treatment approach (five patients) or by
directing the site of biopsy which reduced sampling error and damage to normal
tissues (three patients). Nevertheless, opposite conclusions were suggested by King
et al. (2008) who retrospectively compared the usefulness of FDG PET-CT with
conventional work-up in staging of pre-treatment NPC. The authors found
discordance between the results of PET-CT and MRI and PET-CT did not provide
additional information on cervical lymph node metastasis or distant failure and thus
there was no impact on patient management. In a recent study, Ng and colleagues
(2009) prospectively studied 111 patients who were newly-diagnosed with NPC and
underwent FDG PET-CT and conventional imaging including MRI and showed that
MRI and PET-CT have a complimentary role to each other for initial staging of NPC
patients. Due to the superior tissue contrast of MRI, it is more sensitive to detect
subtle abnormalities around the primary site and the invasion to retropharyngeal
lymph nodes compared to PET-CT (Fig 3.1), which in turn has higher accuracy in
assessment of neck lymph node metastasis, and reasonable diagnostic ability in
assessing distant malignancy.

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Fig 3.1 FDG PET-CT and axial T2W MR images of a NPC patient. The primary
tumor showed intense uptake with contrast enhancement in the FDG PET-CT. A
retropharyngeal lymph node was clearly defined in the MRI but appeared as part of
the primary lesion in both PET and CT. (A): PET-CT fusion, (B): contrast-enhanced
CT, (C): PET, (D): Axial T2W MRI.

Only three series (2 retrospective and 1 prospective) have been published thus
far on the potential prognostic impact of SUV in pre-treatment NPC patients and all

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three studies showed that a high SUV of the primary tumor predicts poorer patient
outcome. Ma and colleagues (2008b) prospectively investigated fifty-seven patients
with locoregionally advanced NPC and reported that only SUV of the primary lesion
is significantly associated with PFS and total SUV (sum of SUV of primary lesion
and neck lymph nodes) predicts local and distant recurrence. In the study by Lee et al.
(2008b), 41 patients with newly diagnosed non-disseminated NPC who were treated
with platinum-based concurrent chemo-radiotherapy later were included. SUVmax 8
at primary site is recommended as a cutoff value for DFS and patients with higher
SUVmax at neck cervical lymph nodes than that of primary site had a worse prognosis.
These findings were confirmed in the series of 62 patients with stage 3 & 4 NPC by
Xie and coworkers (2010a) who further demonstrated that patients with complete
metabolic response resulted in better 5-year OS and DFS than patients with partial
metabolic response after receiving definitive radiotherapy and concurrent and
adjuvant chemotherapy.

3.2 Non-Hodgkins Lymphoma (NHL)

3.2.1 Histological Subtypes and Geographical Disease Spectrum
The World Health Organization (WHO) divides non-Hodgkins lymphoma (NHL)
into B-cell, T-cell and natural killer (NK)-cell lymphomas according to the putative
cell of origin, based on clinical characteristics, morphologic, immunophenotypic and
molecular features (Table 3.3). Compared to Hodgkins lymphoma, NHL has a worse
prognosis and much higher incidence rate. NHL may also be divided according to
clinical symptomatology and rate of growth into indolent and aggressive groups
(Table 3.4) (Rademaker et al., 2007).
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Table 3.3 World Health Organization Classifications for Lymphoma.

B-cell Lymphomas / Leukemias

Precursor B-cell neoplasm
Precursor B-cell Lymphoblastic
Leukemia / Lymphoma (precursor
B-cell acute lymphoblastic leukemia)
Mature (peripheral) B-cell neoplasms
B-cell Prolymphocytic Leukemia
Burkitts Lymphoma / leukemia
Chronic Lymphoma Leukemia / Small
Lymphocytic Lymphoma (CLL/SLL)
Diffuse Large B-Cell Lymphoma
(DLBCL)
Follicular Lymphoma

T-cell & NK-cell Lymphomas /

Leukemias
Precursor T-cell neoplasm
Precursor T-cell Lymphoblastic
Leukemia / Lymphoma (precursor T-cell
acute lymphoblastic leukemia)
Mature (peripheral) T/NK-cell
neoplasms
Adult T-cell Leukemia / Lymphoma
(Human T Lymphotropic Virus Type
1-positive)
Aggressive NK-cell Leukemia
Anaplastic Large Cell Lymphoma,
T/null cell, primary cutaneous type

Hairy Cell Leukemia

Anaplastic Large Cell Lymphoma,

T/null cell, primary systemic type

Lymphoplasmacytic Lymphoma /
Waldenstrms Macroglobulinemia

Angioimmunoblastic T-cell Lymphoma

Mantle Cell Lymphoma

Enteropathy Type T-cell Lymphoma

Marginal Zone Lymphoma

Extranodal NK /T-cell Lymphoma,

Nasal Type

Mediastinal (Thymic) Large B-cell

Lymphoma

Hepatosplenic T-cell Lymphoma

Mucosa-associated Lymphoid Tissue

(MALT)
Nodal Marginal Zone B-cell Lymphoma
Plasma Cell Myeloma / Plasmocytoma
Primary Effusion Lymphoma
Splenic Marginal Zone B-cell
Lymphoma

Mycosis Fungoides / Szary Syndrome

Peripheral T-cell Lymphoma,
Unspecified
Subcutaneous Panniculitis-like T-cell
Lymphoma
T-cell Large Granular Lymphocytic
Leukemia
T-cell Prolymphocytic Leukemia

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Table 3.4 Aggressive and Indolent Lymphomas (Rademaker et al., 2007).

Aggressive Lymphoma
Anaplastic Large Cell Lymphoma,
Systemic Type

Indolent Lymphoma
Anaplastic Large Cell Lymphoma,
Cutaneous Type

Angioimmunoblastic T-Cell Lymphoma Chronic Lymphoma Leukemia / Small

Lymphocytic Lymphoma (CLL/SLL)
Burkitts Lymphoma
Follicular Lymphoma Grade 1 and 2
Diffuse Large B Cell Lymphoma
(DLBCL)
Lymphoplasmacytic Lymphoma
Follicular Lymphoma Grade 3

Mantle Cell Lymphoma

NK-cell Lymphoma

Marginal Zone B-cell Lymphoma Of

Mucosa-associated Lymphoid Tissue
(MALT)

Peripheral T-cell Lymphoma (PTCL)

Marginal Zone Lymphoma

Mycosis Fungoides
T-cell Large Granular Lymphocytic
Leukemia
Data from Hong Kong Cancer Registry (2009) show that in the last two decades,
the incidence rate of NHL has increased by 3.2% (Fig 3.2) and in 2007, NHL
represents the 9th most common cancer in Hong Kong. The incidence of NHL is
higher in males than females and rises with advancing age (Fig 3.3). The spectrum of
NHL in Asian/Oriental countries is different from that in Caucasian populations. A
review of the 10-year experience of NHL in our institution revealed that the incidence
of NK-cell lymphomas to be 6.5% of the NHL cases (Au et al., 2005), giving about
20-30 new cases of NK-cell lymphomas annually in Hong Kong. On the other hand,
NK-cell lymphomas are extremely uncommon in Western populations, with few cases
ever reported. Disease free survival rates for NHL are unsatisfactory with overall
5-year survival of 50-60%, and this is generally poorer for mature T-cell and NK-cell
lymphomas (Au et al., 2009).

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Figure 3.2 showing the trend of NHL incidence in Hong Kong during 1983-2007.

Figure 3.3 showing the number of new NHL cases by 5-year age group in Hong
Kong during 1983-2007.

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3.2.2 Diagnosis and Staging

The presenting signs and symptoms are commonly enlarged lymph nodes, fever,
night sweat, fatigue or weight loss. Since the symptoms are non-specific, diagnosis
may be delayed. Biopsy remains necessary for the final diagnosis of lymphoma and
classifying the specific subtype as treatments are different for various subtypes of
NHL. The initial investigation of NHL includes physical exam, complete blood count,
electrolyte panel, renal and liver function tests, lactate dehydrogenase level and a
bone marrow biopsy (Table 3.5) (Cheson, 2008; Rogers, 2006). Since Epstein-Barr
virus (EBV) can be present in T-cell and NK-cell lymphoma and the quantification of
EBV DNA is a useful surrogate marker for tumor burden, EBV serology is
recommended in the initial evaluation. Furthermore, in situ hybridization for EBV
encoded small RNA (EBER) is suggested for detection of bone marrow involvement
of NK-cell lymphoma which can be subtle and this test is more sensitive and specific
than immunohistochemical staining for CD56 (Kwong et al., 2009)

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Table 3.5 showing the recommended diagnostic investigations for patients with
lymphoma (American Joint Committee on Cancer, 2002).
A. Mandatory procedures
1. Biopsy, with interpretation by a qualified pathologist
2. History, with special attention to the presence and duration of fever, night sweats,
and unexplained loss of 10% or more of body weight in the previous 6 months
3. Physical examination
4. Laboratory tests
a. Complete blood cell count and platelet count
b. Erythrocyte sedimentation rate
c. Liver function tests
5. Radiographic examinations
a. Chest X-ray
b. CT of chest, abdomen, and pelvis
c. Gallium scan
6. Bone marrow biopsy
B. Ancillary procedures
1. Laparotomy and splenectomy if decisions regarding management are likely to be
influenced
2. Liver biopsy (needle), if there is a strong clinical indication of hepatic involvement
3. Radioisotopic bone scans, in selected patients with bone pain
4. CT of head and neck in extranodal or nodal presentation to define disease extent
5. Gastroscopy and/or GI series in patients with GI presentations
6. MRI spine in patients with suspected spinal involvement
7. CSF cytology in patients with Stage IV disease and bone marrow involvement,
testis involvement, or parameningeal involvement

Ann Arbor classification (Table 3.6) is the staging system for both Hodgkins
lymphoma and NHL. This system is based on a number of factors, including the
distribution and number of involved regions, presence of extranodal involvement and
presence of B symptoms (Rademaker, 2007).

