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MEDICAL RADIOLOGY
Diagnostic Imaging
Editors:
A. L. Baert, Leuven
M. Knauth, Göttingen
K. Sartor, Heidelberg
Contents III
Foreword by
A. L. Baert
123
IV Contents
Foreword
In modern society ever more attention is focused on preventive medicine and ever
more resources are allocated to this rapidly growing field of medical activity.
Image-based early detection and correct diagnosis of a whole spectrum of diseases
is the key component of many programmes of population screening.
This book is the most comprehensive up-to-date work on the many, and sometimes
complex, aspects of preventive diagnosis with radiological imaging.
It not only covers the important fundamentals of mass screening and preventive
diagnosis, but also deals systematically and in depth with most clinical areas where
radiological screening has proven its value.
I am very much indebted to the editors of this volume, M. F. Reiser, G. van Kaick,
C. Fink and S. O. Schoenberg – who enthusiastically undertook this difficult task – for
their dedication and tireless efforts to finalize this project successfully in such a rela-
tively short period of time.
I would like to congratulate the editors and contributing authors, both from Europe
and overseas and all carefully chosen for their exceptional expertise in the field, on the
outstanding quality of the different chapters and the wide range of topics covered in
this book.
I strongly recommend this volume to all clinicians involved in population screening
and preventive diagnosis with radiological imaging. It will without doubt support and
guide them in their routine clinical activities.
I am confident that this volume will stimulate great interest within the medical com-
munity and that it will meet with the same success as the other volumes in this series.
Introduction
Modern, non-invasive imaging technologies have developed rapidly and now enable
us to image extended anatomical areas or even the entire body. Outside any screening
programs, ultrasound, e.g., has contributed to early detection of renal cell carcinomas
– simply by being performed for which reason whatsoever. Today, more than 50% of
renal cell carcinomas are detected incidentally, and most frequently in a curable stage.
The range of diseases which can possibly be identified by imaging is wide: Cancer,
atherosclerosis, aneurysms, osteoporosis, brain atrophy, and more.
When whole-body CT as a screening method is offered to the so-called “Worried
Wealthy”, like in the United States, there is legitimate criticism, because its benefit is
unproven, and because ionizing radiation and possibly contrast media are used.
With magnetic resonance imaging, no risks are imposed by ionizing radiation, but all
other concerns remain and must be weighted against the expected benefit: Costs, con-
cerns, time, and the inherent risks of further diagnostic procedures for confirmation of
unclear imaging findings. There are additional ethical issues, e.g., whether insurance
companies must be notified of significant screening findings, or how to deal with signs
of intractable disease, like, e.g., brain atrophy as a possible herald of dementia.
Studies of asymptomatic persons, particularly using MRI, will play a gaining role
for various reasons:
Awareness for health and fitness is increasing, and people may be worried for their
health, even without obvious reason.
Entrepreneurs, physicians and non-physicians who are convinced having detected a
new field of engagement will offer this method to the above-mentioned persons.
Industrial companies developing and producing medical devices suitable for screen-
ing will have legitimate financial interests in that they are used. For ahead planning
of their developments, they also need qualified and realistic advice, which fields may
in future warrant new or dedicated imaging devices.
To assess the benefits of screening is difficult, and hardly ever possible based on
individual fates. Too much are, e.g., survival or time to progression flawed by effects
like the “Lead time bias” or the “Length time bias”. It requires epidemiological meth-
ods to approach this problem, and it may take decades to achieve results.
Today, when high-level health service becomes increasingly unaffordable to the
community, who will pay how much for mass screening and related procedures, are
the expenditures balanced by benefits? If benefits are immaterial, how much are they
worth? Projections for proven methods like the “Papanicolaou-Test” starting with an
age of 20 years calculate 99.000 dollars per life saved. With annual mammography
for early detection of breast cancer between the 55 and 64 years we have to calculate
132.000 dollars, and for colorectal cancer up to 92.000 dollars for each saved person
(Friedenberg, 2002). Although these figures are only rough estimates, they demon-
strate that mass screening has its price and critical projection and calculation of costs
are essential, particularly with limited resources. This unconsidered, the intention of
secondary prevention must not be forgotten: To save lifes, spare harm and grief, and to
avoid costly treatment of advanced disease and disability.
The participation in screening is highly variable – high, e.g., in the Netherlands, but
only between 15 % (men) and 30 % (women) in Germany. Very probably, the participa-
tion will increase if screening is offered to risk groups, and if the persons at risk become
aware of this.
Reading imaging studies in screening requires a profound “change of mind”: Unlike
radiological studies which are clinically indicated, the vast majority of screening stud-
ies are normal, and almost all participants do not have a disease. The first command-
ment “not to harm” means to spare the healthy unnecessary distress or even harmful
diagnostic tests. This requires special training, rigid quality assurance, and regular
auditing. Better no screening than bad screening.
Introduction IX
Without doubt, the “king`s road” of preventive medicine would be primary preven-
tion. If causes of diseases are known – which is the case in only few types of cancer and
vascular diseases – eliminating the cause or possibly antagonizing its harmful effects
(chemo-prevention) might result in true primary prevention. In most instances, how-
ever, the causes are poorly understood, multiple, or impossible (genetic disposition) or
difficult to influence. Who ever tried to “change his lifestyle” can tell how easily this
is said, and how difficult to achieve. So, for most diseases, we are left with secondary
prevention.
Therefore, shall we do nothing because we can not achieve everything? To answer
this, we need large and solid, controlled trials, even if they are difficult and expen-
sive.
So, screening is an entirely unknown terrain. No patients, but clients, no personal-
ized medicine, but standard procedures, and a different attitude of all involved per-
sons. Finally, it must be stressed that secondary radiological prevention does not mean
to open “new markets”. It aims at improving treatment results by early detection of
diseases, and thereby help to a longer life in acceptable health.
Friedenberg, R.M. The 21st Century: The age of screening. Radiology 2002; 223: 1–4.
Contents XI
Contents
3 Pathology
6 Technical Prerequisites
6.2 CT
Chistoph Becker, Anno Graser, and Peter Herzog . . . . . . . . . . . . . . 89
6.3 Ultrasound
Stefan Delorme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
6.4 Mammography
Rüdiger Schulz-Wendtland . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
6.5 PET-CT
Gerald Antoch and Robert Stahl . . . . . . . . . . . . . . . . . . . . . . . . 113
XII Contents
9 Cardiovascular Diseases
9.1 MRI
Susanne Ladd and Harald Kramer . . . . . . . . . . . . . . . . . . . . . . . . 147
9.2 CT
Cristoph R. Becker . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
9.3 Duplex Ultrasound of the Carotid Arteries:
Practical Aspects and Results of Screening for Carotid Disease
Norbert Weiss and Ulrich Hoffmann . . . . . . . . . . . . . . . . . . . . . . 165
10 Oncological Diseases
10.1 Breast Cancer
Karin Hellerhoff, Claudia Perlet, and Thomas Schlossbauer . . . . . . 183
10.2 Renal Cancer - Ultrasound
Dragana Filipas, Sascha Pahernik, and Joachim W. Thüroff . . . . . . . . 193
10.3 Colorectal Cancer
Anno Graser . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
13 Osteoporosis
Andrea Baur-Melnyk and Holger Boehm . . . . . . . . . . . . . . . . . . . . . . . 249
Contents XIII
14.1 Asbestos
Roger Eibel and Dennis Nowak . . . . . . . . . . . . . . . . . . . . . . . . . . 261
14.2 Heavy Smokers
14.2.1 CT Screening for Lung Cancer for High-Risk People
Claudia I. Henschke, Matthew D. Cham,
and David F. Yankelevitz . . . . . . . . . . . . . . . . . . . . . . . . . . 275
14.2.2 Characterization of Lung Nodules Using Radiological Imaging
Christian Fink and Frank Berger . . . . . . . . . . . . . . . . . . . . 285
14.3 Screening for Endometrial Cancer in Asymptomatic Patients
Receiving Tamoxifen Therapy
Sandra A. Polin, Sandra J. Allison, and Susan M. Ascher . . . . . . . . . . 293
15 Genetic Disposition
15.1 Breast Cancer – Screening in Women with an Inherited Risk
Thomas Schlossbauer, Karin Hellerhoff, and Claudia Perlet. . . . . . 311
15.2 Practical Aspects and Results of Screening for Medullary Thyroid Carcinoma
Friedhelm Raue and Stefan Delorme . . . . . . . . . . . . . . . . . . . . . . 323
16 Predisposing Diseases
16.1 Chronic Hepatitis and Liver Cirrhosis
Gerald U. Denk and Ulrich Beuers . . . . . . . . . . . . . . . . . . . . . . . . 329
16.2 Autoimmune Disease, AIDS and Transplanted Patients
Johannes R. Bogner and Michael Fischereder . . . . . . . . . . . . . . . . 335
Part 1:
Fundamentals and Prerequisites
Epidemiology and Statistics 3
CONTENTS 1.1
Introduction
1.2 1.3
Screening as Periodical Application of Inevitability of Side Effects of Screening
Dedicated Tests in a Basically Unaffected
Population Unfortunately, side effects are an intrinsic and
inevitable property of screening. Some of them are
The definition of screening given above implies that test-related and some are related to the crucial role
screening takes place in a population which does not which specificity plays in screening.
carry the disease of interest in its overwhelming major- Examples for test-specific side effects are the
ity, and most of it will never get the disease during exposure to X-ray with mammography screening or
lifetime. For example, in mammography screening, complications with colonoscopy. In the individual
the detection rate within one screening round is about setting of X-ray exposure within diagnostic mam-
3–6 cases per 1000 screened subjects; the lifetime risk mography, it is reasonable to tell the patient that
of getting breast cancer is around 10%. This means the administered dose is on a level which makes
that in about 99.5% of women no breast cancer will personal harm for her very unlikely. However, in a
be found per screening round, and in about 90% of screening population of millions of women, a small
women a breast cancer will never be diagnosed. For rate of, say, 0.004% of induced cancers (see, e.g.,
other cancer sites for which screening appears effec- Jung 2001) implies dozens of cancer cases induced
tive, conditions are not substantially different. by screening. In screening with faecal occult blood
Thus, the screening physician leaves the area of test (FOBT), experience shows that about 1% of
diagnostics and treatment of disease and gets in the tests are positive among which a considerable
touch with qualitatively different problems than in portion requires further diagnostic assessment by
disease-related care by application of a diagnostic test colonoscopy. Serious complications such as perfo-
to a chiefly unaffected clientele (not patients!). A key ration or death through colonoscopy are very rare,
issue of that difference is the ethical assessment of and it is again reasonable to tell the patient in an
potential side effects of the respective screening test. individual diagnostic setting that it is very unlikely
In disease care, the side effects of the diagnostic tests (but not impossible) for him to be harmed by its
are counterbalanced by the progress of the disease administration. In the screening setting with appli-
to be diagnosed if the patient refused their applica- cation of the FOBT to dozens of millions of subjects
tion. The patient will most likely have personal ben- (if compliance is as high as desired by programme
efit by application of diagnostic tests and takes thus authorities), hundreds of thousands of assessment
potential side effects into account. Within screen- colonoscopies have to be carried out, and the small
ing, potential side effects of the screening tests are individual risk of complications extends to dozens
not counterbalanced by progress of disease for most of perforations and several deaths by screening on
screenees, since currently they do not carry the dis- the population level. Unlike mammography screen-
ease and most of them will never carry the disease. ing, where cancer cases due to the cumulative pop-
Thus, the ethically crucial difference between diag- ulation dose of radiation is a statistical quantity,
nostics of disease and screening for disease is that all deaths by FOBT screening are personally identifi-
screenees are target for potential side effects, while able subjects who lose their lives because they par-
the benefit is confined to the comparatively small ticipated in the programme and might even have
group of factual disease carriers which are found by turned out to have been unaffected by colorectal
screening and prevented from death from the disease. cancer.
This setting implicates especially high requirements Inherent side effects of the principle of screening
on the safety and other relevant properties of the test. are false-positive results which increase participants’
It excludes in any way an approach to screening which anxiety and lead to the need for further diagnostic
promotes the free application of a novel test based only investigations which may themselves generate side-
on some early promising findings without proper sci- effects (e.g., additional radiation doses in the case
entific proof of effectiveness and assessment of poten- of radiological assessment, colonoscopy after FOBT,
tial side effects in terms of a benefit – side effect ratio see above) and additional expense. There is inevita-
prior to broad practical application. bly collateral damage from screening since none of
Initially it appears suggestive not allowing for the screening tests so far known has a 100% specifi-
any side effects of screening tests. city (see below).
Epidemiology and Statistics 5
A further screening-related side-effect is over- quantify, are unsuited for proof of effectiveness due
diagnosis and overtreatment (for definition see to uncontrollable screening-related bias.
below). These turn participants – who would never Survival time is necessarily prolonged since
have got cancer without screening – into cancer screening tends to advance the time of diagnosis.
patients and possibly lead to unnecessary treatment Thus, observation time from diagnosis to endpoint
with further – treatment-related – side-effects. of interest, occurrence of the disease or death from
These issues underline the fact that screening the disease, is prolonged to the “left” (see Fig. 1.1),
is ethically only justifiable if evidence is available while the intention of screening is to achieve pro-
that those risks are counterbalanced by a screen- longed survival “to the right” due to earlier start of
ing-related benefit which is larger by magnitudes – and thus more effective – treatment. This implies
than the risks. Thus, it is ethically mandatory that that effective screening would prolong observation
scientific evidence about a clearly positive benefit/ time in both directions. Longer survival can, how-
risk ratio is demonstrated before a novel screening ever, not be distinguished from longer observation
modality is put into application, and that the ben- time just by advanced diagnosis (ineffective screen-
efit/risk ratio remains positive throughout when it ing). Only quantification of the outcome of interest
has been put into practice in the frame of a screen- (incidence of the target disease or mortality from the
ing programme. Assurance of programme quality is target disease) on the population level, i.e. by appro-
thus not optional but condition sine qua non for its priate epidemiological methods, can overcome this
ethical justification. obstacle. This is one reason why epidemiology plays
a crucial role in screening.
Similarly, stage distribution is also uncontrol-
lably biased by screening. Slower growing tumours
are within the preclinically detectable period for a
1.4 longer time span and more likely to be detected by
Inappropriateness of Clinical Parameters screening in this earlier stage than faster growing
for Proof of Effectiveness of a Screening tumours which are more likely to become clini-
Modality cally symptomatic within the interval between two
screening rounds than the slower growing cancers
Unfortunately, the clinical parameters survival (see Fig. 1.2). Thus, the slower growing, less aggres-
and stage distribution, which are so impressively sive tumours occur as early stage tumours with
affected by screening and comparatively easily to a higher proportion among the screen-detected
A B C D E
Biological course of disease
„lead time“
Fig. 1.1. Schematic illustration of
True prolongation of
the biological course of disease with lifetime with effective
a preclinical, screening-detectable screening
1.5
Appropriate Epidemiological Study 1.6
Designs Overdiagnosis
The ideal approach is the prospective randomized Overdiagnosis is defi ned as identification of dis-
screening study. Despite some similarities to ran- ease in subjects which would never have got the
Epidemiology and Statistics 7
Table 1.1. Examples of the positive predictive value (PPV) an established diagnostic test is inadequate. A test
in dependence upon sensitivity, specificity and prevalence which performs well in a clinical setting must not do
of the disease of interest
so under screening conditions. Thus, a comparison
Sensitivity Specificity Predictive value (%) with
with known diagnostic tests can at most serve as a
prevalence of the disease first “knock out” step to exclude tests with a poor
of interest of performance even in a clinical setting.
The appropriate setting for the examination of
0.1% 1%
a screening test is a population group of symptom-
0.5 0.95 1.0 9.2 free subjects which may at most be pre-selected in
0.5 0.975 2.0 16.8 terms of increased risk of getting the respective
0.5 0.99 4.8 33.6 disease, not having it. The test had to be compared
0.75 0.95 1.5 13.2 with a gold standard, or if this is not available, to be
0.75 0.975 2.9 23.3 investigated within a prospective design as outlined
0.75 0.99 7.0 43.1 above. The follow-up serves for the identification
0.9 0.95 1.8 15.4
of those cases which were test-negative but become
symptomatic relatively shortly after testing, i.e. are
0.9 0.975 3.5 26.7
likely to be false-negatives.
0.9 0.99 8.3 41.6
ent or dependent. Statistical dependence must be test. It is straightforward to extend the example to a
assumed if, for example, two different imaging combination of more than two component tests: the
procedures react on the same morphological or tendencies just seen will be enforced in the benefi-
biochemical characteristics of the respective target cial or detrimental direction, respectively, by adding
structure. Thus, basically, independence may not be further component tests.
assumed a priori, but must be verified empirically. The above observation that, for example, under
On the other hand, unconditional independence of the BTP rule the combined sensitivity will be higher
the component tests can never be expected because and the combined specificity will be lower than the
they are related by the respective early signs of the respective component quantities is generally valid
disease to be detected. Otherwise, one or both of independent of whether the tests are conditional
the component tests are likely to be uninformative. independent or correlated. However, if they are cor-
Thus, optimal information is obtained from the related the type of correlation affects the degree by
component tests if they are independent conditional which, for example, the sensitivity may be increased:
on the disease status. This means that – provided the combination of positively correlated tests is less
the disease status is positive – the probability that beneficial than the combination of negatively cor-
the combined test is positive is the product of the related tests to increase the combined sensitivity
probabilities of the component tests being positive, under the BTP rule (for details see, e.g., Lin 1999).
and – provided the disease status is negative – again In the present consideration, it was assumed that
the probability that the combined test is positive is the component tests were used simultaneously, i.e.
the product of the probabilities of the component in parallel. On the other hand, a test combination
tests being positive. can also be used sequentially. Nevertheless, the two
Assuming that in this sense the component tests interpretation rules persist as the only available
T1 and T2 are conditionally independent, the sensi- options, and one can show that sensitivity and spe-
tivity (Se) and specificity (Sp) of the combined test cificity remain the same under either mode of appli-
under the BTP or BTN rule result from the compo- cation (Cebul et al. 1982).
nent sensitivities Se1 and Se2 and specificities Sp1 A further assumption was that the component
and Sp2 according to the simple equations tests were binary, leading to a binary combined test.
However, biomarker-based tests (e.g. serological
SeBTN = Se1uSe2 tests) may alternatively be used quantitatively. Then
SpBTN = 1–(1–Sp1) u(1–Sp2) the combination rules are less straightforward, and
SeBTP = 1–(1–Se1) u(1–Se2) strategies for optimisation can be developed taking
SpBTP = Sp1 uSp2 (2) priorities regarding levels of sensitivity or specifi-
city into account. See for examples and further ref-
The structure of the formulas shows that it is a erences McIntosh and Pepe (2002).
straightforward matter to extend them to a combina- Overall, the potential to create superior tests by
tion of more than two component tests. The positive combination is structurally limited by the statistical
predictive value may be obtained from Equation (1) rules which govern the combination of the probabil-
using the combined sensitivity and specificity under istic quantities sensitivity and specificity.
the BTP or BTN rule, respectively.
The conclusion of this result is that under the BTN
rule the specificity increases at the cost of decreas-
ing sensitivity, and under the BTP rule the sensitiv-
ity increases at the cost of decreasing specificity. For 1.9
example, assuming for the component sensitivities Combination of Outcomes
Se1 = Se2 = 0.8, the combined sensitivity under BTP
gives SeBTP = 1–(1–Se1) u(1–Se2) = 1–0.04 = 0.96, i.e. An issue which is complementary to the combina-
a substantial increase in sensitivity. On the other tion of two or more tests for the more efficient detec-
hand, assuming the corresponding specificities are tion of a specific disease is to apply a specific test to
Sp1 = Sp2 = 0.9, the corresponding combined specifi- a scan for two or more diseases. An example of the
city is SpBTP = Sp1 uSp2 = 0.9u0.9 = 0.81. Thus, a mod- latter is full-body screening.
erate specificity of component tests may inevitably Some of the notions of the previous paragraph
lead to an unacceptably low specificity of a combined also apply to this setting. Obviously, the test outcome
10 N. Becker
will be considered positive if a least one disease was to demonstrate effectiveness and monitor persistent
detected. Thus, the probability of a truly positive out- quality.
come Ppos corresponds in a natural way to the BTP The focus of studies and quality assurance must
interpretation rule in the above paragraph, imply- be the entire screening chain including potentially
ing that the total specificity also behaves according needed diagnostic steps for further assessment
to the corresponding formula. Denoting by Se1, Se2, of positive findings during screening, taking into
Sp1 and Sp2 the specific sensitivities and specificities account potential harm by further diagnostic inter-
for disease 1 and disease 2, the respective formulas ventions.
can be rewritten as Strategies to increase efficiency by combination of
two or more tests for detecting the disease of interest
Ppos = 1–(1–Se1) u(1–Se2) or by scanning for several diseases by a single test
SpTotal = Sp1 uSp2 are only able to achieve a better performance on one
hand at the cost of worse performance on the other.
Thus outcome combination increases the prob- These methodological issues provide the frame-
ability of obtaining any positive outcome and work for approaching full-body screening. Since it
decreases the probability of classifying screening has its particular scope and its specific benefits and
participants which are unaffected by any disease risks, full-body screening has to undergo – for the
of interest truly as screening negative. Obviously, ethical reasons outlined above – the same proof of
in the present setting, correspondence to the BTN effectiveness as any other screening approach. The
interpretation rule does not exist, nor to a sequential statistical considerations of the previous paragraph
application of tests. show that a combined scan for several diseases does
A precondition for using the above combination not just make the early detection of disease more effi-
rules is again independence, in the present instance cient, but may also increase the risk of side-effects to
of the diseases taken into consideration. In the a detrimental level.
present setting even unconditional independence Thus, following the principles outlined above,
may be achievable, though different diseases may be full-body screening may currently not be offered to
related by common risk factors. the population for screening or early detection in
subjects “on demand” outside of well-designed and
externally reviewed epidemiological studies which
must themselves be in accordance with ethical prin-
ciples.
1.10 The scope of studies would be to quantify the
Conclusions and Discussion probability of positive and false positive fi ndings;
the amount of further diagnostic action; side-effects
Side effects are an intrinsic property of screening. including exposure to radiation by the primary scan
It is not intrinsically for screening that it is benefi- (in the case of full-body CT screening) or subsequent
cial for screening participants. Thus, it is ethically diagnostics; the effectiveness to achieve the desired
mandatory to demonstrate (a) before introduction goals – reduction of mortality or morbidity from the
into routine operation that a screening modality is target diseases, respectively.
effective in terms of reduction of mortality or mor- Proper quantification of these parameters can
bidity, respectively, and (b) that effectiveness can only be achieved if the target diseases of the screen-
also be maintained in the long run during routine ing are accurately defined and a precise procedural
operation (“process quality”). The latter implies a strategy determined which signs of illness will be
commitment to ongoing quality assurance. followed by which diagnostic workup. On this basis,
Clinical quantities which are changed under effectiveness and side effects of full-body screening
screening are inappropriate for proving effectiveness has also to be weighed against established dedicated
and assurance of process quality. Well-designed epi- screening modalities for specific target diseases
demiological studies and the quantification of dedi- (e.g. biannual mammography screening for breast
cated epidemiological effect measures are required cancer).
Epidemiology and Statistics 11
CONTENTS
2.1.1 Screening in Oncological Diseases 13 2.1.4 Defi nition of Risk Groups with Potential
2.1.1.1 Defi nition of Screening 13 Benefit from Screening 18
2.1.1.1.1 Screening May Be Harmful 14 2.1.4.1 Familial Adenomatosis Coli (FAP) 18
2.1.1.2 Bias of Screening 14 2.1.4.2 HNPCC 18
2.1.1.2.1 Lead Time Bias 14 2.1.4.3 Hereditary Breast- and Ovarian
2.1.1.2.2 Length Time Bias 14 Cancer 19
2.1.1.2.3 Selection Bias 14 2.1.4.4 Examples of Hereditary Cancer
2.1.1.2.4 Overdiagnosis Bias 14 Predisposition Syndromes 19
2.1.1.2.5 Evaluation of Screening Test 15
2.1.5 Impact of Screening on Therapy 19
2.1.2 Screening Recommendations in 2.1.5.1 Detection of Resectable Disease 19
Oncological Diseases 15 2.1.5.2 Detection of an Early Stage of
2.1.2.1 Colorectal Cancer 15 Disseminated Disease 20
2.1.2.1.1 Screening for Fecal Occult Blood
(FOBT) 15 References 20
2.1.2.1.2 Screening Sigmoidoscopy 15
2.1.2.1.3 Screening Colonoscopy 16
2.1.2.1.4 Virtual Colonoscopy and
CT Colonography 16
2.1.2.1.5 Screening in Average Risk
Individuals 16
2.1.2.1.6 Screening in High Risk Individuals 16
2.1.2.2 Breast Cancer 16
2.1.2.2.1 Mammography in Normal Individuals 2.1.1
Aged t50 Years 16
2.1.2.2.2 Mammography in Asymptomatic
Screening in Oncological Diseases
Individuals Aged 40–49 Years 16
2.1.2.2.3 Mammography in a Genetically Defi ned While there is a general assumption that screening
Risk Group 16 should be a helpful instrument to decrease cancer
2.1.2.3 Cervical Cancer 17 associated mortality, many issues remain unre-
2.1.3 Tumor Entities Without a Screening solved. Therefore, only few disease entities can be
Recommendation 17 defined where screening is supported by prospec-
2.1.3.1 Prostate Cancer 17 tively gained clinical evidence. Specific attention
2.1.3.2 Lung Cancer 17 should be paid that screening does not entail unnec-
2.1.3.3 Ovarian Cancer 18
2.1.3.4 Skin Cancer 18
essary diagnostic procedures and treatment.
2.1.3.5 Adenocarcinoma of the Esophagus 18
2.1.1.1
Definition of Screening
V. Heinemann, MD
Professor, Department of Internal Medicine III, University
Hospitals – Grosshadern, Ludwig-Maximilians-University Cancer screening is performed in asymptomatic
of Munich, Marchioninistrasse 15, 81377 Munich, Germany individuals to search for neoplasias that require
14 V. Heinemann
2.1.2.1.3 2.1.2.2
Screening Colonoscopy Breast Cancer
Colonoscopy may be regarded as the gold standard Screening in breast cancer involves manual self-
of screening. However, also this procedure misses up examination, clinical breast examination or mam-
to 6% of polyps greater than 10 mm in size and up mography. Magnetic resonance imaging of the
to 13% of polyps between 6 mm and 9 mm (Hixson breast may be used when mammography provides
et al. 1990; Rex et al. 1997). uncertain results. While manual self-examination
may raise the awareness of the population at risk, a
2.1.2.1.4 clear benefit of this screening modality has not been
Virtual Colonoscopy and CT Colonography shown with regard to a reduction of breast cancer
related mortality (Thomas et al. 2002).
Virtual colonoscopy using CT colonography has a
substantial clinical potential. It has the advantage 2.1.2.2.1
to be fast and minimally invasive and therefore Mammography in
does not require sedation. Radiation exposure can Normal Individuals Aged t50 Years
be greatly reduced with modern CT technology.
Bowel preparation is, however, comparable to that A reduction of mortality in normal individuals has
needed for the endoscopic procedures. Moreover, been demonstrated for screening mammography.
it needs to be taken into account that colonoscopy Several trials performed in women t50 years of age
has to be performed for any abnormal fi ndings. indicate that mammography alone or in combination
Virtual colonoscopy has reached impressive results with clinical examinations of the breast may reduce
in a highly trained setting. However, it may loose breast cancer related mortality by 20%–30%.
its accuracy in the setting of broader application.
Smaller lesions (< 10 mm), flat polyps and lesions 2.1.2.2.2
at hidden locations may escape detection by vir- Mammography in
tual colonoscopy. Until the issues of reproducibil- Asymptomatic Individuals Aged 40–49 Years
ity and cost-effectiveness have been solved, virtual
colonoscopy is not recommended as a standard of By contrast, the benefit of screening mammography
screening. performed in women aged 40–49 is much less clear.
The greater breast density observed in younger women
2.1.2.1.5 as well as the impact of periodic hormonal changes on
Screening in Average Risk Individuals breast density decrease the sensitivity of mammogra-
phy (Brisson et al. 2000). As a consequence, annual
Individuals at an average risk are recommended screening in this younger age population resulted in
to perform annual FOBT tests starting at the a false-positive detection rate of nearly 50% causing
age of 50 years. A f lexible rectosigmoidoscopy anxiety, as well as unnecessary biopsies and surgi-
should be added every 5 years, alternatively a cal interventions. Screening of women under the age
total colonoscopy every 10 years (Hawk and of 50 years, who are at normal risk, is therefore not
Levin 2005). recommended (Elmore et al. 1998).
2.1.2.1.6 2.1.2.2.3
Screening in High Risk Individuals Mammography in a Genetically Defined Risk Group
Screening colonoscopy starting in young adults In women with a genetically determined higher
is recommended in individuals with a familial or risk of breast cancer, an earlier commencement of
genetically defined high risk to develop colorectal screening is thought to be useful. Women with a
cancer as well as in patients with chronic inflam- BRCA1- or BRCA2-gene mutation typically develop
matory bowel disease. The benefit of screening in breast cancer at a younger age when mammography
this high-risk population still needs to be demon- is notably less sensitive due to the greater density of
strated. the breast. This deficiency in diagnostic sensitivity
Relevant Diseases and Therapeutic Options: Oncological Diseases 17
can only in part be overcome by MRI screening, The prevalence of disease is much greater than the
which, however, bears the advantage that ioniz- actual risk to die from it, and indolent disease is
ing radiation can be avoided. Since patients with expected in 50%–88% of detected cancers. Accord-
an impaired BRCA1 pathway may be specifically ingly, it has been questioned whether screening
sensitive to DNA damage, a more cautious use of truly has an impact on mortality (Klotz 2005; Lu
diagnostic radiation exposure has been recom- et al. 2002).
mended. In the Prostate Cancer Prevention Trial, seven
years of screening resulted in the detection of
prostate cancer in more than 12% of a normal
2.1.2.3 risk population. When after the end of this 7-year
Cervical Cancer follow-up a biopsy was performed in individuals
with normal screening tests, an additional rate of
Screening for cervical cancer involves cervical cytol- 15% prostate cancers was detected. This is con-
ogy and testing for the human papilloma virus. trasted by the observation that the expected prob-
While several cohort- and case-control studies indi- ability to die from prostate cancer is less than 3.5%
cated the benefit from the cervical cytology screen- in males aged t60 years (Thompson et al. 2003).
ing established as the Papanicolaou (Pap) smear, a Moreover, this trial indicates that screening alone
reduction of mortality has not been proven in ran- missed approximately half of the actual prostate
domized trials. cancers.
Regular cervical cytology screening is recom- Based on the available evidence, recommenda-
mended within 3 years of the onset of sexual activity, tions for prostate cancer screening remain con-
but no later than by the age of 21 years. According to troversial. Clearly, the challenge consists in the
the ACS guidelines, cervical screening by Pap smear separation of good risk from bad risk patients. The
should be performed at yearly intervals or every perspective is to use PSA doubling time as a prag-
2 years with liquid-based Pap tests (Saslow et al. matic tool to stratify patients according to the risk
2002). After three subsequently performed normal of tumor progression and to apply either watchful
tests, intervals may be extended to 2–3 years. It may waiting or radical therapy (Klotz 2005).
be safe to stop screening in women above the age of
65 once repeatedly negative Pap smears indicate a
low risk. 2.1.3.2
It can be anticipated that the necessity of screen- Lung Cancer
ing for this tumor entity will be abrogated in a fore-
seeable future once vaccination against the human Several randomised trials have shown that screen-
papilloma virus has become a standard. ing for lung cancer using chest X-ray and sputum
cytology is ineffective with regard to lung cancer-
related mortality (Marcus et al. 2000; Marcus
2001). New diagnostic modalities such as spiral CT
and positron emission tomography (PET) are pres-
2.1.3 ently under investigation. In fact, CT scanning was
Tumor Entities Without a found to be 3–4 times more sensitive than chest
Screening Recommendation radiographs (Henschke et al. 1999; Sobue et al.
2002). While sensitivity for tumor detection has
2.1.3.1 greatly increased, the true impact of these proce-
Prostate Cancer dures on mortality in specified risk groups remains
to be clarified (Manser et al. 2003; Mulshine 2005;
Despite the lack of positive data from prospective Pastorino et al. 2003). A major concern regarding
randomised trials screening for prostate cancer is CT-based screening for lung cancer consists in the
widely used. The applied screening modalities in high rate of false-positive results (5%–50%) which
prostate cancer are digital rectal examination and may require unnecessary lung biopsies (Sobue et
the analysis of prostate-specific antigen (PSA) in al. 2002).
serum. Specifically in prostate cancer, the problem A large randomised trial, the National Lung
of overdiagnosed indolent disease is important. Screening Trial, is recruiting 50,000 high-risk
18 V. Heinemann
genes, namely hMLH1 or hMSH2, have been identi- with BRCA2 mutations (20%) (Narod and Offit 2005;
fied. These defects are associated with microsatellite Risch et al. 2001).
instability (MSI) defined as an elevated frequency Intensified breast cancer screening in genetically
of mutations occurring in microsatellites. In conse- defined high-risk patients is suggestive, but its ben-
quence, HNPCC is a predisposition for the accelerated efit remains to be proven. In addition to self-exami-
development not only of colon cancer, but also of other nation, clinical examination, and mammography,
cancers such as brain, stomach, small bowel, pan- the inclusion of MRI into the routine screening of
creas, biliary tract, renal, ureter, and ovary (Duval women with BRCA mutations is supported by recent
and Hamelin 2002). The lifetime risk of colon cancer data (Robson and Offit 2004). In women with a
in HNPCC patients is between 70% and 90%, whereas family history of ovarian cancer, the combination of
the endometrial cancer risk is 30%–60%. ultrasound and CA-125 screening was recommended
The recommended screening for HNPCC family by the American College of Physicians (American
members is colonoscopy performed at 1- (2-) year CoP). Screening is performed twice a year with an
intervals starting at the age of 20–25 years or at an onset at an early age. In individuals with the highest
age 10 years younger than the earliest case in the genetic risk of breast and ovarian cancer, prophylac-
afflicted family (Garber and Offit 2005; Winawer tic surgery is a valid option and may outweigh the
et al. 2003). In a controlled trial performed over benefit from intensified screening in selected cases.
15 years, surveillance by colonoscopy and polyp-
ectomy at 3-year intervals resulted in a reduction
of CRC by 62% and a 65% reduction of mortality 2.1.4.4
(Jarvinen et al. 2000). Prophylactic colectomy in Examples of Hereditary Cancer Predisposition
HNPCC gene carriers remains a controversial issue Syndromes
(Rodriguez-Bigas 1996).
Apart from colonoscopy, screening in HNPCC Details of hereditary syndromes and associated
patients should also be devoted to the detection of genes are shown in Table 2.1.1.
extracolonic tumors and therefore should involve
abdominal ultrasound and urine cytology as well as
Table 2.1.1. Details of hereditary syndromes and associated
gynecological examinations in female patients. genes
In breast cancer, 5%–10% of cases are associated with a Hereditary non-polyposis colorectal MLH1, MSH2
cancer (HNPCC) syndrome
hereditary predisposition. Specifically mutations of the
BRCA1- and BRCA2-genes have a strong penetrance. Familial adenomatous polyposis (FAP) APC
The probability of a gene mutation increases with breast
cancer occurring at an early age, clustering of breast-
and ovarian cancers (80% BRCA1), and male breast
cancer (66% BRCA2) (Garber and Offit 2005). Breast 2.1.5
cancers with BRCA1 mutations are frequently identi- Impact of Screening on Therapy
fied as basal type cancers characterised by high-grade
tumors, poor differentiation, and negative estrogen-, 2.1.5.1
progesterone-, and HER2-receptors triple-negative Detection of Resectable Disease
breast cancer. BRCA2-associated cancers, by con-
trast, rather resemble sporadic breast cancers and do Screening can be beneficial when diagnosis of
not have a distinct phenotype. The lifetime risk for cancer is made possible at an early time point when
breast cancer associated with BRCA1 mutations is in metastatic spread has not yet taken place and when
the range of 50%–80%, whereas for BRCA2 mutations curative interventions are still possible. Screening
the risk is somewhat lower with a range of 40%–70%. can also detect an early stage of metastatic disease.
The lifetime ovarian cancer risk is greater in BRCA1 In rare cases of oligometastatic disease, surgical
mutation carriers (40%–50%) compared to individuals resection or comparable modalities such as radio-
20 V. Heinemann
frequency ablation or radiation therapy are still toward a new concept of target genes for instability.
options which can either be curative or can result Cancer Res 62:2447–2454
Elmore JG, Barton MB, Moceri VM et al. (1998) Ten-year risk
in prolonged disease-free intervals. of false-positive screening mammograms and clinical
breast examinations. N Engl J Med 338:1089–1096
Garber JE, Offit K (2005) Hereditary cancer predisposition
2.1.5.2 syndromes. J Clin Oncol 23:276–292
Hakama M, Holli K, Isola J et al. (1995) Aggressiveness of
Detection of an Early Stage of
screen-detected breast cancers. Lancet 345:221–224
Disseminated Disease Harris R, Lohr KN (2002) Screening for prostate cancer: an
update of the evidence for the U.S. Preventive Services
In some patients screening may detect an early stage Task Force. Ann Intern Med 137:917–929
of disseminated metastatic disease. In this case, early Hawk ET, Levin B (2005) Colorectal cancer prevention. J Clin
Oncol 23:378–391
diagnosis may help to prevent symptomatic disease, Henschke CI, McCauley DI, Yankelevitz DF et al. (1999) Early
such as pathological bone fractures or respiratory Lung Cancer Action Project: overall design and fi ndings
distress. Greatest benefit can be achieved in sub- from baseline screening. Lancet 354:99–105
groups of patients in whom well tolerated systemic Hixson LJ, Fennerty MB, Sampliner RE, McGee D, Garewal
treatment may cause long-term control of disease. H (1990) Prospective study of the frequency and size dis-
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the benefit from early detection of metastatic disease families with hereditary non-polyposis colorectal cancer.
Gastroenterology 118:829–834
may exceed the lead-time bias. Klotz L (2005) Active surveillance of prostate cancer: for
It should be pointed out that a positive effect of whom? J Clin Oncol 23:8165–8169
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diagnostic steps are clearly defined and when the cancer: screening. Ann Oncol 16(Suppl 2):ii127–ii132
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In the absence of this interaction between screen- colorectal cancer. Eur J Gastroenterol Hepatol 17:317–322
related diagnosis and therapeutic measures, screen- Lu-Yao G, Albertsen PC, Stanford JL et al. (2002) Natural
ing strategies have no impact on mortality. experiment examining impact of aggressive screening
and treatment on prostate cancer mortality in two fi xed
cohorts from Seattle area and Connecticut. BMJ 325:740
Lynch HT, de la Chapelle A (2003) Hereditary colorectal
cancer. N Engl J Med 348:919–932
Lynch HT, Albano WA, Lynch WF et al. (1982) Surveillance
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Relevant Diseases and Therapeutic Options: Vascular Diseases Relevant to Screening 23
CONTENTS 2.2.1
Introduction
N. Weiss, MD
PD, Department of Vascular Medicine, Medical Policlinic,
2.2.2
University Hospitals Munich, Ludwig-Maximilians- Vascular Risk Factors Relevant to Screening
University of Munich, Pettenkoferstrasse 8a, 80336 Munich,
Germany A risk factor is a characteristic or feature of an
U. Hoffmann, MD individual or population that is present prior to the
Professor and Division Head Vascular Medicine, Depart-
ment of Internal Medicine, University Hospital, Ludwig-
development of a disease and is associated with an
Maximilians-University of Munich, Pettenkoferstrasse 8a, increased risk of developing future disease. To be
80336 Munich, Germany considered causal, the risk factor in question must
24 N. Weiss and U. Hoffmann
400
explained by these above-mentioned risk factors.
For example, in the United States nearly half of all
350
cases of myocardial infarction occur in individuals
300 without overt hyperlipidemia (Rubins et al. 1995).
250 Therefore, this chapter also reviews a series of novel
Cancer
200 atherosclerotic risk factors, including homocysteine
150 and lipoprotein(a). In addition, recent developments
Stroke
100 indicate that indices of fibrinolytic function and
50 markers of vascular inflammation may have addi-
0
tional impact on the individual’s risk of developing
1970 1974 1978 1982 1986 1990 1994 1998 2002 atherosclerotic CVD.
Year of Death
predate the onset of disease and must have biologi- The evolution of atherosclerotic vascular lesions
cal plausibility. In the case of CVD, risk factors may involves several highly interrelated processes
be inherited (e.g. family history, gender, and age), a (Fig. 2.2.2). These include exposure to cardiovas-
certain behavior (e.g. smoking), or a clinical or labo- cular risk factors like hyperlipidemia resulting in
ratory measurement (e.g. blood pressure or choles- endothelial dysfunction. This results in recruit-
terol level). Most risk factors used in daily practice ment and accumulation of circulating inflammatory
have demonstrated a graded-response effect. Their cells (i.e. monocytes and T-lymphocytes) within the
evidence has been substantiated by a large series vessel wall. Monocytes accumulate cholesterol and
of prospective studies in broad population groups. become foam cells. Smooth muscle cell proliferation
Several cardiovascular risk factors are modifiable, and foam cell accumulation results in growth of
and intervention trials have demonstrated that low- the plaque. Altered matrix metabolism, remodeling,
ering these factors reduces vascular risk. and further inflammatory responses contribute to
The following chapter reviews the epidemiologi- the propagation of vascular lesions. Platelet acti-
cal evidence underlying the established atheroscle- vation and thrombosis mediate complications of
Fig. 2.2.2. The 7 stages of development of an atherosclerotic plaque. First LDL moves into the subendothelium and is oxi-
dized by macrophage and SMCs (1 and 2). Release of growth factors and cytokines attracts additional monocytes (3 and 4).
Foam cell accumulation and SMC proliferation result in growth of the plaque (6, 7, and 8) [from Faxon et al. (2004)]
Relevant Diseases and Therapeutic Options: Vascular Diseases Relevant to Screening 25
atherosclerosis. A detailed description of the vascu- Trial or the Physicians’ Health Study (Neaton and
lar biology of atherosclerosis is beyond the scope of Wentworth 1992; O’Donnell et al. 1997). The
this chapter, but has been reviewed in detail recently recently published report of the Prospective Collab-
(Faxon et al. 2004). orative Study Group pooled 61 observational studies
in more than 1 million volunteers with a collective
experience of more than 12 million person-years. It
2.2.2.2 showed that the systolic blood pressure level at base-
Hyperlipidemia line was a significantly more informative reading
than diastolic blood pressure for predicting strokes
Extensive epidemiologic data correlate elevations of and CHD (Black 2004).
total cholesterol (TC) or LDL-cholesterol (LDL-C) To underline the causality of hypertension as a
with increased CHD incidence. These data are cardiovascular risk factor, pharmacological reduc-
derived both from between-population and within- tion in diastolic blood pressure of 5–6 mm Hg
population studies. In addition, large cohort studies appeared to reduce the risk of vascular mortality by
showed remarkable consistency. A review of inter- 21%, the risk of CHD by 14%, and the risk of stroke
national studies found a 10% difference in TC to by 40% (Collins et al. 1990). Treating isolated systo-
be associated with an approximate 38% difference lic hypertension has also been shown to be efficient,
in CHD mortality rate in men aged 55 to 64 years at least in the elder population (Staessen et al. 1999;
(Law et al. 1994). Clinical trials using lipid-modi- Sutton-Tyrrell et al. 2003).
fying drugs have unequivocally demonstrated that
lowering LDL-C yields significant reduction in both
morbidity and mortality from CHD in patients with 2.2.2.4
or without established CHD, including patients with Insulin Resistance and Diabetes Mellitus
only average cholesterol values for Westernized
societies. Moreover, LDL-C reduction as secondary CHD accounts for three fourths of all deaths among
prevention significantly increases survival rates diabetic patients (Gu et al. 1998). Diabetic patients
(Tables 2.2.1 and 2.2.2). not only have a dramatically increased risk to
develop CVD but also have a substantially elevated
risk of secondary complications after vascular inter-
2.2.2.3 ventional procedures (Stein et al. 1995; Thourani
Hypertension et al. 1999). Thus, diabetes ranks among the major
cardiovascular risk factors. Insulin resistance, even
Elevated levels of blood pressure consistently cor- before the manifestation of frank diabetes, promotes
relate with elevated risks of stroke and myocardial atherosclerotic vascular disease and has been identi-
infarction. An early meta-analysis evaluated over fied as an independent risk factor for CVD (Despres
5500 cardiovascular events. Every 7 mm Hg eleva- et al. 1996; St-Pierre et al. 2005). The latter find-
tion of diastolic blood pressure was associated with ing has emphasized the importance of the insulin
a 27% increase risk of CHD and a 42% increase in resistance syndrome, which is characterized by
risk of ischemic stroke (MacMahon et al. 1990). the combination of glucose intolerance and hyper-
A more recent meta-analysis including 1 million insulinemia, hypertriglyceridemia, and low HDL
adults above 40 years of age with no previous his- levels, as well as the predominance of small dense
tory of CVD confi rmed these data. Each 20 mm Hg LDL particles (Lewinter 2005).
increase in systolic blood pressure above 115 mm Although randomized trials, like the Diabetes
Hg and each 10 mm Hg increase in diastolic blood Control and Complications Trial and the UK Pro-
pressure above 75 mm Hg was associated with a spective Diabetes Study (UKPDS), provided evi-
more than twofold increase in stroke death rate, dence that intensive glycemic control obtained with
and with a twofold increase in cardiovascular either intensive insulin or oral therapy effectively
death rates (Lewington et al. 2002). slowed the onset and progression of diabetic retin-
Even isolated systolic hypertension has been opathy, nephropathy, and neuropathy in patients
shown to increase the risk for non-fatal myocardial with type 1 and type 2 diabetes, these studies did not
infarction and cardiovascular death in population find a significant (Anonymous 1993) or only a mar-
studies like the Multiple Risk Factor Intervention ginal (Anonymous 1998) benefit on coronary event
26
Table 2.2.1. Summary of major statin clinical event trials in primary prevention
Trial and Agent Follow-up, Subjects Baseline Changes in Primary end point Event rate Other clinical events
years (placebo/verum) LDL-C Lipids
(mg/dl) Statin Placebo RRR ARR NNT
WOSCOPS 4.9 3293/3302 192 LDL-C p 26% Nonfatal MI or CHD 5.5% 7.9% 31% 2.4% 42 No excess non-CVD death
pravastatin 40 mg/d HDL-C n 5% death Total mortality p 22%
TG p 12% CABG or PTCA p 37%
N. Weiss and U. Hoffmann
AFCAPS/TexCAPS 5.2 3301/3304 150 LDL-C p 25% Nonfatal or fatal 3.5% 5.5% 37% 2.0% 50 No excess in total mortality
lovastatin HDL-C n 6% MI, unstable an- CABG or PTCA p 33%
20–40 mg/d TG p 15% gina, sudden cardiac
death
ASCOT-LLA 3.3 5137/5168 133 LDL-C p 33% Nonfatal MI and 1.9% 3% 36% 1.1% 91 All-cause mortality p 13%
atorvastatin 10 mg/d HDL-C l CHD death Fatal and non-fatal stroke p 27%
TG p 22% Total CV events and procedures
p 21%
Table 2.2.2. Summary of major statin clinical event trials in secondary prevention
Trial and Agent Follow-up, Subjects Baseline Changes in Primary end point Event rate Other clinical events
years (placebo/verum) LDL-C Lipids
(mg/dl) Statin Placebo RRR ARR NNT
4s 5.4 2223/2221 188 LDL-C p 35% All-cause mortality 8.2% 11.5% 30% 3.3% 30 CABG or PTCA p 37%
simvastatin 20– HDL-C n 8%
40 mg/d 2223/2221 TG p 10% Nonfatal MI, CHD Post-hoc: Stroke or TIA p 30%
death, resuscit-ated 19.4% 28% 34% 8.6% 12
cardiac arrest
CARE 5.0 2078/2081 139 LDL-C p 32% Nonfatal or CHD 10.2% 13.2% 24% 3.0% 33 No excess non-CVD death
pravastatin HDL-C n 5% death CABG or PTCA p 27%
40 mg/d TG p 14% Stroke p 31%
LIPID 6.1 4502/4512 150 LDL-C p 25% Nonfatal MI and 12.3% 15.9% 24% 3.6% 28 Total mortality p 22%
pravastatin 40 mg/d HDL-C n 5% CHD death CABG or PTCA p 20%
TG p 11% Stroke p 19%
HPS 5 10,267/10,269 131 LDL-C p 29% All-cause mortality 12.9% 14.7% 13% 1.8% 56 Revasularization procedures p 24
simvastatin 40 mg/d HDL-C n 3% Stroke p 25%
10,267/10,269 TG p 14% Fatal or nonfatal
vascular events 19.8% 25.2% 24% 5.4% 19
Relevant Diseases and Therapeutic Options: Vascular Diseases Relevant to Screening 27
rates. Therefore, aggressive control of additional boembolic events as shown in a multicenter obser-
cardiovascular risk factors together with life style vational study (Yap et al. 2001). In contrast to severe
modifications including absence of smoking, regu- hyperhomocysteinemia, mild elevation of plasma
lar exercise, diet, and avoidance of obesity remain homocysteine (> 12 µmol/L) is commonly found in
the primary strategies to reduce the cardiovascular general populations, primarily due to insufficient
risk in diabetics (Patel et al. 2005). dietary intake of folic acid (Weiss et al. 2004).
During the last 20 years, a great number of retro-
spective case-control studies and prospective nested
2.2.2.5 case-control studies nearly uniformally established
Smoking the link between mild hyperhomocysteinemia and
atherothrombotic vascular diseases in the general
Since the first reports in the early 1950s of a strong population. Mild hyperhomocysteinemia appears
positive association between cigarette smoking and to be an independent risk factor for CHD, cerebrov-
CHD a series of prospective studies have consist- ascular disease, and peripheral arterial occlusive
ently and clearly confirmed these observations. disease, as the relationship persists after statistical
Smokers of 20 or more cigarettes per day compared adjustment for conventional risk factors. A meta-
with nonsmokers have a two- to threefold increase analysis by Boushey et al. 1995 using data from
in total CHD. Moreover there is a dose-dependent 27 studies published before 1995 indicated that a
effect of smoking on CHD which starts to increase 5 µmol/L increase in plasma homocysteine above
with as few as one to four cigarettes daily (Willett median levels of 10 µmol/L is associated with a
et al. 1987; Chen and Boreham 2002). Even pas- significant and graded increase in the risk of CHD
sive exposure to smoke has now been recognized (odds ratio 1.6 [95% confidence interval: 1.4 to 1.7]),
to increase coronary risk (Kawachi et al. 1997; cerebrovascular disease (odds ratio 1.5 [1.3 to 1.9]),
Pitsavos et al. 2002). and peripheral vascular disease (odds ratio 6.8 [2.9
In accordance with these findings, quitting smok- to 15.8]). Comparing elevated homocysteine levels to
ing compared to continuous smoking has been found other established vascular risk factors, the authors
to result in a 36% reduction in mortality in patients calculated that a 5 µmol/L increase in plasma homo-
with CHD (Critchley and Capewell 2004). In a cysteine levels is equivalent to a 0.5 mmol/L (20 mg/
primary prevention setting, smoking cessation alone dL) increase in plasma cholesterol levels in increas-
reduces the risk of a first heart attack by nearly 65% ing the risk for myocardial infarction. From data
(Manson et al. 1992). Stopping smoking therefore of a recent case-control study conducted in nine
constitutes the single most important intervention European centers it was estimated that the cardio-
in preventive cardiovascular medicine. vascular risk associated with elevated homocysteine
levels (> 12 µmol/L) is comparable to the risk associ-
ated with hyperlipidemia or smoking, but somewhat
2.2.2.6 lower than that of hypertension (Graham et al.
Hyperhomocysteinemia 1997). From these studies it has been estimated that
10% of the population’s CHD risk appears attribut-
Homocysteine is a sulfhydryl-containing amino acid able to plasma homocysteine levels (Boushey et al.
that is derived from the demethylation of dietary 1995).
methionine. Early clinical studies in children with Prospective cohort studies, however, have yielded
rare inborn errors of homocysteine metabolism, some inconclusive results in linking homocysteine
that lead to markedly elevated plasma homocysteine to vascular disease. Most of the prospective stud-
levels up to 30 times the normal range, suggested ies have provided evidence for mild hyperho-
that severe hyperhomocysteinemia is associated mocysteinemia as a major risk factor for athero-
with the development of premature atherosclero- thrombotic vascular disease after adjustment for
sis and thromboembolism, besides other clinical conventional risk factors (Stampfer et al. 1992;
abnormalities (McCully 1969; Mudd et al. 1995). Arnesen et al. 1995; Perry et al. 1995; Petri et
Untreated patients suffer one thromboembolic event al. 1996; Nygard et al. 1997; A’Brook et al. 1998;
per 25 patient-years (Mudd et al. 1985). Treatment Moustapha et al. 1998; Wald et al. 1998; Bostom et
of hyperhomocysteinemia in these patients leads to al. 1999; Bots et al. 1999; Kark et al. 1999; Ridker et
a significant, more than 90% reduction in throm- al. 1999; Whincup et al. 1999), although some stud-
28 N. Weiss and U. Hoffmann
ies have not (Alfthan et al. 1994; Verhoef et al. bridge to apo(a), a protein of variable length
1994; Evans et al. 1997; Folsom et al. 1998; Kuller with a high sequence homology to plasminogen
and Evans 1998; Ubbink et al. 1998). These conflict- (Berglund and Ramakrishnan 2004). Plasma
ing results might be partly explained by the differ- Lp(a) concentrations are mainly genetically deter-
ent ethnic background and lifestyle of the specific mined, as they vary inversely with the apo(a) iso-
study’s participants and by the sample size. Lifestyle form size (Rader et al. 1994). In addition, they may
issues appear to be especially important as a source vary even within isoform size based on differential
of potential bias owing to multivitamin use by study levels of production (Rader et al. 1994).
subjects. For example, the Atherosclerosis Risk in The normal function of Lp(a) is unknown. Due
Community Trial, the largest prospective trial with a to the close homology between Lp(a) and plasmino-
negative outcome, did not provide detailed informa- gen it has been suggested that this lipoprotein may
tion about vitamin supplementation as a potential inhibit endogenous fibrinolysis by competing with
confounding variable (Folsom et al. 1998; Kuller plasminogen for binding on the endothelial surface
and Evans 1998; Ubbink et al. 1998). (Hajjar et al. 1989).
Several meta-analyses of the retrospective case- Prospective studies that examined the associa-
control and of the prospective population based tion between Lp(a) and cardiovascular risk, have
studies showed similar, consistent results favoring not always found consistent evidence of associa-
hyperhomocysteinemia as a vascular risk factor tion. Some of them supported a positive association
(Boushey et al. 1995; Danesh and Lewington 1998; between either plasma apo(a) or Lp(a) mass and vas-
Wald et al. 1998; Moller et al. 2000; Ueland et al. cular risk (Schaefer et al. 1994; Wald et al. 1994;
2000; Schnyder et al. 2001). These combined data Cremer et al. 1997; Wild et al. 1997), whereas others
indicate that mild hyperhomocysteinemia above did not (Jauhiainen et al. 1991; Ridker et al. 1993,
12 µmol/L increases the risk for CHD by 1.5 and for 1995; Cantin et al. 1998). In conclusion, present
stroke by 1.4 (Fig. 2.2.3) (Bautista et al. 2002). The prospective studies do not establish the importance
debate about hyperhomocysteinemia as a cardiovas- of Lp(a) as a risk factor for future cardiovascular
cular risk factor will continue, as long as results of events. It remains open whether any increased risk
large scaled intervention studies aimed at reducing is restricted to those with the highest levels of Lp(a)
cardiovascular events by homocysteine lowering or whether there is an interaction with other cardio-
treatment, are still pending. vascular risk factors.
2.2.2.7 2.2.2.8
Lipoprotein(a) Markers of Inflammation
Lipoprotein (a) [Lp(a)] consists of an LDL particle As outlined above, inflammation characterizes all
with its apo B-100 component linked by a disulfide phases of atherosclerosis (Faxon et al. 2004). Based
on this pathophysiological concept it is not surpris- women (Ridker et al. 1997, 1998a, 2000a; Rohde
ing, that several markers of low-grade systemic et al. 1999), elderly (Tracy et al. 1997), high-risk
inflammation have shown to be useful for cardiovas- smokers (Kuller et al. 1996), hyperlipidemic sub-
cular risk prediction. These markers include unspe- jects (Ridker et al. 2001), diabetics (Coppola et
cific acute-phase reactants, such as high-sensitive al. 2006), patients with stable and unstable angina
C-reactive protein (hsCRP) and serum amyloid pectoris (Liuzzo et al. 1994; Haverkate et al. 1997;
A (Libby and Ridker 2004), adhesion molecules, Morrow et al. 1998; Rebuzzi et al. 1998; Sabatine
such as VCAM-1, ICAM-1 or P-selectin (Lutters et al. 2002), and in patients that had already suf-
et al. 2004) which mediate monocyte attachment fered a myocardial infarction (Ridker et al. 1998c;
to the vascular endothelium, and cytokines such as Hoffmann et al. 2005). In these studies, individuals
Interleukin-6 and tumor necrosis factor D (Ridker with hsCRPS levels in the upper quartile had relative
et al. 2000b; Steffens and Mach 2004). Among risks of future vascular events three to four times
these markers, hsCRP has created most interest and higher than individuals with lower levels (Fig. 2.2.4).
will possibly prove to be the clinically most useful The effects were independent of all other traditional
marker. It is easy and inexpensive to measure with cardiovascular risk factors (Fig. 2.2.5).
commercial assays, and levels in a given individual Moreover, plasma levels of hsCRP add additional
are quite stable over long periods as long as hsCRP is information to the predictive value of plasma lipid
not measured within 2–3 weeks of an acute inflam- measurements (Ridker et al. 1998b). Patients with
matory stimulus like an intercurrent infection. This elevated levels of hsCRP are more likely to benefit
marker showed a consistent and strong association from lipid-lowering therapy even when their choles-
with cardiovascular risk in several risk groups. terol levels are only slightly elevated (Ridker et al.
These groups included currently healthy men and 2001; Anonymous 2005b; Kinjo et al. 2005).
Fig. 2.2.4. Prospective studies relating baseline CRP levels to the risk of fi rst cardiovascu-
lar events. CHD indicates coronary heart disease; MI, myocardial infarction; PAD, pulmo-
nary artery disease; CV, cardiovascular; MRFIT, Multiple Risk Factor Intervention Trial;
PHS, Physicians’ Health Study; CHS, Cardiovascular Health Study; RHPP, Rural Health
Promotion Project; WHS, Women’s Health Study; MONICA, MONItoring trends and de-
terminants In CArdiovascular disease; HELSINKI, Helsinki Heart Study; CAERPHILLY,
Caerphilly Heart Study; BRHS, British Regional Heart Study; LEIDEN, Leiden Heart Study;
SPEEDWELL, Speedwell Heart Study; WOSCOPS, West of Scotland Coronary Prevention
Study; AFCAPS, Air Force Coronary Atherosclerosis Prevention Study; FHS, Framingham
Heart Study; WHI, Women’s Health Initiative; and HHS, Honolulu Heart Study [from
Ridker (2003)]
30 N. Weiss and U. Hoffmann
TC
LDL - C
sICAM - 1
Serum amyloid A
Apolipoprotein B
TC - HDL - C ratio
hs - CRP
hs - CRP + TC - HDL - C ratio
symptoms of aneurysmatic disease including local established CVD, with type 2 diabetes or multiple
pain or peripheral embolization. other CHD risk factors, are candidates for intensive
Risk stratification of asymptomatic persons fur- risk factor intervention. Non-invasive testing is not
thermore includes a quantitation of the probability required to determine risk factor treatment goals.
of developing future events in a definite period of Intermediate risk patients are persons that have
time. In the case of CHD, and for clinical applica- at least one major risk factor outside the desirable
bility, the absolute risk of a person is categorized range or a positive family history of CHD. These
into three categories. Persons in a high risk group groups of patients may benefit from non-invasive
are estimated to have a > 20% risk in 10 years to testing for further risk assessment to determine
develop CHD endpoints, an intermediate risk indi- risk factor treatment goals. These tests may include
cates a 10%–20% risk in 10 years, and persons in the tests for silent or inducible ischemia (exercise
low risk group are estimated to have < 10% risk in ECG testing, exercise and pharmacological stress
10 years. This risk estimate is based on the Framing- echocardiography, exercise and pharmacological
ham risk score (Anonymous 2001). The risk factor myocardial perfusion imaging, ambulatory ECG
management and further screening strategies for monitoring, positron emission tomography), and
risk assessment should be adjusted by the severity of noninvasive tests of atherosclerotic burden (systolic
the risk. This concept has been adopted in the guide- ankle/brachial pressure index, B-mode ultrasound
line of the National Cholesterol Education Program to measure carotid artery intima-media thickness,
in the United States, the joint European Societies, coronary calcium score measurement by electron
and other organizations. For other manifestations of beam tomography, MRI imaging techniques of
atherosclerotic vascular disease, risk estimates have atherosclerotic disease, endothelial function stud-
not been defined that clearly. However, as peripheral ies or measurement of hsCRP) (Smith et al. 2000).
arterial occlusive disease, cerebrovascular disease Identification of atherosclerotic vascular disease in
and abdominal aortic aneurysms are occurring in these patients would qualify them for more aggres-
individuals with a risk profi le comparable to patients sive risk factor modification.
at risk for CHD, similar algorithms may be used.
2.2.3.2
2.2.3.1 Patients at Risk of Abdominal Aortic Aneurysms
Patients at Risk of Coronary Heart Disease
Abdominal aortic aneurysms (Sakalihasan et al.
Initial risk estimation of CHD in asymptomatic 2005) cause 1.3% of all deaths among men aged 65–
patients is performed in an office-based risk assess- 85 years in developed countries. These aneurysms
ment (Smith et al. 2000; Greenland et al. 2001). are typically asymptomatic until the catastrophic
It first uses the determination of proven causative event of a rupture. Repair of large (> 5.5 cm in diam-
cardiovascular risk factors, including cigarette eter) or symptomatic aneurysms by open surgery
smoking, elevated blood pressure, elevated serum or endovascular repair is recommended, whereas
cholesterol (or LDL cholesterol), low HDL choles- repair of small abdominal aortic aneurysms does
terol, and diabetes mellitus. Conditional risk fac- not provide a significant benefit. The incidence of
tors, including triglycerides, small LDL particles, abdominal aortic aneurysms has increased during
Lp(a), homocysteine, hsCRP, and coagulation fac- the past two decades. This may be due to the aging
tors may or may not be included in the estimate. The of the population, the rise in the number of smok-
latter factors are considered conditional risk factors, ers, and the introduction of screening programs and
when serum levels are abnormally high. Based on improved diagnostic tools.
the above mentioned parameters, individual per- There are many causes of aneurysmal dilatation.
sons may be classified into one of the three risk Few abdominal aortic aneurysms are due to specific
categories. causes like trauma, infection (i.e. salmonellosis, sta-
In a primary prevention setting, patients at a phylococcal infection, brucellosis) (Benenson et al.
low risk for developing CHD (no major coronary 2001), inflammatory diseases (Behcet and Takayasu
risk factor) do not need specific intervention and disease) (Matsumura et al. 1991; Erentug et al.
no further testing besides reevaluation in about 2003), and connective tissue disorders (Marfan syn-
5 years. High risk patients, which are those with drome, Ehlers-Danlos type IV) (Towbin et al. 1999).
32 N. Weiss and U. Hoffmann
Most aneurysms are associated with atherosclerotic ultrasonography to men aged 65–75 years who have
damage of the aortic wall and are thereby a conse- ever smoked (Anonymous 2005a)
quence of atherosclerosis (Johnston et al. 1991). For patients with a known abdominal aortic
The main risk factors for the development of aneurysm which is often detected incidentally, evi-
abdominal aortic aneurysms include tobacco smok- dence recommends periodic ultrasound surveil-
ing, hypertension, chronic obstructive pulmonary lance for those with small abdominal aortic aneu-
disease, hyperlipidemia, male gender, age, and rysms (3.0–3.9 cm in diameter) and elective surgical
family history of the disorder. Smokers have a more repair for those with large abdominal aortic aneu-
than four times higher risk of developing abdominal rysms (t5.5 cm). Two recent randomized controlled
aortic aneurysms compared to people who have never trials have shown that early surgical repair confers
smoked. Smoking confers the single most important no survival benefit compared with periodic surveil-
risk factor for this disorder. First-degree relatives lance for patients with intermediate-sized abdomi-
of patients with abdominal aortic aneurysms have nal aortic aneurysms (4.0–5.5 cm in diameter).
a 15%–19% risk of the disease compared with only Therefore, those patients can also be monitored
1%–3% in unrelated patients (Sakalihasan et al. (Anonymous 2002; Lederle et al. 2002; Powell
2005). and Greenhalgh 2003). Some centers choose to
Screening abdominal ultrasonography in asymp- increase the frequency of monitoring to every 3–
tomatic individuals is an accurate test, with 95% sen- 6 months when the aneurysm size reaches 5.0 cm.
sitivity and near 100% specificity for the detection of In symptomatic patients factors to consider
abdominal aortic aneurysms (Fleming et al. 2005). include the high risk of life-threatening condi-
Death from AAA rupture after negative results on tions, the potential increased risk of death or poor
a single ultrasound scan at age 65 years is rare, and outcome with delay in diagnosis, the limitations of
thereby virtually excludes the risk for future AAA ultrasound in identifying whether symptoms are due
rupture or death. to known or suspected abdominal aortic aneurysm
A recent study evaluated the incidence of abdom- and the timely availability of computed tomogra-
inal aneurysms in a population of patients with phy or other imaging tests. If available, computed
symptomatic CHD (Hanly et al. 2005). A total of 47 tomography is preferred in patients with recent or
aneurysms were detected in 415 patients (9.9%). All severe symptoms, since it is better at detecting retro-
aneurysms were detected in patients over 60 years of peritoneal hemorrhage and other complications and
age (detection rate 11.7%). This study thereby sup- in providing preoperative definition of the anatomy
ports the concept of screening a higher risk popula- (Silverstein et al. 2005).
tion of patients over 60 years of age with CVD for
abdominal aortic aneurysms primarily by ultra-
sound. 2.2.3.3
The effectiveness and cost-effectiveness of Patients at Risk of Peripheral Arterial Occlusive
screening for abdominal aortic aneurysms in the Disease
general population is based on results from four
randomized controlled trials (Scott et al. 1995, Patients’ history of intermittent claudication or even
2002; Ashton et al. 2002; Lindholt et al. 2002; more sophisticated questionnaires on symptoms of
Vardulaki et al. 2002; Norman et al. 2003). A cost- peripheral arterial occlusive disease like the WHO/
effectiveness analysis using a Markov model showed Rose questionnaire are limited by their low sensitiv-
that ultrasound screening of white men beginning ity (< 30%) to detect angiography-positive peripheral
at age 65 is both effective and cost-effective in pre- arterial occlusive disease. Screening for peripheral
venting abdominal aortic aneurysms related death. arterial occlusive disease therefore should include
Such screening would have a small but real impact palpation of lower extremity pulses and measurement
over a 20-year period for these men (Silverstein et of the systolic ankle-brachial pressure index and/or
al. 2005). The Society of Vascular Surgery and the the toe-brachial pressure index. An ankle-brachial
Society for Vascular Medicine and Biology there- pressure index below 0.9 has been shown to be more
fore recommends screening for abdominal aortic than 95% sensitive and nearly 100% specific for the
aneurysms in all men aged 60–85 years (Kent et detection of relevant peripheral arterial occlusive dis-
al. 2004). The U.S. Preventive Services Task Force ease (Dormandy and Rutherford 2000). In patients
restricts their recommendation for screening by with falsely high ankle pressures due to mediasclero-
Relevant Diseases and Therapeutic Options: Vascular Diseases Relevant to Screening 33
sis, measurement of the toe-brachial pressure index Anonymous (1998) Intensive blood-glucose control with
may be used (Williams et al. 2005). sulphonylureas or insulin compared with conventional
treatment and risk of complications in patients with
Several studies have shown that the ankle-bra- type 2 diabetes (UKPDS 33). UK Prospective Diabetes
chial pressure index is a robust and independent Study (UKPDS) Group. Lancet 352:837–853
predictor of all-cause mortality in both men and Anonymous (2001) Executive Summary of the Third Report
women (Vogt et al. 1993; Hooi et al. 2004; Lange of The National Cholesterol Education Program (NCEP)
Expert Panel on Detection, Evaluation, and Treatment
et al. 2005). Therefore, this measurement, a simple,
of High Blood Cholesterol in Adults (Adult Treatment
objective, non-invasive technique which can be used Panel III). J Am Med Assoc 285:2486–2497
in the physician’s office, may be useful for early Anonymous (2002) Long-term outcomes of immediate
identification of patients at high risk for morbidity repair compared with surveillance of small abdominal
and mortality, mainly due to CVD. These patients aortic aneurysms. N Engl J Med 346:1445–1452
Anonymous (2005a) C-reactive protein levels and cardiovas-
should be treated intensively to lower or eliminate cular risk after statin therapy. Nat Clin Pract Cardiovasc
their cardiovascular risk factors. Med 2:118
Besides its usefulness as a screening tool for Anonymous (2005b) Screening for abdominal aortic aneu-
detection of asymptomatic atherosclerosis, identi- rysm: recommendation statement. Ann Intern Med
fication of asymptomatic peripheral arterial occlu- 142:198–202
A’Brook R, Tavendale R, Tunstall-Pedoe H (1998) Homocys-
sive disease and especially early revascularization of teine and coronary risk in the general population: analy-
symptomatic patients has not been shown to result sis from the Scottish Heart Health Study and Scottish
in a reduction of amputation rates or in increased MONICA surveys. Eur Heart J 19 (Suppl):8 (Abstr)
survival (Dormandy and Rutherford 2000). Alfthan G, Pekkanen J, Jauhiainen M, Pitkaniemi J, Karvonen
M, Tuomilehto J, Salonen JT, Ehnholm C (1994) Relation
of serum homocysteine and lipoprotein(a) concentra-
tions to atherosclerotic disease in a prospective Finnish
2.2.3.4 population based study. Atherosclerosis 106:9–19
Patients at Risk of Cerebrovascular Disease Arnesen E, Refsum H, Bonaa KH, Ueland PM, Forde OH,
Nordrehaug JE (1995) Serum total homocysteine and
coronary heart disease. Int J Epidemiol 24:704–709
Atherosclerotic disease accounts for approximately Ashton HA, Buxton MJ, Day NE, Kim LG, Marteau TM,
25% of ischemic strokes. Atherosclerotic stroke is Scott RA, Thompson SG, Walker NM (2002) The Multi-
caused mainly by embolic events from the carotid centre Aneurysm Screening Study (MASS) into the effect
artery bifurcation or the aortic arch, although intra- of abdominal aortic aneurysm screening on mortality in
men: a randomised controlled trial. Lancet 360:1531–1539
cranial thrombosis may occur. Primary prevention
Bautista LE, Arenas IA, Penuela A, Martinez LX (2002) Total
of stroke is critical for patients with risk factors for plasma homocysteine level and risk of cardiovascular
atherosclerosis or manifestation of atherosclerosis in disease: a meta-analysis of prospective cohort studies.
other vascular territories. Stroke can be prevented in J Clin Epidemiol 55:882–887
patients with established atherosclerotic disease by Benenson S, Raveh D, Schlesinger Y, Alberton J, Rudensky B,
Hadas-Halpern I, Yinnon AM (2001) The risk of vascular
identification of patients with carotid artery stenosis infection in adult patients with nontyphi Salmonella bac-
by non-invasive testing and subsequent revascular- teremia. Am J Med 110:60–63
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Black HR (2004) The paradigm has shifted to systolic blood
Duplex Ultrasound of the Carotid Arteries: Practi- pressure. J Hum Hypertens 18:S3–7
cal Aspects and Results of Screening for Carotid Bostom AG, Silbershatz H, Rosenberg IH, Selhub J, D’Agostino
Disease). RB, Wolf PA, Jacques PF, Wilson PW (1999) Nonfasting
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Bots ML, Launer LJ, Lindemans J, Hoes AW, Hofman A, Wit-
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Pathology: General Oncological Aspects of Screening 39
Pathology 3
3.1 General Oncological Aspects of Screening
Stefan Delorme and Gerhard van Kaick
• Activation of proto-oncogenes
Cancer initiating agents and • Inactivation of tumor suppressor
processes genes
(e.g. chemical carcinogens, • Inactivation of genomic stability
mediation, chronic inflammation) genes (e.g. DNA repair genes
• Changes in DNA methylation
patterns
of the breast, prostate, colon, lung (except for small dose exposures (Jung 2001). The large screening
cell lung cancer), kidney, liver, cervix uteri, and oth- studies in the Netherlands and in Sweden have
ers, primary surgery is possible, and the long-term meanwhile clearly shown that the mortality due to
outcome is clearly dependent on the tumor stage breast cancer has decreased in the screened popu-
or size at the time of diagnosis. Comorbidity may lation. So, however high the risks may have been,
preclude surgery, even in the early stages, such as they are more than outweighed by the benefits of
lung emphysema or liver cirrhosis, but minimally screening.
invasive methods may offer similar outcome as sur- Iodine-containing contrast agents are currently
gery (e.g., stereotactic radiotherapy for lung cancer, not used for any screening purpose, and will prob-
or ethanol injection or radiofrequency ablation for ably rarely be so. Gadolinium chelates in MR im-
hepatocellular carcinoma). aging and angiography are necessary for screen-
Mortality is not everything. Even where the ben- ing for vascular diseases, MR mammography for
efit of early detection for long-term outcome is un- high-risk groups, and perhaps, in future, for pa-
clear, the patient may benefit personally by being tients at risk for hepatocellular carcinoma. Their
spared mutilating surgery or morbidity from local risk for serious adverse events is notoriously small.
tumor invasion. This is particularly clear where Very recently, they are discussed as cause for ne-
small, organ-conserving procedures are available, phrogenic systemic fibrosis, and their use in pa-
such as in the breast, lung, cervix, or colorectum. tients with impaired renal function is prohibited
for Gadodiamide and discouraged for other agents
(Michaely et al. 2007).
It has been proven that colonoscopy is efficient
in detecting colorectal cancer early, and that it also
3.1.5 is a mean to remove adenomas, which are the most
Acceptance and Safety of important precancerous lesions. However, the rate
Screening Procedures of fatal perforations is around 1 in 80.000 (see also
the contribution by Becker). Furthermore, in or-
Very obviously, the risks of any screening proce- der to be tolerated, it has to be performed under
dure must be within an acceptable range, and the analgesia and sedation (with their own potential
procedure itself must be tolerated by the screening hazards), and it requires bowel cleansing, which is
participants and not be associated with major dis- anything but comfortable for the patient.
comfort. The medical risk of screening procedures The risks of screening are not only associated
are radiation-induced carcinogenesis, toxicity of with the test itself, but also with all further proce-
contrast media and allergic reactions, hazards dures which are necessary in case of unclear results
caused by ferromagnetic objects inside MR scan- (Friedenberg 2002). These range from ultrasound
ners, and, fi nally, complications of endoscopy. or punch biopsies for suspicious lesions at mam-
Radiation exposure due to screening mammog- mography to colonoscopy for fecal blood, coniza-
raphy is controversially discussed. Clearly there tion for suspicious pap smears, or bronchscopy,
are no empirical data, and all calculations are ex- thoracoscopy, or even open chest surgery for lung
trapolated from those made on occasion of high- nodules, with increasing probability of fatal com-
plications. This shows how important the specificity Jennings SG, Winer-Muram HT, Tann M, Ying J, Dowdeswell
of the screening test is, and how important the skill I (2006) Distribution of stage I lung cancer growth rates
determined with serial volumetric CT measurements. Ra-
of the readers and quality assurance measures. For diology 241:554–563
good reason, the qualifying criteria for readers in Jung H (2001) Is there a real risk of radiation-induced bre-
mammography screening programs are extremely ast cancer for postmenopausal women? Radiat Environ
rigorous. Biophys 40:169–174
Koscielny S, Tubiana M, Le MG et al. (1984) Breast cancer:
relationship between the size of the primary tumour and
the probability of metastatic dissemination. Br J Cancer
49:709–715
Matesich SM, Shapiro CL (2003) Second cancers after breast
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Pathology: Screening for Vascular Pathology 45
Pathology 3
3.2 Screening for Vascular Pathology
James H. F. Rudd, Silvia H. Aguiar, and Zahi A. Fayad
Hypertension Age
Low HDL Diabetes
Family history Metabolic syndrome
Smoking Elevated LDL
Risk Score
Fig. 3.2.1. Screening for atherosclerosis: the use of a combination of risk factor scoring with imaging. From left to right
– measurement of carotid IMT, plaque burden assessed using MRI and coronary calcium quantification by multislice CT
nective tissue within the arterial wall. It is a chronic, of secretion of prostacyclin and nitric oxide (NO),
progressive disease with a long asymptomatic phase which inhibit platelet activation and promote
(Fuster et al. 2005a,b). The fi rst pathological abnor- vasodilatation. In addition NO ameliorates expres-
mality is the fatty streak, caused by an aggregation sion of the endothelial adhesion molecules respon-
of lipid and macrophages in the subendothelial sible for inflammatory cell recruitment. Both the
space. Fatty streaks may be seen in the aorta from barrier function and secretory capacity of the
the second decade of life (Ross 1999; Tzou et al. endothelium become disrupted in atherosclerosis.