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Table 3.6 showing the Ann Arbor Classification for NHL.

Stage

Description

Stage I

Involvement of a single lymph node region (I); or localized

involvement of a single extralymphatic organ or site in the absence of
any lymph node involvement (IE)

Stage II

Involvement of two or more lymph node regions on the same side of

the

diaphragm

(II);

or

localized

involvement

of

single

extralymphatic organ or site in association with regional lymph node

involvement with or without involvement of other lymph node regions
on the same side of the diaphragm (IIE). The number of regions
involved may be indicated by a subscript, as in, for example, II3.
Stage III

Involvement of lymph node regions on both sides of the diaphragm

(III), which also may be accompanied by extralymphatic extension in
association with adjacent lymph node involvement (IIIE) or by
involvement of the spleen (IIIS) or both (IIIE,S).

Stage IV

Diffuse or disseminated involvement of one or more extralymphatic

organs, with or without associated lymph node involvement; or
isolated extralymphatic organ involvement in the absence of adjacent
regional lymph node involvement, but in conjunction with disease in
distant site(s). Any involvement of the liver or bone marrow, or
nodular involvement of the lung(s).

Designations applicable to any disease stage

A

Absence of constitutional symptoms

Presence of constitutional symptoms

Extranodal site

Spleen involvement

Bulky disease; mediastinal widening greater than one third the

diameter of the chest at the T6-7 level or > 10 cm in any single
dimension

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3.2.3 Treatment and Prognosis

NHL is a heterogeneous disease group and treatment approach varies for each
subtype. Treatment options include chemotherapy, immunotherapy, and high-dose
marrow-ablative treatment combined with autologous stem cell transplantation
(ASCT) (Morschhauser et al., 2009). Radioimmunotherapy which combines targeted
monoclonal antibodies with radionuclides is an emerging treatment option for NHL
and promising results have been reported in improved complete response (CR) rate
and PFS in follicular lymphoma (Morschhauser et al., 2008) and DLBCL (Witzig et
al., 2007). Due to the advances in treatment, the 5-year and 10-year OS of NHL
patients have been improved from 50.4% to 66.8% and 39.4% to 56.3, respectively
between 1990-1992 and 2002-2004 (Pulte et al., 2008). However, the prognosis of
T-cell and NK-cell lymphoma patients remains poor with 3-year OS less than 30%
(Lim et al., 2008). Although stage I/II nasal NK-cell lymphoma shows good initial
treatment response, systemic relapses are frequent (Kwong, 2005). Therefore,
stratification of prognostic indicators is essential. Innovative therapies can thus be
employed on high-risk patients and less intensive and toxic treatments can be applied
to those with low-risk. Despite the International Prognostic Index and the Korean
NK/T-cell Prognostic Index has been proven a valuable tool in risk stratification for
nasal NK-cell lymphoma, no clinical or histological factors are useful in prediction
of prognosis for disseminated NK-cell lymphoma for which the median survival is
even poorer (Au et al., 2009).

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3.2.4 Imaging Methods

Traditionally, CT is used for staging of NHL. However, as mentioned before, the
criteria for diagnosis of CT highly depends on size and morphology, with limited
information regarding tumor viability. The role of FDG PET and PET-CT in NHL for
staging (Pelosi et al., 2008), therapy response monitoring (Yang et al., 2009) and
treatment planning (Dizendorf et al., 2003) are now well recognized. Aggressive
NHL are usually FDG-avid and well-visualized, whilst the FDG-avidity of indolent
NHL are more variable. Some subtypes, such as small lymphocytic lymphoma,
splenic maginal zone lymphoma, cutaneous type B- and T-cell lymphoma and
enteropathy-type of T-cell lymphoma, may show very low FDG uptake (Weiler-Sagie
et al., 2010). For those subtypes which are generally FDG-avid and potentially
curable, pre-treatment PET scan is recommended for better delineation of disease
extent. However, for those which are with variably FDG-avidity or potentially
incurable, pre-treatment PET scan is not recommended (Cheson et al., 2007). Pelosi
et al. (2008) compared FDG PET-CT with CT alone and bone marrow biopsy for
staging of Hodgkins lymphoma and aggressive NHL. The accuracy of PET-CT for
NHL staging was 91.4% and the use of PET-CT resulted in correctly upstaging 4 out
of 35 patients of the NHL group. Treatment was thus modified in three of these
patients. SUVmax has been correlated with disease aggressiveness in NHL,
presumably related to the higher demands on energy consumption, and thus
glycolysis, when rate of growth/cellular proliferation is increased. It was found in
one prior study that SUVmax >10 distinguishes aggressive versus indolent lymphomas
with a sensitivity of 71% and specificity of 81% (Schder et al., 2005). Yamane and
colleagues (2004) found that as soon as 1 day after the chemotherapy, there was
significant decrease in FDG accumulation in twelve B-cell lymphoma patients
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SUV dropped from 10.77.9 before treatment to 5.85.8 at day 1 of chemotherapy

(p=0.0002). Furthermore, SUV has also been shown to be useful in predicting
transformation in indolent lymphomas to higher grade ones (Noy et al., 2009). In a
recent study, the grading of follicular lymphomas was correlated with SUVmax and
proliferative index (Ki67) (Tang et al., 2009). The above studies of NHL have been
solely of B-cell lymphomas and there is limited experience with T and NK-cell
lymphomas in the literature due to the rarity of these lymphomas.

To date, there have been seven case series of NK-cell lymphomas published in
the literature (Kako et al., 2007; Karantanis et al., 2008; Khong et al., 2008; Ngeow
et al., 2009; Suh et al., 2008; Tsukamoto et al., 2007; Wu et al., 2010). The findings
in these publications indicate that FDG PET is generally useful for the detection and
thus staging of these tumors. For bone marrow involvement in NK-cell lymphomas,
PET was falsely negative in two out of 28 patients where bone marrow biopsy was
positive for NK lymphoma cells as detected by EBER (Kako et al., 2007; Khong et
al., 2008; Ngeow et al., 2009). Only one study which evaluated response assessment
in 21 patients with extranodal NK/T cell lymphoma using FDG PET examined the
use of SUV in prognostication and found SUVmax to be the sole independent
predictor for disease-specific survival and a high FDG uptake (SUVmax >5.5) was
associated with poorer patient outcome (Suh et al., 2008). However, the authors of
this study also acknowledged the limitations of short follow-up after therapy, limited
number of patients and retrospective design. For the nasal tumors in NK-cell
lymphoma patients, MRI may provide additional information on soft-tissue and bone
and this is helpful in treatment planning (Kwong et al., 2009).

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3.3 Research Objectives

We aim to investigate the role of semi-quantitative parameters of

18

F FDG

PET-CT in its clinical application to two common malignancies in Hong Kong

populations, nasopharyngeal carcinoma and non-Hodgkins lymphoma:

Nasopharyngeal carcinoma
1. The correlation between semi-quantitative parameters (SUVmax, TV, TLG)
of PET-CT and AJCC staging of NPC patients
2. The prognostic values of the semi-quantitative parameters of PET-CT in
patient outcome
Non-Hodgkins Lymphoma
Compare the metabolic activity among various subtypes of NHL, with
particular focus on NK-cell lymphoma

3.4

Hypotheses
The following hypotheses were tested and evaluated in the studies:

1.

The semiquantitative parameters SUVmax, TV and TLG reflect the

aggressiveness of the primary tumor and there is a significant correlation
between these parameters and the AJCC TNM staging system of NPC patients.

2.

SUVmax of the primary tumor and cervical lymph node metastases can predict
treatment outcome of NPC patients.

3.

FDG PET, using SUVmax to reflect metabolic activity, is able to characterize the
metabolic phenotype of the various subtypes of NHL, namely aggressive and
indolent B-cell lymphoma, T-cell lymphoma and NK-cell lymphoma. We have
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special interest in the latter NHL subtype, the NK-cell lymphoma, as it is rarely
reported in the literature. Determining the metabolic phenotype may help in
prognostication and guiding treatment planning.

3.5 Significance and Value

Both NPC and NHL are common malignancies and two of the top ten major
causes of cancer death in Hong Kong. NK-cell lymphoma, is extremely uncommon
in the West and almost exclusive to Asia. It is an aggressive lymphoma subtype with
median 5-year OS only 40-59% (You et al., 2004) especially in patients with
advance-stage disease. Although NPC is highly sensitive to both radiotherapy and
chemotherapy, the reported 5-year survival rate of NPC was only 32% - 62% (Farias
et al, 2003). The project may find a role of the semi-quantitative indices of 18F FDG
PET-CT in diagnosis, prognostication and treatment response assessment of patients
with NPC and NHL, especially for the less well-investigated NK-cell lymphoma
subtype. Such knowledge may help to advance a new diagnostic imaging algorithm
for disease assessment, which in turn may lead to better patient care.

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CHAPTER 4

CHAPTER 4

4.1

KS CHAN

PET-CT PROTOCOL

Patient Preparation

Prior to the examination, patients were instructed to:

1.

Fast, except water for at least 6 hrs before appointment.

2.

Avoid any exercise the day before examination and remain seated during uptake
time to avoid muscle uptake.

3.

Stop Chinese medicine for three days before examination to avoid physiological
uptake in bowel.

Upon arrival at the PET-CT Unit:

1.

Body weight and height was recorded.

2.

500 ml water was given to patients for hydration before injection of 18F FDG.
900ml barium solution and 30ml Esopho-CAT was given to patients during the
60 min uptake time to improve visualization of bowel structures and
differentiation of trachea and esophagus respectively.

3.

If intravenous contrast medium was used, detailed history of allergy, asthma,

use of metformin for diabetes mellitus, renal function of the patients would be
checked. Patients would be instructed to stop metformin for 48 hours after
injection of contrast medium.

4.

Blood glucose levels were checked and should be below 8 mmol/l before
injection of 18F FDG.

5.

If the blood glucose level was higher than 8 mmol/l, 2 units of insulin were
intravenously administered to reduce the blood glucose level. Sixty minutes
after injection of insulin, blood glucose level was measured again. If the blood
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glucose level was still higher than 8mmol/l, another 2 units of insulin were
given. If patients showed signs of hypoglycemia (cold sweaty skin, dizziness
etc), oral glucose solution was given. 18F FDG was injected at least 60 min
after the injection of the last dose of insulin (Roy et al., 2009).
6.

Patients were instructed to empty the bladder before scan to avoid intense
uptake of urine.

4.2 Scanning Protocol

For all patients, whole-body 18F FDG PET-CT (from base of skull to upper 1/3
of thighs) was performed with a combined PET-CT scanner (Discovery VCT;
64-MSCT, GE Healthcare Bio-Sciences Corp., NJ, USA; field of view, 50 cm; pixel
size, 3.91 mm; spiral CT pitch, 0.984:1; gantry rotation speed, 0.5 s) using a
standardized protocol. After 6 hours of fasting (blood glucose <8 mmol/l), an
intravenous injection of 222-370MBq (4.8 MBq/kg) of weight adjusted 18F FDG was
administered, and after a 60-minute uptake time, whole body emission PET scan was
obtained with six bed positions of 2 minute 30 second acquisition time in each bed
position. Attenuation-corrected PET images with CT data were reconstructed with an
ordered-subset expectation maximization iterative reconstruction algorithm (14
subsets and two iterations), and fused with CT images (Advanced Workstation 4.3,
GE Healthcare Bio-Sciences). The CT imaging parameters were as follows: 120 kVp,
200-400 mA, 0.5s per CT rotation, pitch 0.984:1, 2.5mm intervals, with or without
60-100 mls (1.5 ml/kg) intravenous contrast medium.

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4.3 Image Analysis

The PET-CT images were reviewed using the automatic PET-CT fusion software
on the workstation (Advanced Workstation 4.3, GE Healthcare Bio-Sciences). A
volumetric ROI around the outline of lesion was placed on the axial PET images
using the semi-automatic software. The borders of the ROI were adjusted manually
by visual inspection of tumor outline to avoid overlapping on adjacent FDG-avid
structures or lesions. A threshold of 40% of the maximum signal intensity was
selected to delineate TV. SUVmax (corrected for lean body mass), SUVmean (corrected
for lean body mass) and TV were then automatically calculated by the PET-CT
fusion software.

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CHAPTER 5

KS CHAN

NASOPHARYNGEAL

CARCINOMA: RELATIONSHIP BETWEEN 18F

FDG PET-CT MAXIMUM STANDARDIZED
UPTAKE VALUE, METABOLIC TUMOR
VOLUME AND TOTAL LESION GLYCOLYSIS
WITH TNM-CLASSIFICATION
5.1 Introduction
Several studies have shown that SUV may reflect the aggressiveness of the local
tumor and the risk of metastatic spread in NPC patients (Chan et al., 2009; Lee et al.,
2008b) and the incorporation of tumor volume into the current staging system has
been suggested because of its correlation with the prognosis and survival (Chen et al.,
2004; Chu et al., 2008; Lee et al., 2008a). To our knowledge, few studies to date have
examined the relationship between metabolic parameters SUVmax, TV or TLG and
the AJCC TNM staging system in NPC. As these semi-quantitative PET parameters
also reflect tumor aggressiveness, they may serve as an adjunct to disease staging by
characterizing the metabolic phenotype of tumors. In the present study, we analyze
the relationship between SUVmax, TV and TLG of the primary tumor and TNM
classification in patients with initially-diagnosed NPC.

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5.2 Materials and Methods

5.2.1 Patient Cohort
We retrospectively analyzed the

18

F FDG PET-CT findings of 57 consecutive

newly diagnosed NPC patients with the mean age of 48.9 years (range, 15-80 years),
between May 2007 and April 2009. There were 44 (77.2%) males, mean age 48.2
years (range, 15-80 years) and 13 (22.8%) females, mean age 51.4 years (range,
39-78 years). All patients were scanned prior to commencement of treatment. Of the
57 patients, two, 12, 24 and 19 had stage I, stage II, stage III and stage IV disease
respectively according to the AJCC/UICC TNM staging system (American Joint
Committee on Cancer, 2002). Staging investigations for all patients consisted of
complete history and physical examinations, nasopharyngoscopy, chest x-ray, CBC
count, liver and renal biochemistry, 24 hours urine for creatinine clearance, CT/MRI
of the NP and neck. CT thorax, ultrasound/CT liver, bone scan or whole body FDG
PET-CT were performed if initial investigation showed abnormal findings suggestive
of metastases. All patients had biopsy-proven NPC at the primary site and the
histological type was undifferentiated carcinoma in all except poorly differentiated
squamous cell carcinoma in one. Patient characteristics are listed in Table 5.1.

5.2.2 PET-CT Protocol

All patients were scanned using the standardized PET-CT protocol as described
in Chapter 4.

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5.2.3 Image Analysis

SUVmax (corrected for lean body mass), SUVmean (corrected for lean body mass)
and TV were automatically calculated by the PET-CT fusion software and these
values were recorded from the workstation. TLG was calculated by multiplying
SUVmean and TV of the primary tumor (Larson et al., 1999). Both radiologists who
conducted the measurements were blinded to the clinical details and results were
averaged. SUVmax of 2.5 was chosen as cutoff (Ma et al., 2006) in order to eliminate
partial volume artifacts of small tumors in SUVmax measurement. After applying the
cutoff, a final total of 55 cases were included for analysis.

5.2.4 Statistical Analysis

The results were analyzed using SPSS 16.0 (Chicago, IL, USA). 2-tailed
Spearmans correlation was used to analyze the relationship between T-stage and the
following parameters, SUVmax, TV and TLG. This was followed by multiple linear
regression analysis to study the simultaneous influence of these factors on T-stage.
All of the above analyses were repeated for N-stage, M-stage and the combined
AJCC stages. The relationship between TV and SUVmax was also analyzed.
Association between these factors was assessed using Spearmans correlation
coefficient at 5% level of significance.

5.3 Results
The mean values of SUVmax, TV and TLG of the primary site were 8.73.8
(range, 2.6 to 16.6), 12.214.1 cm3 (range, 1.9 to 73.4 cm3) and 94.1161.7 (range,
8.4 to 1068.8), respectively.
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Using Spearmans correlation analysis, there were significant correlations

between T-stage and SUVmax (p<0.001, R=0.516), TV (p<0.001, R=0.504) and TLG
(p<0.001, R=0.620) (Fig. 5.1, 5.2 and 5.3). Multiple linear regression analysis
revealed TV and SUVmax to be the independent variables that significantly affected
T-stage (p<0.001, adjusted R2=0.370). SUVmax, TV, TLG of primary tumor for T-,
N-, M-staging are tabulated in Table 5.2, 5.3 and 5.4. No positive correlation was
found when the analysis was repeated for N-, M- and overall AJCC stages. The
relationship between SUVmax and TV was found statistically significant (p<0.001,
R=0.517).