2005), and develop primarily in regions of endothe- This manifests as an increase in permeability to
lial dysfunction. Endothelial cells in these regions, blood-derived lipids and inflammatory cells.
often occurring in branch or bifurcation points of Once oxidized, LDL is retained within the sub-
the arterial tree (VanderLaan et al. 2004), have endothelial space and attracts monocytes by trig-
decreased production of nitric oxide as a result of gering the release of monocyte chemoattractant pro-
their experiencing low wall shear stress (Ku et al. tein-1 (MCP-1) from endothelial cells (Cushing et
1985). In contrast, chronic exposure to high shear al. 1990). The newly expressed endothelial adhesion
stress causes the cells to show an atheroprotective molecules, including vascular cell adhesion mole-
phenotype (Traub and Berk 1998). cule-1, intercellular adhesion molecule-1, E-selectin,
The major atherogenic risk factors such as and P-selectin, facilitate the internalization of more
smoking, elevated low density lipoprotein (LDL) monocytes into the sub-endothelium. Once there,
levels, hypertension, and diabetes mellitus have monocytes transform into macrophages, and bind
all been shown to impair endothelial function and internalize oxLDL via their scavenger recep-
(Cunningham and Gotlieb 2005). Normal tors (Hamilton et al. 1999; Ross 1999). OxLDL also
endothelium has anti-thrombotic, anti-inflam- induces the production of macrophage colony-stim-
matory and vasomodulatory functions as a result ulating factor (M-CSF) by vascular cells and mac-
Pathology: Screening for Vascular Pathology 47
rophages, which inhibits macrophage apoptosis and This may trigger the clotting cascade, with throm-
sustains proliferation (Hamilton et al. 1999). Even- bus formation and, if extensive, complete vessel
tually, the subendothelial accumulation of modified occlusion.
LDL and macrophage-derived foam cells leads to the Symptoms are not inevitable after plaque cap
formation of the atheromatous lipid core. disruption however. Up to 70% of plaques causing
Given favourable conditions (ongoing presence of significant arterial stenosis contain histological evi-
atherogenic risk factors), the lipid core may develop dence of previous subclinical plaque rupture with
over time into a mature atherosclerotic plaque. It subsequent repair (Davies 1995). This is particu-
becomes bounded on its luminal side by an endothe- larly likely to occur if high blood flow through the
lialized fibrous cap consisting of vascular smooth vessel prevents the accumulation of a large occlu-
muscle cells (VSMC) and connective tissue, in par- sive thrombus. Additionally, the body’s natural
ticular collagen. VSMCs migrate from the medial fibrinolytic pathways can deal with some thrombi,
layer of the artery and synthesize extracellular allowing subsequent healing of the cap and overly-
matrix components such as elastin and collagen to ing endothelium. This process of repeated rupture
form the fibrous cap. The fibrous cap also contains and repair may allow plaques to grow in a step-wise
inflammatory cells, predominantly macrophages, fashion.
but sometimes T-lymphocytes and mast cells. As Atherosclerosis is a dynamic process in which
the plaque enlarges, the affected artery grows out- the balance between the destructive influence of
wards (by expansion of the external elastic lamina) inflammatory cells and the reactive, stabilizing
so that lumen diameter and therefore blood flow effects of VSMCs determines outcome. The balance
is initially preserved [a process known as positive can be tipped toward plaque rupture by factors such
remodeling (Glagov et al. 1987)]. As wall stress as an atherogenic lipoprotein profi le, high levels of
increases with outward remodeling, eventually fur- lipid oxidation, local free radical generation, and
ther expansion becomes impossible and the plaque individual genetic variability. Alternatively, the
starts to encroach into the lumen of the vessel. This balance can be pushed toward plaque stability by a
may cause symptoms by compromising blood flow. reduction in plaque inflammation or an increase in
Mature plaques may also become calcified, a process VSMC-driven repair. Lipid reduction, by whatever
that preferentially affects the intima of the artery. means, reduces clinical events. Evidence that this
Very advanced plaques will also often be perforated may be due to a plaque-stabilizing effect comes from
by new blood vessels under the influence of ang- animal studies that showed that statins reduced
iogenic factors, a process called ‘neovascularisation’. inflammatory cell and increased VSMC content of
However, these new vessels are structurally fragile, plaques (Shiomi et al. 1995; Williams et al. 1998),
and have a tendency to undergo spontaneous haem- changes that would be expected to enhance stabil-
orrhage which can destabilize the plaque(Fuster ity. Dietary lipid lowering in rabbits also reduced
et al. 2005b) leading to clinical syndromes such as the number of microvessels in the aortic intima,
heart attack. suggesting another mechanism of favorably alter-
Atherosclerotic plaques may remain quiescent for ing the biology of plaques (Aikawa et al. 1998).
decades. However, when they initiate clot formation It has become clear that the cellular and extracel-
in the vessel lumen they can become life-threaten- lular composition of the plaque is the primary deter-
ing. This may occur either as a result of fibrous cap minant of plaque stability. Lesions with a large lipid
rupture, with consequent exposure of the thrombo- core, thin fibrous cap, a preponderance of inflam-
genic extracellular matrix of the cap and the tissue matory cells and few VSMCs are at the highest risk
factor (TF)-rich lipid core to circulating blood. Less of rupture. Inflammatory cells, particularly mac-
commonly, there can be erosion of the endothelial rophages, produce metalloproteinases which break
cell layer overlying the fibrous cap, again potentially down the matrix proteins in the fibrous cap. In addi-
leading to intravascular thrombosis. Endothelial tion, they secrete inflammatory cytokines, in partic-
erosion accounts for around 30% of plaque rupture ular interferon J (IFN-J), which inhibit VSMC pro-
events overall and seems more common in women liferation and collagen synthesis. Other cytokines
for unknown reasons (Farb et al. 1996). Both forms secreted by inflammatory cells such as interleukin
of plaque disruption invariably lead to local platelet 1E, tumour necrosis factor-D and IFN-J are cyto-
accumulation and activation at the site of rupture toxic to VSMCs. Activated macrophages can also
ulceration with subsequent thrombus formation. induce VSMC death by direct cell-cell contact (Boyle
48 J. H. F. Rudd, S. H. Aguiar, and Z. A. Fayad
2005). Furthermore, VSMCs in the fibrous cap have Risk scoring will provide a patient with an esti-
a reduced proliferative capacity and a propensity to mated risk of a clinical event over the following
apoptosis. Consequently, the inflammatory process 10 years (usually heart attack, stroke or a diagno-
within the lesions tends towards destruction of the sis of angina). Subjects can be stratified into three
fibrous cap and subsequent thrombosis, and there is groups: low-risk (10-year risk of less than 10%);
a dynamic balance within the plaque between mac- intermediate risk (10-year risk between 10% and
rophages, which promote erosion and rupture of the 20%) and high-risk (10-year risk greater than 20%).
fibrous cap, and VSMCs which nourish and repair The 10-year risk is then used to set lipid level tar-
it. These processes are independent of plaque size. gets for treatment with statin drugs, and to recom-
Consequently, small asymptomatic and angiograph- mend further evaluation with imaging if necessary
ically invisible plaques can rupture to precipitate a (Grundy et al. 2004; Nasir et al. 2005a,b; NCEP
fatal clinical event, whilst some large plaques which Expert Panel 2002).
obstruct flow to produce symptoms such as angina, Low-risk patients can be reassured and given
may be stable and not life threatening. There is an appropriate lifestyle advice. At the other end of
urgent need to discriminate “stable” from poten- the spectrum, high-risk individuals will undergo
tially “unstable” lesions in clinical practice. aggressive (probably invasive) investigation and
will receive intensive drug and lifestyle manage-
ment, without the need for further non-invasive
testing.
The most difficult group to advise are those that
3.2.3 fall into the intermediate Framingham risk score cat-
Screening and Therapeutic Implications egory, estimated to represent about 40% of the adult
US population (Greenland et al. 2001). Within this
Screening of patients at risk of vascular disease group, the risk score model is poor at discriminat-
(primary prevention) is desirable for a number of ing those who will actually suffer a hard event. The
reasons. Pre-symptomatic identification of high- addition of non-invasive imaging to the office-based
risk patients enables the prescription of lifestyle score is most appropriate in this setting.
changes or drug treatment aimed at either halt- Although risk scoring is a simple way of cat-
ing or even reversing the disease. Statin drugs are egorizing a patient’s 10 year potential for vascular
very useful in this regard and have been shown to events, the ability of the score to accurately predict
reduce both death rates and cardiovascular out- events on an individual basis has been questioned
comes in asymptomatic high-risk patients (LIPID (Cooper JA et al. 2005; D’Agostino Sr et al. 2001).
Study Group 1998; Shepherd et al. 1995). Recently, This has led to the increasing emphasis on the
developments in imaging technology, computer detection of subclinical atherosclerosis using imag-
software and the discovery of an array of cellular ing technology.
and molecular imaging targets has accelerated the Several supplemental investigations have been
effort toward the identification of high-risk athero- considered, including carotid intima-media thick-
sclerotic disease. ness (IMT) and black-blood MR imaging (mark-
The initial recommendation for screening of ers of carotid atherosclerosis), the ankle-brachial
asymptomatic patients is for the calculation of an pressure index (a surrogate marker of periph-
office-based risk score. This score is a multivariable eral vascular disease) and direct assessment of
statistical model that takes into account the pres- coronary calcium deposits using either electron
ence or absence of several risk factors including age, beam or multislice computed tomography (CT)
sex, diabetes, hypertension and lipid abnormalities. (Greenland et al. 2004) – Fig. 3.2.1. The result of
The commonest risk scoring system in the US uses non-invasive testing can help to refi ne the inter-
data from the Framingham study, and is endorsed mediate Framingham risk score, either moving the
by the National Cholesterol Education Program patient up or down one risk category. Positive test-
(NCEP) (NCEP Expert Panel 2002). Slight modi- ing would place the subject in the high risk Fram-
fications were made to this score to reflect the find- ingham group, with further appropriate investiga-
ings of recent large clinical trials (Grundy et al. tion required. However a negative non-invasive test,
2004). Similar scoring systems are used in Europe such a zero calcium score, would give reassurance
(Conroy et al. 2003). to both patient and doctor. The choice of which test
Pathology: Screening for Vascular Pathology 49
3.2.4
Risk Assessment in Asymptomatic Women
Many of the established non-invasive tests used D‘Agostino RB Sr, Grundy S, Sullivan LM, Wilson P (2001)
in men perform less well in women, with poorer Validation of the Framingham coronary heart disease
prediction scores: results of a multiple ethnic groups
predictive values (both positive and negative). The investigation. JAMA 286:180–187
National Heart, Lung and Blood Institute (NHLBI)- Davies MJ (1995) Acute coronary thrombosis–the role of
sponsored project Women’s Ischemia Syndrome plaque disruption and its initiation and prevention. Eur
Evaluation (WISE) is an ongoing prospective, multi- Heart J 16(Suppl L):3–7
center observational study of diagnostic modalities Farb A, Burke AP, Tang AL, Liang TY, Mannan P, Smialek
J, Virmani R (1996) Coronary plaque erosion without
for reliable cardiovascular assessment of ischemic rupture into a lipid core. A frequent cause of coronary
heart disease in women, and will hopefully provide thrombosis in sudden coronary death. Circulation
better guidelines for non-invasive assessment in this 93:1354–1363
patient group (Lerman and Sopko 2006; Pepine Fuster V, Fayad ZA, Moreno PR, Poon M, Corti R, Badi-
2006). mon JJ (2005a) Atherothrombosis and high-risk plaque:
part II: approaches by noninvasive computed tomogra-
phic/magnetic resonance imaging. J Am Coll Cardiol
46:1209–1218
Fuster V, Moreno PR, Fayad ZA, Corti R, Badimon JJ (2005b)
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Screening and Preventive Diagnosis with Radiological Imaging. Diagnostic Algorithms for Whole-Body Exams 53
tients with known malignancy. For the purpose of PET/CT allows one to co-register and fuse PET
screening, however, such a whole-body CT approach and CT data, thus combining the functional infor-
is limited by the high radiation exposure and poten- mation of PET with the high spatial resolution of CT
tial risk of radiation-related cancer mortality. For (Fig. 4.3). Various studies indicate that fused PET
example the estimated dose to the lung or stomach and CT image data provides an added value over that
from a single whole-body CT exam is 14–21 mGy, of the separate methods and results in an improved
which corresponds to a regional dose that may be diagnostic accuracy in the diagnosis of oncologic
associated with an increased risk of cancer mortality diseases compared to PET and CT alone. Again, the
[Brenner Radiology 2004 Sep;232(3):735–738]. Thus, high radiation dose of PET/CT limits the practical
the value of whole-body CT for screening purposes value of this imaging test for the purpose of screen-
in asymptomatic individuals is limited. ing, but has its value in the field of surveillance.
a b
Fig. 4.1. a Example of an MRA exam of the lower body part including the abdominal aorta and renal arteries, iliac arteries and
vessels of the lower extremity. b Example of a CTA exam of the same anatomic area. View from anterior and posterior
Screening and Preventive Diagnosis with Radiological Imaging. Diagnostic Algorithms for Whole-Body Exams 55
Fig. 4.3. Fused images of PET and CT with physiological FDG uptake
in the brain and kidney and excretion of FDG into the renal pelvis and
the bladder. In this patient suffering from colon cancer, multiple areas
of increased FDG- uptake in the liver indicate metastatic spread
56 H. Kramer
4.3 4.4
Magnetic Resonance Imaging (MRI) Considerations for Cardiovascular Whole-
Body MRI Protocols
For a long time MRI has been restricted to imag-
ing of a defi ned body part and also suffered from Cardiovascular whole-body MRI can be performed
long data-acquisition times. Recent developments as a clinical exam in patients suffering from ath-
in hard- and software contributed to overcome erosclerosis or as a check-up exam in asymptom-
these restrictions. With the implementation of atic individuals with a defi ned risk-profi le. A dedi-
multi-channel MR technology with multiple re- cated cardiovascular whole-body MRI consists of
ceiver coils it is now possible to image the entire a complete cardiac exam and a whole-body MR
body within one comprehensive whole-body MRI angiography (MRA). A state-of-the-art compre-
exam (see also chapter 6.1 Dietrich O, Schoenberg hensive cardiac exam includes functional imaging
SO. Technical prerequisites). For this approach, of the left ventricle, myocardial perfusion imag-
the patient is covered with multiple receiver coils ing as well as a delayed contrast-enhanced scan to
(Fig. 4.4). Due to a large range of table movement detect infarcted myocardium (Fig. 4.5). Adequate
all anatomic areas can be positioned in the iso- temporal resolution is a mandatory requirement
center of the magnet one after the other without for functional cardiac imaging because a too low
repositioning the patient. With parallel acquisi- temporal resolution (> 50 ms) leads to an overesti-
tion techniques (PAT) the acquisition time of MRI mation of the endsystolic volume and an underesti-
can be greatly reduced without compromise in mation of the ejection fraction (Wintersperger et
image quality. On the other hand, image quality al. 2003). Perfusion imaging of the left ventricular
is superior, when the same acquisition times are myocardium can be performed at rest and at phar-
employed (Kramer et al. 2005). This flexibility of- macologically induced stress. At rest only coronary
fers several new opportunities when dealing with artery stenoses of more than 90% are detectable,
systemic disease. Typical indications for whole- while pharmacologically-induced stress enables to
body MRI are the assessment of cardiovascular diagnose even lower grade stenoses that are hemo-
and malignant disease. dynamically significant. When adenosine is used
Fig. 4.4a,b. Matrix coil system with multi element coils. Before the exam all required coils are positioned on the patient
and are electronically selected during the exam
Screening and Preventive Diagnosis with Radiological Imaging. Diagnostic Algorithms for Whole-Body Exams 57
for pharmacologically-induced stress, a low rate the assessment of stenoses because measurement
of severe complications of less than 2% is found. of the degree of area stenosis is much more accu-
When performing whole-body MRI as a check-up rate than only measuring the diameter stenosis
exam the question nevertheless arises if it is legally (Fig. 4.6).
justifiable to induce stress by administering ade- The combination of all these different exams
nosine in asymptomatic individuals because of the requires a complex imaging protocol as well as a
potentially related risks. Participants of preventive tailored contrast agent injection scheme. Perfusion
exams have to be informed about the possibility of imaging of the left ventricular myocardium has to
side effects and have to give informed consent. For be performed as the fi rst contrast-enhanced exam
the selection of individuals to be subjected to stress because prior contrast agent application would
perfusion imaging, assessment of coronary calcifi- confound the results of the semi-quantitative per-
cations and traditional risk factors may be useful fusion analysis. In subsequent MRA examinations,
to identify those subgroups with an intermediate a subtraction mask is acquired which allows to
risk of a major cardiac event (see also Chap. 5.1 eliminate tissue enhancement due to prior contrast
Schoenberg SO, Reiser MF. Personnel and struc- injection. To avoid false negative results of delayed
tural prerequisites for screening-programs). contrast enhancement imaging in infracted myo-
Whole-body MRA has to be performed employ- cardium, this exam is performed approximately
ing standards of good clinical practice. It is not ac- 15 min after the previous contrast agent applica-
ceptable to reduce acquisition time at the expense tion. To reduce the standby time between the differ-
of spatial resolution, when this is associated with ent contrast agent applications contrast-enhanced
a decrease in diagnostic accuracy. In contrast en- scans of the brain, thorax and abdomen can be per-
hanced MRA data acquisition has to be confi ned formed (Table 4.1). A complete cardiovascular MRI
to the fi rst pass of the contrast material bolus pas- protocol including a comprehensive cardiac exam,
sage and venous contamination has to be excluded. whole-body MRA as well as scans of the brain,
With isotropic high spatial resolution, multi-planar thorax and abdomen results in an in-room time of
reformations of 3D datasets can be performed. This about 60 min (Goyen et al. 2002, 2003; Kramer et
substantially improves the diagnostic accuracy in al. 2005; Herborn et al. 2004).
a b
Fig. 4.5a,b. Functional imaging of the left ventricular myocardium (a) as well as delayed contrast enhancement imaging
(b). Due to the implementation of parallel imaging techniques at high field strength (3 Tesla) spatial and temporal resolution
can be maintained at a high level while acquisition time is reduced to a single breath-hold
58 H. Kramer
Fig. 4.6. MR Angiography of the abdominal aorta and the renal arteries with an isotropic spatial
resolution of 1 × 1 × 1mm3 allowing for multiplanar reformations. This is very important for accu-
rate assessment of vessel stenosis by determining area stenosis in addition to diameter stenosis
Table 4.1. Protocol of a cardiovascular whole-body MRI exam. Dedicated whole-body MR systems allow for pre and post
CA imaging of the entire body without repositioning of the patient. The time interval between the contrast agent (CA) ap-
plication and the recommended delay for imaging of myocardial infarction by delayed contrast enhancement (DCE) is used
for post CA imaging of the chest and abdomen
20 T1, T2 pre CA
diffusion; TOF
40 function, perfusion carotids, calves
60 DCE abd. aorta, thighs VIBE post CA VIBE, FLASH
post CA
Screening and Preventive Diagnosis with Radiological Imaging. Diagnostic Algorithms for Whole-Body Exams 59
4.5 4.6
Cardiovascular Whole-Body MRI in High- Oncologic Whole-Body MRI
Prevalence Risk Groups
Radiological imaging is essential for the staging,
Diabetes is one of the major causes for morbidity follow-up and surveillance of cancer. Depending
and mortality in the world. Prevention, diagnosis upon the particular tumor entity, various imaging
and therapy of diabetic long-term complications modalities and combinations thereof are usually
are extremely important. Due to the combination employed in a multi-modality stepwise diagnos-
of systemic manifestations such as diffuse mi- tic algorithm. In diagnostic algorithms for tumor
cro- and macroangiopathy and silent myocardial staging, imaging modalities that apply ionizing ra-
infarction as well as local disease such as osteo- diation are still the backbone of clinical work-up
myelitis or neuropathic foot, diabetes offers great including CT, scintigraphy and PET-CT. However,
diagnostic challenges. Accelerated atherosclerosis for the surveillance of cured cancer patients, there
of the whole arterial vasculature, including the is a growing need for comprehensive imaging al-
coronary arteries the neck and lower leg arteries gorithms without the use of ionizing radiation or
is a frequent consequence of longstanding diabe- nephrotoxic contrast agents. This is particularly
tes. Therefore, patients with diabetes are at a high true in young patients with early manifestations
risk of experiencing myocardial infarction, stroke of cancer such as breast cancer patients or patients
and critical limb ischemia. The combination of with lymphoma.
microvessel disease and neuropathy may result in MRI offers a unique soft tissue contrast and
ulceration of the skin and cellulites and osteomy- proved highly effective in the diagnostic assessment
elitis of the feet. of a variety of tumor entities. Whole-body MRI
Preventive imaging has to include the potential exams in oncologic patients should include STIR
manifestations of diabetes in the whole body. Whole and T1 weighted SE (spin echo) imaging in coronal
body MRI has already been used as a comprehensive planes. The lungs should be also examined with axi-
non-invasive examination of patients with diabetes al STIR and HASTE (half-Fourier acquisition single
mellitus and a large proportion of asymptomatic shot turbo spin echo) pulse sequences. Before the
disease manifestations could be detected. The pro- administration of contrast agent T2w fat-saturated
tocol for a whole-body MRI included the cardiovas- imaging of the liver as well as T1w SE and STIR se-
cular system in the same way as described earlier quences of the spine in sagittal orientation should be
in this chapter. In order to detect neuropathic and acquired. During contrast agent application an axial
inflammatory disease manifestations in the feet, na- dynamic 3D GRE (gradient echo) exam of the liver is
tive and contrast enhanced T1-weighted spin echo recommended followed by T1w and T2w axial brain
sequences and STIR (short tau inversion recovery) scans and T1w fat-saturated axial 2D GRE scans of
images of the lower leg and feet were acquired. For the abdomen (Table 4.2).
the assessment of cerebral micro-vascular lesions, When a sophisticated examination technique is
T2* and diffusion imaging was additionally per- employed, whole body MRI enables to precisely as-
formed (Weckbach 2006). sess the T- and M-stage in good correlation with
Other potential applications of whole-body MRA PET/CT. Recent studies show an overall diagnos-
for screening of risk groups with high disease preva- tic accuracy for TNM-staging of 96% for PET-CT
lence include diseases such as vasculitis or congeni- compared to 91% for whole-body MRI. For N-stage
tal vascular diseases such as Marfan’s or Ehlers- alone, PET-CT seems to be superior with an ac-
Danlos’. Takayasu’s arteritis as one representative curacy of 93%–97% in the detection of malignant
vasculitis of large vessels is known to affect multiple lymph nodes compared to 78%–82% for MRI. For
territories at the same time with inflammatory ste- the detection of distant metastases PET-CT and
nosis of the subclavian arteries, aorta, mesenteric MRI perform equally with an accuracy of 93% and
arteries, renal arteries and other vessels. In Marfan’s 94%, respectively (Schmidt et al. 2006). The accu-
or Ehlers-Danlos’ disease, multifocal involvement racy of both whole-body MRI and PET/CT greatly
by aneurysms or dissections is a typical complica- depends on the site of the primary tumor. In head
tions which may already occur in children and ado- and neck tumors and lung cancer PET/CT is supe-
lescents. rior, while whole-body MRI is more accurate in tu-
60 H. Kramer
mors of the nervous and musculoskeletal system. matic again with clinical manifestation of pain or
Recently, whole-body MRI at 3 Tesla has been to elevated tumor markers whole-body MRI detected
surveillance of breast cancer patients after suc- metastatic cancer with an accuracy exceeding 90%
cessful cure. In those patients that became sympto- (Schmidt et al. 2008) (Fig. 4.7).
Table 4.2. Protocol of an oncologic whole-body MRI exam for tumor staging containing STIR
and T1 imaging of the entire body as well as pre and post CA imaging of the chest and abdo-
men, the brain and the entire spine
STIR cor STIR cor STIR cor STIR cor STIR cor
HASTE/STIR T2 liver
cor/ax ax
3D VIBE liver
T1 fs + CA
T1, T2 + CA
ax
Fig. 4.7. Surveillance of a previously cured breast cancer patient with newly rising tumor markers. Whole-body MRI de-
tects multifocal involvement of the liver by breast cancer metastases while the corresponding PET-CT shows only one site
of hepatic metastasis
Screening and Preventive Diagnosis with Radiological Imaging. Diagnostic Algorithms for Whole-Body Exams 61
Fig. 5.1. Role of the radiologist in the screening algorithm of diseases with high prevalence
proceeding in this direction but rather referring the (Grundy 2001). Although there is no clear correla-
patient to an invasive diagnostic work-up by cath- tion between the amount of calcified plaques within
eter X-ray coronary angiography. the coronary arteries and the presence of a coronary
If the participant is completely asymptomatic it artery stenosis the presence of atherosclerotic dis-
is still highly desirable to gain knowledge about any ease is confirmed. As a variable the quantified abso-
pre-existing disease in order to increase the pre-test lute mass of calcium independently affects the calcu-
likelihood of the diagnostic procedure. According lation of the so-called modified Framingham score
to Bayes-Theorem the positive predictive value of a and thus allows to potentially shift an asymptomatic
diagnostic test is strongly dependent on the preva- screening individual from the low probability group
lence of the disease. Since screening cohorts typical- into the intermediate probability group as a trigger
ly reveal a low disease prevalence measures should for further non-invasive imaging assessment of coro-
be taken to increase the pre-test likelihood by care- nary artery disease (Fig. 5.2).
fully designed selection criteria within the general
population. This is particularly important for diag- 5.1.1.2
nostic tests with high costs, technical complexity and Follow-Up and Treatment Recommendations
potential side effects such as magnetic resonance
myocardial perfusion imaging with pharmacologi- Once an individual has undergone a diagnostic
cally induced stress by adenosine. In these patients screening procedure, the screening interval for the
the Framingham score can be used to increase the next screening visit has to be determined. In ad-
pre-test likelihood for coronary artery disease. If the dition suspicious findings have to be verified with
Framingham score is less than 10 the patient has a regard to their clinical significance and significant
less than 10% risk of experiencing a myocardial inf- findings have to be managed by the appropriate
arction within the next 10 years and thus the risk for a treatment recommendations.
positive finding of coronary artery disease is too low For determining of the appropriate screening in-
to warrant a more extensive diagnostic assessment. terval one has to understand the biology and patho-
In contrast, if the Framingham score ranges between physiology of the underlying disease to be screened.
10 and 20 the participant falls in the intermediate risk The three major types of disease evolution are a
group for a future cardiac event and thus is a typical steady progression of the disease, acceleration or de-
candidate for a further non-invasive assessment for celeration of the disease process or a de novo mani-
coronary artery disease. This typically includes pro- festation of disease in between the screening visits
cedures such as ergometry, myocardial scintigraphy also known as interval disease. Another important
or magnetic resonance myocardial perfusion imag- consideration is the question if the disease is poten-
ing. If the score is above 20 direct invasive assess- tially reversible by modification of the risk factors.
ment of coronary artery disease by coronary X-ray Although atherosclerosis shows a relatively steady
catheter angiography should be considered in select- progression various findings may warrant a modi-
ed risk groups such as diabetic patients or patients fication of the screening follow-up scheme. While
with cardiac insufficiency. Within the last 5 years for example a 30% stenosis of the carotid artery may
the concept of coronary artery calcium mass quan- be safely followed by ultrasound in 2-year inter-
tification as an independent factor for determination vals, a 60% stenosis needs to be reassessed within
of the Framingham pre-test likelihood has evolved 6 months since it is well known from the NASCET
Personnel and Structural Prerequisites for Screening-Programs 65
Fig. 5.2. A 58-year-old heavy smoker with dyspnoea on exertion without symptoms of coronary artery disease who was
referred to whole-body MRA by his internal medicine physician to rule out any significant stenosis. By his initial Framing-
ham score he was in the low-risk group for a cardiovascular event, however, using the modified score including the coro-
nary calcium mass, he was shifted into the intermediate risk group. Thus, the decision was made to include a cardiac MR
perfusion scan with adenosine stress into the whole-body MRA algorithm which revealed a perfusion defect in the anterior
midpapillar myocardium as a sign for a significant stenosis of the left anterior descending artery
trial that progression to a 70% stenosis puts the pa- it is known that approximately between 20% and
tient at much higher risk for a cerebrovascular inci- 60% of all breast cancers arise within the interval
dent and implies surgical or interventional repair. between the screening time points depending on the
Similar data is available for renal artery stenoses. fact if a yearly, 2-year or 3-year follow-up is applied.
Patients with a 75% stenosis that is considered he- For example, in Germany screening mammography
modynamically significant are known to progress is advised in a 24-month-interval in the age group of
towards end-stage renal disease with dialysis within 50–70 year-old-women to minimize the size of these
the next 2 years. cancers at the time of detection during the next
In malignant diseases continuous growth of the screening visit.
tumor is related to an exponential increase of ma- Besides selection of the appropriate screening
lignant cells with a direct correlation to metastatic interval a clear algorithm needs to be established
spread and survival. Thus screening for malignant with regard to the defi nition of a significant posi-
diseases requires detection of the tumor at a very tive fi nding as well as the diagnostic procedures to
small size, which has direct impact on the selection confi rm or exclude a fi nding of questionable sig-
of the appropriate screening interval in between nificance. In this algorithm the sequence of con-
normal studies. The screening interval represents fi rmatory procedures has to be carefully balanced
a trade-off between patient compliance minimizing against potential side effects from more invasive
negative effects such as from ionizing radiation and diagnostic procedures on one hand and false posi-
detection of cancers that have arisen in between the tive fi ndings that entail unnecessary treatment on
screening interval. For example in a mammography the other hand. Early attempts on screening for
66 S. O. Schoenberg and M. F. Reiser
lung cancer before the ELCAP trial (early lung can- from crossing vessels, thereby improving the reli-
cer action project) reported a higher morbidity in ability of the assessment. It is important to acquire
patients that had been systematically screened for the data sets with a minimum slice thickness of at
lung cancer compared to the non-screened popula- least 1 mm without motion artifacts; thus multi-slice
tion (Marcus et al. 2000). This higher morbidity CT scanners with a minimum number of 16-detec-
was related to substantial side effects from invasive tor rows should be utilized to allow for breathhold
diagnostic procedures for lesion confi rmation as times of less than 15 s. As already mentioned, PET
well as operative treatment on false positive fi nd- and particularly PET-CT have evolved as powerful
ings. The design of the ELCAP trial has aimed at techniques for lesion characterization based on the
systematically avoiding these complications by de- amount of 18fluorodeoxyglucose (FDG) uptake. In
signing a clear algorithm for lesion confi rmation combination with CT this uptake can reliably re-
with non-invasive imaging procedures (Henschke lated to malignant lesion within the size range of
et al. 2006). For base line screening a positive re- 8–10 mm or larger.
sult on the initial low-dose scan was defined as the
identification of at least one solid or partly solid 5.1.1.3
non-calcified pulmonary nodule of 5 mm or more Surveillance
in diameter. If none of the non-calcified nodules
identified met the study criteria for positive re- A number of chronic diseases predispose patients to
sults or if the test was negative a CT was repeated significant clinical complications including malig-
12 months later. For nodules 5–14 mm in diameter nant transformation of chronic inflammatory states
the preferred option was to perform another CT or tissue infarctions in chronic vascular diseases.
at 3 months. If the image showed growth of the The role of screening in these groups with under-
nodule then biopsy ideally by fi ne needle aspira- lying pre-existing disease is of particular interest
tion was to be performed, whereas if there was not since the prevalence of diseases is significantly high-
growth the work-up was stopped. Optionally PET er compared to secondary screening in the normal
could be immediately performed and biopsy was asymptomatic population. Per definition this is not
initiated if the results were positive. For nodules of screening in the true sense of searching for disease
15 mm in diameter or larger irrespective of their in an asymptomatic population but rather surveil-
composition immediate biopsy was warranted. In lance of symptomatic patients for early manifesta-
all participants with completed work-up or biopsy tion of disease complications. Surveillance is of high
without diagnosis of lung cancer CT was to be re- importance since a number of treatment options ex-
peated 12 months after the base-line CT. For mul- ist for addressing these complications with potential
tiple non-solid nodules identified on base-line CTs impact on patient survival. Any screening technique
with high suspicion of infection a 2-weeks course of that is used for surveillance has to be as minimally
antibiotics followed by CT one to two months later invasive as possible and at the same time be able to
was considered an alternative option for lesion fol- reliably detect all potential complications arising
low-up (Libby et al. 2006). However, it is important from the underlying disease. In addition, the costs
to realize that a minimum amount of diameter in- of the screening technique have to be reasonably
crease within 3 months follow-up still correlates to balanced against the survival gain for the patients
a substantial increase in tumor volume of a malig- in order to limit the expenses in view of relatively
nant pulmonary nodule. short screening intervals. For appropriate selection
With a standard approach for measurements of of the screening intervals detailed knowledge about
tumor extension by assessment of the longest diam- the natural history of the particular disease, the
eter according to the RECIST criteria subtle growth incidence of complications as well as their relation
might be missed within this short follow-up interval. to the stage of disease and the potential options for
In the past few years specific software has become treatment is mandatory.
commercially available for volumetric assessment of One major field for surveillance constitutes the
these small nodules in thin-section multi-slice CT assessment of cured cancer patients who are either
thereby allowing a much more accurate determina- at risk for relapse of their primary cancer or for ther-
tion of lesion growth by looking at the total tumor apy-induced secondary cancers in the later phases
volume rather than the longest diameter. Also this after initial cure. Traditionally these patients have
approach allows to clearly differentiate nodules undergone surveillance with a multi-modality ap-
Personnel and Structural Prerequisites for Screening-Programs 67
proach of chest X-ray, abdominal ultrasound and for the screening exam and the appropriate interac-
bone scintigraphy optionally complemented by CT tion with the referring physician. He or she has to
scans. The time interval and organ systems for fol- have the appropriate level of training and experi-
low-up were usually defined with respect to the time ence to insure a consistent and reproducible quality
post-therapy and the typical routes of metastatic in interpreting screening exams and maintaining
spread. Narrow screening intervals are typically the appropriate technical quality of the studies.
chosen in the early phase of post-treatment follow- Since the infrastructure is cost-intensive and re-
up, while in the later phases the time intervals in ferral depends on marketing and advertisement,
between these screening time points are prolonged. the physician often fi nds himself within an area
Recently, several studies have been published sug- of confl ict between fi nancial, ethical and clinical
gesting evidence that a more intensified and more motivation.
systemic approach for surveillance might be war-
ranted in certain tumor entities. In oncology, this 5.1.2.1
is of particular interest for malignant diseases for Training and Experience
which a number of therapeutic options exist in met-
astatic disease such as renal cell carcinoma. In renal Apart from the general requirements for board
cell carcinoma, the rate of recurrence for pathologic certification in the field of radiology there are spe-
stages T1 and T2 is reported to range between 0% cific training requirements to conduct screening
and 5%, while it is increased to rates between 9% studies. Although no generally mandatory require-
and 22% in stages T3A and B. On the other hand sur- ments exist for most of the diseases to be screened,
vival rates range between 63% and 75% after surgi- the individual subspecialty organizations have
cal resection of a locally recurrent tumor with 40% published recommendations in terms of number
of the patients remaining in long-term remission of screening studies to be completed for an appro-
(Stephenson et al. 2004). Therefore, surveillance priate skill level. Defi nite criteria for determination
for early stages of recurrence is warranted. A recent of the radiological skill level exist for X-ray mam-
study recommended abdominal CT 6, 12, 24 and 36 mography. According to the EUSOMA guidelines
months postoperatively (Stephenson et al. 2004). currently only those physicians are approved for
Likewise, patients with surgical treatment of a soli- participating in X-ray mammography screening
tary bone metastasis have an improved survival programs who read more than 5000 studies per
compared to those with multiple metastases (Fuchs year (Perry 2001). Recent results from the orga-
et al. 2005). Interestingly, in patients with a low risk nized screening programs in Canada have shown
for recurrence according to the UISS criteria meta- that the positive predictive value was increased by
static disease occurs most frequently outside the 34% for those radiologists reading volumes over
abdomen. While the overall 5-year-disease-free in- 2000 mammograms vs volumes of 480–699 mam-
terval is greater 90%, 75% of all relapses occur in the mograms per year (Coldman et al. 2006). How-
thorax (Lam et al. 2005). This highlights the neces- ever, on the contrary neither the cancer detection
sity for an extended anatomic coverage for surveil- rate nor the abnormal interpretation rate varied by
lance including at least thorax and abdomen. While reading volume.
this is still the domain of spiral CT, whole-body MRI Besides the appropriate training for conducting
offers the potential to include other important or- screening studies the experience of the physician
gan systems such as the central nervous and muscu- has to be assessed by means of his intra- and inter-
loskeletal system into the diagnostic algorithm. This observer variability for reading the studies. Several
holds promise to replace the time-intensive multi- studies have shown that inter-observer variability
step multi-modality approach by a single-step com- greatly affects the consistency of results if several
prehensive diagnostic assessment (Fig. 5.3). expert readers are involved in the reading process.
Thus, these readers need to train themselves for a
minimum amount of variation among the different
5.1.2 observers to insure consistency of the reported re-
Role of the Radiologist in Screening sults. This also refers to repetitive readings by the
same observer, which should reveal a minimum
The radiologist that aims at conducting a screening amount of variation to allow reproducible assess-
study has to defi ne the appropriate infrastructure ments in longitudinal screening studies.