5.4 Discussion
Apart from qualitative assessment in the detection of metastases, PET provides
the opportunity of a semi-quantitative measure of tumor glycolysis using SUV. In the
present study, we found significant correlation between metabolic parameters
SUVmax, TV and TLG, and T-stage in patients with initially-diagnosed NPC. In
addition, significant correlation was also observed between SUVmax and TV. T-stage
of the AJCC/UICC classification system describes lesion size and direction of tumor
growth, whilst SUV, has been associated with neoplastic grade and histological and
immunohistochemical markers of aggressiveness in head and neck cancers
(Kitagawa et al., 2003; Minn et al., 1997). Thus, our findings are in keeping with the
notion that more aggressive nasopharyngeal carcinomas, as reflected by glycolytic
uptake, invade more extensively the surrounding tissues and result in a larger-sized
tumor and thus an advanced T-staging. Whilst SUVmax is a robust and convenient

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quantitative measure, it has been argued that since it is a measurement of a single

pixel with the highest radiotracer concentration within the ROI, it may not reflect the
heterogeneous nature of the tumor. Moreover, the value may arise from random error
(Berkowitz et al., 2008). Thus TLG has been proposed as a more accurate parameter,
taking into account the SUVmean throughout the lesion, multiplied by tumor volume.
We also found a significant positive association between TLG and advancing T-stage
in this study, although the correlation was only slightly improved as compared to
SUVmax or TV. We experienced challenges in volume and SUVmean measurement in
some patients whose primary tumor coalesced with a retropharyngeal lymph node
and potentially, this difficulty may arise with the brain cortex if there was intracranial
extension. Therefore, CT imaging is important in obviating this pitfall by providing
anatomical correlation. This inaccuracy in tumor contouring may also explain why
TLG was not found to be an independent predictor for T-staging.

Recent studies in NPC patients have found that primary tumor volume measured
using MRI was significantly correlated with T-stage (Chong et al., 2006; Zhou et al.,
2007). We found similar results but using TV instead. There has been controversy
regarding the delineation methods of TV because they are largely affected by the
window-level setting. Burri et al. (2008) compared the TV of head and neck tumors,
using various SUV thresholds, and CT-derived volumes with pathologic specimens
and suggested that PET is superior to CT and a threshold 40% of maximum SUV for
measurement of TV had the best correlation with pathologic and radiographic
volume. Thus, this threshold was used in the present study.

It has been reported that regardless of the size of primary tumor, about 50% -

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90% of patients have cervical lymph node metastases at clinical presentation (Weber
et al., 2003). For a tumor cell to metastasize, it must first separate from the primary
tumor and then enter a blood or lymphatic vessel for circulation (Ruoslahti, 1996).
The location of the initial detachment will most likely affect the route and chance of
spread. Therefore, the location of the primary tumor relative to the blood (Folkman,
1995) or lymphatic vessel (Nathanson, 2003; Shayan et al., 2006), and the degree of
lymphangiogenesis and neovascularization in the tumor microenvironment may
affect its metastatic potential. Moreover, there are other complex factors which affect
the occurrence of metastases in specific organs according to the seed-soil
hypothesis which proposes that host organ factors are necessary for the growth of
metastatic lesions (MacDonald et al., 2002). Therefore, even if the primary tumor is
actively growing, metastases may still not occur in some organs. This may explain
why no correlation could be found between all these metabolic parameters and Nand M-stage, and thus overall AJCC staging. This similar lack of correlation between
SUVmax and stage was found in another recent study on NPC patients (Lee et al.,
2008b).

5.5 Conclusion
The metabolic parameters derived from

18

F FDG PET-CT were positively

correlated with T-stage but not N- and M-stage in primary NPC. Our findings may
suggest a complementary role of these parameters to TNM staging in prognostication
of NPC patients.

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Figures:

Fig. 5.1 Spearmans correlation between SUVmax and T-stage (p<0.001, R=0.516).

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Fig. 5.2 Spearmans correlation between TV (cm3) and T-stage (p<0.001, R=0.504).
Both circle and asterisk represent the outliers. The circle denotes the outlier that
bigger than Q3+1.5*IQR but smaller than Q3+3*IQR; or smaller than Q1 1.5*IQR
but bigger than Q1 3*IQR. The asterisk denotes the outlier that bigger than
Q3+3*IQR; or smaller than Q1 3*IQR. (Q, quartile; IQR, interquartile range; *=
multiply)

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Fig. 5.3 Spearmans correlation between TLG and T-stage (p<0.001, R=0.620). Both
circle and asterisk represent the outliers. The circle denotes the outlier that bigger
than Q3+1.5*IQR but smaller than Q3+3*IQR; or smaller than Q1 1.5*IQR but
bigger than Q1 3*IQR. The asterisk denotes the outlier that bigger than Q3+3*IQR;
or smaller than Q1 3*IQR. (Q, quartile; IQR, interquartile range; *= multiply)

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Tables:
Table 5.1 Patient Demographics (n=57)
Characteristics
Age
Median, 48 years
Range, 15-80 years
Gender
Male
Female
Histology
Undifferentiated Carcinoma
Poorly differentiated Squamous Cell Carcinoma (SCC)
AJCC/UICC TNM Stage
I
II
III
IV

47

No. of patients

(%)

44
13

77.2
22.8

56
1

98.2
1.8

2
12
24
19

3.5
21.1
42.1
33.3

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Table 5.2 SUVmax, TV and TLG of Primary Tumor according to T-staging

T-stage
SUVmax
TV (cm3)
Range
Mean (SD)
Range
Mean (SD)
1 (n=10)
1.8 - 7.8
4.21.8
1.86 - 7.73
5.161.7

TLG
Range
9.71 - 28.89

Mean (SD)
19.286.46

2 (n=23)

4.8 - 16.0

8.93.3

2.35 - 28.75

7.915.43

12.29 - 212.75

55.9250.52

3 (n=17)

2.6 - 14.4

9.63.4

3.72 - 36.97

13.339.81

8.43 - 543.99

115.25127.65

4 (n=5)

7.5 - 16.6

12.64.5

5.38 - 73.35

41.628.87

37.3 - 1068.81

348.17410.43

Abbreviations. SUVmax, maximum standardized uptake value; TV, metabolic tumor volume; TLG, total lesion glycolysis.

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Table 5.3
N-stage
0 (n=9)

KS CHAN

SUVmax, TV and TLG of Primary Tumor according to N-staging

SUVmax
TV (cm3)
Range
Mean (SD)
Range
Mean (SD)
3.1 - 11.1
7.52.7
4.79 28.75
9.467.40

TLG
Range
Mean (SD)
13.27 212.75
57.1261.05

1 (n=13)

2.6 - 16.6

7.64.3

1.86 68.56

13.4418.02

9.71 188.54

52.9053.55

2 (n=24)

2.9 15.9

9.73.8

2.35 73.35

13.4015.32

8.43 1068.81

124.50214.35

3 (n=11)

1.8 - 16.0

7.64.6

3.03 36.97

8.819.66

4.63 543.99

90.87157.81

Abbreviations. SUVmax, maximum standardized uptake value; TV, metabolic tumor volume; TLG, total lesion glycolysis.

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Table 5.3
N-stage
0 (n=49)
1 (n=8)

KS CHAN

SUVmax, TV and TLG of Primary Tumor according to M-staging

SUVmax
TV (cm3)
Range
Mean (SD)
Range
Mean (SD)
1.8 16.0
8.44.0
1.86 73.35
11.4912.46
5.2 - 16.6

9.03.6

3.33 68.56

14.4322.04

TLG
Range
Mean (SD)
4.63 1068.81
95.34170.68
18.85 188.54

64.7355.36

Abbreviations. SUVmax, maximum standardized uptake value; TV, metabolic tumor volume; TLG, total lesion glycolysis.

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CHAPTER 6

CHAPTER 6

KS CHAN

PROGNOSTIC STRATIFICATION

USING STANDARDIZED UPTAKE VALUE OF 18F

FDG PET-CT IN NASOPHARYNGEAL
CARCINOMA

6.1 Introduction
The most important prognostic factor for NPC is the clinical stage which has
traditionally been based on anatomic imaging like CT and MRI. The T and N stages
mainly reflect the extent of disease and indirectly tumor load. Additional prognostic
factors that complement the TNM staging prognostication are needed to better
stratify patients for customized treatment, e.g. patients with early stage disease but at
risk of distant failure should be treated with chemoradiotherapy also (Ma et al.,
2008a). Some factors that have been studied include pre-therapy circulating EBV
DNA load (Leung et al., 2006), post-treatment decline of EBV DNA (Chan et al.,
2002), tumor volume (Chua et al., 1997) and timing of histological remission
(Kwong et al., 1999).

In our previous study described in Chapter 5 (Chan et al., 2010), we have found
a strong correlation between SUVmax, TV and total lesion glycolysis with T-stage in
NPC patients. Most reports in the literature have studied the role of FDG PET or
PET-CT for staging, RT planning and therapy monitoring of NPC, with only a few
having longitudinally evaluated the prognostic impact of these semi-quantitative
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parameters on survival.

In this study, we evaluate the relationship between FDG uptake and TV with
outcome after treatment of NPC to see if PET uptake can be of prognostic value. This
may help treatment stratification, in particular for selecting patients with more
aggressive tumor for intensification of treatment.

6.2 Materials and Methods

6.2.1 Patient Population
We retrospectively analyzed the

18

F FDG PET-CT findings of 49 newly

diagnosed NPC patients with the mean age of 48 years (range, 16-79 years) who
were consecutively imaged in the PET-CT Unit of the University of Hong Kong,
between May 2007 and May 2009. There were 38 (77.6 %) males, mean age 49 years
(range, 16-79 years) and 11 (22.4 %) females, mean age 46 years (range, 31-64
years). All eligible patients had biopsy-proven NPC at the primary site and the
histological type was undifferentiated carcinoma in all except poorly differentiated
squamous cell carcinoma in one. All patients were scanned prior to commencement
of treatment. Of the 49 patients, two, seven, 20 and 20 had stage I, stage II, stage III
and stage IV disease respectively according to the AJCC/UICC TNM staging.
Patients who were detected with distant metastasis at presentation were excluded.
Patient characteristics are listed in Table 6.1.

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6.2.2

KS CHAN

PET-CT Protocol

All patients were scanned using the standardized PET-CT protocol as described
in Chapter 4.

6.2.3

Image Analysis

SUVmax (pSUVmax) and TV of primary tumor were automatically calculated by

the PET-CT fusion software and these values were recorded from the workstation.
Same method was used for measuring SUVmax of the cervical nodal metastases, and
the cervical lymph node with the highest SUVmax was selected (nSUVmax). SUVmax
was corrected for lean body mass for both the primary tumor and cervical nodal
metastases.

6.2.3

Treatment

All patients received IMRT. Patients were immobilized with a custom-made

thermoplastic cast from head to shoulders with a mouth bite during treatment
planning and RT. IMRT was administered as 2 Gy daily fraction using 4-6 MV
photon beams (Varian Medical Systems, Palo Alto, USA), 5 days per week, for a
total dose of 70 Gy to gross tumor volume (GTV), 66 Gy to planning target volume
(PTV) including prophylactic nodal irradiation in upper neck. The lower neck was
irradiated with a matching anterior cervical with midline shield to 60Gy. GTV
included the nasopharynx (NP) tumor and any tumor extension outside NP as
identified clinically and on PET-CT and MRI. Enlarged cervical lymph nodes were

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localized as separate GTV. Clinical target volume (CTV) included at least 1cm
around GTV and potential areas of disease spread including the sphenoid sinus,
cavernous sinuses, the base of skull (including the petrous tip, inferior orbital fissures,
foramen ovale and foramen spinosum), the clivus, the posterior third of the nasal
cavity and maxillary antrum, parapharyngeal spaces, prevertebral muscles and
anterior one-half of the arch of cervical vertebrae 1 (C1). PTV was obtained with
additional 2mm margin to CTV.

Forty-five patients received concurrent chemotherapy and twenty of these 45

patients received also adjuvant chemotherapy. Chemotherapy consisted of cisplatin
100mg/m2 on day 1, 22 and 43 of RT and adjuvant chemotherapy with PF (cisplatin
80mg/ m2, day 1 and 5-fluorouracil 1g/m2 day 1 to 4) for 3 cycles. Induction
chemotherapy was given to 14 patients with stage III or IV disease to relieve
symptoms and slow disease progression while waiting for investigations and
preparation for RT. 1-2 cycles of induction PF was given to these patients and in
order to limit the total number of courses of PF to 3 cycles, the number of cycles of
adjuvant chemotherapy after RT was reduced accordingly.

6.2.4

Study Design and Statistical Analysis

After completion of treatment, patients were followed up at the NPC clinic every
month during the first year, every 2 months in the second year and then every 3-6
months afterwards. DFS, loco-regional relapse-free survival (LRFS) and distant
relapse-free survival (DRFS) were measured from the date of the start of treatment to
the earliest date of event, last contact or censoring (30 April, 2010). Data was

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obtained from electronic patient medical records. After primary treatment, if

persistent disease was found in NP or cervical region, time to failure was taken as
zero. Statistical analysis was done using SPSS 16.0 (Chicago, IL, USA). DFS, LRFS
and DRFS rates were calculated using Kaplan-Meier methods. The thresholds of
pSUVmax, nSUVmax and TV were chosen by using discriminant analysis with a range
of SUVmax (from 5.0 to 8.5) and TV (6.0-10.0cm3) values as independent variables
against DFS, LRFS and DRFS, and selecting the best discriminant. The prognostic
factors: age (<40 or 40), gender, T-stage (T1-2 or T3-4), N-stage (N1-2 or N3-4),
pSUVmax (<7.5 or 7.5), nSUVmax (<6.5 or 6.5) and TV (<8.0cm3 or 8.0cm3)
were examined by univariate and multivariate analysis using log-rank test and the
Cox proportional hazards regression model. 2-tailed Spearmans correlation was used
to analyze the relationship between N-stage and nSUVmax. P value <0.05 was
considered significant.

6.3 Results
The mean values of pSUVmax and TV of the primary tumor and nSUVmax of
cervical lymph node metastases were 8.54.5 (range, 1.8 to 21.3), 12.6414.90cm3
(range, 1.86-73.35cm3) and 7.74.7 (range, 1.5 to 20.9) respectively. The mean
values of pSUVmax, nSUVmax and TV of the patients who had no evidence of relapse
were 7.9 (range, 1.8-16.0), 7.3 (range, 1.5-16.5) and 10.74cm3 (range, 1.86-73.35cm3)
respectively, whilst the mean values of pSUVmax and nSUVmax of the patients with
treatment failures were 11.1 (3.821.3), 9.6 (range, 2.6-20.9) and 21.07cm3 (range,
3.81-69.10cm3) respectively. The mean follow-up period for all patients was
20.26.9 months (range, 9.0-33.7 months). For patients without relapse, the mean
follow-up period was 19.67.3 months (range, 9.0-33.7 months) and for patients with
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relapse, the mean time to relapse was 10.87.6 months (range, 0-20.4 months).
Two-year DFS, LRFS and DRFS were 69.1%, 79.1% and 74.7% respectively.
Treatment failure was found in six patients. Among these six patients, two patients
had nasopharyngeal relapse, two patients had nodal failures and five patients with
distant failures were observed. One patient was found to have nasopharyngeal, nodal
and distant failure and another suffered both nodal and distant failure.

6.3.1

Univariate Analysis

Both pSUVmax 7.5 (p=0.022) and nSUVmax 6.5 (p=0.036) were associated
with significantly lower 2-year DFS (Figure 6.1 and 6.2). For LRFS, significantly
poorer prognosis was found in patients with pSUVmax 7.5 (p=0.041) and nSUVmax
6.5 (p<0.001). nSUVmax 6.5 (p<0.001) yielded the highest significance level for
predicting DRFS, followed by pSUVmax 7.5 (p=0.028). Patients with age 40,
T3-4 stage, N2-3 stage and TV > 8.0cm3 showed poorer prognosis, however the
difference was not significant.

6.3.2

Multivariate Analysis

Cox regression was carried out to examine the statistically significant variables
associated with DFS, LRFS and DRFS and showed that only pSUVmax (p=0.04) of
the primary tumor was significant independent prognostic indicator of DFS whilst no
prognosticators were found for LRFS or DRFS.

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6.3.3

KS CHAN

Spearmans Test

Using 2-tailed Spearmans test, nSUVmax was found to be strongly associated

with N-stage (p=0.001). However, no significant correlation was found between
nSUVmax and T-stage.

6.3 Discussion
Identification of prognostic factors is important for treatment stratification and
potentially improving treatment outcome. It is especially beneficial if it is achieved
non-invasively. AJCC TNM staging system has been widely used for planning
treatment and predicting prognosis for NPC patients. It has been shown that the
AJCC system is better than other staging systems including the Hos system from
Hong Kong in predicting prognosis and distributing patients more evenly between
stages (Cooper et al., 1998; Hong et al., 2000; Ma et al., 2001). However, the need of
modification to the latest 6th AJCC classification system has been suggested. Mao
and colleagues (2009) shows that using the AJCC system, no significant difference
could be found in local relapse-free survival among patients with T1, T2 and T3
disease. In addition, using nodal size as N-staging criteria shows no significant
prognostic impact on overall survival and distant metastasis-free survival (Mao et al.,
2009). Numerous studies using CT and MRI for volume contouring have shown that
a large primary tumor volume is associated with significantly worse treatment
outcome (Chen et al., 2004; Lee et al., 2008a; Sze et al., 2004). Nevertheless, there is
a large variation (15cm3 - 64cm3) of cutoff point and contouring methods of tumor
volume between studies (Chang et al., 2002; Chu et al., 2008; Chua et al., 2004;
Willner et al., 1999).
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Encouraging results on the prognostic value of intensity of FDG uptake in

different malignancies, represented as SUV, have been reported (Javeri et al., 2009;
Liao et al., 2009; Yen et al., 2008). In the present study, we found that NPC patients
with high FDG uptake of primary tumor (pSUVmax 7.5) had poor prognosis and
pSUVmax was significant prognosticator of DFS and our findings are similar to
findings by other authors who have found a cutoff pSUVmax value of 8.0 may predict
the treatment outcome of NPC patients (Lee et al., 2008b; Xie et al., 2010a).
Although previous work of Lee et al. (2008b) and Chan et al. (2009) has that a higher
SUVmax favors distant failure and poorer prognosis, and our previous report (Chan et
al., 2010) of correlation of SUV and total lesion glycolysis correlates with TMN
staging, the current study is the first study on prognostic and risk stratification in
using pSUVmax and nSUVmax in predicting DFS, LRFS and DRFS.