68 S. O. Schoenberg and M. F. Reiser
Fig. 5.3. A 70-year-old-male patient with new onset of diffuse pelvic pain 2 years after nephrectomy of the left kidney be-
cause of a renal cell cancer. Due to the non-specific symptoms a pelvic X-ray study was initially performed which revealed
a destruction of the upper margin of the right iliac bone suspicious for a large osseous metastasis. This was confi rmed by a
consecutive CT study. Both CT and an additional radionuclide bone scan did not detect any further osseous metastases. On
the contrary, whole-body MRI exactly delineated the extent of the pelvic metastasis and identified two additional metastases
in the right femur which showed progression on successive CT studies
Personnel and Structural Prerequisites for Screening-Programs 69
On the other hand, the reimbursement codes for resent a reassurance for the individual or impose
screening are not well defined yet, potentially giv- a psychological stress particularly in the case of
ing rise to a primarily financially motivated recruit- falsely positive fi ndings. A large recent survey in
ment of those screening participants that are willing the United States concluded that the major per-
to pay high rates for participating in the screening centage of the population has a high interest to
study. This might artificially induce a selection bias participate in a screening program. In this survey,
towards a wealthier subgroup of the population most individuals would be willing to participate
which does not necessarily represent a balanced in a study, if the detected diseases could be po-
cross-sectional cohort for a particular disease en- tentially cured and if the program participation
tity. In addition, young participants who are not true was for free. The majority would be still willing
candidates for a certain screening program of a par- to participate, if they had to pay for the exam.
ticular age-related disease might be attracted which Interestingly, still approximately two thirds of the
may further reduce the overall prevalence within surveyed individuals declared their willingness for
the screening population and potentially increase participation even if the detected diseases could
the number of false positives. False positive fi ndings not be cured (Brant-Zawadski 2006). However,
are considered a major cost factor since further in- this requires a strong alliance with the referring
vasive confirmation does not result in a reduction partners because management of the participants
but rather a potential increase in morbidity and thus after a completed screening study has to be car-
is of no socio-economic value. ried out co-jointly with these physicians. This is
of particular importance for true and false positive
fi ndings. In case of true clinical fi ndings from the
5.1.3 screening study the referring physician often has
Referring Partners to deal with further management of the patient
in terms of an invasive treatment. For fi ndings of
Participation in a screening program can be in- questionable clinical significance the judgment of
creased by the initiative of health care providers, the referring physician is crucial to either reas-
self referral or advertisement. Generally, health sure the participant that these fi ndings are insig-
care providers have an interest to raise the lev- nificant and can be neglected until a repeated fol-
el of participation in those screening programs low-up exam is performed or to defi ne the least
that potentially can reduce morbidity and thus invasive confi rmatory diagnostic test together with
decrease health care costs. So far only a few ap- the screening radiologist to defi nitely rule out any
plications fall in this category including screening significance of the fi ndings (Fig. 5.4).
for breast, colon and prostate cancer. Newly aris- Particular problems arise if the detected dis-
ing programs such as screening for colon cancer ease cannot be cured. In that case a clear strategy
with CT and MRI colonography, screening for needs to be designed together with the patient in
cardiovascular disease with whole-body MRI or order to provide the best treatment option to pro-
screening for lung cancer with low dose chest-CT long the patient’s life and secure best possible qual-
may benefit from systematic advertisement. This, ity of life. Also clinical and psychological support
however, has to be done on a medically justified needs to be provided to those patients who errone-
basis in close coordination with a referring and ously underwent invasive treatment for a false posi-
treating physician. Self referral of the screening tive finding with the consequence of a transient or
participant is motivated by various reasons rang- persistent increase in morbidity. If the latter two
ing from knowledge about the threat of certain groups of screening participants are left alone with
diseases to the wish for ruling out any existence their screening exams there is a high likelihood of
of an undefined and potentially life threatening dissatisfaction. This discontent might transform
disease. into anger on the referring physician or screening
radiologist with potential legal conflicts resulting
5.1.3.1 hereof. Thus, a co-joint and transparent advertise-
Patient Satisfaction vs Advertisement ment of screening programs with clear specification
of the pros and cons as well as management of the
It is of ongoing debate, if screening programs with potential patient is a key prerequisite for participant
potentially clinically significant fi ndings do rep- satisfaction.
Personnel and Structural Prerequisites for Screening-Programs 71
Fig. 5.4. Critical issues for the further management of individuals related to the results of screening studies
readings, discussion of the separately assessed find- were subjected to third reading. 2.6% of these cases
ings in consensus or by resolving discrepancies be- underwent further assessment by imaging (1.6%) or
tween the readers by a third reader with fi nal author- histological verification (1%) (Willgeroth et al.
ity. In the ELCAP-trial each low dose CT was read 2005).
separately by two board certified chest radiologists.
The findings on the presence and number of nod-
ules were separately recorded and then discussed, 5.2.2
and the consensus findings were documented for Scientific Evaluation
the study. When the two readers could not reach
consensus the case was presented to a third expert 5.2.2.1
reader and the adjudicated reading became the final Study Design
(Henschke et al. 1999).
Similar designs were chosen for dedicated breast The aim of a well designed screening study is to
cancer screening programs according to the Euro- generate statistically valid data that are applicable
pean guidelines for quality assurance in mammog- to the general population. One of the key issues of a
raphy screening. Similar to the ALCAP-trial dis- prospectively designed study is the selection of the
crepant findings are resolved by arbitration through number of cases to be screened in order to prove
a third reader. One of the well established screen- the significance of a test result. This case estimate
ing programs in Europe is the Dutch Nationwide is based on the assumed prevalence and incidence
Breast Cancer Screening Program, that was gradu- of findings, the presumed accuracy of the screen-
ally implemented between 1989 and 1997 and offers ing test as well as the expected difference in test
biannual screening mammography to women aged performance compared to apparently established
50–69 years with an overall attendance rate of about algorithms. Particularly for the latter aspect, an ap-
80%. In this program, screening mammograms are propriate case estimate is of high importance since
read independently by two radiologists, who must insignificant results for the performance of a new
reach a consensus as to weather the woman should screening test compared to traditionally established
be referred for further examination. If consensus algorithms may be solely related to an underpow-
about the referral necessity is not reached between ered study.
the initial two radiologists the screening mammo- In risk groups with a presumed higher prevalence
gram is subjected to arbitration by a panel of three of disease compared to the general population ben-
randomly selected screening radiologists. Out of efits of screening can only be proven if the findings
a total of 65,779 women who underwent screen- are compared to a healthy control group. Otherwise
ing mammography the two screening radiologist the high incidence of positive findings may be con-
initially disagreed about the necessity of referral in sidered entirely artifactual if the prevalence of these
0.5% of the cases. Consensus could not be reached findings is unknown for the general population.
in 0.28% of the cases after viewing these discrepant One important example has been the screening for
cases together. The arbitration panel referred 89 of hepatocellular carcinoma in individuals exposed to
these 183 women for further examination reveal- thorotrast. In this risk group a significantly higher
ing breast cancer in 20 cases. However, given the incidence as well as mortality from hepatocellular
relatively small group of overall discrepancies and carcinoma could be proven by systematically com-
the relatively low costs of further diagnostic assess- paring the findings to an age matched control group
ment, the authors of the study considered referral in a prospectively designed longitudinal study (van
of all women in cases of initial reader disagreement Kaick 2006).
still being acceptable in terms of cost effectiveness. In addition, the parameters for conducting the
They therefore concluded that an arbitration panel screening study have to be designed in advance. This
may not be necessary in cases in which two readers refers to technical parameters related to the data ac-
cannot reach a consensus (Duijm et al. 2004). In the quisition itself as well as to parameters indicating
Bavarian Mammography Screening the role of the the performance for data analysis. One thorough
third reader in case of discrepancies between fi rst – fully defined list of performance indicators is list-
and second reader is not arbitration but referral of ed in the European guidelines for quality assurance
the women for further assessment. Out of 88,300 in breast cancer screening and diagnosis. Here, for
women, who have been screened, 6.7% of the cases example, both technical parameters such as target
Personnel and Structural Prerequisites for Screening-Programs 73
optical density, spatial resolution or glandular dose ticularly for category 3 (probably benign finding). In
are defined as well as minimum requirements that one study the discordance with reporting category 3
address the rate of screening participation in the exceeded 50% with overlap both to lower and higher
target population, the percentage of participants for categories (Lehman et al. 2002). The problem is that
further assessment, the breast cancer detection rate, this may result both in over-diagnosis (biopsy for
interval cancer rate as well as the proportion of in- category 2 lesions) and under-diagnosis (normal
vasive screen-detected cancers with negative lymph interval follow-up in category 4). It can be consid-
nodes. These performance indicators are crucial to ered a weakness of standardized reporting systems
define the quality levels during the course of a study if too many categories with only subtle differences
in order to generate appropriate data that prove the among each category are provided. The more sub-
hypothesis of a screening study. tle these differences are, the better the training has
to be for those radiologists using these systems on a
5.2.2.2 regular basis. In a recent study from Florence on 12
Data Evaluation dedicated breast radiologists with little prior work-
ing knowledge of BI-RADS who were reading a set
The key requirement for valid analysis of data aris- of 50 breast lesions (29 malignant, 21 benign) major
ing from a screening study is the consistent, clearly disagreement occurred for intermediate categories 3
defined and reproducible reporting of the findings and 4 with insufficient intra- and interobserver con-
in a standardized reporting scheme. This reporting sistency (Ciatto et al. 2006). Thus, familiarizing
scheme has to fulfi l several requirements. First, it radiologists with a standardized reporting system
has to be able to balance the different positive and and limiting the number of categories to those with
negative findings in terms of their significance as clearly defined differences are key prerequisites for
well as to unambiguously subcategorize the find- data evaluation in a screening setting.
ings in those that do not require further manage-
ment, those that have to be followed up by further
imaging studies and those that immediately require 5.2.3
invasive confirmation preceding treatment. In addi- Screening Center vs Radiological Department
tion, the rating scheme must have a low intra- and with Screening
inter-observer variability, e.g. the rating has to be
reproducible among different readers as well as by For the decision of establishing a specialized screen-
the same reader in repetitive assessments. Addition- ing center vs performing screening studies within
ally, it has to be accepted internationally among the a clinical radiological department different aspects
radiology community. have to be taken into account including statistical
Probably the most known categorizing system considerations, workflow and clinical expertise.
is the Breast Imaging Reporting and Data System One has to be aware of the fact that individuals for
(BI-RADS) initially published by the American Col- secondary screening should be by definition asymp-
lege of Radiology in 1992. BI-RADS has been well tomatic without clinical manifestation of a disease.
accepted and has been increasingly adopted as a This results in three major differences to those in-
system for breast imaging reporting particularly dividuals who are being referred for symptoms. As-
for mammography. It has evolved over time to also ymptomatic screening participants are usually self-
categorize the lesions found on breast sonography motivated, expect reassurance of their healthiness
and MRI. This system aims at standardizing the lan- and usually require no further invasive diagnostic
guage for defining and grading of radiologic find- work-up or treatment in the majority of cases. Also,
ings within the breast and recommending the ap- the radiologist expects the prevalence of findings to
propriate further diagnostic and therapeutic steps. be lower than in a pre-selected symptomatic patient
However, studies found only a moderate overall in- cohort even for those diseases that have a relatively
tra- and interobserver agreement for the BI-RADS high prevalence in the general population and are
classifications. While there is relatively high agree- thus ideally suited for screening. These reasons have
ment for category 1 and 2 (negative study and be- led to the trend to assess asymptomatic individu-
nign finding, respectively) as well as for category 5 als in dedicated screening centers in order to not
(finding highly suggestive of malignancy), there has mix their group characteristics with those of symp-
been a relative high percentage of discordance par- tomatic patients. It can be argued that this indeed
74 S. O. Schoenberg and M. F. Reiser
increases participation in the screening program, slice CT scanner with four respectively eight detec-
ensures a more standardized screening approach tor rows in combination with 3D visualization of
and reduces overestimation of the true prevalence the colon while the latter study was performed on
of a disease. single-, dual- and four-slice CT with 2D visualiza-
In a clinical radiological department with a broad tion of the data.
diagnostic and therapeutic spectrum, on the other In addition, state-of-the-art equipment is man-
hand, the radiologists might encounter certain dis- datory for those diagnostic exams exposing the pa-
eases more frequently due to pre-selection of the re- tient to ionizing radiation. In a study by Graser et
ferred patients. For those patients with a known dis- al. (2006) radiation exposure from CT colonography
ease the workflow for further diagnostic work-up and could be reduced by approximately 30% using mod-
treatment is frequently optimized. This also includes ulation of the tube current, a technique that has just
the use of expensive or complex imaging modalities been recently introduced.
for disease verification that can only be operated eco- In conclusion, high-end equipment is frequently
nomically if used for patients and positive screen- mandatory for screening particularly in rapidly
ing individuals together. Examples of this are the evolving fields. In order to justify the costs, this
follow-up of small 5–14 mm pulmonary nodules on equipment should be primarily installed in centers
high-resolution multi-slice CT data sets using volu- with high throughput of screening studies to ensure
metric post-processing software or the characteriza- its economic use. In areas of rapidly advancing tech-
tion of these nodules by PET or PET-CT, respectively. nology, some financial commitment of the screen-
Of course, this further work-up can also be initiated ing individuals may be unavoidable for the sake of
through a dedicated screening center by referral to a adequate quality.
clinical department; however, this requires thorough
optimization of the work-flow in order to not increase
the rate of study drop outs or under-diagnosis.
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cer 37:159–172 268
Technical Prerequisites: Whole-Body MRI 77
Technical Prerequisites 6
6.1 Whole-Body MRI
Olaf Dietrich and Stefan O. Schoenberg
CONTENTS
In contrast to organ-related MRI, which is usually
6.1.1 Technical Basics of Whole-Body MRI 77 focused on a relatively small anatomic region such
6.1.1.1 Hardware Restrictions 77 as the brain or the abdomen, data from a substantial
6.1.1.2 Acquisition Strategies 78 portion of the human body – ideally from head to
6.1.1.3 RF Coil System 80
toe – is acquired in whole-body imaging. An early
6.1.2 Hardware for Whole-Body MRI 80 demonstration is given in the article by Edelstein
6.1.2.1 Conventional MR Systems 80
6.1.2.2 Rolling-Table-Platform MRI 80 et al. (1980) with axial MRI sections from the head,
6.1.2.3 Dedicated Whole-Body MRI Systems 81 thorax, abdomen, and the thighs of a subject.
6.1.3 Parallel Imaging 81 Whole-body MRI in the broader sense includes
6.1.3.1 Accelerating MRI 81 all kinds of protocols that acquire data from an
6.1.3.2 Technical Implementation of extensive scan range in head-foot direction – not
Parallel Imaging 82 necessarily with identical scan parameters, image
6.1.3.3 Advantages and Disadvantages of
Parallel Imaging 82 contrasts, or pulse sequence types for all examined
6.1.4 MR Protocols and Pulse Sequences 84
anatomic regions. In the narrower sense, whole-
body MRI refers to the integrated acquisition of data
References 86
with identical contrast from a substantial portion of
the human body such that it can be composed to a
6.1.1 single large data set after the acquisition. In the past,
Technical Basics of Whole-Body MRI this appealing comprehensive approach was highly
restricted due to limitations in speed and spatial res-
Magnetic resonance imaging (MRI) has the substan- olution of the acquisitions. Only new MRI technol-
tial advantage over other imaging modalities that an ogy and acquisition techniques introduced in recent
excellent soft-tissue contrast for assessment of mor- years enabled the fast acquisition of high-quality
phology can be combined with evaluation of func- and high-resolution data from a large scan range in
tion and metabolism. Due to the lack of exposure to head-foot direction as described below.
radiation or iodinated contrast agents, imaging can
be multiply repeated and extended to the entire body
within a single MR scan. Thus, it is not surprising 6.1.1.1
that whole-body MRI has been discussed since the Hardware Restrictions
early beginnings of clinical MRI, and is mentioned,
e.g. in articles by Lauterbur (1980), Mansfield et All acquisition strategies for whole-body MRI are
al. (1980), and Edelstein et al. (1980). limited by two geometrical restrictions of each MRI
system: the maximum possible field of view in head-
O. Dietrich, PhD foot direction and the maximum possible range of
Department of Clinical Radiology, University Hospitals – table movement within the magnet (Fig. 6.1.1). The
Grosshadern, Ludwig-Maximilians-University of Munich, choice of the most adequate or efficient whole-body
Marchioninistraße 15, 81377 Munich, Germany imaging technique depends on these system prop-
S. O. Schoenberg, MD
Professor, Department of Clinical Radiology, University Hospital
erties.
Mannheim, Medical Faculty Mannheim, University of Heidel- The maximum possible field of view in head-foot
berg, Theodor-Kutzer-Ufer 1–3, 68167 Mannheim, Germany direction is typically somewhere between 30 cm
78 Olaf Dietrich and Stefan O. Schoenberg
Maximum possible
field of view in Fig. 6.1.1a,b. Hardware restric-
head-foot direction
tions relevant for whole-body
MRI. a The maximum possible
b field of view (shown in light
blue) in head-foot direction re-
stricts the anatomic range that
can be acquired in a single scan;
its typical size is about 50 cm.
b The maximum possible range
of table movement restricts the
total field of view accessible in a
whole-body protocol; this range
is typically between 160 cm and
Maximum possible range of table movement 210 cm
Time t
Station 4
a Whole-body MRI with 5-station approach Station 5
Table position z
Time t
b Moving-table MRI, axial acquisition
Table position z
Fig. 6.1.2 a–c. Acquisition strategies for whole-body MRI. a Whole-body acquisition in five separate stations (colour-coded
from red to blue); each station is acquired in coronal orientation. b Moving-table MRI with acquisition of axial slices. Dur-
ing scanning, the patient is being moved continuously through the magnet. c Moving table MRI with coronal acquisition.
The patient is continuously moved as in b, but data is acquired in coronal orientation
every station, restricted only by the capabilities of However, it is generally more time-efficient than mul-
the post-processing software. Disadvantages of the tiple consecutive acquisitions and less sensitive to
multi-station approach are geometric distortions in geometric distortions since the field of view in axial
areas that are distant (in axial direction) from the direction can be restricted to a relatively small area
isocentre of the magnet. These distortions can com- in the exact isocentre of the magnet, which is par-
plicate the fusion of the acquired data sets, in partic- ticularly advantageous in scanners with ultra-short
ular, since distortions generally look different at the magnets. An obvious precondition for this approach
superior and inferior border of the field of view. In is that the table can be moved automatically during
addition, the multi-station approach is less time-effi- scanning and is controlled by the pulse sequence in-
cient than continuous scanning since the acquisition stead of the conventional user interface at the magnet.
must be paused during table movement. Finally, the Numerous acquisition schemes have been proposed to
current development of scanners with reduced fields implement continuously moving table MRI for differ-
of view in head-foot direction requires an increased ent pulse sequences or different image orientations.
number of stations to cover the whole body. E.g. in- A relative simple approach is the continuous acquisi-
stead of four stations with a head-foot field of view tion of a single axial slice in the isocentre during table
of 50 cm and 5 cm overlap to cover a total length of movement using an ultra-fast or single-shot sequence
180 cm, some newer scanners require protocols with (Barkhausen et al. 2001). In this case, only the slice
35-cm fields of view in head-foot direction and, thus, position must be updated appropriately in order to
need six stations (including station overlap) to cover reconstruct the whole-body data set. However, acqui-
the same volume. This further reduces the time-ef- sitions with slower sequences, coronal orientation, or
ficiency of the multi-station approach. three-dimensional Fourier encoding require more
Scanning during continuous table motion requires substantial changes to the sequence and reconstruc-
specific scanner hardware, pulse sequences and re- tion technique in order to correct for motion effects
construction algorithms, and, thus, is more compli- during the acquisition (Dietrich and Hajnal 1999;
cated to implement than the multi-station approach. Kruger et al. 2002).
80 Olaf Dietrich and Stefan O. Schoenberg
6.1.2 6.1.2.2
Hardware for Whole-Body MRI Rolling-Table-Platform MRI
(integrated in the magnet). Compared to a set of isocentre that actively receive signals is consider-
surface coils lying directly on top of the patient, the ably lower than the total number of coil elements;
fi ll factor and signal-to-noise ratio of the BodySURF/ typically, 20–30 elements can be used in parallel for
AngioSURF system is still reduced, but, on the other RF reception requiring 20–30 parallel RF channels.
hand, the coil setup is less complex and the patient Providing up to 32 parallel RF channels is also an
comfort is slightly increased. important precondition for the flexible application
This rolling-table-platform approach has been of parallel imaging as described below.
used in various whole-body applications, e.g. for In addition to enhanced RF technology, dedi-
whole-body MR angiography with data acquisition cated whole-body scanners require also appropriate
in five (Ruehm et al. 2000) or six (Herborn et al. image reconstruction systems. By receiving data in
2004) stations or for whole-body STIR MRI in sev- parallel from 32 RF channels, the total amount of
eral stations (Ghanem et al. 2006). It is also com- image data is increased by a factor of 32 compared
patible with acquisitions during continuous table to conventional MRI systems. This huge amount of
movement as demonstrated by Barkhausen et al. data should be processed and reconstructed in rea-
(2001) using a real-time TrueFISP sequence and a ta- sonable time requiring both a large RAM of several
ble speed of 5 cm/s. With this approach, whole-body gigabytes and fast main processor technology.
examinations with a 150-cm field of view in axial
direction could be performed in a total scan time of
about 30 s which is comparable to CT examination
times. However, the obtained spatial resolution of
only 2 × 4 × 8 mm³ voxel size is substantially lower 6.1.3
than in dedicated state-of-the-art MRI scans. Parallel Imaging
6.1.2.3 6.1.3.1
Dedicated Whole-Body MRI Systems Accelerating MRI
Recently, several MRI systems have been introduced MRI acquisitions can be very time-consuming since
that were specifically designed for whole-body ap- k-space data is typically acquired line by line and
plications (Schmidt et al. 2004; Kramer et al. 2005; the pulse sequence must be repeated for each of
Schlemmer et al. 2005; Fenchel et al. 2005). In these lines in order to build up a full data set in k-
contrast to earlier approaches, whole-body MRI is space. Even with the minimum possible echo times
made possible with these newer systems in a rea- and repetition times, the total acquisition time of a
sonable examination time and, in particular, with data set may be unacceptably long for many state-of-
an image quality comparable to the one of a dedi- the-art MRI applications such as fast dynamic MR
cated examination of an anatomic region. This is angiographies, perfusion MRI, MR imaging of the
achieved by combining different techniques such as cardiac function, or, in particular, for high-resolu-
newly developed surface matrix coil systems, fully tion whole-body MRI with very large data sets.
software-controlled table movement, improved im- Consequently, accelerating MRI has been one of
age post-processing software, and accelerated im- the key incentives that resulted in the enormous
age acquisition using parallel-imaging techniques technical progress of MRI during the last two dec-
(described in detail in Sect. 6.1.3). ades. While early milestones in the history of accel-
A key feature of these dedicated whole-body MRI erated MRI were fairly general improvements such
scanners is an optimized multi-element surface coil as the introduction of fast gradient-echo or turbo-
system that covers the patient completely and allows spin-echo pulse sequences or the partial-Fourier ap-
MRI with high signal-to-noise ratio. These matrix proach in the mid-1980s, subsequent developments
coil systems consist of up to about 100 coil elements became more and more specific and limited to cer-
(cf. Fig. 3 in chapter “Diagnostic algorithms for tain applications. These include in particular tech-
whole-body exams” by H. Kramer) that are simulta- niques such as key-hole imaging or echo sharing
neously connected to the scanner hardware and can that were especially designed for fast dynamic MRI
be selected individually or automatically as saved applicable only with a small number of very specific
in the protocol. The number of coil elements in the pulse sequences and imaging protocols.
82 Olaf Dietrich and Stefan O. Schoenberg
In contrast to these specifics approaches, an idea densities in two phase-encoding directions is pos-
for accelerated acquisitions proposed in the second sible in 3D MRI and results in higher total reduction
half of the 1990s has found wide acceptance in virtu- factors. The maximum reduction factor is limited by
ally all areas of MRI: this approach is now known as the number of independent coil elements or sepa-
parallel imaging, parallel MRI, (partially) parallel rate receiver channels of an MRI system. Thus, the
acquisition (PPA), or parallel acquisition techniques most important precondition for the applicability
(PAT) (Dietrich et al. 2002; Heidemann et al. 2003; of parallel imaging is a multi-channel MRI system
Bammer and Schoenberg 2004; Schoenberg et al. with several parallel receiver channels as well as ap-
2007). propriate multi-channel coil systems.
Parallel imaging soon turned out to provide ex- Technically, data acquisition for parallel MRI is
traordinary advantages in almost all areas of MRI, very similar to acquisition schemes of conventional
and thus, became one of the most important techni- pulse sequences. Most relevant techniques of MRI
cal advances in current MRI technology. This was can relatively easily be adapted to parallel imaging,
possible since parallel imaging can be applied to since the data acquisition is essentially equivalent
practically all types of pulse sequences and imaging to an acquisition of a reduced (rectangular) field of
protocols, ranging from high-resolution morpho- view in phase-encoding direction.
logical imaging over various functional imaging To reconstruct images from undersampled k-
techniques to ultra-fast dynamic MRI. In addition to space data, it is important to know the coil sensitiv-
substantially accelerated imaging, parallel MRI has ity profi les of each coil element, which describe the
been found to increase robustness of MR examina- spatial intensity distribution of the received signal
tions and to reduce blurring of single-shot acquisi- as shown in Figure 6.1.3a. Coil sensitivity profi les
tions as well as susceptibility and motion artefacts. can be measured either at the beginning of an ex-
amination for a specific coil configuration or inte-
grated in the accelerated scan as additional k-space
6.1.3.2 lines, which are also referred to as auto-calibration
Technical Implementation of Parallel Imaging signals. The integrated acquisition of coil sensitivity
profi les slightly increases the scan duration but sub-
The basic idea of parallel imaging is to employ sev- stantially improves the robustness of acquisition,
eral independent receiver coil elements in parallel to since the influence of motion between the measure-
reduce the number of required phase-encoding steps ment of the coil sensitivities and the actual scan is
for a given matrix size. Thus, a certain amount of the reduced.
spatial encoding originally achieved by the phase- As mentioned above, image reconstruction of
encoding gradients is now substituted by evaluating parallel-imaging raw data is algorithmically and
data from several coil elements with spatially differ- computationally much more demanding than con-
ent coil sensitivity profi les. The reduction of phase- ventional Fourier-transform reconstruction, and
encoding steps is achieved by reducing the sampling considerable efforts have been made to develop op-
density in k-space as illustrated in Figure 6.1.3, i.e. timized reconstruction algorithms. Today, several
k-space is undersampled by acquiring only every alternative reconstruction techniques are used for
second or, more general, every R-th line for an R-fold parallel imaging (Blaimer et al. 2004; Griswold
acceleration. As a consequence, a straight-forward 2007); the most common approaches are known
conventional image reconstruction of these data sets by the acronyms SENSE (Pruessmann et al. 1999),
would result in several images (one from each coil SMASH (Sodickson and Manning 1997), and
element) with reduced field of view in phase-encod- GRAPPA (Griswold et al. 2002).
ing direction and, hence, severe aliasing artefacts.
In order to reconstruct a single image set without
aliasing artefacts, specific parallel-imaging recon- 6.1.3.3
struction algorithms are required, which are sub- Advantages and Disadvantages of
stantially more complicated than the conventional Parallel Imaging
Fourier transform.
Raw data reduction factors (R) between 2 and 6 The major challenge for the successful implementa-
can typically be achieved with parallel imaging in a tion of parallel imaging in clinical routine was the
single direction; a combination of reduced sampling required multi-channel MRI technology which ini-
Technical Prerequisites: Whole-Body MRI 83
Fig. 6.1.3a–c. Data acquisition and image reconstruction in parallel MRI. a Data is acquired by four coil elements with
different spatial sensitivity profi les in parallel. b Four sets of reduced raw data are available for image reconstruction. Each
of these data sets corresponds to an aliased image from one of the coil elements. c Specific reconstruction algorithms are
required to reconstruct the image in parallel MRI (with permission from: Schoenberg SO, Dietrich O, Reiser MF (2007)
Parallel imaging in clinical MR applications. Springer, Berlin Heidelberg New York)
tially limited its widespread use. Only few MRI sys- tion, SNR will be locally decreased if the coil geom-
tems had already provided this ability when parallel etry (i.e. the spatial arrangement of coil elements) is
imaging became generally known, but since then not ideal with respect to the chosen phase-encoding
the number of receiver channels has been substan- direction and acceleration factor. This influence is
tially increased from year to year. Simultaneously, described by the g-factor, a spatially varying quan-
the image reconstruction systems became substan- tity with values greater than or equal to one. Thus,
tially faster such that large parallel-imaging data the signal-to-noise ratio, SNR R, of a parallel-imag-
sets could be processed. Thus, parallel imaging can ing acquisition with acceleration factor, R, can be
now be clinically used at the vast majority of all summarized (Pruessmann et al. 1999) as
clinical and research sites.
The main disadvantage of parallel imaging apart
from hardware requirements is a reduced signal-to-
noise ratio (SNR), which is described by two factors:
the effects of the reduced scan time and the so-called where SNR0 is the SNR without parallel imaging and
geometry factor (g-factor). Accelerating an acquisi- g is the g-factor.
tion by a factor, R, reduces the SNR by the same ex- It should be noted that a particular difficulty aris-
tent as decreasing signal averaging from R-fold to 1, ing from the spatially varying g-factor and, thus,
i.e. SNR is reduced to the square root of 1/R. In addi- from the spatially varying noise level is the reliable
84 Olaf Dietrich and Stefan O. Schoenberg
measurement of signal-to-noise ratios in images ac- weighted MRI, short-TI inversion-recovery (STIR)
quired with parallel MRI. Due to the variable noise MRI, or contrast-enhanced whole-body MR angi-
level it is not possible to determine the image noise ography (MRA). In the following paragraphs, some
in a background region and extrapolate this value typical protocol parameters are presented that can
to the foreground region of interest; instead, more be realized with dedicated state-of-the-art whole-
sophisticated techniques of SNR measurement must body MRI systems.
be employed for parallel imaging data (Dietrich et An example of a whole-body MRA examina-
al. 2005; Reeder 2007). tion is shown in Fig. 6.1.4a. The protocol consists
The most important advantage of parallel imag- of four stations covering the carotid arteries, the
ing is of course the reduced acquisition time or, if abdominal vessels, the upper-leg, and the lower-leg
the scan time is held constant, the increased spa- arteries, and is acquired with two separate injec-
tial resolution. This is particularly important in tions of a gadolinium chelate contrast agent. Ul-
breath-hold applications with sufficient SNR such tra-fast three-dimensional spoiled-gradient-echo
as contrast-enhanced pulmonary or renal MR angi- sequences are used for all stations. The carotid
ography where the SNR loss due to parallel imaging MRA is acquired fi rst immediately followed by a
is not critical. Further advantages of reduced scan table movement to the lower-leg territory. If this
times are higher temporal resolution in dynamic table movement is sufficiently fast, i.e. faster than
MRI, less sensitivity to motion, and increased pa- the transit time of the contrast bolus passing from
tient through-put. In addition, several single-shot the carotid arteries to the lower legs, this allows the
techniques such as echo-planar imaging or single- acquisition of a pure arterial contrast in the lower
shot turbo-spin-echo sequences benefit from paral- legs. A second injection is performed to acquire
lel imaging, since shorter echo trains result in re- data of the abdomen and the upper legs. Using a
duced blurring as well as decreased susceptibility 3-Tesla whole-body system with dedicated surface-
effects and geometric distortions. coil systems and parallel imaging with acceleration
High-resolution whole-body MRI in particular factors of R = 2 or R = 3, an isotropic spatial reso-
benefits from acceleration with parallel-imaging lution of less than 1 × 1 × 1 mm³ can be obtained
techniques because of the very large amount of data in the carotid and the lower-leg territory. In the ab-
typically acquired in these examinations. Therefore, domen and the upper legs, a slightly lower isotropic
dedicated whole-body MRI systems (cf. Sect. 6.1.2.3) spatial resolution of less than 1.2 × 1.2 × 1.2 mm³
are now designed for the flexible application of par- is obtained due to the larger slab volume and the
allel imaging in all slice orientations. This includes required shorter scan times. Similar protocols with
a large number of (e.g. 32) parallel receiver chan- slightly reduced spatial resolutions are also feasi-
nels and coil arrays with elements that are arranged ble on dedicated 1.5-Tesla whole-body scanners
around the subject and allow for high acceleration (Kramer et al. 2005).
factors in all spatial directions. In order to cope with Examples of whole-body MRI with STIR and T1
the large amount of acquired data and the compli- contrast are shown in Fig. 6.1.4b,c, respectively.
cated image reconstruction algorithms, the recon- These data sets are acquired with two-dimensional
struction systems have also been extended accord- turbo-spin-echo sequences in coronal orientation
ing to the demands of parallel-imaging techniques. covering five stations from head to toe on a 1.5-Tesla
whole-body scanner. Again, dedicated surface coil
systems and parallel imaging with acceleration fac-
tors of R = 2 or R = 3 were applied. T1-weighted
images are acquired with an in-plane resolution
6.1.4 of 1.1 × 1.3 mm², STIR images with a resolution of
MR Protocols and Pulse Sequences 1.3 × 1.8 mm²; the slice thickness was 5 mm in all
body regions. The total acquisition time for all five
Today, whole-body MRI can be performed with an stations is about 17 min for the T1-weighted scans
image resolution and signal contrast comparable and 11 min for the STIR scans (Schmidt et al. 2005).
to the one of dedicated imaging of a single organ. In screening protocols, these whole-body acquisi-
Whole-body MRI may comprise several different tions are typically combined with further examina-
morphological and functional whole-body exami- tions such as perfusion and functional cardiac MRI,
nations including whole-body T1-weighted or T2- high-resolution HASTE imaging of the lungs, or dif-
Technical Prerequisites: Whole-Body MRI 85
a b c
Fig. 6.1.4a–c. Examples of whole-body acquisitions. a Contrast-enhanced MR angiography, acquired in four stations; shown
is a maximum-intensity projection (MIP) reconstruction of the three-dimensional data set. b STIR MRI acquired in five
stations. c T1-weighted MRI acquired in five stations
become feasible for T1-weighted or STIR acquisi- Whole-body MR angiography using a novel 32-receiving-
tions in reasonable scan times. channel MR system with surface coil technology: fi rst cli-
nical experience. J Magn Reson Imaging 21:596–603
Whole-body applications based on continuous Ghanem N, Lohrmann C, Engelhardt M, Pache G, Uhl M,
table movement have not yet reached the spatial res- Saueressig U, Kotter E, Langer M (2006) Whole-body MRI
olution which is routinely obtained with the multi- in the detection of bone marrow infi ltration in patients
station approach although considerable progress with plasma cell neoplasms in comparison to the radio-
logical skeletal survey. Eur Radiol 16:1005–1014
has been made recently. E.g., Zenge et al. (2005) de-
Griswold MA (2007) Basic reconstruction algorithms. In:
scribed sagittal and coronal moving-table MRI with Schoenberg SO, Dietrich O, Reiser MF (eds) Parallel ima-
an in-plane resolution of 1.6 × 1.6 mm²; however, ging in clinical MR applications. Springer, Berlin Heidel-
they only acquired 13 slices of 10 mm thickness with berg New York, pp 19–36
a slice gap of 15 mm. The total acquisition time was Griswold MA, Jakob PM, Heidemann RM, Nittka M, Jellus
V, Wang J, Kiefer B, Haase A (2002) Generalized autoca-
119 s for a coronal whole-body acquisition. Thus, the librating partially parallel acquisitions (GRAPPA). Magn
moving-table approach appears particularly useful Reson Med 47:1202–1210
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whole-body MRA protocols using continuous table K, Stoesser D, Ruehm SG, Debatin JF (2004) Whole-body
movement. Considering the increasing availability 3D MR angiography of patients with peripheral arterial
of ultra-short magnets and the continuing develop- occlusive disease. AJR Am J Roentgenol 182:1427–1434
Kramer H, Schoenberg SO, Nikolaou K, Huber A, Struwe A,
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Technical Prerequisites: CT 89
Technical Prerequisites 6
6.2 CT
Christoph Becker, Anno Graser, and Peter Herzog
Conventional mechanical CT scanners with an cation of calcified coronary lesions, the workstation
X-ray tube and detector ring rotating around the may automatically display the quantities of coronary
patient have also increased in speed within the re- calcium as Agatston score, volume equivalent and
cent years. The scan mode dedicated to coronary absolute mass. According to the method proposed
CT is called retrospective ECG gating (Flohr and by Agatston, any dense structure in the CT image
Ohnesorge 2001). For this technique the spiral CT > 130 HU in density is defined as calcification. The
scan is acquired with a small pitch (table feed per area of this calcification is multiplied by a factor that
gantry rotation < 0.3). The following image recon- depends on the peak density of the lesion. A factor
struction is then performed also in the slow mo- between 1 and 4 is used for a peak density of 130–
tion diastolic phase of the cardiac cycle. Coronary 199 HU, 200–299 HU, 300–399 HU and > 400 HU, re-
calcium quantities measured with the first clinical spectively. The sum of all lesions in all four coronary
available multi-detector-row CT (MDCT) scanner vessels (left main, left anterior descending, circum-
with 4-detector-rows and a temporal resolution of flex and right coronary artery) then corresponds to
250 ms are well comparable to data derived from the total Agatston score (Agatston et al. 1990). This
EBCT (Becker et al. 2000; Carr et al. 2005). algorithm requires specific EBCT image quality and
A 4-detector-row CT with 500 ms gantry rotation non-overlapping slice thickness of 3 mm. Therefore;
time is the minimal requirement for a coronary cal- the Agatston quantification method is only of lim-
cium measurement with MDCT. Coronary calcium ited value for MDCT and even difficult to reproduce
screening can be performed without contrast media by different EBCT scanners.
and with 3-mm slices. Retrospective ECG gating is Originally, the investigation with the first EBCT al-
superior to acquire the entire volume without any lowed only for acquisition of half of the entire heart
gaps and to reconstruct the images with overlapping because not more than 20 slices could be acquired at
increment. An overlapping slice reconstruction may once. The limited reproducibility by this approach
help to improve the reproducibility (Ohnesorge et became obvious (Hernigou et al. 1996) and because
al. 2002). Depending on the MDCT scanner used the of that various authors suggested algorithms to im-
scan time is in the range of 5–20 s and the entire in- prove the reproducibility. To track the progression
vestigation can be completed within 5 min. In total of calcium in the course of a therapeutic treatment,
40–80 slices are generated for one complete investi- it was necessary to introduce the calcium volume
gation. equivalent (Callister et al. 1998). With isotropic in-
As a fundamental requirement for screening the terpolation, overlapping slice acquisition can be sim-
radiation exposure for coronary calcium scanning ulated by a workstation and the reproducibility of the
needs to be reduced to a minimum (approximately quantification can be improved to a certain degree.