Cervical lymph node metastasis is commonly seen in NPC patients. In a

retrospective study of 4768 NPC patients, 75.8% patients presented with neck mass
at initial diagnosis (Lee et al., 1997). The status of cervical nodal metastases at
presentation has been found to significantly affect the OS and distant failure of NPC
patients and nodal control rate dropped from 90% for patients with N0 and N1
disease to 70% for patients with N2 and N3 disease (Chua et al., 2001). At present,
we have found that patients with nSUVmax 6.5 had significantly shorter DFS, LRFS
and DRFS period than those with nSUVmax < 6.5. Our results may offer additional
information on the prognostic role of SUVmax of cervical lymph nodes metastases
which has been addressed by other investigators. Lee et al. (2008b) has found that
patients with nodal SUV higher than primary tumor SUV had worse prognosis and

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the result has been confirmed by Xie et al. (2010a) and the authors suggested that it
may be due to the more aggressive nature of these tumors in metastasis and relative
growth conditions.

Although both pSUVmax and nSUVmax were found significantly correlated

with LRFS and DRFS, Cox regression analysis failed to demonstrate that these
parameters were independent prognostic indicators of these two survival endpoints.
Our results may be affected by the relatively small sample size - among the 49
patients, only six was found to have persistent disease or relapse. The limited number
of patients may have contributed to our inability to determine an independent
predictor of LRFS or DRFS. Further study with a larger study cohort will be helpful.

Xie and colleagues (2010b) evaluated 41 patients with NPC who were treated
with radiotherapy underwent pre- and post-treatment PET-CT scans and they found
that TV of 30cm3 or larger correlated positively with worse 5-year OS and DFS.
However, our study failed to identify a cutoff TV at the nasopharynx as a significant
prognosticator. A possible reason for this discrepancy may be due to the small tumor
size of our patient cohort. Of our 49 patients, twenty-seven were with T1 and T2
disease and the median TV was 6.94cm3. Because of the relatively small tumor size,
the effect of TV on DFS may not be significant. In addition, currently the optimal
method and SUV threshold for delineation of TV has not been established. The
methods used for delineation of TV were different in different centers. Xie and
colleagues (2010b) used SUV>2.5 as threshold for delineation of volume whilst we
used 40% maximum signal intensity as threshold.

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In conclusion, we have shown that SUVmax measured on FDG PET-CT is a

valuable tool for risk stratification of NPC patients. Our results suggest that a cutoff
pSUVmax of the primary tumor at 7.5 and nSUVmax of cervical lymph nodes at 6.5 are
associated with poor patient outcome. This study shows that using PET-CT scan and
the pSUVmax and nSUVmax, we now have a method of not only prognostic indication
but also risk stratification such that the patients who have higher risk of disease
relapse, local or distant recurrence can be identified. Hence future research can be
designed to assess whether modification of therapy or addition of adjuvant therapy
can improve e the outcome and survival of these groups of patients with lower DFS,
LRFS and DRFS.

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Figures:

Fig 6.1 2-year disease-free survival (DFS) according to maximum standardized

uptake values of primary tumor (pSUVmax) in nasopharyngeal carcinoma (NPC)
patients. DFS of patients with pSUVmax < 7.5 (solid line) versus DFS of patients with
pSUVmax 7.5 (broken line) (p=0.022).

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Fig 6.2 2-year disease-free survival (DFS) according to maximum standardized

uptake values of cervical lymph node metastasis (nSUVmax) in nasopharyngeal
carcinoma (NPC) patients. DFS of patients with nSUVmax < 6.5 (solid line) versus
DFS of patients with nSUVmax 6.5 (broken line) (p=0.036).

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Table:
Table 6.1: Patient Demographics (n=49)
Characteristics
No. of patients
Age
Median, 48 years
Range, 16-79 years
Gender
Male
38
Female
11
Histology
Undifferentiated Carcinoma
48
Poorly differentiated Squamous Cell
1
Carcinoma (SCC)
Overall AJCC/UICC Stage
I
2
II
7
III
20
IV
20
AJCC/UICC T-stage
T1
12
T2
15
T3
14
T4
8
AJCC/UICC N-stage
N0
6
N1
11
N2
19
N3
13
AJCC/UICC M-stage
M0
49
M1
0
RT
Intensity-modulated radiotherapy
49
Chemotherapy
45
Concurrent
45
Adjuvant
20
Induction
14

63

(%)
78
22
98
2

4
14
41
41
24.5
30.6
28.6
16.3
12.2
22.5
38.8
26.5
100
0
100
90
90
40
28

CHAPTER 7

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METABOLIC ACTIVITY

MEASURED BY PET IN NK-CELL LYMPHOMA

COMPARED TO AGGRESSIVE B- AND T-CELL
LYMPHOMAS

7.1 Introduction
As NHL is a diverse disease with considerable differences in survivals between
sub-groups, stratification by non-invasive markers that may help characterize disease
aggressiveness and tumor metabolic phenotype may have implications on staging,
prognostication and treatment planning. There are numerous studies available that
cover PET and PET-CT for staging (Pelosi et al., 2008), therapy response monitoring
(Yang et al., 2009) and treatment planning (Dizendorf et al., 2003) of Hodgkins
lymphoma and B-lineage lymphomas but only few studies covering the use of this
anatomic-functional imaging technique in NK-cell lymphoma. The purpose of this
study is to compare the glucose metabolic activity, as reflected by SUVmax, in the
various histological subtypes of NHL in a single center in a Chinese population with
a larger proportion of the NK-cell lymphoma subtype.

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7.2 Materials and Methods

7.2.1 Patient Population
The study, approved by the Institutional Review Board, retrospectively reviewed
the pre-therapeutic initial staging PET-CT scans of all consecutive biopsy proven
NHL patients between June 2007 and October 2009. Patients were excluded if they
had underlying infection or if they had received prior radiotherapy or chemotherapy.
Lymphoma diagnosis was based on the WHO lymphoma classification, and all
pathology materials were centrally reviewed. There were 122 patients in total, of
whom 65 were aggressive B-cell lymphomas, 31 were indolent B-cell lymphomas,
16 were NK-cell lymphomas and 10 were T-cell lymphomas. Patient demographics
and the clinicopathological and PET features of NK-cell lymphomas are tabulated in
Table 7.1 and 7.2. Five patients (2 DLBCL, 2 NK-cell lymphomas and 1 anaplastic
large T-cell lymphoma, cutaneous type) were excluded from the quantitative analysis,
as they were on either long-term or high-dose corticosteroid before scanning, which
might lead to a reduction of 18F FDG accumulation (Brepoels et al., 2007).

7.2.2 PET-CT Protocol

All patients were scanned using the standardized PET-CT protocol as described
in Chapter 4.

7.2.3 Statistical Analysis

The lesion with the highest SUVmax (corrected for lean body mass) in each

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patient was recorded by the same operator (WKSC) on the axial PET images using
the semi-automated software on the workstation (Advanced Workstation 4.3, GE
Healthcare Bio-Sciences). The mean, median and standard deviation (S.D.) were
calculated for each subtype and also for four major groups of lymphoma; aggressive
B-cell lymphoma (n=63), aggressive T-cell lymphoma (n=9) and NK-cell lymphoma
(n=14), and indolent B-cell lymphoma (n=31). As Levenes test showed significantly
different variance among the groups (p<0.001) which violated the assumption of a
regular ANOVA, comparison of the SUVmax among four groups of lymphoma; three
aggressive groups and one indolent group, was therefore carried out using One-way
ANOVA with Brown-Forsythes F test, and post-hoc analysis was performed using
Games-Howells test. NK-cell lymphomas were further divided into two groups:
nasal group (confined to nasal cavity and upper airway region, n=5) and extranasal
group (primary tumor originated from extranasal sites or disseminated disease
without nasal involvement, n=9), and comparison was performed by unpaired
Student t test. P value <0.05 was considered as statistically significant.

7.3 Results
SUVmax (mean S.D.) was 9.24.5 in NK-cell lymphomas, 14.1 6.4 in
aggressive B-cell lymphomas, 5.33.1 in indolent B-cell lymphomas and 7.63.9 in
T-cell lymphomas (Fig. 7.1 and table 7.2). SUVmax of NK-cell lymphoma was
significantly lower than aggressive B-cell lymphoma (p=0.013) as were SUVmax of
indolent B-cell lymphomas (p<0.0001) and T-cell lymphomas (p=0.003). The
SUVmax of NK-cell lymphoma was significantly higher than that of indolent B-cell
lymphoma (p=0.039), but no significant difference was found with T-cell lymphoma.

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There was no significant difference between nasal and extranasal NK-cell lymphoma
groups. Representative PET-CT images of patients with aggressive B-cell lymphoma
(Fig. 7.2A, B and C) and NK-cell lymphoma (Fig. 7.3A, B and C), both with
nasal/nasopharyngeal lesions, are illustrated.

7.4 Discussion
In this single center study with a predominant Chinese population, we have
described the metabolic phenotypes characterized by FDG uptake in the various
NHL subtypes. Although NK-cell lymphomas have high metabolic activity, it was
significantly lower compared to aggressive B-cell lymphomas, but significantly
higher than indolent B-cell lymphomas. SUVmax of T-cell lymphoma was not found
to be significantly different from NK-cell lymphoma. In keeping with the literature,
SUVmax of indolent B-cell lymphomas in our study was significantly lower than
aggressive B-cell lymphomas.

The following observations may explain the relatively lower metabolic activity
in NK-cell lymphoma compared to its aggressive B-cell counterparts. Firstly,
although NK-cell lymphoma is a clinically aggressive disease with poor prognosis
(median survival is usually less than a year) despite intensive treatment, the clinical
course of NK-cell lymphomas are such that they do not proliferate as rapidly as
B-cell lymphomas, and as a result, NK-cell lymphomas are usually smaller in
volume. Indeed, the poor prognosis of NK-cell lymphomas is related to its
refractoriness to chemotherapy, rather than aggressive tumor growth as observed in
B-cell lymphomas. Secondly, NK-cell lymphomas show pathologically various

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degrees of angioinvasion leading to tissue destruction and coagulative necrosis, with

the neoplastic lymphoid cells scattered in a background of inflammatory cells
secondary to local production of cytokines (Kwong et al., 1997). Therefore,
metabolic activity of the tumor may represent increased glucose metabolism from
both scattered tumor cells and the background infiltrating inflammatory cells, unlike
aggressive B-cell lymphomas which on histology are densely packed tumor cells (Li
et al., 2006). Whether this is related to differences in glucose transporter expression,
as postulated in T and B-cell lymphomas (Tang et al., 2009) remains unexplored.

In two studies where NK-cell lymphomas were represented together with B-cell
and T-cell lymphomas, a similar trend in SUV as ours was observed, although an
actual statistical comparison among the subtypes had not been performed (Ngeow et
al., 2009; Tsukamoto et al., 2007). Methodologies varied greatly between the centers
in the method of attenuation correction, FDG dose, uptake time and SUV
normalization, making comparison of SUV values between the centers impossible.

It has been shown repeatedly that NK-cell lymphoma that is disseminated has a
significantly worse overall survival rate than if limited to the nasal cavity and upper
airway (Au et al., 2009). However, we did not find any difference between the
intensity of

18

F FDG uptake of these two subgroups. As the histologic features of

localized and disseminated NK-cell lymphomas are identical, the SUVmax may
therefore be expected to be comparable.

7.5 Conclusion
In summary, in our NHL cohort, we found metabolic activity of NK-cell
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lymphoma to be high, but significantly lower than its aggressive B-cell counterpart.
This may reflect a slower proliferative rate, and the large amount of coagulative
necrosis and inflammatory component seen on histopathology which reduces the
overall metabolic activity. This relatively lower uptake is also in keeping with the
relatively slower tumor growth rate of NK-cell lymphomas compared to aggressive
B-cell lymphomas. Thus, further evaluation with larger cohorts of individual
subtypes is necessary to understand the metabolic differences among the subtypes.

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Figures:

Fig 7.1 Boxplot of maximum standardised uptake values (SUVmax) by four major
lymphoma groups, aggressive B-cell lymphoma, indolent B-cell lymphoma, NK-cell
lymphoma and aggressive T-cell lymphoma. The circle denotes the outlier that
bigger than Q3+1.5*IQR but smaller than Q3+3*IQR; or smaller than Q1 1.5*IQR
but bigger than Q1 3*IQR. (Q, quartile; IQR, interquartile range; *= multiply)

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Fig 7.2 PET-CT images of a (M/72) patient with diffuse large B-cell lymphoma. (A)
Maximum intensity projection (MIP) image shows a nasopharyngeal mass (SUVmax
= 23.0) (arrow) and multiple cervical lymphadenopathy (SUVmax range from 5.0 to
14.7) (arrow heads). (B) Contrast enhanced axial CT image shows a bulky enhancing
soft tissue mass lesion in the left nasopharynx (arrow) which extends to the tonsil
and the base of the tongue. (C) Axial fused PET-CT image shows the
nasopharyngeal mass (arrow) to be markedly hypermetabolic (SUVmax=23.0).

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Fig 7.3 PET-CT images of a (F/26) patient with NK-cell lymphoma. (A) Maximum
intensity projection (MIP) image shows the nasal lesion (SUVmax=8.6) (arrow),
extensive hypermetabolic lymphadenopathy from neck to pelvis (SUVmax range from
2.4 to 7.6) and multiple bony lesions (arrow heads). (B) Contrast enhanced axial CT
image shows a soft tissue mass in right nasal cavity and soft tissue thickening at the
posterior wall of nasopharynx (arrows). (C) Axial fused PET-CT image shows the
tumor to be highly metabolic (SUVmax=8.6) (arrows), but less so than the
nasopharyngeal diffuse large B-cell lymphoma (Figure 7.2).

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Tables:
Table 7.1: Clinical Characteristics of Study Population (n=122)
Histology
n
Aggressive B-cell lymphoma
Diffuse Large B-Cell Lymphoma (DLBCL)
Burkitts lymphoma
Follicular Lymphoma (FL) grade 3
Indolent B-cell lymphoma
Follicular Lymphoma (FL) grade 1 & 2
Mantle Cell Lymphoma(MCL)
Marginal Zone Lymphoma (MZL)
Splenic Marginal Zone Lymphoma (SMZL)
Mucosa-Associated Lymphoid Tissue (MALT)
Lymphoplasmacytoid
Chronic Lymphoma Leukemia/Small Lymphocytic
Lymphoma (CLL/SLL)
NK-cell Lymphoma
Nasal
Extranasal
T-cell Lymphoma
Angioimmunoblastic T-Cell Lymphoma (AITL)
Peripheral T-Cell Lymphoma (PTCL)
Anaplastic Large T-Cell Lymphoma (T-ALCL),
systemic
Anaplastic Large T-Cell Lymphoma (T-ALCL),
cutaneous
Enteropathy-type T-cell lymphoma

73

65
54
8
3
31
14
3
3
1
5
2
3

Age (y)
Median Range
64
11-91
65
17-91
38
11-71
64
49-72
57
35-87
55
35-85
66
50-77
58
40-60
52
55
49-81
82
76-87
57
37-57

16
5
11
10
2
4
2

46
54
46
57
62
57
64

64

39

16-83
41-61
16-83
49-79
51-73
51-59
49-79

CHAPTER 7

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Table 7.2 Clinicopathological and PET Features of NK-cell Lymphoma Patients

Sex/Age (yrs)
Sites
1
F/41
Spleen, BM, groin LN
2
F/57
Spleen, aorto-caval, para-aortic and iliac LN
3
F/16
Suprarenal space, BM, adrenal glands
4
M/66
Eye, maxillary sinus, pericardium, small bowel, testis
5
M/24
Nasal, pleura, chest wall, liver, cervical, mediastianl and para-aortic LN, BM
6
M/45
Nasal, lacrimal gland, cervical LN
7
F/40
Skin, lung, BM, muscle
8
F/26
Eye, nasal, cervical, hilar, precaval, para-aortic and iliac LN, spleen, small bowel, BM
9
F/76
Axillary, mediastinal and peripancreatic LN, BM
10
F/83
Vestibule of oral cavity, BM, skin
11
M/48
Nasal
12
M/41
Nasal
13
M/71
Nasal
14
M/30
Nasal
15
M/61
Nasal, hilar LN
16
F/47
Nasal, submandibular LN

74

Stage
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
I
I
I
I
II
II

Highest SUVmax
2.8
3.9
12.2
7.1
15.1
7.4
6.9
8.6
7.9
7.7
7.6
8.5
3.2
10.8
4.6
21.2