1–2 mSv for coronary calcium screening). In par- However, real overlapping slice acquisition and re-
ticular, for the assessment of coronary atheroscle- construction is always superior to isotropic interpola-
rosis in asymptomatic subjects, it is desirable to tion and should be applied when MDCT (Ohnesorge
avoid any redundant radiation. Based on the ECG et al. 2002) with retrospective ECG gating is used.
signal, the X-ray tube current can be switched to The volume equivalent as well as the Agatston score
its nominal value during the diastolic phase and is limited by the fact, that the quantity of the calcium
may be reduced significantly during the systolic volume depends on the image quality and on scan pa-
phase of the heart beat, respectively. The technique rameters and therefore these values cannot easily be
is called prospective ECG tube current modulation transferred from EBCT to MDCT.
or ECG pulsing. This technique is most effective in In general, it is possible to quantify the abso-
patients with low heart rates and only works with lute amount of coronary calcium by using a stand-
regular sinus rhythm. If the heart rate is around 60 ard calibration phantom in CT (Ulzheimer and
beats per min, the radiation exposure will be re- Kalender 2003). For this standardization the
duced by approximately 50% by using ECG pulsing calibration phantom must be scanned with those
(Jakobs et al. 2002). parameters, which will later be used for the patient
Even the tiniest calcification will become visible investigation. As the mass of the calcium particles
by the reconstruction with a dedicated non-edge en- in the phantom are known, it is possible by measure
hancing soft tissue kernel. After the reconstruction the volume and density of the calcium from the CT
the image data need to be analyzed and post-proc- image and then to determine the calibration factor
essed using a dedicated workstation. After identifi- for absolute quantification.
Technical Prerequisites: CT 91
However, in investigations of patients the accu- ticular in a screening setting, a lower tube voltage
racy of the measurement may also be influenced by of 100 kVp or 80 kVp can be employed to further
the different patient sizes. The X-ray absorption is decrease the radiation dose (Huda 2002). Recon-
different in thin as compared to obese patients, in struction should be performed using a medium
whom beam hardening will occur, resulting in dif- sharp lung kernel and an overlapping increment.
ferent densities for the same amount of calcium de- Reconstructed slice thickness should be slightly
pending on the patients size. Therefore, the calibra- greater than collimation to reduce noise and to
tion phantom needs to be scanned with “fat rings” smooth pitch artefacts.
simulating different patient sizes and delivering With recent generations of MDCT scanners, a da-
different calibration factors. In investigations of pa- tasets of 500–600 axial images is created for further
tients the scout view will be used to determine the post-processing. A secondary reconstruction with
diameter of the chest for the selection of the appro- a greater section thickness (e.g. 6 mm) can be ob-
priate calibration factor. In practice, the calibration tained in order to generate a second data set with a
phantom is measured without, one and two fat rings, reasonable number of images suited for fi lming or
respectively. For a chest diameter < 30, 30–38 and printing.
> 38 cm the calibration factor with no, one and two Reading should be performed using a worksta-
fat rings is used, respectively. tion. To avoid reading an excessive number of in-
Recently an “International Consortium on Stand- dividual axial slices (500–600) image by image, a
ardization in Cardiac CT” has tried to establish a thin sliding MIP, MPR or VRT reconstruction can
standardized algorithm for coronary calcium meas- be used for a more effective reading. Thin sliding
urements for all different CT vendors. This consor- MIPs have already proven to be the most suitable for
tium also tries to built up a database by collecting delineating small pulmonary nodules and to distin-
data obtained in a standardized fashion to provide guish them from pulmonary vessels.
reference values for the absolute mass of coronary Typical patterns of calcification and fatty tissue
calcium (McCollough et al. 2003). within a pulmonary nodule are highly suggestive of
a benign lesion.
Thin slices enable to better analyze the internal
structure of a nodule while thicker slices may ob-
scure fat or small calcifications due to partial vol-
6.2.3 ume effects. Those subtle features the benign na-
Screening for Lung Cancer ture of a particular intrapulmonary nodule, e.g. a
hamartoma.
MDCT, with the ability of examining the entire Histogram analysis may be useful to detect cal-
thorax with thin slice sections in one breath hold, cifications or fat when present only in few voxels.
aids in the non-invasive evaluation of indetermi- The number of voxels containing fat and calcium
nate pulmonary nodules. A collimation of 1 mm densities as well as the overall density can be deter-
or below should be selected for scanning. The mined.
pitch can be increased up to 1.75, depending on Appropriate histogram analysis can only be ob-
the capabilities of the scanner and the number of tained when thin slices are used so that major par-
detector rows. Scan time should not exceed 25 s tial volume effects are excluded whereas thick slices
for a acceptable breath hold time. If only the lung would show average densities around soft tissue
parenchyma has to be evaluated for pulmonary values. The best way to obtain such histograms is
nodules, as it is the case in lung cancer screening, to apply the algorithm generating the histogram to
tube current and the resulting radiation dose can a segmented 3D-dataset. When using segmented
be drastically reduced compared to a staging CT data, the histogram will contain only data from the
of the thorax (Swensen 2002). In such cases no nodule. Using 3D-data ensures that the histogram
i.v. contrast material needs to be administered. contains data from the entire nodule and not only
For appropriate evaluation of the mediastinum from individual slices in which relevant areas may
and the chest wall, standard radiation dose set- not be included. Generating segmented datasets and
tings and intravenous contrast administration is applying them to histogram analysis require dedi-
required. In most cases, a tube voltage of 120 kV cated software that is not yet implemented in stand-
is appropriate for examining the thorax. In par- ard PACS environments.
92 C. Becker, A. Graser, and P. Herzog
The segmentation of 3D-datasets is a mathemati- be the most suitable method for the non-invasive
cal process that divides the dataset in areas with the characterization of lung lesions and help to avoid
same properties. When segmenting pulmonary nod- unnecessary invasive procedures with the morbid-
ules, each voxel of the dataset is evaluated and clas- ity and mortality inherent to it.
sified as either being part of the nodule or not. In this Whether lung cancer screening will be accept-
process, the greyscale image data are transformed ed as a beneficial method to be recommended for
into a binary image (2 value image). The algorithm populations at increased risk of lung cancer largely
determines the borders (surface) of the nodule based depends on its ability to reduce mortality and/or
on HU-values of the individual voxel. For this rea- morbidity at acceptable costs and harmful effects.
son the segmentation process is primarily based on In order to achieve this, it is mandatory to reduce
a thresholding processes. A threshold of 200 HU radiation exposure as much as possible, to avoid in-
has proven to be most efficient for the segmentation vasiveness in the work up of suspicious lesions and
of round pulmonary lesions. While a solid soft tis- to guarantee the highest possible accuracy in the
sue mass has higher HU-values than -200 HU (most management of screened individuals.
commonly around 70–80 HU if not calcified), even
with thin slice isometric data a higher threshold
would cause underestimation of the nodule size or
shape due to partial volume effects. This algorithm,
of course, can only segment a nodule that has no 6.2.4
contact to other non-nodular structures. Screening for Colon Cancer
Therefore, the segmentation of lesions that are at-
tached either to vessels, bronchi or the pleura is a con- CT colonography (CTC) has great potential of becom-
siderable challenge for all segmentation algorithms. ing an important alternative technique to screen for
Such structures should be identified and then sepa- colorectal neoplasia. Imaging the colon traditionally
rated from the nodule. One possible solution is to use required use of an endoscope. Theoretically, con-
an algorithm that aims at fitting a spherical outline ventional video endoscopy allows for visualization
into each identified structure and reducing its radius of the entire colon as well as removal of lesions for
until both structures are separated. This method has histopathologic work up. Data from several centers
the disadvantage of changing the number of voxels suggest that CTC surpasses barium enema and ap-
defining the nodule; thereby also changing the vol- proaches conventional colonoscopy in the detection
ume of the nodule. A more suitable method is to use a of colorectal adenomas (Pickhardt et al. 2003; Yee
morphological opening filter to smooth the surface of et al. 2001). In this chapter, technical prerequisites
a nodule and to eliminate structures connected to its for CT colonography will be summarized.
surface. This is a quite common method in digital im- The arrival of multidetector row CT (MDCT) made
age processing but has not yet found widespread use CT colonography faster and enabled screening for
in the context of medical imaging. Using mathemati- small colonic lesions due to its superior spatial reso-
cal operators, irregularities of the contour are elimi- lution. Technical limitations of single slice CT, such
nated by erosion and the “shrinking” of the volume is as long scanning times and poor resolution could be
compensated by a final dilatation procedure. overcome. Large volume coverage and thin collima-
This, potentially, is a rather effective, albeit sim- tion at very short scan times of as little as 7–8 s per pa-
ple way of distinguishing nodules from surround- tient position has become reality with the introduction
ing structures and to eliminate the latter. This way, of 64-MDCT scanners. In order to achieve ultra high
most of the lesions attached to vessels, bronchi or resolution, image reconstructions should be based
the pleura can be separated correctly. Other algo- on overlapping sub-millimeter slices. The enormous
rithms have been developed and are already in the amount of data per examination has to be handled by
process of clinical evaluation which may further PACS and the 3D post-processing workstation. The im-
facilitate segmentation of pulmonary nodules from portance of image postprocessing and three-dimen-
surrounding structures (Kido et al. 2002). sional image reconstructions has been emphasized by
With thin slice MDCT-data accurate CT-volum- several authors (Pickhardt et al. 2003; Vos et al. 2003;
etry can be performed based on automated segmen- Yasumoto et al. 2006). These technical prerequisites
tation algorithms as described above. Since growth will help to cut reading time and increase sensitivity as
is the very hallmark of malignancy, such tools may opposed to evaluation of axial slices only.
Technical Prerequisites: CT 93
Before CT data acquisition, the patient is required this preparation is called “wet prep”. Combining
to undergo certain preliminary steps to produce a PEG with bisacodyl increases bowel peristalsis and
diagnostic study. Fundamental to the performance may help reducing these residues.
of high quality CT colonography examinations is Studies comparing the efficacy of oral sodium
complete cleansing colon and good distension of the phosphate and polyethylene glycol electrolyte so-
colon, thus allowing for optimum sensitivity and lutions before fiberoptic colonoscopy have found
specificity for polyp and cancer detection. Incom- no significant difference in the quality of bowel
plete cleansing of the colon may result in false-nega- cleansing between these two agents (Afridi et al.
tive and false positive readings. Poor distension of 1995; Marshall et al. 1993) or that sodium phos-
the colon may cause missing of lesions and simulate phate is more effective than the lavage solution
annular carcinoma (Fletcher et al. 1999). Current (Cohen et al. 1994).
CT colonographic protocols include scanning in su-
pine and prone positions so that segments of the co-
lon with poor cleansing or collapse in one position 6.2.4.2
can be re-evaluated in the opposing position. Colonic Distension
continuous insufflation using a dedicated device current of 120 kV and mAs settings of 100 mAs (su-
(Burling et al. 2006). Distension will be better us- pine position) and 40 mAs (prone position). In addi-
ing an automated CO2 insufflator. Moreover, there is tion, sophisticated x, y, and z-axis dose modulation
less risk of complications as the maximum pressure algorithms allow for further reduction of radiation
is limited by the device and there is no interaction exposure by 35% (Graser et al. 2006).
with the insufflation process. CT colonography is dealing with a high-contrast
The use of hyoscine-N-butylbromide (buscopan; situation, namely the contrast between the air or CO2
not FDA approved), an anticholinergic drug, or glu- within the lumen at 1000 Hounsfield Units (HU)
cagon for CTC has been investigated. Rogalla et al. and the colonic wall itself which normally measures
found that buscopan significantly improves colonic around 40–50 HU. Therefore, scans can be acquired
distension as compared to glucagon, and that gluca- using low dose settings.
gon helps to distend the colon as compared to proto-
cols without pre-medication (Rogalla et al. 2005).
6.2.4.3
References
Stool and Fluid Tagging
Afridi SA, Barthel JS, King PD, Pineda JJ, Marshall JB (1995)
Currently patients are required to undergo a full Prospective, randomized trial comparing a new sodium
bowel cleansing regimen before CT colonography. phosphate-bisacodyl regimen with conventional PEG-ES
Reportedly, this is the most tedious part of the en- lavage for outpatient colonoscopy preparation. Gastroin-
test Endosc 41:485–489
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easier differentiation from the homogeneous soft
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tissue density of polyps. This technique has been the quantification of coronary artery calcification. AJR
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CTC with a “minimal prep” protocol may be almost (1998) Coronary artery disease: improved reproducibility
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Technical Prerequisites: Ultrasound 97
Technical Prerequisites 6
6.3 Ultrasound
Stefan Delorme
perform worse than CT or MRI. Second, ultrasound there are also recommendations of standard sec-
performs particularly badly for small metastases, tions together with key structures.
detecting less than 30%. This is not only a matter Still, three issues remain:
of size, but likewise of contrast. This is nicely dem- ● How to document healthy organs
onstrated by recent studies with contrast-enhanced ● How to document uncountable lesions exten-
ultrasound, the sensitivity of which is very well com- sively (thyroid nodules, breast cysts, liver cysts,
parable with that of CT – simply by increasing the etc.)
echogenicity of liver, but not of metastases (Giorgio ● How, in the latter case, to document their loca-
et al. 2004; Konopke et al. 2005; Passamonti et al. tion well enough to make them easy to retrieve
2005; Quaia et al. 2003). at follow-up
is mandatory for the breast, and advantageous for Ultrasound is already in wide use for pre- and
thyroid, lymph nodes, or testes. A color Doppler postnatal screening for various abnormalities. For
option, although not mandatory, may be of help in transabdominal examinations of the pregnant,
individual cases, and is usually already available on curved arrays are most commonly used, like for
advanced scanners. other abdominal studies. However, with the amni-
Intracavitary devices are occasionally used for otic fluid as an acoustic window, less absorption is
screening purposes, particularly for cancer of the ova- encountered, and higher transmit frequencies can
ries or the prostate. Here, by nature, either mechani- be used. Postnatal, abdominal scans require high-
cal sector scanners are used, or tightly curved arrays frequency curved arrays; the hip is usually scanned
with a highly divergent field of view. The scanning with a linear probe at 5 MHz or above.
frequencies range between 5 and 10 MHz.
For the abdomen, curved probes with a frequency
range between 1.5 and 6 MHz are typically used.
Sector scanners may be a useful adjunct in patients
who are difficult to scan, but the resulting images References
are poor for the near field. Linear probes are insuf-
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(1992) Detection of malignant tumors in end-stage cir-
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Whether or not ultrasound contrast agents should Röntgenstr 175:835–843
Konopke R, Kersting S, Saeger HD, Bunk A (2005) Kontrast-
be used is difficult to judge at the present stage. mittelsonographie in der Detektion von Leberraumfor-
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of hepatic metastases with low MI real time contrast
(Hohmann et al. 2003; Oldenburg et al. 2005), enhanced sonography and SonoVue(R). Ultraschall Med
while their value in screening still needs to be evalu- 26:277–284
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power imaging: comparison with contrast enhanced
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be given for screening, be their value proven or not. Porena M, Vespasiani G, Rosi P et al. (1992) Incidentally
Ultrasound, simply by being done for a variety of detected renal cell carcinoma: role of ultrasonography.
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1992; Terada et al. 1989), and in a limited stage with in 160 patients. Eur Radiol 13:475–483
a definite chance for cure (Porena et al. 1992). Again, Terada Y, Ueki T, Horiuchi D (1989) A study on six cases of
renal cell carcinoma detected by renal ultrasound during
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Technical Prerequisites: Mammography 101
Technical Prerequisites 6
6.4 Mammography
Rüdiger Schulz-Wendtland
CONTENTS 6.4.1
Technical Prerequisites for Mammography
Screening Exams
6.4.1 Technical Prerequisites for
Mammography Screening Exams 101
6.4.1.1 Quality Control (QC) 101
Screening for breast cancer by means of mammog-
6.4.1.2 QC Measurements and Frequencies 102 raphy has been proven to reduce mortality from
breast cancer.
6.4.2 Role of Conventional and This was only possible by standardisation – the
Digital Mammography 102
6.4.2.1 Digital Mammography System with
European guidelines for quality assurance in breast
FDA Licence 104 cancer screening and diagnosis (Commission of
6.4.2.1.1 Senographe 2000 D (GE Medical Systems, the European Communities 2006).
Waukesha, USA) 104 A prerequisite for a successful screening is that
6.4.2.1.2 SenoScan (Fischer Imaging, Denver, the mammograms contain sufficient diagnostic
USA) 104
6.4.2.1.3 LDBI (Hologic/Lorad, Bedford, information to be able to detect breast cancer, using
USA) 104 as low a radiation dose as is reasonably achievable
6.4.2.1.4 Selenia (Hologic/Lorad, Bedford, USA), (ALARA). This quality demand holds for every
Novation (Siemens, Erlangen, Deutschland), single mammogram. Quality control (QC) must
Digital Mammography Systems
Manufactured by Agfa, Instrumentarium,
therefore ascertain that the equipment performs at
Giotto 104 a constant high quality level.
6.4.2.1.5 FCR 5000MA (Fujifi lm, Tokyo, Japan; In the framework of “Europe Against Cancer”
Siemens, Erlangen, Deutschland) 104 (EAC) (Commission of the European Communi-
6.4.3 Results from Clinical Studies 104
ties 2003), an European approach for mammog-
6.4.3.1 Results from Senographe 2000 D raphy screening is chosen to achieve comparable
(GE Medical Systems, Waukesha, high quality results for all centres participating in
USA) 104 the mammography screening programme. Within
6.4.3.2 Results from SenoScan (Fischer Imaging, this programme, quality assurance (QA) takes into
Denver, USA) and LDBI (Hologic/Lorad,
Bedford, USA) 105 account the medical, organisational and technical
6.4.3.3 Results from Selenia (Hologic/Lorad, aspects.
Bedford, USA), Novation (Siemens, The technical prerequisites include the basic test
Erlangen, Deutschland), Digital procedures, dose measurements and their frequen-
Mammography Systems Manufactured by
cies. The use of these tests and procedures is essen-
Agfa, Instrumentarium, Giotto 106
6.4.3.4 Results from FCR 5000MA (Fujifi lm, tial for ensuring high quality mammography and
Tokyo, Japan; Siemens, Erlangen, enables comparison between centres – a minimum
Deutschland) 106 standard for implementation throughout the EC
Member States.
6.4.4 Soft Copy Reading 106
that mammography has special requirements vis-à- In digital mammography, conventional screen
vis the quality of images, and digital imaging meth- film mammography is replaced by an electronic
ods are not capable of meeting these requirements detector that absorbs the incoming X-rays and pro-
just like that. Traditional screen fi lm mammography duces an electric signal. This signal is digitalised in
is – so far – the only imaging technique that has an analogue-to-digital converter and can therefore
led to a reduction in breast cancer mortality when be processed and stored on a computer. In conven-
uses as a regular screening tool (Schreer 2001). tional film screen mammography, the entire imaging
Its advantages include its comparatively low costs, process is linked to the radiograph, whereas in digi-
a high resolution in the high contrast area (up to tal radiography, the actual imaging is split into three
20 lp/mm), and easy viewing on a viewbox. In addi- steps: recording, processing, and reproduction. This
tion to having to find a compromise between defi- means that each individual step can be optimised,
nition and exposure, the disadvantage of the SFM and in addition an opportunity arises for electronic
imaging system includes its low effective quantum imagine transfer in the sense of teleradiology. A digi-
efficiency (DQE). Owing to the sigmoid gradation tal mammogram consists of a finite number of pixels,
curve of conventional screen fi lm system, each which are arranged in a two-dimensional image
system can be usefully employed only when radia- matrix. The distance between two adjacent pixels is
tion dosages are clearly defined. known as the sampling frequency or, more gener-
The information conveyed by a radiograph is ally, as the pixel size. The grey value of each individ-
best described with the so-called signal to noise ual pixel is quantified – i.e., represented by a finite
ratio (SNR). This ratio depends on the radiation number of signals. These values range from 0 to 2n–1,
dose and the quantum flow that was used to obtain with n equalling the number of bits that are used to
the image, but also on the structural attributes of digitalise the variation of the analogue signal in the
the imaging system. The DQE is a further impor- detector. Systems than can be used for mammogra-
tant measure to gauge the capacity of a mammog- phy capture the data with a depth of up to 16 bit/pixel,
raphy system by indicating how effectively the SNR equalling 216 = 65,536 shades of grey. The greater the
or the information contained in the radiograph number of pixels and shades of grey, the greater the
– produced by X-rays that have passed through the storage requirement of an individual mammogram.
breast – is transferred on to the mammogram. The The digital mammography systems that are cur-
ideal is a transfer ratio of 1:1, i.e. a DQE of 100%. rently licensed by the US Food and Drug Adminis-
Real equipment, however, is not capable of such tration achieve a resolution of 5–12.5 lp/mm (max)
high effectivity, owing to noise and other processes to reach the very high resolution of conventional
that reduce the contrast. The resulting quality of the fi lm screen mammography (of up to 20 lp/mm). Dig-
image is therefore always reduced, and the DQE falls ital detectors would have to have a maximum pixel
to less than 100%. The reduction in the SNR results size of 25 µm, which would mean an image matrix of
in an inferior assessment (visualization?) of small 7200 × 9600 = 69.1 million pixels for a detector area
details in the breast, such as microcalcifications. for 18 × 24 cm2. Nishikawa et al. (1987), however,
The DQE is dependent on the radiation dose and found in 1987 that the detection of critical struc-
the local frequency. With the same dose, a system tures is limited more by an SNR that is too low and
with a high DQE produces images with less noise, or has too little contrast than by the resolution of the
it produces images of equal quality with a smaller digital imaging system. In spite of this finding, the
radiation dose than a system with a lower DQE. The quality of resolution and its importance in assessing
DQE enables objective comparison between differ- a digital mammography system were the centre of
ent radiographical imaging systems on the basis of technical discussions for a long time. At an Euro-
the image quality and dose efficiency. Currently no pean level, work is being done on an addendum to
standardised procedures exist to determine the DQE the section covering “digital mammography” in the
for mammography imaging systems, and especially European protocol for Quality control of the physi-
not for complete mammography workstations with cal and technical aspects of mammography screen-
a complete set of components, including images ing (EPOQ), to introduce the threshold contrast vis-
viewers. The DQE values provided by manufactur- ibility as the crucial measure of image quality. The
ers of digital mammography systems can therefore lower requirements vis-à-vis local contrast visibility
not be compared and can be used only as approxi- for digital mammography systems are being justi-
mate information. fied with the fact that lesions are detected because
104 R. Schulz-Wendtland
6.4.2.1.2 6.4.3
SenoScan (Fischer Imaging, Denver, USA) Results from Clinical Studies
results or slight superiority (not significant) of the authors did not fi nd significant differences in the
digital technique. Grebe et al. (2000) and Schulz- detection rate but a higher rate of air ingress and
Wendtland et al. (2002) also found no significant average parenchymal dose for the digital system
differences between the two systems. In a com- than for the conventional system. This study has
parative study of 692 female patients, Venta et al. met with substantial criticism with regard to dif-
2001 found agreement of conventional fi lm screen ferent variables, and in addition the results are
mammography and digital mammography in 82%, diametrically opposed to those of Hermann et al.
part-agreement in 14%, and no agreement in 4% of (2000, 2002b), who found a dose reduction of 25%
results, which they explained with interobserver for digital mammography compared with conven-
variability. Another study by Lewin et al. (2001) tional mammography. Skaane and Skjennald
that included 4945 female patients comparing con- (2004) published a further study (Oslo II) with
ventional and digital mammography and found a 10,303 patients examined with conventional and
total of 35 cases of breast cancer – the conventional 3985 patients with digital techniques. The detec-
system detected 22 cases and the digital system tion rate of cancers was 0.54 and 0.83, respectively
21 cases. The authors found no significant differ- – the results for the digital mammography were
ence in the detection rate, but a lower recall rate in significantly better. Skaane confi rmed this with a
digital mammography than in conventional mam- learning curve of the investigators by working every
mography (11.5% vs 13.8%, respectively). They did day with the digital mammography. This confi rms
not fi nd a significant difference in the rate of posi- that adequate training (2–3 months) with digital
tive biopsies (19% vs 30%). Lewin et al. (2002) in a mammography is required in order to achieve a
study with 6736 patients whose condition was gen- significantly higher accuracy, in contrast to con-
erally diagnosed through both imaging modalities, ventional screen fi lm mammography.
found 42 malignancies in 181 biopsies, of which
15 were detected exclusively though conventional
mammography and only 9 through digital mam- 6.4.3.2
mography. They did not fi nd a significant differ- Results from SenoScan
ence in the detection rate for malignancy, but a (Fischer Imaging, Denver, USA) and
lower recall rate for digital mammography. The LDBI (Hologic/Lorad, Bedford, USA)
study by Skaane et al. (2003) included 1832 women
who were examined with both techniques (addi- Studies with small-field detectors, such as the one
tionally generally double reading) (Oslo I). The published by Undrill et al. (2000) i.e. full-field
106 R. Schulz-Wendtland
6.4.3.3 6.4.5
Results from Selenia (Hologic/Lorad, Bedford, CAD
USA), Novation (Siemens, Erlangen,
Deutschland), Digital Mammography Systems CAD is the computer-assisted detection and diagno-
Manufactured by Agfa, Instrumentarium, Giotto sis in mammography, respectively. The whole process
includes image acquisition, segmentation, post-pro-
Investigations with an amorphous selenium detec- cessing and detection. The following systems are on
tor (phantom study) resulted in significantly better the market: ImageChecker M 1000 (R2-Technology),
results in clarity of detail for the digital system as Second Look (CADx Medical Systems), Mammex
compared to conventional screen fi lm mammog- TR (Scanis Inc.) and iCad (Fischer) (Table 6.4.2). In
raphy without significant interobserver variability all these systems, conventional mammograms are
(Schulz-Wendtland et al. 2003b). secondarily digitized, which is problematic. In the
literature, the detection rate of microcalcifications
is 86%–100% (Birdwell et al. 2001; Freer and
6.4.3.4 Ullssey 2001; Funovics et al. 2001), for lesions we
Results from FCR 5000MA (Fujifilm, Tokyo, have sensitivities of 67%–89% (Freer and Ullssey
Japan; Siemens, Erlangen, Deutschland) 2001; Malich et al. 2001), spiculated lesions are
detected with a sensitivity of 100% (Kegelmeyer
The available studies, among other by Schulz- et al. 1994). In double reading, CAD systems enable
Wendtland et al. (2000, 2002b), show equivalence the sensitivity of the investigators to be increased
of luminescence radiography and conventional by up to 20% (Jiang et al. 2001). Karssemeijer et al.
fi lm screen mammography and. significantly better (2003) found that diagnostic accuracy of radiolo-
results (Ideguchi et al. 2004) of high resolution gists less experienced in mammography will profit
luminescence mammography, respectively. more from CAD than more experienced mammog-
The results published by the Digital Mammogra- raphers. In addition, the interobserver variability
phy Imaging Screening Trial (DMIST) Investigators has to be considered with 15%–90% (Jiang et al.
Group under the guidance of E. Pisano online in the 2001; Karssemeijer 2000). The problem with CAD
N Engl J Med (16.09.2005) (Pisano et al. 2005), the systems is the high number of false-positive markers
only prospective, randomised clinical trial includ- up to 95% (Bick 1996; Freer and Ullssey 2001).
ing a total of 49,000 women, all examined with both
techniques (conventional screen fi lm mammogra-
phy and digital systems of different manufacturers)
separately evaluated in 11 institutions were: same
detection rate of cancer for all patients with signifi- 6.4.6
cantly better results for the digital mammography Discussion
systems in women under 50 years, radiologically
dense breasts and pre- and perimenopausal women, As of yet, few clinical studies have compared con-
respectively. ventional and digital mammography. Phantom and
Technical Prerequisites: Mammography 107
Normal Tomosynthesis
mammogram
Fig. 6.4.4. 3D digital mammography, Tomosynthesis (Novation DR TOMO, Sie-
Normal Tomosynthesis
mammogram
(Selenia, Lorad/Hologic)
synthesis, contrast-enhancement and dual-energy later detected with screening mammography and the
(Dieckmann et al. 2005; Jong et al. 2003; Lewin et al. potential utility of computer-aided detection. Radiology
219:192–202
2003; Niklason et al. 1997; Schulz-Wendtland et al. Busch HP (1999) Digitale Projektionsradiographie. Techni-
2006) (Figs. 6.4.4, 6.4.5), integrated in a PACS (Picture sche Grundlagen, Abbildungseigenschaften und Anwen-
Archiving and Communication System)-system. dungsmöglichkeiten. Radiologe 39:710–724
Cole E, Pisano E, Brown M, Kuzmiak C, Braeuning P, Kim
H, Jong R, Walsh R (2004) Diagnostic accuracy of Fischer
Senoscan Digital Mammography versus screen-fi lm
mammography in a diagnostic mammography popula-
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Technical Prerequisites: PET-CT 113
Technical Prerequisites 6
6.5 PET–CT
Gerald Antoch and Robert Stahl
Bar-Shalom et al. 2003; Lardinois et al. 2003). The imaging, it contributes to the maximal resolution
following chapter will summarize technical aspects of the technique, which is approximately 2 mm for
of PET/CT imaging and discuss its clinical value in FDG-PET.
diagnostic imaging of primary tumors and recur- Today most PET-systems and all PET/CT-systems
rent disease. provide a full-ring PET detector (360° coverage)
which surrounds the patient’s table. The size of each
detector crystal defines the spatial resolution of the
tomograph, whereas the number of detector crystals
installed in series define the axial field-of-view per
6.5.2 bed position. In modern PET and PET/CT the axial
Technical Aspects of PET and PET/CT field of view per bed position is approximately 15 cm.
Therefore PET imaging is performed discontinu-
6.5.2.1 ously for different bed positions. Depending on the
FDG-PET image quality desired, on the type of detector mate-
rial, on the amount of radioactive tracer applied as
FDG is produced by labelling deoxyglucose with 18F, well as on the patient`s weight, the acquisition time
a positron emitter with a half-life of 109 min. 18F for a single bed position may vary. In oncology typi-
decays to the stable 18O by emission of a positron cal acquisition times for FDG-PET and FDG-PET/CT
and a neutrino. The positron (e+) is an antimat- are 2–5 min per bed position.
ter particle of the negatively charged electron (e −). The PET annihilation quanta are attenuated when
The positron annihilates an electron releasing two travelling from the point of annihilation to the de-
511-keV gamma rays which travel in opposite direc- tectors of the PET scanner. The extent of PET attenu-
tions (Fig. 6.5.1). These 511-keV gamma rays are de- ation is dependent on different factors: in adipose
tected by two photoluminescent crystals and, based patients, for example, PET annihilation quanta are
on their angle of travel of approximately 180°, the attenuated more strongly than in non-adipose pa-
point of origin of these annihilation quanta can be tients. However, the extent of attenuation affects the
calculated precisely by a computer. However, be- tracer quantification on PET. Thus, PET data need
fore annihilation occurs the positron may travel for to be attenuation-corrected if quantitative image
some millimeters within tissue before the annihila- analysis is desired. In PET imaging attenuation cor-
tion occurs. Thus the point of origin calculated for rection of the acquired data is performed based on
the annihilation differs minimally from the location an additional transmission scan using gallium-68
of the radiotracer. While this slight inaccuracy is transmission sources. These transmission sources
generally considered insignificant for clinical PET are integrated into the PET gantry. The attenuation
of the gallium-68 transmission scan by the patient`s
body is used to calculate the attenuation-coefficients
for PET.
PET data may be analysed both, qualitatively
and quantitatively. While qualitative image evalua-
tion relates to the detection of regions with focally
increased tracer uptake, quantitative image evalu-
ation is based on the measurement of tracer activi-
ties in the lesion and calculation of the standardized
511 keV uptake value (SUV). The SUV correlates the activity
511 keV
concentration within the lesion with the amount of
180q
injected tracer activity and the patient`s body weight
Fig. 6.5.1. 18F decays to the stable 18O by emission of a posi- or body surface area:
tron (e+) and a neutrino (ν). The positron is an antimatter
particle of electrons (e-). The positron annihilates with an activity concentration of lesion (MBq/ln)
electron releasing two 511-keV gamma rays which travel SUV =
in the opposite direction. These gamma rays are detected injected activity (MBq) / patient’s weight (g)
by two photoluminescent crystals followed by computer-
based calculation of the point of origin of these annihila- The benefit of SUV determination in PET imaging
tion quanta has, however, been discussed controversially. While
Technical Prerequisites: PET-CT 115
some authors have tried to define cut-off values for with 18Fluor which is being taken up by cells accord-
differentiation of malignant from benign lesions ing to their glucose metabolism. Within the cell FDG
(Kang et al. 2004; Rasmussen et al. 2004), others is metabolised to FDG-6-phosphate which is then
argue that the SUV may not add any relevant infor- trapped (Fig. 6.5.2). The brain and the heart repre-
mation to qualitative image evaluation alone (Keyes sent organs with physiologically high glucose metab-
1995). Today in most PET and PET/CT centers the olism; thus FDG-uptake is physiologically intense in
SUV is used as an additional means to support the these organs. Malignant tumors often go along with
diagnosis based on qualitative image evaluation. In increased glucose metabolism compared to their
patients undergoing PET to follow up tumor therapy surrounding tissue, which leads to focally increased
the SUV serves as an indicator to assess therapy re- FDG-uptake in these tumors. Therefore tumor diag-
sponse. A decrease in the SUV in a patient undergo- nosis on FDG-PET is based on the detection of fo-
ing therapy indicates a responding tumor. cally increased glucose metabolism, and additional
Many radioactive tracers are available for PET quantitative measurements may support the correct
imaging worldwide. Most PET examinations in on- diagnosis. False positive results may occur in pa-
cology are, however, performed using FDG. Based tients with inflammatory disease. Tissue inflamma-
on its fairly long half-life of approximately 109 min, tion is associated with increased glucose metabolism
even sites which do not have their own cyclotron for as well, and the differentiation of an inflammatory
FDG-production are able to have the tracer deliv- lesion from a malignant tumor may prove difficult
ered. FDG represents glucose radioactively labelled with FDG-PET and FDG-PET/CT (Fig. 6.5.3).
Fig. 6.5.3. A 57-year-old male with cervical lymphadenopathy. PET/CT detected several lymph-nodes in the left cervical
region with increased glucose metabolism (maximal SUV: 12,5). Lymph node metastases of an unknown primary tumor
were suspected based on the PET/CT examination. Histology later verified lymph node tuberculosis. PET/CT was false-posi-
tive for malignancy
116 G. Antoch and R. Stahl
a b c
Fig. 6.5.4 a–c. Breathing-induced artefact on PET. Free breathing during the CT acquisition caused an artefact of the liver
dome on CT (arrow in a). Attenuation correction of PET was based on the CT data which led to translation of the artefact
into the PET (b) and PET/CT images (c)
a b
c d
118 G. Antoch and R. Stahl
these artefacts on PET, non-attenuation-corrected assessing the TNM-stage of different malignant dis-
PET images should be read additionally in question- eases (Bar-Shalom et al. 2003; Antoch et al. 2004c)
able cases. While there are no alternatives to posi- which potentially impacts on patient management
tive contrast agents for intravenous opacification, in a considerable number of cases.
water-equivalent oral contrast agents may be used
for intestinal distension instead of barium or iodine.
These water-equivalent agents do not increase atten- 6.5.3.1
uation on CT, thus avoiding PET artefacts (Antoch Head and Neck Tumors
et al. 2004b). While contrast-associated artefacts
may cause interpretative problems on qualitative In patients with head and neck tumors accurate as-
image evaluation, no clinically relevant effect has sessment of the N-stage must be considered cru-
been detected on tracer quantification (Dizendorf cial to determine further therapeutic steps such
et al. 2003; Nakamoto et al. 2003). as surgery or radiation therapy. The sensitivity of
Depending on the tracer in use and the amount FDG-PET to detect lymph node metastases in head
of tracer applied, radiation exposure attributable to and neck tumors has been reported to reach 90%;
the PET component may vary. For FDG-PET a ra- in CT this sensitivity has only been approximately
diation dose of approximately 7 mSv applies. How- 65% (Kutler et al. 2006). Based on physiologically
ever, the more relevant part of radiation exposure increased FDG-uptake in muscles of the neck, in
is caused by CT, if the CT component of the PET/CT salivary glands, or in brown fat the interpretation
is acquired in a diagnostic manner (mAs typical for of PET images may be somewhat challenging. By
stand-alone CT acquisition). Scanning the patient providing CT information to PET the number of
from head to the upper thighs will add approxi- equivocal FDG-avid lesions can be reduced on initial
mately 15 mSv of radiation exposure from the CT tumor staging both, locally and when assessing po-
component thus raising the overall dose of the PET/ tential distant metastases (Syed et al. 2005; Ha et al.
CT to more than 20 mSv (Brix et al. 2005). The ra- 2006). Thus an increase in diagnostic accuracy over
diation burden set upon the patient may be reduced the two imaging modalities alone may be expected.
if the CT is performed “low-dose” with 40–80 mAs However, reported sensitivities of PET/CT of up to
or even less. Cases in which a diagnostic CT may not 100% should be interpreted with caution (Chen et al.
be necessary are, for example, patients undergoing 2006). In patients with suspected tumor recurrence
PET/CT for assessment of therapy response or those anatomical imaging modalities may be inconclusive
with a diagnostic CT scan performed shortly before due to tissue alteration by surgery and radiotherapy.
the PET/CT. Similarly, on PET alone a persistent FDG uptake
due to sterile inflammation can often be detected
in patients after radiotherapy (Schoder et al. 2004).
PET/CT aids in localizing elevated FDG uptake in
over 90% of cases and may clarify 60% of equivocal
6.5.3 lesions (Goshen et al. 2005).
Clinical Aspects of PET and PET/CT Cervical nodal metastases from cancers of un-
in Oncology known primary (CUP-syndrome) account for 1%–
2% of head and neck malignancies. The median
The considerable effective radiation dose for a survival for patients with CUP is poor but may be
whole-body examination makes PET-CT inadequate elevated from 12 to 23 months in cases where an
for preventive screening. It is mainly applied in on- identified primary site is subsequently treated with
cological patients for tumor-node-metastasis (TNM) specific therapy (Raber et al. 1991). The detection
system staging or to detect tumor recurrence. A rap- of the primary lesion may, therefore, impact patient
idly expanding body of literature demonstrates that management. However, the detection rate of primary
the interpretation of coregistered PET and CT im- tumor sites has been reported to be low with con-
ages obtained from one examination leads to im- ventional imaging modalities (including CT). FDG
proved diagnostic performance compared to that PET has been reported a valuable diagnostic tool in
of PET alone, CT alone, and visually correlated PET patients with cervical CUP with detection rates of up
and CT images obtained from separate scans. Initial to one third of patients (Bohuslavizki et al. 2000).
studies reported that PET/CT is more accurate in PET/CT does not seem to further increase the detec-
Technical Prerequisites: PET-CT 119
tion rate of primary lesions compared to PET alone been shown that CT acquired in shallow breathing
(Freudenberg et al. 2005). As could be expected seems inadequate for comprehensive cancer staging
from the PET literature, FDG-PET/CT proved more as small lesions may be missed in over a third of
accurate than CT when defining the primary lesion all patients (Allen-Auerbach et al. 2006; Aquino
in CUP patients. Different hypotheses exist concern- et al. 2006). Thus, a CT in breath-hold technique
ing the large number of tumors remaining undetec- should be acquired as part of the PET/CT.
ted even on a PET and PET/CT scan. Some authors FDG-PET is more accurate than CT in the staging
hypothesize that the primary tumor may be small or of non-small cell lung cancer (NSCLC) (Fig. 6.5.6)
may even disappear after seeding. Additional fi nd- and the most significant prognostic factor for sur-
ings may alter patient management when assessing vival in these patients (Kramer et al. 2006). Par-
CUP with FDG-PET/CT. Even without detection of ticularly in NSCLC initial TNM-staging can be fur-
the primary tumor detection of yet unknown metas- ther improved with PET/CT (Antoch et al. 2003a;
tases has been reported in over 20% of patients with Lardinois et al. 2003; Halpern et al. 2005) mainly
FDG-PET/CT, modifying the stage of disease with due to the better differentiation between tumor and
potential impact on patient management (Nanni et adjacent atelectasis. In posttherapeutically distorted
al. 2005; Pelosi et al. 2006). anatomy PET/CT can also improve the localization
of suspicious FDG accumulation if tumor recur-
rence is suspected (Keidar et al. 2004). It has been
6.5.3.2 shown that a decrease in FDG-uptake and a reduc-
Lung Tumors tion of the SUV on PET/CT scans after chemother-
apy correlates with the histopathologic response to
In patients with suspected lung tumors or lung me- the therapy (Hoekstra et al. 2005; Pottgen et al.
tastases from other primaries, FDG-PET/CT can give 2006) (Fig. 6.5.7).
morphological and functional information on pul- In the field of image-modulated radiation therapy
monary lesions. In a solitary pulmonary nodule po- (IMRT) the use of PET/CT has some theoretical ad-
tential FDG-uptake may hint at malignancy whereas vantages. Fusion of function and morphology may
FDG-PET negative nodules are more likely to be be- improve the definition of the treatment volume when
nign (Reinhardt et al. 2006). However, FDG-PET compared with morphological imaging alone. Fusion
is well known to be less sensitive in small pulmo- of metabolic and anatomical information basically
nary lesions (below 1 cm) due to breathing-induced reduces interobserver variability when estimating
“smearing” of FDG-uptake. Gating of the PET can the gross tumor volume (GTV) (Ciernik et al. 2003;
compensate for this limitation, however, at the cost van Baardwijk et al. 2006). In the primary lung
of longer examination times. PET/CT can increase tumor integration of functional data often leads to
the sensitivity in patients with small FDG-negative a decrease of the target volume. The major cause for
nodules compared to PET alone by providing the this decrease seems to be the ability of PET to differ-
CT component. However, in recent studies it has entiate viable tumor areas from adjacent atelectasis
a b c
Fig. 6.5.6 a–c. A 63-year-old male with NSCLC of the right upper pulmonary lobe. On CT N2 disease was suspected based
on a pathologically enlarged lymph node in the mediastinum (arrow in a). FDG-PET (b) and FDG-PET/CT (c) demonstrate
homogeneous tracer distribution without focally increased FDG uptake staging this patient as N0. Histopathology verified
an N0 nodal status
120 G. Antoch and R. Stahl
b
Fig. 6.5.7 a,b. NSCLC before and after combined chemotherapy/radiation therapy. CT, FDG-PET, and FDG-PET/CT before initia-
tion of the treatment (a) demonstrate large tumor at the right pulmonary hilum. The follow-up examination (b) demonstrates
good response of the tumor to the combined chemo-irradiation
(Ciernik et al. 2003). On the other hand PET may re- it may be of benefit to assess the N-stage and M-
sult in an increase of the target volume, mainly due stage. Accurate assessment of the tumor stage will
to identification of nodal disease (Ashamalla et al. aid therapy decision and might play an important
2005). This higher accuracy when defining the target role in radiation therapy planning of breast cancer
volume will improve therapy results. In the case of patients (Zangheri et al. 2004). PET/CT correctly
radiotherapy with a curative intent, the dose to non- characterized more malignant lesions than did CT
tumorous tissue has been shown to be the dose-limit- (Tatsumi et al. 2006). Compared to PET alone, PET/
ing factor. In patients with NSCLC modelling studies CT may reduce the number of false-positive findings
demonstrated that the use of FDG-PET/CT scanning by identifying benign areas of mild FDG-uptake in
information reduces the radiation exposure of the es- brown fat (Heiba et al. 2005; Rousseau et al. 2006).
ophagus and lungs thus allowing a substantial radia- In restaging, an initial study by Fueger et al. did not
tion dose escalation (De Ruysscher et al. 2005; van detect a statistically significant difference between
Der Wel et al. 2005). Further studies have to evaluate PET/CT and PET alone in detecting tumor recur-
if this higher accuracy when defining the radiation rence (Fueger et al. 2005). Theoretically, however,
target with PET/CT translates into better patient out- accurate localization of FDG-uptake after therapy
come (Messa et al. 2005). may improve differentiation of a recurrent tumor
from posttherapeutic tissue alteration.
6.5.3.3
Breast Cancer 6.5.3.4
Gastrointestinal Tract
Currently there is little literature available on po-
tential advantages of FDG-PET/CT in breast can- In initial staging of patients with colorectal carci-
cer. While PET and PET/CT will not be performed noma, FDG PET alone has been reported to be highly
in patients to assess the primary tumor (T-stage), sensitive in the detection of distant metastases. With
Technical Prerequisites: PET-CT 121
the addition of a CT the diagnostic accuracy in initial therapy. FDG-PET and FDG-PET/CT may be of
tumor staging can be further improved based on ac- benefit over CT alone in depicting recurrent tumor
curate localization of areas with potentially increased after radiofrequency ablation (RFA) of liver me-
FDG-uptake (Cohade et al. 2003; Gearhart et al. tastases (Barker et al. 2005; Joosten et al. 2005;
2006). This has been shown to increase the detection Veit et al. 2006a). Other authors report promis-
rate of lymph node metastases by 19% (Gearhart et ing results when following-up patients with liver
al. 2006). Veit et al. (2006b) demonstrated the feasi- metastases undergoing therapy with application of
bility of a PET/CT staging protocol with integrated 90Y microspheres (Lewandowski et al. 2005) or
PET/CT colonography. This protocol suggests fur- neoadjuvant therapy (Goshen et al. 2006).
ther benefits in primary tumor staging, particularly
in patients with incomplete colonoscopy. However,
the most important indication for FDG-PET/CT in 6.5.3.5
colorectal tumors is detection of potential tumor re- Lymphoma
currences. Differentiation of scar tissue from tumor
recurrence or residual tumor has been shown to be Accurate staging in patients with Hodgkin disease
challenging when applying morphological imaging (HD) and non-Hodgkin lymphoma (NHL) is cru-
procedures. FDG-PET/CT appears to be very prom- cial to assure a stage-adapted therapy. FDG-PET
ising for distinguishing a viable tumor from fibrous has been reported to have both higher sensitivity
tissue after therapy, thereby avoiding unnecessary and specificity for detection of malignant lesions
laparotomy (Even-Sapir et al. 2004b; Votrubova than CT in lymphoma patients (Hicks et al. 2005).
et al. 2006). Particularly in rectal tumors accurate On the one hand, staging performed with PET and
anatomical localization must be considered an ad- PET/CT upstages the disease in a third of HD and
vantage of PET/CT over FDG-PET. In this setting NHL patients compared to CT staging alone. On the
fusion of increased FDG-uptake with a lesion on CT other hand the disease may be downstaged in 15% of
helps differentiating pathological FDG-uptake from HD patients but only in 1% of NHL patients. Thus,
physiological uptake, such as accumulation within patient management is altered by PET and PET/CT
the bladder. in approximately a quarter of NHL and a third of
The value of FDG-PET for detection of liver HD patients (Raanani et al. 2006). Therefore PET
metastases has been discussed controversially. and PET/CT have a substantial impact on diagnos-
While some authors report FDG-PET to be supe- tic accuracy and patient management (Tatsumi et
rior to CT in detecting colorectal liver metasta- al. 2005; Hutchings et al. 2006; Raanani et al.
sis (Abdel-Nabi et al. 1998; Rohren et al. 2002; 2006). In addition, the evaluation of treatment re-
Arulampalam et al. 2004), others report the op- sponse with functional data has been reported to be
posite. The accuracy of PET seems to be depend- more sensitive than morphology alone (Metser et
ant on the lesion size within the liver. PET data are al. 2004; Schaefer et al. 2004). However, compar-
acquired in shallow breathing, thus small lesions ing FDG-PET with FDG-PET/CT did not reveal a
may be missed on FDG-PET due to breathing-as- statistically significant difference in patients with
sociated smearing of FDG-uptake. This limitation lymphoma, both, for initial staging and follow-up
of PET can be compensated for by adding the CT in patients undergoing therapy (Hutchings et al.
component. In this case the examining physician 2006; Freudenberg et al. 2004).
must specifically focus on the CT protocol as part
of the PET/CT. It has been shown, that if the CT is
performed with intravenous contrast agents more 6.5.3.6
hepatic lesions can be detected than on non-en- Further Perspectives
hanced PET/CT (Setty et al. 2005). PET/CT has
been shown to be able to differentiate between FDG accumulates in tumors as well as in non-
extrahepatic disease and tumor recurrence in the tumorous pathologic lesions (e.g. inflammation) and
liver before and after liver surgery (Delbeke and in normal tissue (e.g. brain). New and potentially
Martin 2004; Erturk et al. 2006; Khan et al. effective radioactive tracers for PET are being de-
2006); (Selzner et al. 2004). Further applications veloped rapidly and are expected to be more specific
of PET/CT in patients with colorectal liver metas- for certain tumors than FDG (Table 6.5.1). Typically
tases include follow-up-examinations of local liver these specific tracers provide fewer anatomical land-
122 G. Antoch and R. Stahl
11C-acetate Lipid synthesis Prostate (Oyama et al. 2002), hepatoma (Ho et al.
2003), brain (Liu et al. 2006)
11C-choline Lipid synthesis Prostate (Farsad et al. 2005), head and neck (Khan
et al. 2004)
18F-choline Lipid synthesis Prostate (Kwee et al. 2005, 2006; Schmid et al. 2005),
brain (Spaeth et al. 2006)
O-[11C]methyl-l-tyrosine (CMT) Amino acid transport Brain (Ishiwata et al. 2005), general (Tsukada et al.
2006)
(18)F-fluoro-ethyl-l-tyrosine (FET) Amino acid transport Brain (Spaeth et al. 2006)
O-(18)F-fluoromethyl tyrosine Amino acid transport General (Tsukada et al. 2006)
O-(2-[(18)F]fluoroethyl)-l-tyrosine Amino acid transport Head and neck (Pauleit et al. 2006)
(FET)
[(11)C]-metomidate Hormone precursor Adrenal cortical tumours (Eriksson et al. 2005)
6-[(18)F]-fluorodopamine Hormone precursor Phaeochromocytomas (Eriksson et al. 2005)
18F-DOPA Hormone precursor Carcinoid (Hoegerle et al. 2001)
[(11)C]-hydroxyephedrine Hormone precursor Phaeochromocytomas (Eriksson et al. 2005)
[(11)C]-5-hydroxytryptophan Hormone precursor Carcinoid, endocrine pancreatic tumours (Eriksson
et al. 2005)
alpha-[(11)C]-Methyl-l-tryptophan Cell proliferation Brain (Juhasz et al. 2006)
(AMT)
[(11)C]-l-dihydroxyphenylalanine Hormone precursor Carcinoid, endocrine pancreatic tumours (Eriksson
et al. 2005)
18F-thymidine DNA synthesis Breast (Pio et al. 2006), brain (Jacobs et al. 2005)
11C-methionine Amino acid transport Prostate (Toth et al. 2005), brain (Jacobs et al. 2005;
Borbely et al. 2006), lung (Ishimori et al. 2004)
18F-fluoroestradiol Hormone receptor Breast (Van Den Bossche and Van de Wiele 2004)
18F-flurodihydrotestosterone Hormone receptor Prostate (Van Den Bossche and Van de Wiele 2004)
124-Iodine Hormone component Thyroid (Freudenberg et al. 2004)
18F-fluoroide Bone compound Bone (Even-Sapir et al. 2004a)
Gluc-Lys([(18)F]FP)-TOCA Somatostatin receptor Carcinoid (Meisetschlager et al. 2006)
[(111)In]DTPA-octreotide Somatostatin receptor Carcinoid (Meisetschlager et al. 2006)
[(68)Ga]DOTATOC Somatostatin receptor Carcinoid (Meisetschlager et al. 2006)
60Cu-ATSM Tumor hypoxia Cervical (Dehdashti et al. 2003a), lung (Dehdashti
et al. 2003b), head and neck (Chao et al. 2001)
18F-fluoromisonidazole ((18)F- Tumor hypoxia Head and neck (Eschmann et al. 2005; Thorwarth et
FMISO) al. 2005), lung (Gagel et al. 2006)
(18)F-labeled nitroimidazole com- Tumor hypoxia General (Piert et al. 2005)
pound fluoroazomycin arabinoside
((18)F-FAZA)
sigma-Ligands Cellular proliferation General (van Waarde et al. 2006)
18F-Galacto-RGD Angiogenesis Malignant melanoma (Beer et al. 2005)
Labeled monoclonal antibodies To be designed for spe- General
cific binding sites
Technical Prerequisites: PET-CT 123
marks than FDG on the PET image which increases rodeoxyglucose whole-body PET: correlation with histo-
pathologic and CT fi ndings. Radiology 206(3):755–760
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Freudenberg et al. reported the feasibility of PET/ and neck cancer. Eur J Nucl Med 25(9):1255–1260
Allen-Auerbach M, Yeom K, Park J et al. (2006) Standard
CT with iodine-124 in patients with differentiated PET/CT of the chest during shallow breathing is inad-
thyroid carcinoma before radio-iodine therapy and in equate for comprehensive staging of lung cancer. J Nucl
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higher lesion detectability compared to established uptake: a potential artifact in contrast-enhanced dual-
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Risks of Screening and Preventive Diagnosis 127
meet stringent quality requirements, taking into ac- radiation, is the most important of these studies.
count the need to include all parts of the program. The LSS provides data with good epidemiologic evi-
From these formal screening programs, it is im- dence and, therefore, is generally used for predicting
portant to differentiate more informal arrangements radiation-induced risks for the general population.
in which clinical guidance and/or patient choice Hereby, risk coefficients (risk per dose) have been
result in an ad hoc screening. The most prominent derived using the so-called linear, non-threshold
example is whole-body CT screening, which is pro- (LNT) hypothesis, which is based on the assump-
moted – especially in the USA – by private providers tion that:
in the last years. As long as there is lack of evidence 1. Any radiation dose – no matter how small – may
underpinning the screening tests on offer, this op- cause detrimental health effects.
portunistic screening potentially puts individuals 2. The probability of these effects is directly propor-
at risk. Furthermore, the service is unlikely to be tional to the dose absorbed in the tissue.
properly quality assured or coordinated. Individu-
als are also unlikely to receive sufficient information There is, however, considerable controversy re-
to enable them to make an informed decision as to garding low-level radiation, typical for diagnostic ra-
whether or not to undertake the screening test. diation exposures, since the risks evaluated at these
Even for well established screening programs, dose levels are not based on experimental evidence.
the balance between benefits and undesired adverse Given this lack of evidence, the risk coefficients,
health effects is narrow. Due to the typically low derived from high doses, have been extrapolated
prevalence of serious diseases in an asymptomatic down to low dose levels by various scientific bod-
population, the vast majority of individuals un- ies, including ICRP, UNSCEAR, and BEIR. Although
dergoing screening are not affected by the disease. the risks evaluated at low dose levels are hypotheti-
These individuals do not derive a direct health ef- cal, the proponents of the LNT model argue that it
fect, but can only be harmed. The adverse effects is conservative to presume that these risks exist,
most relevant in any screening are false-positive re- and that the LNT model represents an upper bound
sults and overdiagnosis. for them. It is for this reason that current radiation
With respect to screening using radiography, CT or protection standards as well as risk assessments are
PET examinations, health effects induced by ionizing generally based on the LNT hypothesis.
radiation have additionally to be taken into account.
While adverse health effects – at least in part – are
difficult to be assessed quantitatively, risk estimates 7.1.3
for detrimental radiation effects are available. Dosimetric Quantities and Dose Values for
some Relevant Diagnostic Procedures
(Table 7.1). These factors indicate the relative pro- tine as well as for screening and preventive diagnosis
portion of each organ or tissue to the total health are summarized in Table 7.2. For each examination
detriment − in terms of the risk of fatal cancers and considered, radiation exposure to asymptomatic
hereditary defects − resulting from a uniform irra- persons is lower than that to patients, which means
diation of the whole body. If the body is exposed in that the scan protocols used for screening are – at
a non-uniform manner, as for example in a person least to some extent – optimized from a radiation-
undergoing a CT or PET examination, the sum of the hygienic point of view. Table 7.2 also gives estimates
products of the organ dose and the corresponding tis- of the dose to breast parenchyma of females that are
sue weighting factor determined for each of the vari- calculated under the assumption that both breasts
ous organs or tissues exposed has to be computed: are completely in the imaged body region. The lat-
ter data make it possible to compare the stochastic
risk for breast cancer induced by CT and PET proce-
Table 7.1. Tissue weighting factors wT given in ICRP Publi-
cation 60 (ICRP 1990) reflecting the relative susceptibility of dures with the corresponding risk of a conventional
various tissues and organs to ionizing radiation screening mammogram.
In practice, neither organ nor effective doses can
Tissue or organ wT be measured directly. In order to overcome this diffi-
Gonads 0.20 culty, operational dose quantities are defined, which
can easily be measured. Examples are the dose-area
Bone marrow, lungs, colon, stomach 0.12
product or the entrance-surface dose in radiography,
Liver, thyroid, esophagus, breast, bladder 0.05 the computed tomography dose index or dose-length
Bone surface, skin 0.01 product in CT scanning, and the activity of a radio-
pharmaceutical administered to a patient in case of
Remaining organsa 0.05
a PET examination. These quantities can not only be
a The ‘remaining organs’ consists of a group of additional used for comparison of different protocols within a
organs and tissues with a lower sensitivity for radiation particular diagnostic modality (e.g., CT or PET) but
induced effects for which the average dose must be used: small also form the basis for the estimation of organ and
intestine, brain, spleen, muscle tissue, adrenals, kidneys, pan-
creas, thymus and uterus effective doses. In the latter case, operational dose
quantities have to be combined with conversion or
dose coefficients computed by Monte-Carlo calcu-
lations for anthropomorphic mathematical models
or by dose measurements in an anthropomorphic
phantom.
The resulting quantity is denoted as effective
dose, E, and expressed in the unit Sievert (Sv). On
the basis of the effective dose, it is possible to as- 7.1.4
sess and to compare the probability of stochastic Assessment of Radiation Risks
radiation effects resulting from different radiation
exposures – as for example diverse X-ray or nuclear The risk estimates proposed by ICRP and UNSCEAR
medicine procedures yielding a different pattern of (ICRP 1990; UNSCEAR 2000) – for use in radiation
dose distribution in the body. protection – are based on risk coefficients and effec-
It should be mentioned, however, that the weight- tive doses, as mentioned above. They provide simple
ing factors provided by the ICRP are generic rather and robust estimates for the lifetime excess risk to
then individual because age and gender of the per- die from radiation-induced cancer. But they facili-
son examined are not taken into account. They are tate only an over-all, not an organ-specific estimate
thus not suited for the assessment of radiation risks and are aimed at large, age and gender averaged
to individual persons or sub-groups of the popula- collectives such as the working population or the
tion with a distribution of age and gender differing whole population of a country.
from that of the general population. Furthermore, An assessment of radiation risks induced by
the weighting factors are supposed to be changed screening procedures such as X-ray mammography
significantly in the next future (ICRP 2005). or CT has to take into account that these procedures
Representative effective dose values for various typically are aimed at members of a certain popula-
diagnostic imaging procedures used in clinical rou- tion, such as – for example – women between 50 and
130 J. Griebel, G. Brix, and H. Kramer
Table 7.2. Effective dose and dose to breast parenchyma of some radiological examinations
a Representative dose values relate to the examination of both breasts in two views
b Effectivedoses (mean r SD) of multi-slice CT examinations carried out in patients were determined in a nationwide survey
performed in Germany in the year 2002 (Brix et al. 2003). The range of CT doses given for screening examinations are from
a review of recent publications. Representative doses to breast parenchyma are calculated from the CTDIvol values and a dose
coefficient given in Brix et al. (2005)
c Paired examination in supine and prone position
d Dose values given for a representative PET examination using 370 MBq of 18F-labeled fluorodeoxy-glucose are calculated using
the dose coefficients given in ICRP publication 80 (ICRP 1996)
e Dose values (mean r SD) given were determined in a multi-center study performed in Germany in 2004 (Brix et al. 2005). The
body region scanned by CT extended from the symphysis at the lower limit to the thyroid at the upper limit
The excess relative risk, err(e,a,D,S), for specific For typical CT related screening procedures, age,
organs is usually derived from cancer incidence gender and organ specific risk estimates for radia-
data of the LSS, whereby a linear dose dependency tion induced cancer have been performed, for ex-
is commonly assumed for solid tumors, while a lin- ample, by Brenner (2004), Brenner and Elliston
ear-quadratic approach provides better results for (2004) and Brenner and Georgsson (2005) using
leukaemia. Since the LSS data are regularly updated, a somewhat simpler approach as described above.
a variety of different models can be found in the lit- Furthermore, the risk estimates refer to a popula-
erature, reflecting the currently evaluated observa- tion with US normal risk rates, which differ from
tion period. Well established models are applied for European countries in some cancer entities, e.g.
the calculation of probabilities of causation, which breast cancer. The underlying organ dose estimates
serve the needs of official institutions in adjudicat- result from calculations which essentially take into
ing cancer claims fi led by persons exposed to radia- account one typical CT scanner, respectively. The
tion (for example, Chmelevsky 1995; HHS 2003). resulting excess absolute lifetime risks, considering
The excess absolute lifetime risk, EAR, for a per- typical screening frequencies and periods – as dis-
son of gender S who was exposed at age e to a or- cussed in the literature, are summarized in Table 7.3.
gan dose D is easily calculated by summing up all In addition, the corresponding data for breast can-
err(e,a,D,S) values between the age of exposure and cer screening are provided.
the age of 85 years, commonly used for lifetime risk For the CT screening procedures mentioned
estimates: above, radiation induced cancer of the lung, female
breast, colon and stomach as well as leukemia is the
dominant cause of detrimental radiation effects.
This is especially valid for whole-body CT, where all
of these organs are involved, being exposed to organ
doses of about 10 mGy and more (Brenner and El-
Please note that the excess relative risk, liston 2004). In CT colonography, colon and stom-
err(e,a,D,S), is set to zero in the interval between a=e ach are of major concern, being exposed to similar
and a=e+∆t, where ∆t denotes the minimum latency organ doses (Brenner and Georgsson 2005). In
period during which radiation induced cancer typi- CT lung cancer screening, major contributors are
cally does not show clinical symptoms. A period of lung and female breast. Here, the organ doses are
about 5 years for carcinoma and of about 2 years for significantly lower as compared to whole-body CT
leukaemia is widely applied for incidence data. (Brenner 2004). Furthermore, it has to be consid-
Table 7.3. Excess absolute lifetime risks for typical screening procedures using X-ray or CT
screening CT between 50 and 75 years of age; the lifetime risk is estimated only for radiation-
induced lung-cancer, ignoring radiation-induced breast cancer risk in females
c According to Brenner and Georgsson (2005); the estimate refers to a 50-year-old person who
undergoes one screening CT; it ignores radiation-induced risks to the uterus and the female
gonads
d According to Brenner and Elliston (2004b); the estimate refers to a person who undergoes
annual screening CT between 45 and 75 years of age; in the paper, the lifetime risk of cancer mor-
tality is estimated as about 1.9%. Taking into account that overall cancer incidence is roughly three
132 J. Griebel, G. Brix, and H. Kramer
ered, that estimates of organ doses are highly depen- Defining the benefit of the screening as the num-
dent on the scanner settings. However, up to now, no ber of breast cancer deaths prevented in the screen-
standard CT protocols are available for screening. ing population and the risk as the number of radia-
Furthermore, even for identical CT parameter set- tion-induced breast cancer deaths due to the repeated
tings, the dose estimates show significant scanner- X-ray mammographies, a risk-benefit analysis has
to-scanner variations (Nagel 2002). been performed by SSK (2002) and Nekolla (2005).
Compared to the breast cancer screening pro- Under the assumption that screening reduces breast
grams, established in various countries, the excess cancer mortality by 20%, it is concluded that the
absolute lifetime risks for screening approaches us- benefit outweighs the risk by a factor of about 12–50,
ing CT are relatively high (see Table 7.3). So, for an- depending on the epidemiologic models used for the
nual whole-body CT screening between the age of risk assessment.
45 years and 75 years, the lifetime risk to be diseased
with a radiation-induced cancer is about 5%–6%,
while the normal lifetime cancer risk for a 45-year-
old person – concerning the entities outlined above
– is about 25%–30% for the USA (Ferlay et al. 1999). 7.2
The corresponding risks for breast cancer screening Risks Related to
by X-ray mammography are < 0.10% and about 10%, Magnetic Resonance Imaging Procedures
respectively.
As mentioned before, CT protocols used for In MR imaging three variants of magnetic fields
screening are by no means standardized at this time. are employed to form cross-sectional images of the
The same is true for the time schedule, discussed human body: a high static magnetic field generating
in the literature for CT screening approaches. CT a macroscopic nuclear magnetization, rapidly alter-
protocols, optimized with respect to dose, as well nating magnetic gradient fields for spatial encoding
as prolonged screening intervals and later onset of of the MR signal, and radio-frequency (RF) electro-
screening could significantly reduce dose and, thus, magnetic fields for excitation and preparation of the
radiation-induced risk. spin system. Because no ionizing radiation is used,
MRI is deemed safer than CT in terms of health
risks. Nevertheless, there are possible risks and
7.1.5 health effects associated with the use of diagnostic
Risk-Benefit Assessment MR devices that have to be considered (Ordidge et
al. 2000; Shellock 2001). In this context, a funda-
It is important to notice, that at the moment – in con- mental difference between ionizing and non-ioniz-
trast to screening X-ray mammography – no valid ing radiation has to be noted: radiation doses related
data from prospective, randomized clinical studies to diagnostic X-ray or nuclear medicine procedures
are available, indicating a significant reduction in result in stochastic effects, whereas biological effects
cancer mortality due to CT screening approaches. of magnetic fields are deterministic. A stochastic
Therefore, risk-benefit analyses are not possible, at process is one in which the exposure determines
least at the moment, for CT based screening ap- the probability of occurrence but not the magni-
proaches in asymptomatic persons. tude of the effect. In contrast, deterministic effects
In contrast, for breast cancer screening by X- are those for which the magnitude is related to the
ray mammography, statistically sufficient data for level of exposure and a threshold may be defined
a risk-benefit analysis are available from various (ICNIRP 2002). As a consequence, the probability
randomized trials in Europe and the USA. See IARC of detrimental effects caused, for example, by CT
(2002) for a recent reassessment of theses studies. or PET examinations performed over many years
The IARC expert’s panel concludes that there is suf- accumulate, whereas physiological stress induced by
ficient evidence that inviting women 50–69 years of MR procedures is related to the acute exposure levels
age to screening reduces their mortality from breast of a particular examination and does, to our present
cancer by about 20%–30%. knowledge, not accumulate over the years.
Risks of Screening and Preventive Diagnosis 133
7.2.1 7.2.2
Interaction Mechanisms and Exposure Limits
Biological Effects of Magnetic Fields
To minimize health hazards and risks to patients
The basic actions of static magnetic fields are trans- undergoing MR procedures, exposure limits for
lation and orientation effects of metallic objects or the three different magnetic fields used in MRI are
macro-molecules, electrodynamic forces on moving specified in:
electrolytes, and effects on electron spin states of The product standard IEC 60601-2-33 provided
chemical reaction intermediates. Until now, most MR by the International Electrotechnical Commission
examinations have been performed using static mag- (IEC 2002) for manufacturers of MR equipment
netic fields up to 3 T, although whole-body MR sys- to follow
tems with static magnetic fields up to 8 T are already The safety recommendation issued by the Inter-
used in clinical tests. The literature does not indicate national Commission on Non-Ionizing Radiation
any serious adverse health effects from the exposure Protection (ICNIRP 2004)
of healthy human subjects up to 8 T. However, sensa-
tions of nausea, vertigo, and metallic taste may occur All major manufacturers of MR equipment have
in magnetic fields above 2 T. The greatest potential adopted the regulations of the IEC product standard
hazard comes from metallic, in particular ferromag- and ensure compliance with the specified exposure
netic materials (such as scissors, coins, pins, oxygen limits (which are with one exception identical with
cylinders) that are accelerated in the inhomogeneous those of the ICNIRP recommendation) by integrated
magnetic field in the periphery of an MR system and monitor systems.
quickly become dangerous projectiles. This risk can With respect to the examination of patients in
only be minimised by a strict and careful manage- clinical routine, both the IEC standard and the IC-
ment of both patients and staff (cf. MDA 2002). NIRP recommendation give exposure limits for two
Rapidly switched magnetic gradient fields induce different modes of operation: In the normal operating
electric fields in the human body, which, if of suf- mode none of the outputs have a value that may cause
ficient magnitude, can produce nerve and muscle physiological stress to patients. In the controlled op-
stimulation. The induced electric field is propor- erating mode, on the other hand, one or more outputs
tional to the time rate of change of the magnetic reach a value that may cause physiological stress to
field, dB/dt. From a safety standpoint, the primary patients. Examinations in the controlled mode thus
concern with regard to time varying magnetic fields require not only a thorough clinical decision balanc-
is cardiac fibrillation, because it is a life-threatening ing possible side effects against foreseen benefits but
condition. In contrast, peripheral nerve stimulation also medical supervision of patients. Up to now, there
is of practical concern because uncomfortable or in- are no recommendations published by regulatory
tolerable stimulations would interfere with the ex- bodies or scientific communities specifying expo-
amination (e.g., due to patient movements) or would sure limits to be considered for MR procedures used
even result in a termination of the examination. to screen asymptomatic persons. In any case, they
Time-varying electromagnetic fields with frequen- should be adapted in relation to the risk-profile of the
cies above 10 MHz (RF fields) deposit energy in the hu- individual to be examined.
man body that is mainly converted to heat. The param-
eter relevant for the evaluation of biological effects of
RF fields is the increase in tissue temperature, which is 7.2.3
dependent not only on localized power absorption and Contraindications
the duration of RF exposure, but also on heat transfer
and the activation of thermoregulatory mechanisms Pregnant females undergoing MR examinations are
leading to thermal equalization within the body. Since exposed to the combined magnetic and electromag-
temperature changes in the various organs and tissues netic fields used in MR imaging. The few studies on
of the body during an MR procedure are difficult to pregnancy outcome in humans following MR ex-
measure in clinical routine, RF exposure is usually aminations have not revealed any adverse effects,
characterized by means of the ‘specific absorption rate’ but are very limited because of the small numbers of
(SAR in W/kg), which is defined as the average energy patients involved and difficulties in the interpreta-
dissipated in the body per unit of mass and time. tion of the results. Pregnancy should be an absolute
134 J. Griebel, G. Brix, and H. Kramer
contraindication for MR screening of asymptomatic for purposes of patient treatment and diagnosis
persons. The same holds for persons with electri- when a justification is present which indicates that
cally, magnetically, or mechanically activated im- the presumable advantage outweighs the hazards
plants (e.g., cardiac pacemakers and defibrillators, of ionizing radiation. Screening mammography in
cochlear implants, electronic drug infusion pumps) asymptomatic female individuals has been intro-
as well as for persons with passive implants or other duced in Germany by law and extensive measures
objects of ferromagnetic or unknown material (e.g., of quality assurance had been taken. Any other im-
aneurysm and haemostatic clips, orthopedic im- aging method employing ionizing radiation needs a
plants, pellets, and bullets). Lists of implants and justification based on the personalized analysis of a
materials tested for safety or compatibility in asso- particular patient’s clinical symptoms, history, and
ciation with MR systems have been published and risk factors, respectively.
updated (e.g., Shellock 2005)
7.3.1
Informed Consent
SP, Beyer T (2005) Radiation exposure of patients under- ICNIRP (2004) International Commission on Non-ioniz-
going whole-body dual-modality 18F-FDG PET/CT ex- ing Radiation Protection. Medical magnetic resonance
aminations. J Nucl Med 46:608–613 (MR) procedures: protection of patients. Health Phys
Chmelevsky D, Nekolla E, Barclay D (1995) Strahlenepide- 87:197–216
miologische Tabellen – Die Berechnung von Verursa- IEC (2002) Particular requirements for the safety of mag-
chungswahrscheinlichkeiten bösartiger Neubildungen netic resonance equipment for medical diagnosis (2nd
nach vorausgegangener Strahlenexposition. Schriftreihe edn). International Electrotechnical Commission IEC
Reaktorsicherheit und Strahlenschutz. BMU-1995–420 60601-2-33
Ferlay J, Bray F, Sankila R, Parkin DM (1999) EUCAN: cancer MDA (2002) Guidelines for magnetic resonance equipment
incidence, mortality and prevalence in the European Union in clinical use. Medical Devices Agency. http://www.
1995, version 2.0. IARC CancerBase No 4. IARC Press, Lyon medical-devices.gov.uk
HHS (2003) Report of the NCI-CDC working group to revise Nekolla EA, Griebel J, Brix G (2005) Einführung eines
the 1985 NIH radioepidemiological tables. US Depart- Mammographie-Screening-Programms in Deutschland
ment of Health and Human Services – Erwägungen zu Nutzen und Risiko. Der Radiologe
IARC (2002) Handbooks of cancer prevention, vol 7. IARC 3:245–253
Breast Cancer Screening. Lyon: International Agency for Ordidge R, Shellock FG, Kanal E (2000) Special issue: MR
Research on Cancer, World Health Organisation safety. J Mag Reson Imaging 12
ICRP (1990) 1990 recommendations of the International Shellock FG (ed) (2001) Magnetic resonance procedures:
Commission on Radiological Protection. Publication 60. health effects and safety. CRC Press, Boca Raton
International Commission on Radiological Protection, Shellock FG (2005) Reference manual for magnetic resonance
New York safety, implants, and devices: 2005 edition. Biomedical
ICRP (1998) Radiation doses from radiopharmaceuticals. Research Publishing Company, Los Angeles, CA
Publication 80. International Commission on Radiologi- SSK (2002) Mammographie-screening in Deutschland: Bew-
cal Protection, New York ertung des Strahlenrisikos. Strahlenschutzkommission,
ICRP (2005) Recommendations of the International Commis- Heft 31
sion on Radiological Protection (draft report). Interna- UNSCEAR (2000) Sources and effects of ionizing radiation.
tional Commission on Radiological Protection, New York United Nations Scientific Committee on the Effects of
ICNIRP (2002) International Commission on Non-ionizing Atomic Radiation,1994 Report to the General Assembly,
Radiation Protection. General approach to protection with scientific annexes. Volume II: Effects, Annex G.
against non-ionizing radiation. Health Phys 82:540–548 United Nations, New York
Ethical Aspects of Screening and Preventive Diagnosis with Radiological Imaging 137
8.7 Application of the Enriched Informed Ethical issues have been addressed in diagnostic
Consent Model 142 and in therapeutic fields of radiology especially in
8.7.1 Invitation to Participate in a Screening Anglo-American publications. Barron and Kim
Program 142 (2003) articulate doubts if American radiologists,
8.7.1.1 Threshold Elements 142
8.7.1.2 Information Elements 142 when faced with increasing technological oppor-
8.7.1.3 Counselling Elements 142 tunities of imaging, adequately apply the Ethics
8.7.1.4 Elements of Relationship 142 Code of the American College of Radiology in
8.7.1.5 Consent Elements 143 their doctor-patient relationship. The radiology
ethics debate in the U.S. includes concerns regard-
ing research and its regulation; patient rights;
S. Reiter-Theil, PhD informed consent and funding sources (Cooper
Professor and Director, Institute for Applied Ethics and 2005a,b). The European ethical debate in radiol-
Medical Ethics, University of Basel, Missionsstrasse 21a ogy, especially in the German speaking area, is
4055 Basel, Switzerland
N. Stingelin Giles, MA
still developing with some pilot work or educa-
Institute for Applied Ethics and Medical Ethics, University tional activities (Reiter-Theil and Hiddemann
of Basel, Missionsstrasse 21a, 4055 Basel, Switzerland 2000). Ethical issues here are mostly studied from
138 S. Reiter-Theil and N. Stingelin Giles
• True positive: a disease being diagnosed that has a prima facie moral commitment. “Prima facie” is
already manifested symptoms. a term introduced by the English philosopher W.