CHAPTER 7

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Table 7.3: Comparison of SUVmax between various lymphoma subtypes in aggressive and indolent B-cell, NK-cell and T-cell lymphomas
Histology
n
SUVmax
Range
Median
MeanSD
Aggressive B-cell lymphoma *
63
3.7-29.5
13.7
14.16.4
Diffuse Large B-Cell Lymphoma (DLBCL)
52
3.7-29.5
13.9
14.66.5
Burkitts lymphoma
8
4.3-21.8
14.3
13.16.1
Follicular Lymphoma (FL) grade 3
3
5.3, 6.9, 10.2
Indolent B-cell lymphoma#
31
1.3-12.2
4.4
5.33.1
Follicular Lymphoma (FL) grade 1 & 2
14
1.3-12.2
4.5
5.32.9
Mantle Cell Lymphoma(MCL)
3
3.0, 3.8, 4.3
Marginal Zone Lymphoma (MZL)
3
1.9, 5.7, 9.5
Splenic Marginal Zone Lymphoma (SMZL)
1
1.6
Mucosa-Associated Lymphoid Tissue (MALT)
5
3.2-10.9
9.3
7.94.0
Lymphoplasmacytoid
2
2.8, 7.8
Chronic Lymphoma Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)
3
1.6, 3.1, 5.0
NK-cell Lymphoma#
14
3.2-21.2
7.8
9.24.5
Nasal
5
3.2-21.2
7.6
9.07.1
Extranasal
9
6.9-15.1
7.9
9.32.8
T-cell Lymphoma
9
3.3-16.0
8.0
7.63.9
Angioimmunoblastic T-Cell Lymphoma (AITL)
2
5.1, 16.0
Peripheral T-Cell Lymphoma (PTCL)
4
7.7
4.1-9.8
Anaplastic Large T-Cell Lymphoma (T-ALCL), systemic
2
3.8, 8.0
Enteropathy-type T-cell lymphoma
1
5.3
Only 117 patients were included for statistical analysis.5 patients (2 DLBCL, 2 NK-cell lymphoma and 1 T-ALCL, cutaneous) were excluded.
*P<0.05 for aggressive B-cell lymphoma vs. indolent B-cell, NK-cell & T-cell lymphoma.
#P<0.05 for indolent B-cell lymphoma vs. NK-cell lymphoma.

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CONCLUSION SUMMARY AND

FUTURE STUDIES

18

F FDG PET-CT is a fast developing imaging modality for cancer imaging. It

not only provides anatomical, but also functional information. Semi-quantitative

markers SUV, TV and TLG allow objective measurement of metabolic activity and
size of tumors and treatment response monitoring.

AJCC TNM classification system is the most important prognostic factor and
treatment guideline for NPC patients. In our study, we showed that SUVmax, TV and
TLG of primary nasopharyngeal tumor strongly associated with the T-stage (see
Chapter 5) whilst the highest SUVmax of cervical lymph node metastases significantly
correlated with N-stage. We also found that patients who had primary nasopharynx
tumor and nodal metastases with FDG uptake 7.5 and 6.5 respectively had
significantly lower 2-year DFS, LRFS and DFRS (see Chapter 6). Since AJCC
classification system highly depends on the size of tumor and lymph nodes, the
semi-quantitative parameters derived from PET-CT may have a complementary role
to the system by providing the metabolic phenotype of tumor. Our study was limited
by the relatively short follow-up time. Further studies with longer follow-up time
(5-year and 10-year) would be needed to establish the prognostic value of SUV in
NPC patients. Epstein-Barr virus (EBV) is always detected in NPC. In recent years,
the viral antigen expressed by tumor cells has been used as potential targets in
immunotherapy for

NPC

patients.

Preliminary results

76

have

shown

that

CHAPTER 8

KS CHAN

immunotherapy is well-tolerated with little side-effects and clinically beneficial to

some patients by inducing significant immune response (Comoli et al., 2005; Lin et
al., 2002; Straathof et al., 2005). Objective assessment of the immune response of
immunotherapy is not yet available and studies using pre- and post-immunotherapy
PET-CT for assessment of treatment efficacy may be useful. Regarding other
emerging treatment options including angiogenesis inhibitors (Wen et al., 2009) and
cytotoxic treatment (Hui et al., 2009), promising results have been reported in phase
I trial. The use of PET-CT along with the semi-quantitative parameters may be useful
for assessing the treatment efficacy when phase II trial is carried out.

NK-cell lymphoma is an extremely rare disease, especially in Caucasian society.

We found that the metabolic activity, as represented by SUVmax, of NK-cell
lymphoma was significantly lower than that of aggressive B-cell lymphoma but
significantly higher than that of indolent B-cell lymphoma (see chapter 7). The
difference may be due to the slower growth rate compared to aggressive B-cell
lymphoma and a large amount of necrosis present in NK-cell lymphoma. Further
studies to understand the biological basis of the lower metabolic uptake, e.g.
correlation with proliferative index, Ki67, and other immunostaining and real time
polymerase chain reaction (RT-PCR) analysis etc., may shed light on this relatively
rare and less-well investigated tumor. Prognostic factors of NK-cell lymphoma have
not yet been established and it would be beneficial to develop prognostic factors
which may help to individualize treatment strategies which in turn may improve
treatment outcome. Future studies investigating the prognostic impact of SUVmax on
NK-cell lymphoma with a larger study cohort would be useful.

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To conclude, 18F FDG PET-CT is a promising imaging modality which provides

valuable information about the metabolic phenotype of NPC and NK-cell lymphoma.
It is our hope that our research may contribute in improving the overall survival and
the quality of life of the patients.

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REFERENCE LIST

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LIST OF FIGURES

Fig 1.1

The process of annihilation reaction.

Fig 1.2

The process of 18F FDG uptake.

Fig 3.1

FDG PET-CT and axial T2W MR images of a NPC patient.

Fig 3.2

The trend of NHL incidence in Hong Kong during 1983-2007.

Fig 3.3

The trend of new NHL cases by age-group in Hong Kong during

1983-2007.

Fig 5.1

Spearmans correlation between SUVmax and T-stage of NPC patients.

Fig 5.2

Spearmans correlation between TV and T-stage of NPC patients.

Fig. 5.3

Spearmans correlation between TLG and T-stage of NPC patients.

Fig 6.1

2-year DFS according to pSUVmax in NPC patients.

Fig 6.2

2-year DFS according to nSUVmax in NPC patients.

Fig 7.1

Boxplot of SUVmax by four major lymphoma groups.

Fig 7.2

PET-CT images of a patient (M/72) with DLBCL.

Fig 7.3

PET-CT images of a patient (F/26) with NK-cell lymphoma.

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LIST OF TABLES

Table 2.1

The main cancer sites of Hong Kong in 2007.

Table 3.1

NPC: AJCC/UICC TNM Classification System, 6th Edition.

Table 3.2

NPC: Stage grouping.

Table 3.3

WHO classification for lymphoma.

Table 3.4

Aggressive and indolent lymphoma.

Table 3.5

Recommended diagnostic investigations for lymphoma patients.

Table 3.6

Ann Arbor Classification for NHL.

Table 5.1

Patient demographics of NPC patients.

Table 5.2

SUVmax, TV and TLG of NPC according to T-staging.

Table 5.3

SUVmax, TV and TLG of NPC according to N-staging.

Table 5.4

SUVmax, TV and TLG of NPC according to M-staging.

Table 6.1

Patient demographics and treatment protocol of NPC patients.

Table 7.1

Clinical characteristics of NHL patients.

Table 7.2

Clinicopathological and PET features NK-cell lymphoma patients.

Table 7.3

Comparison of SUVmax between various lymphoma subtypes in

aggressive and indolent B-cell, NK-cell and T-cell lymphomas.

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BIBLIOGRAPHY OF THE AUTHOR

KS CHAN

PUBLICATIONS AND PRESENTATIONS RELATED TO

THE THESIS

Publications
1.

Chan WKS, Tse EWC, Fan YS, Zhang J, Kwong YL and Khong PL. Positron
emission tomography/computed tomography in the diagnosis of multifocal
primary hepatic lymphoma. J Clin Onocol 2008;26:5479-5480.

2.

Chan WKS, Mak HKF, Huang BS, Yeung DWC, Kwong DLW and Khong PL.
Nasopharyngeal carcinoma: relationship between

18

F-FDG PET-CT maximum

standardized uptake value, metabolic tumor volume and total lesion glycolysis
and TNM classification. Nucl Med Commun 2010;31:206-210.
3.

Chan WKS, Au WY, Wong CYO, Liang R, Leung AYH, Kwong YL and
Khong PL. Metabolic activity measured by F-18 FDG PET in NK-cell
lymphoma compared to aggressive B- and T-cell lymphomas. Clin Nucl
Med.2010;35:571-575.

Conference presentations
1.

Chan WKS, Mak HKF, Ngan SSC, Kwong DLW, Khong PL. Nasopharyngeal
carcinoma: relationship between

18

F-FDG PET/CT maximum standardized

uptake value and lesion size with TNM-classification. 55th Society of Nuclear
Medicine Annual Meeting, New Orleans, U.S.A., 14-18 June, 2008. Oral
presentation. (J Nucl Med 2008;49:146P.)
2.

Chan WKS, Au WY, Wong CYO, Liang R, Leung AYH, Kwong YL and
Khong PL. Metabolic activity measured by 18F FDG PET in NK-cell lymphoma
compared to aggressive B- and T-cell lymphomas. 3rd Joint Scientific Meeting
of The Royal College of Radiologists & Hong Kong College of Radiologists
and 17th Annual Scientific Meeting of HKCR, Hong Kong, 31 October-1
November 2009. Oral Presentation.

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