• True positive: a disease being diagnosed in its a- D. Ross (Ross 1930); it means that the principle
symptomatic phase. is binding unless it conflicts with another moral
• A grey area of various probabilities that a disease principle. If it does, we have to choose between
is present. them. The four-principle approach is neither an
• A predisposition being identified that a disease algorithm nor a pre-fixed hierarchy of values to
will develop (with predisposition being defined be applied like a simple recipe, but “is a common
as being a susceptibility to develop a disease, set of moral commitments, a common moral lan-
noting that an increase or decrease in suscepti- guage, and a common set of moral issues” (Gillon
bility can result from environmental influences, 1994). The particular ethical challenges of screen-
and life-style choices of the individual). ing go beyond the individualistic orientation of
• True negative: a disease is not present, nor could much medical ethics, and reach into the dimen-
any predisposition be identified. sion of public health ethics. The “general moral
considerations” that apply to the population when
Each band of classification of predictive value of ethically evaluating public health interventions
a given test result along the continuum of firm test can be seen as being the following (Childress
positive-firm test negative has a specific set of ethi- et al. 2002):
cal issues. • Producing benefits
• Avoiding, preventing, and removing harms
• Producing the maximal balance of benefits over
harms and other costs
• Distributing benefits and burdens fairly (distrib-
8.4 utive justice) and ensuring public participation,
Moving Towards Identifying General including the participation of affected parties
Ethical Aspects of Screening and (procedural justice)
Preventive Diagnosis • Respecting autonomous choices and actions,
including liberty of action
In order to identify ethical aspects of screening • Protecting privacy and confidentiality
and preventive diagnosis, we need a framework • Keeping promises and commitments
of relevant ethical concepts and normative prin- • Disclosing information as well as speaking hon-
ciples. The Belmont Report (1979) has been a estly and truthfully (often grouped under trans-
cornerstone in the modern codification of ethi- parency)
cal principles for research on human subjects • Building and maintaining trust
(Tröhler and Reiter-Theil 1998); it proposed
that the basic medical ethical principles are respect Just as with medical ethics, public health benefits
for persons, beneficence, and justice. The concept and harm should include not only physical, but also
of self-determination is derived from the principle mental and social well-being. To these principles
of respect for persons that is expressed in the should be added expressing and promoting solidar-
doctrine of informed consent (“IC”); other rules ity with the population. Some of these moral con-
derived from respect for persons are the right to siderations, especially benefiting others, preventing
privacy and confidentiality, and the duty to pro- and removing harm, will justify many activities
tect the vulnerable. In the same year as the Bel- aimed at improving public health (Childress et al.
mont Report appeared, Beauchamp and Childress 2002). It seems at first glance that most of the listed
established a framework comprising the ethical topics are also convincing candidates for an individ-
principles of respect for autonomy, beneficence, ualized ethics. However sometimes a society cannot
non-maleficence and justice (Beauchamp and simultaneously realize its obligations to promote
Childress 2001). This set of four principles have public health and at the same time respect the rights
been widely appreciated and debated in medical due to individuals, such as autonomy, privacy and
ethics and beyond. Each of the four principles is confidentiality.
140 S. Reiter-Theil and N. Stingelin Giles
(Reiter-Theil 2003). A particularity of the screen- any departure from this principle (without consent
ing process is that a-symptomatic individuals may of the patients) requires substantial justification. In
enter a program believing themselves to be well, the event that a genetic test result is of importance
and be diagnosed as either having a condition, or for the health of family members, and the patient
having a likelihood or predisposition for a disease does not wish to communicate the results, opinions
developing. This differs from a clinical setting more vary in the field of medical ethics as to what extent
familiar to patients in which persons seek medical health care professionals are justified in seeking to
advice when they are already symptomatic. Fur- persuade the patient to disclose, or in some cases
thermore an uncertain screening diagnosis can be a to interpret the right to privacy as being a quali-
distress for an individual and their family; knowing fied right that should be overridden by substan-
that one has a likelihood or predisposition can be tial grounds, e.g., for reasons of preventing severe
benefit or burden. It can therefore be argued that damage of others. It should be reflected whether or
having counselling available is not only desirable, not a screening test could at all play a similar role as
but should be part of a good program. a genetic test result for third parties and next of kin.
Bearing all this in mind, for some individuals in Regarding the possible abuse of screening results
some situations the burden of exercising autonomy by insurance or employers confidentiality should be
and independently deciding what action to take can assured. However in cases where due to the nature
be a strain. Can or should counsellors offer such a of the employment pursued by an individual others
recommendation, or should they remain ‘neutral’? could be put at risk of harm should the disease
Indeed one can argue that the right to autonomy is develop, keeping the health status confidential is
best expressed by counsellors offering their profes- ethically problematic. Thus we see very clearly that
sional advice and recommendation, based on facts the freedom of the individual and respecting his or
fully and understandably explained, and based on her rights to confidentiality meets their limits when
their understanding of the individual’s situation, respecting these rights interferes with the rights of
trusting the client to be able to absorb and consider others, especially when the others are in a dependent
this input when making their own deliberations position (such as children).
and arriving at their autonomous decision. Further
arguments for counsellors making a recommenda-
tion are that counsellors are likely to have specific
knowledge and expertise that they are obliged to
share with the client, and have an obligation to help 8.8
those seeking advice. However any recommenda- Open Questions Put to Discussion
tion should be laid on the table for discussion, and
not communicated as being a directive. There is an 8.8.1
important difference between offering advice, and How to Deal with Questionable Diagnoses
being paternalistic or coercive, even an effort to per- Resulting from Screening Studies?
suade may collide with the respect-component of
the approach. A health care professional will need Although any test with a low predictive value that
good reasons and a robust evidence of patient ben- has accordingly a significant risk of false diagno-
efit to try to persuade him or her to do something sis being made should not be used in screening
he or she is not yet convinced of. An adequate rec- programs, many radiological procedures may have
ommendation should contextualize the information sufficient predictive value across the board to jus-
for a particular individual in order to link cognitive tify a program, whilst not precluding that some test
bits of information with emotional significance and results will not allow a conclusive diagnosis to be
practical experience. made. A questionable diagnosis, being a diagno-
sis with less than certain predictive value, brings
8.7.2.3 with it special ethical considerations from a health
Elements of Relationship care professional perspective. The doctrine of I.C.
and „Shared Decision Making“ informs that han-
The principle of confidentiality of medical informa- dling such situations must be a joint undertaking
tion is an established part of the traditional medi- between the individual, health care profession-
cal ethos as well as of modern medical ethics, and als or counsellors. Assuming that the individual
Ethical Aspects of Screening and Preventive Diagnosis with Radiological Imaging 145
indicates that they desire to know the test result, and recommend treatment. As identified above, the
an individual should in line with the principle of doctrine of I.C. requires however acknowledging
the right to know be fully informed of the results, that the fact that an individual who consented to
including if the test was inconclusive, and why it screening did not automatically consent to ther-
was inconclusive. Optimally a screening candidate apy, and that the decision as to whether and how a
will have been fully informed before entering the patient should be treated must respect the patient’s
screening program of the reliability of the screen- right to self-determination (respect for autonomy).
ing test, i.e. the rate of false positives and false Although the recommendation based on medical
negatives and the chance of the predictive value factors for an a-symptomatic true positive result
of the result being less than 100%. One must be may essentially be to proceed with treatment, the
aware, however, that concepts such as reliability or following components should guide the physician-
probability are not easily understood by lay people patient communication:
(and not even by all health care professionals as we • Full and transparent information on the reliabil-
learn from cognitive psychological studies show- ity of the screening test result must be given.
ing that severe errors occur in interpreting risk • Facts on the therapeutic options available: their
ratios). The health care professional should make a benefits and risks (side effects) must be given.
balanced recommendation based on medical facts • Variations in response or non-response to thera-
(such as the severity of the disease, and the rapidity pies should be outlined.
of progress of the disease in question), contextual- • The speed of progression of the disease should be
ized factors specific to the individual, and by reflec- stated.
tion and analysis using as an ethical framework • How the disease will manifest itself in its various
the enriched model of Informed Consent and the stages must be outlined.
principles of respect for autonomy, beneficence,
non-maleficence and justice. The contextualized Regarding a predisposition or probability that a
recommendations can include monitoring health disease will develop, or whether treatment should
and repeating the screening procedure after some be recommended from a medical point of view may
time has elapsed, or to commence any preventive depend on weighing up a number of factors. These
or curative therapy available assuming a worst case include:
scenario of the inconclusive results. Recommenda- • The predictive value of the diagnosis of a predis-
tions may include preventive medications, life style position
changes that will reduce risk of disease developing, • The time scale of the possible progression (if it
and regular further check-ups. An ethical point of occurs at all) of the disease
view does not reduce empirical uncertainty, but • The gravity of early symptoms and their revers-
it may contribute to a responsible attitude and ibility
practice. • If resources are available to offer to repeat the
screening procedure
• Whether the predisposition can be reduced by
8.8.2 non-medical intervention changes in life-style,
Should a Patient be Treated on the Basis of the noting that some predispositions can be stimu-
Results of a Screening Exam Although He or She lated and worsened by environmental factors
is A-Symptomatic? outside the control of the medical profession or
the individual
It is ethically relevant to differentiate between a dis-
ease being firmly diagnosed in its a-symptomatic For both a diagnosis of a disease being present
phase, and a result that suggests a predisposition or in its a-symptomatic phase, and the identification of
a probability that a disease will develop. The ethical a predisposition, in making a recommendation and
responsibilities of the health care professionals in arriving together with the patient at a decision as to
formulating a sound recommendation can be anal- how to proceed, not only medical harms and ben-
ysed using the framework of their having a duty of efits but also social and psychological elements as
beneficence, a duty to prevent harm, and a duty of outlined above from the patients perspective need
justice. Regarding a firm diagnosis, it is prima facie to be contextualized and included in the decision
in accordance with the duty of beneficence to offer making process.
146 S. Reiter-Theil and N. Stingelin Giles
Part 2:
Organ-Related Examinations
Cardiovascular Diseases 9
9.1 MRI
Susanne Ladd and Harald Kramer
3D sequences (Prince 1994), MR angiography well as late-enhancement studies for the detection
(MRA) has experienced a noteworthy expansion. of myocardial scars have already entered clinical
Today it is possible to image the whole peripheral routine (Barkhausen et al. 2001; Hunold et al.
arterial tree from the carotids to the ankles with 2002) (Fig. 9.1.3). MRI of the heart has evolved as the
high contrast to the surrounding structures within gold standard for the evaluation of filling volumes
a short time in a single examination (Goyen et al. (Rajappan et al. 2002). The important structures
2002) (Fig. 9.1.2, Table 9.1.1). Comparative stud- for diagnosing coronary heart disease (CHD) are
ies have demonstrated the high accuracy of MRA, the coronary arteries; however, coronary imaging is
with sensitivities and specificities for the presence not yet ready for being implemented into a routine
of stenoses and occlusions of more than 94% in cardiac MRI protocol. But even when “only” cin-
PAD (Meaney et al. 1999; Goyen et al. 2002) ematic studies and late enhancement studies for the
and especially in internal carotid artery stenoses depiction of myocardial infarctions are performed,
(Borisch et al. 2003). Moreover, MRA produces this renders important information, as the rate of
recordable images and renders an interobserver- CHD in general and particularly unknown previ-
agreement which is higher than that for digital ous myocardial infarctions are not to be neglected
subtraction angiography (DSA) (Schoenberg et (Lundblad and Eliasson 2003). Additionally, per-
al. 2002). Certainly other radiological modalities fusion imaging of the left ventricular myocardium
such as digital subtraction angiography (DSA) or can also be performed. There are two options for
computed tomography angiography (CTA) pro- performing perfusion imaging. The first option is
vide higher spatial resolution than MRA, and DSA perfusion imaging at rest. In this case only non-
additionally offers dynamic information. But both perfused myocardial areas or areas distal to a high
modalities have to deal with the disadvantage of grade coronary artery stenosis can be detected by
ionizing radiation and potentially nephrotoxic means of a perfusion defect. The likelihood of an
contrast agents (CA). DSA additionally implies unknown myocardial infarction or a high grade
other well known risks from arterial puncture and coronary artery stenosis detected by perfusion
catheterization. Thus, neither mentioned modali- imaging at rest in non-symptomatic individuals is
ties can be used for imaging healthy individu- very low. Thus, if perfusion imaging of the myo-
als participating in a screening exam. The pos- cardium is performed in screening individuals, it
sibility to image all these vessels within a single should be performed at stress. This second method
short whole-body MR angiography examination for performing perfusion imaging requires the
has already changed the diagnostic procedure in pharmacological induction of stress, which allows
many radiological departments. one to detect also coronary artery stenoses of less
Finally, the heart must be assessed. Ischemic heart than 80%. This raises the question whether it is
disease can be imaged to advantage with MRI (van medically and legally justifiable to perform phar-
der Wall et al. 1997). Fast cine-imaging for the macological induced stress perfusion imaging in
evaluation of global and regional contractility as check-up clients.
Fig. 9.1.1. TOF MRA of the intracranial vessels as well as pre- and post-contrast agent admin-
istration morphologic imaging of the brain to detect intracerebral vessel abnormalities, e.g.
aneurysms, and intracranial masses
Cardiovascular Diseases: MRI 151
Table 9.1.1. Injection scheme of whole-body MRA when using a dedicated whole-body MR sys-
tem equipped with a matrix coil system and wide table movement
Fig. 9.1.3. Cine imaging of the left ventricular myocardium with up to 11 short axis slices in one breathhold. Additionally
two and four chamber view series can be acquired. To calculate functional parameters high temporal resolution is very
important. If it is less than 50 ms, end systolic volume is over- and ejection fraction under-estimated
152 S. Ladd and H. Kramer
As a second step, whole-body MR angiography movement and a large field of view, venous con-
is performed. Meanwhile, a variety of different tamination can be eliminated in nearly all cases
MRA methods exists, primarily depending on by use of an optimised imaging protocol. In this
the MRI system used. The MRI technique usually protocol the patient is positioned head first in
employed consists of the consecutive acquisition the magnet during the whole MRI exam. MRA
of contrast-enhanced three-dimensional data sets datasets are acquired in two steps with two CA
of 4–5 stations of the body. When utilizing a stan- injections. The first step consists of imaging of
dard MRI system without dedicated platforms the thoracic aorta and cervical vessels as well as
and with restricted table movement of 150 mm imaging of the lower legs and feet. The possibility
maximum, whole-body MRA is performed in two to move the table from the cervical station down
parts. In part one, the patient is positioned head to the lower legs offers the chance to “overtake”
first in the magnet, and MRA of the thoracic aorta the CA bolus after the cervical vessels have been
and the cervical arteries is acquired. The second imaged, and to perform MRA of lower legs and
part consists of MRA of the abdominal aorta and feet without venous contamination. The second
the arteries of the lower extremity. For this pur- step with a second injection of CA covers the
pose, the patient is repositioned feet first in the abdominal aorta and thigh vessels in two consecu-
magnet, and four consecutive MRA slabs from the tive MRA blocks (Fig. 9.1.4b). Another option is
abdominal aorta to the feet are acquired. When the so-called “venous compression” (Herborn et
using a dedicated rolling platform like the Angio- al, 2003). With this technique, the venous return
SURF system, whole-body MRA can be performed of the contrast agent is delayed by use of a mid-
without repositioning the patient. The patient is femorally positioned thigh cuff with a pressure of
placed on the rolling platform and is manually 60 mm Hg.
pulled from one station to the next. Five consecu- Cardiac imaging consists of a T2-weighted axial
tive MRA slabs are acquired from the scull base “dark blood” sequence for a gross morphologic
down to the feet (Fig. 9.1.4a). A problem that can survey of the heart; this sequence can be extended
occur with both methods is venous contamination cranio-caudally to additionally cover the entire
in the lower legs. When using a dedicated whole- lung; this technique has shown to be quite sensi-
body MRI system with both a large range of table tive for the detection of lung nodules (Vogt et al.
Cardiovascular Diseases: MRI 153
2004). Cardiac functional imaging with ultrafast allows to calculate functional parameters such as
gradients (optimal image quality can be reached enddiastolic and systolic volumes, ejection frac-
with T2/T1-contrasts) as well as “late enhance- tion and myocardial mass normalized to patient’s
ment” studies with preparing inversion pulses body surface. Cardiac imaging can be comple-
for optimal contrast of myocardium vs scar is mented by perfusion imaging to detect perfusion
performed in short and long axes. Here, the late defects and thus to assess the status of the coro-
enhancement imaging makes use of the previ- nary arteries. When performing perfusion imag-
ously administered contrast agent (for MR angi- ing at rest, only coronary artery stenoses of more
ography); a re-administration of contrast agents is than ~80% or vessel occlusions can be detected. If
not required. Cine imaging of the left-ventricular perfusion imaging is performed using pharmaco-
myocardium not only depicts potential wall move- logically induced stress, even lower grade stenoses
ment dysfunction as indicator of CHD, but it also can be detected.
Fig. 9.1.4. a AngioSURF system: the images show the patient outside the magnet to demonstrate the five fi xed table positions.
The rolling platform is pulled manually through the magnet. To increase contrast an integrated spine array as well as an an-
terior positioned body array is used. Lower images show five consecutive acquired MRA steps from the skull-base down to the
feet. b Coil setup for whole-body MRI when using a matrix coil system in combination with a dedicated whole-body MR system.
Before starting the exam all necessary coils are placed at the patient, whilst the exam they can be selected individually
154 S. Ladd and H. Kramer
be included – great care should be taken not to alarm pathologies was quite low (Goehde et al. 2005) (my-
the client unnecessarily on the one hand and not to ocardial infarctions 0.3%, cerebral infarctions 0.6%,
understate relevant findings on the other hand: significant internal carotid artery stenoses 1%, sig-
Stenoses and occlusions of the arteries including nificant renal artery stenoses 0.3%, significant lower
the precise location and degree of the vessel ob- extremity artery stenoses 1%). Altogether, mani-
struction. Variants of the vascular anatomy should festations of atherosclerosis were detected in 7%.
also be mentioned. In one client a renal cell cancer was detected. Two
Previous infarctions and signs of chronic ischemia subjects had previously undiagnosed intracerebral
of the brain and myocardium. aneurysms. The total number of clinically relevant
Vascular malformations, aneurysms, valvular ste- incidental findings was 5%–9%.
noses and regurgitation, hypertrophy, scarring Another study evaluated 200 individuals partici-
and inflammation within the myocardium. pating in a healthcare program of their company.
Incidental findings which are not primarily in the In these subjective healthy individuals, 19 cardiac
focus of the cardiovascular screening exam have pathologies (like wall motion abnormalities or per-
also to be mentioned. Additional diagnostic im- fusion defects) as well as 42 vascular pathologies
aging might be required in order to clarify these (like hemodynamically significant stenoses or ves-
findings. sel occlusions) were found (Kramer 2006).
The low prevalence in manifestations of athero-
It is definitely not enough just to write a report. sclerosis in a non-selected group of asymptomatic
The radiologist performing screening exams has a individuals may indicate that it might be more ef-
great responsibility. He or she must ensure that the ficient to include only those patients who have a
client really understands the result of the exam and higher risk, e.g. diabetics or patients with manifes-
that the adequate measures are taken. This is true tations of atherosclerosis in one vascular territory
both for the findings related to the cardiovascular such as coronary heart disease, stroke or lower ex-
system but also for incidental fi ndings, which may tremity ischemia. This approach, however, would no
have even greater importance, such as lesions suspi- longer constitute a screening test in the strict sense
cious of malignant neoplasms. First results on pre- but rather a new algorithm in the management of
dominantly asymptomatic subjects actually show diseases which are due to atherosclerosis in differ-
that the number of incidental findings can exceed ent vascular territories. One example of a disease as-
the number of relevant atherosclerotic target lesions sociated with vascular disease is diabetes mellitus.
(Goehde et al. 2005). Weckbach 2006 showed that the presence of vascu-
It may be useful to contact the physician of the lar pathologies in a risk group like that is much more
client directly or to recommend a specialist. frequent than in subjective healthy individuals.
Does MR imaging find the same pathologies as
detected by conventional exams like chest X-ray,
ECG at rest and at stress, Doppler-ultrasound of the
vessels, ultrasound of the abdomen, etc.? A feasibil-
9.1.4 ity study for MRI as a screening exam for atheroscle-
Results of rotic disease showed good correlation between MRI
Cardiovascular Screening Programs and conventional exams. Individuals included in
this study were participants of companies´ health-
Published results of MRI based cardiovascular care programs and yearly underwent “check-up” ex-
screening programs are limited by small collectives ams looking for atherosclerotic as well as malignant
and inhomogeneous study populations. Most pub- disease. Results of the conventional exams were not
lications deal with technical aspects and results in accessible before the MR exam and were correlated
small collectives. Therefore, prospective random- to the MR findings after the exam. The only pathol-
ized trials are needed before cardiovascular screen- ogy not detected by MRI was thickening of the ar-
ing with MRI can be recommended as an effective terial wall as diagnosed by ultrasound. The vessel
method. wall is not accessible by contrast enhanced MRA as
In a group of nearly 200 mainly healthy, execu- good as it is with ultrasound because MRA renders
tive individuals (mean age 50 years, otherwise non- only a luminogram. Thus, the correlation between
selected), the prevalence of relevant atherosclerotic conventional exams and MRI concerning the find-
156 S. Ladd and H. Kramer
ings from conventional exams was excellent. On the manifestations of various systemic or multifocal
other hand, numerous relevant additional patholo- diseases, which may result in lesion findings in
gies were detected by MRI. Peripheral vessel sten- the whole body or multiple sites. Promising results
oses or occlusions as well as internal carotid artery have been reported in individuals with malignant
stenoses and restriction of myocardial function tumors, inflammatory joint diseases and diseases of
were not detected by conventional exams. Another the skeletal muscle. The combination of whole body
important advantage of MRI is the reproducibility MR-angiography with a comprehensive examina-
and the good inter reader agreement. In this study tion of the heart and imaging of various target or-
all MR exams were read by two radiologists blinded gans opens the opportunity to detect manifestations
to each other and the results correlated thereafter. of atherosclerosis in all vascular territories. This
Kappa values of 0.66–0.90 stand for a good to excel- approach may also be used for early diagnosis and
lent inter reader agreement. prevention. This type of atherosclerosis screening
Does the performance of an atherosclerosis can be performed within acceptable examination
screening MR improve one’s future health status? times and great diagnostic accuracy is achieved,
For this purpose, a prospective randomized study if high performance equipment and sophisticated
was started in 2003. This study consists of two imaging techniques are employed. Further studies
groups of subjects (55–75 years old) without known are required to explore suitable populations at risk
CHD, who are followed up for 3–6 years. One group and to assess effectiveness and outcome of such an
is examined by an initial atherosclerosis screen- approach.
ing MR; the other only gets blood tests. With yearly
questionnaires and a follow up MR for either group
the physical and mental health status is assessed and
can be compared for the two groups. Will one of the
groups suffer from cerebral or cardiac infarctions
more frequently? Or have potential earlier therapeu- References
tic efforts lead to a reduction in disease progression?
Anderson KM, Wilson PWF, Odell PM, Kannel WB (1991)
Preliminary results of this study show relatively low An updated coronary risk profi le: a statement for health
rates of malignancies or vascular pathologies, com- professionals. Circulation 83:356–362
parable to the results of the “manager study”. The Barkhausen J, Ruehm SG, Goyen M, Buck T, Laub G, Deba-
study will also answer the question if people with tin JF (2001) MR evaluation of ventricular function: true
fast imaging with steady-state precession versus fast low-
positive findings for atherosclerosis actually change angle shot cine MR imaging: feasibility study. Radiology
their lifestyles and follow the radiologists’ recom- 219:264–269
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raphy and duplex sonography with digital subtraction
tion will be gained concerning false positive and angiography. AJNR Am J Neuroradiol 24:1117–1122
false negative results of relevant and potentially ma- Fiehler J, Remmele C, Kucinski T et al. (2005) Reperfusion
lignant side findings, as also late contrast enhanced after severe local perfusion deficit precedes hemorrhagic
axial imaging is added at the end of the MR exam; transformation: an MRI study in acute stroke patients.
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this was added to eliminate the need for subsequent
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additional MR visits due to potentially dimly visible vention without radiation–a strategy for comprehensive
side findings in the arteriograms. early detection using magnetic resonance tomography.
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diovascular and tumor MRI for early detection of disease:
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Conclusion three-dimensional MR angiography with a rolling ta-
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Cardiovascular Diseases: CT 159
Cardiovascular Diseases 9
9.2 CT
Christoph R. Becker
ham (Wilson et al. 1998), PROCAM (Assmann et risk. All of the currently available risk stratification
al. 2002) and SCORE (Conroy et al. 2003) provide schemes suffer from the lack of accuracy to deter-
an estimation of the mid-term (10 years) risk for mine correctly the risk and also uncertainty exists
an individual subject to experience a cardiac event of how to treat subjects who have been identified
(Fig. 9.2.1). According to most of the international to be at intermediate risk. Further tools providing
guidelines, subjects with a mid-term risk of < 10% information about the necessity to either reassure
are considered to be at low risk and usually only or to treat these subjects are warranted. Currently,
require advice for a healthy lifestyle but no specific besides testing for myocardial ischemia, e.g. by
therapy. Subjects with a mid-term risk of > 20% are treadmill testing, assessment of the atherosclerotic
considered to be at high risk and therefore may also plaque burden is considered to provide valid infor-
be regarded as subjects with a CAD equivalent. Simi- mation for further risk stratification in this cohort
lar to patients with established CAD, these asymp- (Greenland et al. 2000).
tomatic subjects may require intensive intervention Tests for myocardial ischemia such as ECG stress
for risk reduction such as lifestyle changes and life- testing are better suited to investigate patients with
time medial treatment. ischemic CAD than to assess clinically silent ath-
Approximately 40% of the population is con- erosclerosis in the coronary arteries. Determina-
sidered to have a moderate (10%–20%) mid-term tion of the intima-media thickness (IMT) and ankle
a b
brachial index (ABI) by ultrasound and Doppler are amount of coronary calcium. It has recently been
focusing on the assessment of the atherosclerotic hypothesized that the combined use of the Framing-
plaque burden in the carotid and peripheral arter- ham risk assessment and the calcium measurement
ies, respectively. However, only CT and MRI may is superior to the selected use of the Framingham
have the ability to assess non-invasively the extent risk assessment alone (Greenland et al. 2004). In
of the atherosclerotic plaque burden in the coronary the Framingham risk algorithm, higher age be-
arteries. MRI is superior to CT in terms of soft tis- comes the predominant factor above all others.
sue differentiation (Fayad et al. 2000). However, CT This assumption certainly doesn’t fit all subjects.
is currently superior to MRI in terms of spatial and Therefore, Grundy (2001) has proposed an alterna-
temporal resolution to image the small and con- tive scheme in which the age score in Framingham
stantly fast moving structures such as the coronary is replaced by a scheme which takes the coronary
arteries. Therefore, CT is the only reliable and prac- calcium percentiles into account. If the amount of
ticable tool to investigate the entire coronary artery coronary calcium is in between the 25th and 75th
tree and to quantify the atherosclerotic plaque bur- percentile the Framingham risk score remains un-
den non-invasively (Nikolaou et al. 2003). changed. If the amount of calcium is below the 25th
or above the 75th percentile the score is the same
as for subjects approximately 10 years younger or
older, respectively (Table 9.2.1).
The progression of coronary calcium in subjects
9.2.3 with hypercholesteremia may depend on the in-
Clinical Value of Coronary Calcium tensity of the statine therapy. In asymptomatic hy-
percholesteremic persons without therapy, statins
Coronary calcium is a specific marker for coronary and > 120 mg/dL and < 120 mg/dL cholesterol, the
atherosclerosis. Initially, such calcifications were annual progression rate of coronary calcium was
detected by fluoroscopy or conventional chest ra- 52% ± 36%, 25% ± 22% and −7% ± 23%, respec-
diography. EBCT (electron beam computed tom- tively (Callister et al. 1998). However, a regression
ography) allowed to detect coronary calcifications of coronary calcium appears very unlikely from the
more sensitively than fluoroscopy. In a cohort of patho-physiological point of view. The reproduc-
584 patients coronary calcium could be detected in ibility in the measurement of coronary calcium by
52% and 90% by fluoroscopy and EBCT, respectively. CT is in the range of 10%, and therefore a regression
However, only 109 patients within this entire cohort below this value may be very difficult to determine.
had proven CAD, so detection of coronary calcium Furthermore, it has not yet been proven, that the
by EBCT is not appropriate to discriminate between progression of coronary calcium really results in an
patients with and without CAD (Agatston et al. increased risk for a cardiac event.
1990).
Arad et al. (1996) were the first to report the at-
tempt to predict cardiac events with coronary cal-
cium as detected by the EBCT. In their cohort of 1173
Table 9.2.1. Summary of coronary calcium score values be-
patients they observed 26 soft (PTCA and bypass tween the 25th and 75th percentile depending on age and
grafting) and hard (myocardial infarction and death) gender according to Schmermund et al. (2006). Any score
events within a follow-up period of 19 months. If the value below and above will reduce or increase the estimate
Agatston score was above 160 the odds ratio for an cardiovascular risk according to the conventional risk fac-
event was 20 to 35.4. Raggi et al. (Raggi et al. 2000) tors by approximately 10 years, respectively
used age and gender specific percentiles derived Age Male Female
from nearly 10,000 patients to identify patients at
45–49 0–45 0–3
increased risk for an event. Of patients with an un-
heralded myocardial infarction (n = 172), 70% were 50–54 0–70 0–3
above the 75th percentile with their calcium score as 55–59 4–166 0–11
compared to an asymptomatic cohort (n = 632). 60–64 8–236 0–22
All currently advocated strategies provide two 65–69 13–249 0–41
different values for the risk estimation, one by the
70–75 36–671 0–205
conventional risk assessment and another by the
162 C. R. Becker
Greenland P, Abrams J, Aurigemma GP et al. (2000) Pre- Raggi P, Callister TQ, Cooil B et al. (2000) Identification of
vention Conference V: Beyond secondary prevention: patients at increased risk of fi rst unheralded acute myo-
identifying the high-risk patient for primary prevention: cardial infarction by electron-beam computed tomogra-
noninvasive tests of atherosclerotic burden: Writing phy. Circulation 101:850–855
Group III. Circulation 101(1):E16–22 Sangiorgi G, Rumberger JA, Severson A et al. (1998) Arterial
Greenland P, LaBree L, Azen SP, Doherty TM, Detrano RC calcification and not lumen stenosis is highly correlated
(2004) Coronary artery calcium score combined with with atherosclerotic plaque burden in humans: a histolo-
Framingham score for risk prediction in asymptomatic gic study of 723 coronary artery segments using nonde-
individuals. JAMA 291(2):210–215 calcifying methodology. J Am Coll Cardiol 31(1):126–133
Grundy SM (2001) Coronary plaque as a replacement for age Schmermund A, Mohlenkamp S, Stang A et al. (2002) Assess-
as a risk factor in global risk assessment. Am J Cardiol ment of clinically silent atherosclerotic disease and esta-
88(2-A):8E–11E blished and novel risk factors for predicting myocardial
Hoffmann U, Siebert U, Bull-Stewart A et al. (2006) Evidence infarction and cardiac death in healthy middle-aged sub-
for lower variability of coronary artery calcium mineral jects: rationale and design of the Heinz Nixdorf RECALL
mass measurements by multi-detector computed tomo- Study. Risk Factors, Evaluation of Coronary Calcium and
graphy in a community-based cohort – consequences for Lifestyle. Am Heart J 144(2):212–218
progression studies. Eur J Radiol 57(3):396–402 Schmermund A, Mohlenkamp S, Berenbein S et al. (2006)
Horiguchi J, Shen Y, Akiyama Y et al. (2005) Electron beam Population-based assessment of subclinical coronary
CT versus 16-MDCT on the variability of repeated coro- atherosclerosis using electron-beam computed tomogra-
nary artery calcium measurements in a variable heart phy. Atherosclerosis 185(1):177–182
rate phantom. AJR Am J Roentgenol 185(4):995–1000 Stanford W, Thompson BH, Burns TL, Heery SD, Burr MC
Nelson JC, Kronmal RA, Carr JJ et al. (2005) Measuring co- (2004) Coronary artery calcium quantification at multi-
ronary calcium on CT images adjusted for attenuation detector row helical CT versus electron-beam CT. Radio-
differences. Radiology 235(2):403–414 logy 230(2):397–402
NHLBI (2000) NHLBI lanches 10-year study on early detec- Stary HC, Chandler AB, Glagov S et al. (1994) A defi nition of
tion of heart disease. National Heart, Lung and Blood initial, fatty streak, and intermediate lesions of atheroscl-
Institute, 2000. (Accessed at http://www.nhlbi.nih.gov/ erosis. A report from the Committee on Vascular Lesions
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Nikolaou K, Poon M, Sirol M, Becker CR, Fayad ZA (2003) ciation. Circulation 89(5):2462–2478
Complementary results of computed tomography and Stary HC, Chandler AB, Dinsmore RE et al. (1995) A defi-
magnetic resonance imaging of the heart and coro- nition of advanced types of atherosclerotic lesions and
nary arteries: a review and future outlook. Cardiol Clin a histological classification of atherosclerosis. A report
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O´Malley P, Taylor A, Gibbons R et al. (1999) Rationale and on Arteriosclerosis, American Heart Association. Circu-
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a screening test for coronary artery disease and as an (2000) Lessons from sudden coronary death. A com-
intervention for risk factor modification among young, prehensive morphological classification scheme for
asymptomatic, active-duty United States Army person- atherosclerotic lesions. Arterioscler Thromb Vasc Biol
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Cardiovascular Diseases: Duplex Ultrasound of the Carotid Arteries... 165
Cardiovascular Diseases 9
9.3 Duplex Ultrasound of the Carotid Arteries:
Practical Aspects and Results of Screening for Carotid Disease
Norbert Weiss and Ulrich Hoffmann
CONTENTS 9.3.1
Duplex Ultrasound of the Carotid Arteries
– Technical Prerequisites
9.3.1 Duplex Ultrasound of the Carotid Arteries
– Technical Prerequisites 156
9.3.1.1 Principles of Vascular Ultrasound 165 9.3.1.1
9.3.1.2 Examination Technique for Carotid Artery Principles of Vascular Ultrasound
Ultrasound 166
9.3.2 Detection of Early Atherosclerosis in
Ultrasound is the use of sound waves with frequen-
Carotid Arteries 168
9.3.2.1 Measurement of cies above those heard by the human ear. Ultrasound
Intima-Media-Thickness 168 units used for imaging in medicine generate fre-
9.3.2.1.1 Defi nition of quencies of 2–15 million cycles per second (MHz).
Intima-Media-Thickness 168 In these systems, electronic voltage is transmitted
9.3.2.1.2 Standardized Measurement of
Intima-Media-Thickness 1695
to an oscillator within an ultrasound transducer, a
9.3.2.2 Implications of Intima-Media-Thickness crystal in the oscillator vibrates and emits an ultra-
Measurement for Cardiovascular Risk sound beam with a defined frequency. The ultra-
Assessment 169 sound beam hits various targets in its path (i.e., soft
9.3.3 Duplex Ultrasound for Diagnosis,
tissue, bone, and flowing blood) and is reflected back
Treatment, and Follow-Up Monitoring of
Carotid Artery Stenosis 170 to the crystal.
9.3.3.1 The Clinical Problem 170 The ultrasound units available today use B-mode
9.3.3.2 Grading of Internal Carotid Artery (“brightness”) technology to provide a real-time,
Stenosis 171 gray-scale image. In the case of vascular ultra-
9.3.3.3 Characterization of the Carotid Plaque 9.3-9
9.3.3.3.1 Visual Characterization of the Carotid
sound, B-mode provides the operator with a “live”
Plaque 173 image of the blood vessel that is updated several
9.3.3.3.2 Visual Plaque Classification and Degree times per second. High-frequency transducers (i.e.,
of Stenosis as Predictors of Ipsilateral 10–15 MHz) provide excellent image resolution of
Hemispheric Events 173 superficial structures; however, the beam attenu-
9.3.3.3.3 Computerized Evaluation of Plaque
Echogenicity: Gray-Scale Median 175 ates rapidly as depth increases. Such high-frequency
9.3.3.4 Efficiency and Cost-Effectiveness of transducers are used to image extracranial carotid
Screening for Carotid Artery Disease 176 arteries, in arterial and venous mapping studies,
9.3.3.4.1 Symptomatic Patients 176 and to clearly delineate plaque morphology. Low-
9.3.3.4.2 Asymptomatic Patients 177
References 178
frequency transducers (i.e., 2–4 MHz) are better
able to visualize deeper structures while sacrificing
image resolution. Low-frequency transducers are
N. Weiss, MD
PD, Department of Vascular Medicine, Medical Policlinic, used for abdominal imaging such as the renal arter-
University Hospitals Munich, Ludwig-Maximilians-University ies, abdominal aorta, and mesenteric arteries and
of Munich, Pettenkoferstrasse 8a, 80336 Munich, Germany veins.
U. Hoffmann, MD The term “duplex” ultrasound refers to B-mode
Professor and Division Head Vascular Medicine,
Department of Internal Medicine, University Hospital,
real-time imaging and pulsed Doppler analysis
Ludwig-Maximilians-University of Munich, Pettenkofer- of the velocity of flowing blood in arteries and
strasse 8a, 80336 Munich, Germany veins. Christian Doppler described the physics
166 N. Weiss and U. Hoffmann
of ultrasound by identifying the Doppler shift Examination begins in the B-mode after optimiz-
(Bollinger and Partsch 2003). Color flow sonog- ing the gray scale image. Imaging starts from caudal
raphy provides a “road map” for the identification to cranial in transverse sections, beginning with the
of the carotid vessels and flow within them. Using common carotid artery, and continuing upwards to
this technique, flow velocities within the vessel are the carotid bifurcation and the external and internal
color-coded. The intensity of color is a function of carotid artery in transverse sections. This allows a
the velocity. Flow towards or away from the trans- rapid orientation of the anatomy, of surrounding soft
ducer is coded either as red or blue. There is general tissues, and of the diameters of the carotid arteries.
agreement that blood flow towards the transducer In adults, normal diameters of the common carotid
is coded in red and away from the probe is coded artery are in the range of 6–7 mm (up to 7.5 mm in the
in blue. Areas of stenosis are depicted as a reduced carotid bifurcation). The internal and external carotid
lumen with a red to blue shift due to “aliasing”, artery measure 4–5 mm each. Furthermore, these
a Doppler artifact occurring when velocities are cross sections may give an impression on the filling of
higher than the pulse repetition frequency. Post- the internal jugular vein and whether it can be com-
stenotic areas may have a mosaic color Doppler pressed or not (due to jugular vein thrombosis).
pattern due to multiple velocities and flow rever- Then the extracranial carotid arteries are iden-
sal in a boundary separation zone. In the face of a tified in longitudinal images. Relevant diagnostic
nearly occluded lumen, a narrow hairline string of images will simultaneously visualize the outer and
color through the plaque called the “string sign” inner contours of the vessel walls, as well as the per-
may be seen. fused lumen (Fig. 9.3.1). Most lesions can already
Exact qualitative and quantitative analysis of be identified in the transverse survey, whereby ves-
blood flow in vessels is obtained by spectral analysis sels are better defined in the longitudinal sections.
of Doppler signals and recording of flow velocities. Furthermore, B-mode imaging of the vessel wall is
The velocity of blood in vessels can be measured used for quantitation of the intima-media-thickness
using the variables of velocity of flowing blood, (IMT) and plaque morphology (see below).
velocity of sound in tissue, the difference between After optimization of the B-mode (gray scale)
frequency of transmitted and reflected sound, and image, the PRF and color gain is adjusted in a way
the cosine of the angle of the ultrasound beam to that the color pixels completely fi ll the vessel of
the direction of flowing blood. This is the basis for interest, at least during systole. Extraluminal color
all vascular ultrasonography, thus allowing quanti- bleed should be avoided. The flow image in non-
fication of degree of stenosis; as an artery narrows, stenotic vessel sections should be free of aliasing,
blood flow velocity increases. i.e. no red to blue color shift (Fig. 9.3.2). The exam-
iner monitors the color flow pattern for evidence of
abnormalities.
9.3.1.2 Afterwards, Doppler spectra are recorded in the
Examination Technique for Carotid Artery longitudinal scan plane. Analysis of angle-corrected
Ultrasound Doppler spectral wave forms are used for quantita-
tion of flow or of degree of stenosis (see below). Fur-
Duplex ultrasound of the carotids should be per- thermore, they are used for distinguishing the inter-
formed with a high-resolution linear array trans- nal carotid artery from the external carotid artery.
ducer (7.5 MHz, or broad spectrum 5–12 MHz). The internal carotid artery shows a typical mono-
Three modalities must be used: (1) B-mode gray phasic (antegrade diastolic) flow with low pulsatility
scale imaging, (2) color flow Doppler, on both on (Fig. 9.3.3).
transverse and longitudinal planes, and (3) spectral Flow in the external carotid artery is more pul-
Doppler velocity analysis on longitudinal planes. satile, with low diastolic flow velocities. Temporal
For ultrasound examination of the neck vessels, tapping is positive in the external carotid artery,
the patient is placed in supine position with the head whereas it is negative in the internal carotid artery
slightly extended. The examiner can either sit on (Fig. 9.3.4).
the patient’s right side, or behind the patient’s head. The common carotid artery exhibits a mixed pic-
The patient is instructed not to speak and swallow to ture between both flow patterns (Fig. 9.3.5).
prevent artifacts due to the motion of the laryngeal An exact angle correction is a prerequisite for the
bones and soft tissues. reliable measurement of flow velocities and quanti-
Cardiovascular Diseases: Duplex Ultrasound of the Carotid Arteries... 167
Fig. 9.3.1. Longitudinal section of a normal common carotid Fig. 9.3.4. Spectral analysis of Doppler flow of the external
artery with simultaneous visualization of the outer and in- carotid artery showing a pulsatile flow with a low diastolic
ner vessel wall contour, including the intima-media thick- flow velocity and positive temporal tapping
ness, and the perfused lumen
Fig. 9.3.2. Longitudinal section of a normal common carot- Fig. 9.3.5. Spectral analysis of Doppler flow of the common
id artery with color Doppler imaging showing homogenous carotid artery
monochrome color flow of the vessel lumen
ated with future cerebrovascular and cardiovascu- which at least in children IMT values may guide
lar events. This association persisted even after cor- decision to start treatment to targets early.
rection for several cardiovascular risk factors.
In addition, statin-intervention trials such as
ASAP (Smilde et al. 2001), REGRESS (de Groot et
al. 1995, 1998) and ARBITER-I (Taylor et al. 2002),
have underscored the value of carotid artery IMT 9.3.3
as an efficient parameter to assess efficacy of lipid- Duplex Ultrasound for Diagnosis,
lowering treatment. Both ASAP and ARBITER-I Treatment, and Follow-Up Monitoring of
showed that aggressive lipid lowering with 80 mg Carotid Artery Stenosis
of atorvastatin was associated with a decrease in
carotid artery IMT as opposed to no change or pro- 9.3.3.1
gression in the comparative low-dose-statin arms. The Clinical Problem
Additional intervention studies that confirmed that
lowering cholesterol levels reduces carotid artery Stroke is one of the leading causes of death in west-
IMT have been recently reviewed (Kastelein et al. ern countries. One third of strokes are fatal, and
2004; Wiegman et al. 2004b). survivors usually have prolonged or irreversible
Taken together, carotid IMT has proven to be a disabilities. Four out of five strokes are ischemic
well-standardized and validated surrogate marker events, half of them are caused by atherosclerotic
for cardiovascular disease burden and is particularly disease of the carotid or intracranial arteries. Of
closely correlated with the incidence and extent of these obstructions, 50%–60% are localized in the
coronary artery disease and the incidence of cardio- carotid bifurcation and/or the internal carotid
vascular events such as acute coronary syndrome, artery, and another 5%–10% in the common carotid
myocardial infarction and stroke (Bots et al. 1997; artery (Landwehr et al. 2001). Atherosclerotic ste-
Hodis et al. 1998; O’Leary et al. 1999; Chambless et noses of the carotid artery therefore are a leading
al. 2000; Demircan et al. 2005). However, it does not cause of all strokes, accounting for around 30% of
fulfi l the characteristics of an accepted risk factor all events. The risk of ipsilateral stroke gradually
(Touboul et al. 2004). In contrast, carotid IMT has increases with the grade of stenosis and is higher
not been shown to be associated with restenosis in patients with previous ipsilateral transient focal
after femoropopliteal percutaneous transluminal neurological symptoms compared to asymptomatic
angioplasty (van der Loo et al. 2005) or secondary patients (Fig. 9.3.7) (Inzitari et al. 2000).
cardiovascular events after coronary bypass surgery Consequently, the effect of correcting a carotid
(Aboyans et al. 2005). Standardized measurements artery stenosis by endarterectomy in regard to stroke
of carotid IMT may therefore be useful in epide- risk has been studied during the last 20 years. First
miological and interventional trials dealing with results were obtained in patients with prior focal
vascular diseases to improve characterization of the neurological symptoms related to the brain hemi-
population investigated. sphere dependent on a stenotic carotid artery. Two
In contrast to predicting cardiovascular risk randomized studies in symptomatic patients, the
in large populations, carotid IMT is not useful in North American Symptomatic Carotid Endarterec-
predicting individual risk, since it is a continu- tomy Trial (NASCET) (Anonymous 1991a; Gasecki
ous variable without a threshold value. Data from et al. 1995; Ferguson et al. 1999) and the European
the Rotterdam Study showed that adding common Carotid Surgery Trial (ECST) (Anonymous 1991b,
carotid IMT to a risk function with established risk 1996) both showed that patients with high-grade
factors has no additional value to predict the coro- (t70%) internal carotid artery stenosis based on the
nary heart disease and cerebrovascular disease risk angiographic estimation of the degree of stenosis
(del Sol et al. 2001). Therefore a recent consensus did clearly benefit from carotid surgery compared
statement concluded that there is no need to treat with the group receiving conservative treatment.
IMT values nor to monitor IMT values in individual Published data have generally reported a 1%–3%
patients apart from few exceptions (Redberg et al. incidence of perioperative mortality and a 2%–10%
2002; Touboul et al. 2004). These exceptions may incidence of perioperative stroke. In pooled data
include patients with familial hypercholesterolemia from both large studies, surgery reduced the 5-year
(Wittekoek et al. 1999; Wiegman et al. 2004a), in risk of any stroke or death by 21.2% in patients with
Cardiovascular Diseases: Duplex Ultrasound of the Carotid Arteries... 171
n
0%
9%
4%
4%
9%
e
io
as
<5
−5
−7
−9
−9
s
se
clu
stenosis the risk of ipsilateral stroke is significantly
Di
50
60
75
95
Oc
No
lower than in symptomatic patients (Fig. 9.3.7). The Degree of Stenosis on Angiography
effect of carotid endarterectomy in asymptomatic
has been studied in two large scaled trials, the asymp- Fig. 9.3.7. Risk of ipsilateral stroke during 5 years of follow
up depending on the degree of stenosis on angiography in
tomatic carotid surgery trial (ACST) conducted asymptomatic and symptomatic patients. From Inzitari et
mainly in Europe (Halliday et al. 1994, 2004), al. (2002): The causes and risk of stroke in patients with as-
and the asymptomatic carotid atherosclerosis trial ymptomatic internal-carotid-artery stenosis. North Ameri-
(ACAS) conducted in North America (Anonymous can Symptomatic Carotid Endarterectomy Trial Collabora-
1995). In patients younger than 75 years of age with tors. N Engl J Med 342:1693–1700
carotid diameter reduction about 70% or more on
ultrasound (many of whom were on aspirin, anti-
hypertensive, and, in recent years, statin therapy), and series in high-volume centers (Bergeron et al.
immediate carotid endarterectomy halved the net 5- 2005) indicate that long-term results up to five years
year stroke risk from about 12% to about 6% (includ- are comparable to carotid endarterectomy. How-
ing the 3% perioperative hazard). Half of this 5-year ever, as stenting with protection does not appear
benefit involved disabling or fatal strokes. Subgroups to be inferior to carotid endarterectomy, this is not
analysis, however, showed, that the beneficial effect a license for the widespread use of stenting, but it
was restricted to men, but did not occur in women, should indicate that patients, before stenting, need
and was restricted to younger patients below the age to be assessed as thoroughly and appropriately as
of 75 (Chambers and Donnan 2005). Outside trials, those being considered for endarterectomy to define
inappropriate selection of patients or poor surgery which patient might profit from any intervention at
could even obviate these benefits (Halliday et al. the carotid arteries.
2004).
Carotid artery stenting has evolved as an alterna-
tive to carotid endarterectomy during the last decade 9.3.3.2
(Dieter and Laird 2005). Data from registries and Grading of Internal Carotid Artery Stenosis
unrandomized studies indicated that carotid artery
stenting is not less safe than carotid endarterec- Using color Doppler sonography, areas of stenosis
tomy in the hands of experienced interventionalists are depicted as a reduced lumen with a red to blue
(Yadav et al. 2004; Anonymous 2005). The carotid shift due to “aliasing”. The latter phenomenon is
revascularization using endarterectomy or stenting a Doppler artifact that occurs when velocities are
systems (CaRESS) phase I study, a multicenter, pro- higher than the pulse repetition frequency. Postste-
spective, nonrandomized trial designed to address notic areas may be detectable by a mosaic turbu-
the question of whether carotid stenting (CAS) with lent color Doppler pattern due to multiple veloci-
cerebral protection, is comparable to carotid end- ties and flow reversal in a boundary separation
arterectomy (CEA) in patients with symptomatic zone (Middleton et al. 1988; Hallam et al. 1989;
and asymptomatic carotid stenosis, showed that the Steinke et al. 1998). In a nearly occluded lumen,
30-days and 1-year risk of death, stroke, or MI with a narrow hairline string of color through the plaque
carotid artery stenting is equivalent to that with may be seen. In this case power Doppler sonography
carotid endarterectomy (Anonymous 2005). Fur- may be helpful to visualize the residual lumen as this
thermore, registry data, like the ELOCAS and CAS mode is more sensitive to lower velocities (Steinke
registries (Bosiers et al. 2005; Zahn et al. 2005) et al. 1997; Koga et al. 2001).
172 N. Weiss and U. Hoffmann
Flow velocity is the main parameter for evaluat- 1988; Moneta et al. 1993, 1995; Nicolaides et al.
ing the degree of a carotid artery stenosis. This is 1996; AbuRhama et al. 1998; Elgersma et al. 1998;
achieved by obtaining a B-mode gray scale image Filis et al. 2002; Hwang et al. 2002; Nederkoorn
of the vessel and placing the sample volume in the et al. 2002; Staikov et al. 2002; Strandness 2002;
center of the presumed stenosis. An angle of 60q Thomas et al. 2002).
should be kept between the Doppler beam and the To summarize these different classification sys-
longitudinal axis of the vessel. Doppler spectrum tems, a multidisciplinary panel under the auspices
of the carotid flow is then displayed. Flow velocity of the Society of Radiologists in Ultrasound drew
must be sampled through the whole area of the pre- up and published a consensus statement on the
sumed stenosis up to the distal end of the plaque. performance of Doppler sonography for the diag-
This ensures that the site of the highest velocity has nosis of ICA stenosis (Grant et al. 2003). Based on
been detected (Grant et al. 2003) (Fig. 9.3.8). these recommendations, degree of stenosis in the
ICA can be classified into five categories based on
two primary parameters, the ICA PSV and plaque
size, and on two secondary parameters, ICA/CCA
PSV ratio and ICA EDV (Table 9.3.1). The ICA/CCA
PSV ratio is especially helpful when flow changes
are induced by severe bilateral stenoses of the ICA,
or by proximal CCA stenosis or occlusion. Further-
more it is helpful when high or low ICA velocities
are registered. This might occur in hyperdynamic
states such as in young patients, or vice versa, in
hypodynamic states such as in patients with low
cardiac output that will have proportionally lower
PSV for a given degree of stenosis. Hemodynami-
cally relevant stenosis starts at a diameter reduc-
tion equal or greater than 50%. In clinical terms,
identification of a 70%–99% stenosis is most
Fig. 9.3.8. High grade internal carotid artery stenosis iden- relevant.
tified by a turbulent flow, an intrastenotic peak systolic ve- Comparing different flow velocity criteria for the
locity > 300 cm/s, and an enddiastolic velocity of 150 cm/s quantification of ICA stenosis with duplex sonog-
raphy compared to angiography calculated by the
NASCET method, a PSV t200 cm/s has a sensitiv-
Various studies that related Doppler sonographic ity of 90% (95% CI, 84%–94%) and a specificity of
velocity recording to angiographic assessment of 94% (95% CI, 88%–97%), and an ICA/CCA ratio t4
stenosis showed a considerable spread of values, is associated with an 80% sensitivity (95% CI, 70%–
which affects sensitivity and specificity as well as 90%) and 88% specificity (95% CI, 83%–93%) for
the positive and negative predictive values of the diagnosis of a stenosis t70% (Jahromi et al. 2005).
sonographic tests (Sabeti et al. 2004; Jahromi Using the above-mentioned criteria, Doppler sonog-
et al. 2005). Furthermore, depending on whether raphy and angiography have shown agreement in
the patients are asymptomatic or symptomatic at least 90% of the cases in the grading of stenosis
and related to the risk of subsequent stroke and (Alexandrov et al. 1997; Chen et al. 1998).
the anticipated benefit from carotid artery revas- Taken together, color Doppler sonographic grad-
cularization, some authors suggest adjustment ing of carotid artery stenosis offers a non-invasive,
of the interpretation to reflect these relative risk reproducible and accurate tool for initial evaluation
(Moneta et al. 1993, 1995). Based on the determi- and follow-up of patients with suspected or known
nation of intrastenotic peak systolic velocity (PSV) carotid artery stenosis. As long as technically appro-
and end-diastolic velocity (EDV) in the internal priate measurements are obtained, this method
carotid artery (ICA), and on the ratio of PSV in allows stratification of patients with carotid artery
the ICA/common carotid artery (CCA), several stenosis that may or may not benefit from carotid
classifications of the degree of carotid artery ste- artery revascularization, and therefore should be
nosis degree had been proposed (Robinson et al. used as the initial imaging modality.
Cardiovascular Diseases: Duplex Ultrasound of the Carotid Arteries... 173
Table 9.3.1. Spectral Doppler velocities and plaque estimate correlated with degree of internal carotid artery
stenosis diameter. Modified from Moneta et al. (1995); Grant et al. (2003)
Stenosis Plaque estimate (%) ICA PSV (cm/s) ICA/CCA PSV ratio ICA EDV (cm/s)
9.3.3.3.1 9.3.3.3.1.1
Visual Characterization of the Carotid Plaque Plaque Echogenicity
Apart from the degree of stenosis, plaque morphol- Plaque echogenicity varies from anechogenic (dark
ogy has emerged in recent years as an important con- on ultrasound) through mixed forms to hyperecho-
tributory factor in stroke risk. The main mechanism genic (bright on ultrasound) plaques. According to a
of stroke related to pathology of the carotid artery is recent consensus meeting on plaque characterization
thought to be embolism from a fissured or ruptured (De Bray et al. 1996), echogenicity should be stan-
plaque. Recent pathological studies of postmortem dardized against flowing blood for anechogenicity,
and arterectomy specimens have shown that plaque sternocleidomastoid muscle for isoechogenicity,
vulnerability is related to the size of the athero- and the adjacent transverse apophysis of the cervi-
matous core, the thickness of the fibrous cap, and cal vertebrae for hyperechogenicity. According to
to inflammation within the cap (Bassiouny et al. Geroulakos et al. (1993), plaques may be grouped
1997). Unstable plaques prone to rupture have a thin into five types, as outlined in Figure 9.3.9.
fibrous cap with a necrotic core near to the surface.
Rupture of the plaque exposes the thrombogenic 9.3.3.3.1.2
atheroma to circulating blood. This initiates throm- Plaque Texture
bus formation which may lead to thromboembolism
into the brain and subsequent ischemic stroke. Plaque texture reflects the distribution of the gray-
As discussed above, recent multicenter trials have scale levels in a given area of the plaque and may be
established the benefit of carotid endarterectomy or either homogenous or heterogenous irrespective of
stenting in symptomatic and asymptomatic patients their echogenicity. Heterogenous plaques therefore
with high-grade stenosis of the ICA. A remarkable contain both hypoechogenic and hyperechogenic
portion of patients on medical treatment alone, areas with either a smooth or an irregular surface.
however, remained free of symptoms during the Homogenous plaques have a uniform texture with a
follow-up period. In addition, in some rare cases, smooth and regular surface (Reilly et al. 1983).
patients with more moderate degrees of stenosis
also developed neurological events. This indicates 9.3.3.3.1.3
that the degree of stenosis alone does not completely Plaque Surface
predict stroke risk.
Therefore high resolution ultrasound has been The surface of a plaque is either defined as smooth
used for characterization of carotid plaque morphol- and regular, mildly irregular, or ulcerated. Mildly
ogy based on visual analysis of plaque echogenicity, irregular plaques show height variations between
texture and surface. Morphological appearance of 0.4 and 2 mm on the contour of the plaque. Ulcer-
174 N. Weiss and U. Hoffmann
Fig. 9.3.9. Grading of plaque chogenicity. Type 1: uniformly anechogenic with an echogenic fibrous cap. Type 2: predomi-
nantly anechogenic but with echogenic areas representing less than 25% of the plaque. Type 3: predominantly hyperecho-
genic but with anechogenic areas representing less than 25% of the plaque. Type 4: uniformly echogenic plaque. Type 5:
unclassified plaque reflecting calcified plaques with may have zones of acoustic shadowing which obscure the deeper part
of the arterial wall as well as the vessel lumen. Adapted from Sztajzel (2005)
ations correspond to an irregularity or break in the cantly (approximately twofold) higher event rate
surface of the plaque that must be visualized on than echogenic plaques (Langsfeld et al. 1989;
two different planes, must be at least 2 mm deep Mathiesen et al. 2001; Grogan et al. 2005). In
and 2 mm long, must have a well defined wall at addition, data from the Tromso study, a prospective
its base, and must exhibit an area of reversed flow study of more than 200 subjects each with carotid
(Sztajzel 2005). stenosis or controls matched for age and gender,
showed that the presence of echolucent plaques at
9.3.3.3.2 baseline was associated with an increased risk of
Visual Plaque Classification and Degree of Stenosis ischemic cerebrovascular events independent of the
as Predictors of Ipsilateral Hemispheric Events degree of stenosis and other cardiovascular risk fac-
tors. As many ischemic events in this study occurred
Most studies on ultrasonographic plaque morphol- in a vascular territory different from that supplied
ogy and risk of subsequent neurological symptoms by the artery with the echolucent plaque, this addi-
performed so far agreed that anechogenic or heter- tionally suggests that plaque echolucency may be
ogenous plaques carry a higher risk compared with rather a marker of a higher stroke risk than a direct
echogenic or homogenous plaques. cause of the cerebrovascular event (Mathiesen et
In 293 asymptomatic patients with more than al. 2001).
75% stenosis of the carotid bifurcation, the inci- Three studies that evaluated the association
dence of transitory ischemic attacks and stroke between plaque texture and risk for subsequent neu-
during 5 years of follow-up was 100% in the group of rological events uniformly have shown that in both
patients with soft plaques compared of only 60% of symptomatic and asymptomatic patients heterog-
those with dense plaques (O’Holleran et al. 1987). enous plaques compared to homogenous plaques
Several other studies could not reproduce this very were significantly associated with an increased risk
high incidence of neurological events in patients of stroke or transient ischemic attacks (Sterpetti
with carotid artery stenosis, but also showed that et al. 1988; O’Farrell and FitzGerald 1993;
echolucent plaques were associated with a signifi- AbuRhama et al. 2002).
Cardiovascular Diseases: Duplex Ultrasound of the Carotid Arteries... 175
Interpretation and generalization of the results of ing method, and the GSM value of the adventitia
all these studies that rely on operator dependent and to 185–195. After these normalizations, the plaque
subjective methods of plaque characterization, how- is outlined and its overall brightness evaluated by
ever, are significantly restricted by several facts. using GSM with a gray-scale rate ranging from 0
Although the majority of studies conducted so far (black) to 255 (white) (Fig. 9.3.10) (El-Barghouty
to correlate ultrasound plaque morphology with his- et al. 1995).
tological findings indicate that anechogenic plaques An initial case-control study analyzed 148
represent either necrotic or hemorrhagic lesions, plaques producing more than 50% ICA stenosis in
and echogenic plaques rather a fibrotic tissue, these 87 patients. Sixty-nine plaques were in asymptom-
studies cannot be reliably interpreted or compared atic patients, the remaining in patients with amau-
because of incomparable or poorly reported histol- rosis fugax, transient ischemic attacks or stroke.
ogy methods (Lovett et al. 2005). The few studies Fifty-three plaques were associated with ipsilateral
that documented inter- and intraobserver agreement brain infarction detected by computed tomogra-
on visual plaque characterization have shown that phy. Plaques with a GSM higher than 32 (echogenic
reproducible grading of ultrasound images is not plaques) were significantly less associated with
consistently achievable using a visual grading system, bran infarction (11%) compared to plaques with
even among experienced observers, and that within- a GSM below or equal to 32 (echolucent plaques,
observer agreement may vary with time. Therefore 55% incidence of brain infarction) (El-Barghouty
visual ultrasound characterization of carotid plaque et al. 1995). These finding could be reproduced by
morphology used in clinical trials so far may be asso- the same group of investigators in a larger patient
ciated with unacceptable low levels of reproducibility sample (El-Barghouty et al. 1996a), as well as by
(De Bray et al. 1998; Arnold et al. 1999). others (Biasi et al. 1999).
9.3.3.3.3
Computerized Evaluation of Plaque Echogenicity:
Gray-Scale Median
and performing carotid endarterectomy would, increased in those with arterial hypertension and
on average, yield 11.33 QALYs at a cost of $30,400. coronary or hypertensive heart disease. More than
Duplex ultrasound was both less expensive and one of every five patients in this specific popula-
more effective than all other strategies, including tion was found to have occult carotid artery ste-
digital subtraction angiography. Adding MR angi- nosis, compared to 8% in an age-matched popu-
ography to duplex ultrasound results in increased lation (Rockman et al. 2004). Therefore screening
sensitivity and specificity, and in a slight benefit for occult carotid artery stenosis may be useful in
in terms of clinical outcome, but at extremely high patients with known coronary or hypertensive heart
costs (cost-effectiveness ratio > $1,665,000 per QALY disease. However, studies on the efficiency of screen-
gained). Therefore, the authors conclude that duplex ing programs in this population are still missing.
ultrasound performed without additional imaging is
the most cost-effective strategy to select symptom- 9.3.3.4.2.2
atic patients suitable for endarterectomy. Additional Patients with Peripheral Arterial Occlusive Disease
imaging strategies therefore should be restricted to
patients with difficult to interpret or inconsistent The prevalence of significant carotid artery steno-
duplex ultrasound findings. sis is increased as much as 50% in patients with
peripheral arterial disease, as shown in the SMART
9.3.3.4.2 study (Simons et al. 1999). In addition, a number of
Asymptomatic Patients reports on smaller screening programs suggested
that male patients with symptomatic lower extrem-
Carotid endarterectomy in asymptomatic patients ity atherosclerosis (de Virgilio et al. 1997; Cheng
with high grade stenosis is associated with sig- et al. 1999a), elder patients with cardiovascular risk
nificantly higher costs per QALY up to $52,700 per factors (Ahn et al. 1991), and patients with ankle-
QALY compared to symptomatic patients (Benade brachial index less than 0.7 (Marek et al. 1996) may
and Warlow 2002). Therefore carotid duplex ultra- qualify for screening.
sound performed as a screening test for carotid
artery stenosis currently is not recommend in 9.3.3.4.2.3
the general population and is not reimbursed by Patients with Abdominal Aortic Aneurysms
Medicare in the U.S. As the pretest probability of
detecting high-grade carotid artery stenosis signifi- Several studies have shown that patients with
cantly influences the cost-effectiveness of screening abdominal aortic aneurysms have an increased
and treatment strategies, patients population have incidence of carotid artery stenosis. The incidence
to be defined which most likely may benefit from of high-grade carotid artery stenosis (> 70%) ranges
screening and preventive treatment. These popu- from 2.9%–18% (Deville et al. 1997; Cheng et al.
lations may include patients with established ath- 1999b; Axelrod et al. 2002). There is no evidence,
erosclerotic vascular disease in other vascular ter- however, that carotid endarterectomy performed
ritories like patients with coronary artery disease, prior to aneurysm repair reduces the risk of peri-
peripheral arterial occlusive disease, and abdominal operative stroke. A recent cost-effectiveness analy-
aortic aneurysms, patients with carotid bruits, and sis of screening for carotid disease in patients with
patients after radiation therapy for head and neck abdominal aortic aneurysms showed that most
cancers, but not patients with atherosclerotic risk patients with advanced carotid artery stenosis (71%
factors alone. of 206 patients screened) had clinical evidence of the
disease including transient ischemic attacks, amau-
9.3.3.4.2.1 rosis fugax, a complete stroke, or a history of prior
Patients with Known Heart Disease carotid surgery. The absence of clinical evidence of
the disease had a negative predictive value of 99%.
In community-based stroke screening programs, Routine screening for carotid artery disease would
carotid artery stenosis was the most commonly result in additional costs of $5,445 per case, whereas
diagnosed treatable cause of potential stroke, and screening for advanced carotid stenosis in patients
patients with known heart disease have a more than with an appropriate history or symptoms would
doubled risk to have carotid artery stenosis than reduce costs to one fifth. From the data available,
those without heart disease. The risk is further routine diagnostic screening for the identification
178 N. Weiss and U. Hoffmann
of asymptomatic carotid artery stenosis in patients mended to routinely screen all patients undergoing
with abdominal aortic aneurysms may not be justi- open elective heart surgery for atherosclerotic coro-
fied, and should be restricted to those with clinical nary artery disease and performing carotid revascu-
symptoms of the disease. larization either operatively under local anesthesia
or by carotid artery stenting.
9.3.3.4.2.4
Patients after Contralateral Carotid Endarterectomy 9.3.3.4.2.6
Patients with Carotid Bruits
Progression of contralateral carotid artery stenosis
after carotid endarterectomy is relatively common Carotid auscultation is thought to be a useful screen-
(Raman et al. 2004). A recent study identified an ing procedure for the detection of carotid stenosis
8.3% annual rate of progression of contralateral or occlusion. In a series of 145 patients, the negative
carotid artery stenosis and a 4.4% annual rate of predictive value of a normal auscultation was found
progression to severe stenosis or occlusion. Clinical to be 97%. The sensitivity of carotid auscultation for
and demographic factors did not predict the risk the detection of a 70%–99% stenosis of the common
of progression. Therefore, routine follow-up of the or extracranial internal carotid artery was 56% and
contralateral carotid artery in patients after carotid specificity was 91%. The positive predictive value
endarterectomy may be useful, although cost effec- of a bruit found during carotid auscultation, how-
tiveness analysis of duplex scanning in this popula- ever, was only 27% (Magyar et al. 2002). These data
tion have not been performed so far. suggest that the clinical finding of a carotid bruit
requires confirmation by carotid ultrasound.
9.3.3.4.2.5
Patients Scheduled for Elective Coronary Artery 9.3.3.4.2.7
Bypass Surgery Patients after Radiation Therapy for Head and Neck
Cancer
Extracranial internal carotid artery stenosis is a risk
factor for perioperative stroke in coronary artery Cervical radiation for head and neck cancer is asso-
bypass surgery. Although both selective and non- ciated with an increased incidence of carotid artery
selective methods of preoperative carotid screening stenosis. During the 10 years following radiation
have been advocated, it is unclear which approach treatment up to 40% of patients develop significant
is most clinically efficacious. A recent study com- carotid artery stenosis (Steele et al. 2004). Whether
pared selective screening in patients with either an or not focused screening of this high-risk population
age of more than 65, carotid bruit, or a history of may be effective and medically beneficial is cur-
cerebrovascular disease with routine screening in rently under investigation.
all patients, followed by carotid endarterectomy
under local anesthesia in those with critical carotid
stenosis (De Feo et al. 2005). Routine screening vs
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Oncological Disease: Breast Cancer 183
Oncological Disease 10
10.1 Breast Cancer
Karin Hellerhoff, Claudia Perlet, and Thomas Schlossbauer
CONTENTS 10.1.1
Physical and Technical Quality Control
10.1.1 Physical and Technical Quality Successful mammography screening has to keep
Control 183 the radiation exposure as low as reasonably achiev-
10.1.2 Radiographical Performance 184 able (ALARA) to obtain high quality images with
10.1.2.1 Mammographic Examination 184 sufficient diagnostic information. Quality control
10.1.2.2 Image Quality 184 in screening units has to cover all parts of the
imaging chain like X-ray generation, Bucky and
10.1.3 Radiological Performance 184
image receptor, fi lm processing and viewing con-
10.1.3.1 Viewing Conditions 186
10.1.3.2 Reporting System 186 ditions. A nominated radiographer of the screen-
ing unit should be responsible for consistency tests
10.1.4 Radiological Assessment 187 which have to be performed daily and weekly (see
10.1.4.1 Additional Mammography Views 187 Table 10.1). More complex measurements have to be
10.1.4.2 Ultrasound 188
10.1.4.3 MRI 188 undertaken either at acceptance, yearly or every six
months covering the X-ray source (focal spot size,
10.1.5 Image Guided Sampling source to image distance, alignment of X-ray field,
Techniques 189 radiation leakage), tube voltage reproducibility and
10.1.5.1 Fine Needle Aspiration Cytology 190
beam quality (Half Value Layer), automatic expo-
10.1.5.2 Needle Core Biopsy 190
10.1.5.3 Vacuum Assisted Needle Core sure control (reproducibility and security cut-off),
Biopsy 190 tube voltage compensation, dosimetry and exposure
time (Perry et al. 2006). Performance indicators are
10.1.6 Perspectives 191 listed in Table 10.2.
References 191
Table 10.1. Physical and technical quality control parameter
Table 10.2. Performance indicators for physical aspects and radiographical performance (European Guidelines, 4th edn)
PGMI criteria for mediolateral oblique view PGMI criteria for cranio-caudal view
All the breast tissue clearly shown As much as possible of the lateral part of the breast is shown
Pectoral muscle to nipple level If possible, the pectoral muscle is shown at the posterior edge of the
mammogram
Symmetrical images Symmetrical images
Nipple in profi le Nipple in profi le
Inframammary angle clearly visible Medial border is visible
Table 10.4. Performance and impact indicators of screening mammography (European Guidelines, 4th edn)
vide high quality images, to read mammograms and specificity of the reader are the detection rate of
with optimal sensitivity and specificity meeting the initial and subsequent screens related to the back-
targets of the given performance and impact param- ground incidence of the population, the proportion
eter and to take care of the timely follow-up assess- of screen-detected small invasive cancers < 10 mm
ment for women with abnormal mammograms. and screen-detected DCIS as a proportion of all
Performance standards representing the sensitivity screen-detected cancers (see Table 10.4).
186 K. Hellerhoff, C. Perlet, and T. Schlossbauer
The radiologist should be involved with symp- one or two radiologists it should be reviewed by an
tomatic breast assessment and be experienced in expert radiologist who is able to arbitrate.
all biopsy techniques including ultrasonography,
ultrasound guided core biopsy, stereotactic guided
vacuum biopsy and preoperative localisation pro- 10.1.3.2
cedures such as wire placement. Radiologists per- Reporting System
forming histologic assessments should attend mul-
tidisciplinary review boards to be involved in the Reporting screening mammograms should use stan-
preoperative and postoperative therapy decisions. dardized terminology to describe mammographic
Interval carcinoma is defined as breast cancer lesions and give standardized recommendations for
becoming symptomatic after attending mammogra- the further assessment. Inconsistencies and confu-
phy and before the next subsequent screen. Although sions among the radiologists being involved in the
interval carcinoma are inevitable, the rate should further follow-up of a woman have to be avoided.
be kept low. Monitoring and reviewing of interval A simple five-point classification system is used
cancer is essential for further improvement of radio- widely in European screening programmes:
logical skills. If any interval cancer is observed it R1 Normal/benign
should be evaluated whether it is due to failures in R2 A lesion having benign characteristics
the reading of mammograms or in further assess- R3 Abnormality of indeterminate significance
ment procedures. True interval carcinoma with R4 Features suspicious of malignancy
negative screening fi lm should be differentiated R5 Malignant features
from occult carcinoma remaining without mam-
mographic manifestations and cases of minimal The increasingly used BI-RADS system allows a
mammographic signs retrospectively detectable in more precise classification including recommenda-
screening mammograms. tions for the need of further follow-up (ACR 2003).
The breast density is included into the report,
because it has an important impact on the accuracy
10.1.3.1 of mammography. The sensitivity of 80% in women
Viewing Conditions with fatty breast tissue (ACR 1) decreases to 30% in
women with very high density (ACR 4) (Mandelson
The luminance of viewing boxes should be well et al. 2000). Screening mammograms of women with
related to the ambient light level. Generally it should dense breast tissue were 30% more likely to have
be in the range of 3000–6000 cd/m2. lesion-assigned discordant assessments and recom-
Collimation should be provided as well as the use mendations compared with those of women with
of magnifying glasses. To prevent inhomogeneities fatty tissue (Lehman et al. 2002).
of the permeating light as a result of dust, the boxes Breast tissue density according to the BI-RADS
should be cleaned regularly. The ambient light in system is classified as follows:
the viewing room should not exceed 50 lux. Viewing ACR Mammographic appearance
conditions have to be controlled yearly. 1 Mostly fatty
Digital full field mammograms should be read as 2 Fibroglandular tissue
soft copies. The work station must provide at least 3 Heterogeneously dense
two high resolution monitors (2.5 × 2 K). Since the 4 Completely dense
luminance of these monitors is lower than the aver-
age luminance of viewing boxes, the ambient light Mammographic lesions are differentiated as fol-
should be diminished as far as possible. lows.
Previous mammograms should be displayed at Mass: a mass is a lesion which can be seen in two
the time of screen reading if ever possible. Double different views (otherwise it should be described as
reading should be performed routinely, since the density). It should be described by its shape (round,
detection rate increases by 15% compared to single oval, lobular, irregular), its margin (well-defined
reading (Thurfjell et al. 1994). If double reading is and smooth, microlobulated, obscured by surround-
performed, the second reader should be experienced ing tissue, indistinct and spiculated) and its density
with a minimum of 5000 mammograms per year. If (higher, lower or equivalent) compared to the sur-
the mammogram is considered to be abnormal by rounding glandular tissue.
Oncological Disease: Breast Cancer 187
Calcifications: these are classified for different among 18 community radiologists was determined
appearances and distributions. A monomorphic by Lehman et al. (2002). The assessment with the
and smoothly shaped appearance indicates typical highest rate of discordance between BI-RADS
benign calcification. Amorphous or pleomorphic assessments and recommendations (53.5%) was
calcifications are of indeterminate character. Linear the BI-RADS 3 category “probably benign finding”.
or branching calcifications indicate ductal origin Although the overall discordance between the BI-
with higher suspicion of malignancy. The distribu- RADS assessments was low (3%), further improve-
tion is described as diffuse, clustered or linear and ment was observed over a period of 4 years with
segmental, the latter indicating higher suspicion of exception of the high discordance rates of the BI-
malignancy. RADS 3 category persisting across all of the study
Architectural distortion: the regular tissue archi- years.
tecture is disturbed without a recognizable definite The European Guidelines for quality assur-
mass. ance therefore recommend that for screening pur-
Lesions should be correctly described for their poses “BI-RADS category 3 should be avoided or
location including the side (left, right), the involved restricted to a minimum of < 1% of women”, since
quadrant (I–X), the location according to the face early recall is associated with low predictive value
of the clock and the location related to the nipple but creates uncertainty and anxiety. Breast cancer
(nipple-lesion distance, subareolar, central, prepec- detected by early recall is defi ned as interval cancer
toral). by some programmes, because the diagnosis is
The size should be evaluated using two views. delayed.
Associated mammographic findings like skin retrac-
tion or thickening, nipple retraction and axillary
adenopathy should also be described. Whenever
possible, previous examinations should be available
to compare previous and current status in order to 10.1.4
evaluate changes of appearance or size of a lesion. Radiological Assessment
Moreover, previous screens enable the recognition
of anatomical variants like asymmetric breast tissue 10.1.4.1
or intramammary lymph nodes. Additional Mammography Views
BI-RADS definitions of mammographic lesions
and concordant recommendations for further Additional views are helpful to visualize mammo-
assessment are listed in Table 10.5. graphic lesions in two orientations allowing correct
The concordance of assessments and recom- localization of a lesion. Commonly used additional
mendations assigned to screening mammograms views are listed in Table 10.6.
Mediolateral view Preoperative localization and biopsy planning with perpendicular views
Visualization of “tea-cup” appearance of microcalcifications of mastopathic origin
Lateromedial view Visualization of medially localized lesion in cc view
XCC view Visualization of lesions seen in oblique view and suspected to be localized laterally
Cleavage view Visualization of dorsally and medially located lesions
Torquated cc view Localization of lesions seen in cc view but not in oblique view. Lateral movement of
the breast will induce a lateral shift of lesions located in the upper quadrants and
induce a medial shift of lesions located in the lower quadrants of the breast
Paddle compression spot views To improve the visualization of distortion and possible mass
To resolve pseudolesions, overlying tissue and asymmetry
Microfocus magnification image Further assessment of microcalcifications
20%–30%, open biopsy can be avoided in 70%–80% increases with the number of samples, at least five
of patients (Liberman et al. 1998; Laquement et al. tissue specimens should be obtained to ensure a
1999). Lesions classified as BI-RADS 3 should not be definitive diagnosis. Moreover the samples can be
routinely sampled, since the malignancy rate among used for the assessment of steroid receptor status
these lesions is much less than 2%. In BI-RADS 5 and Her2/Neu status.
lesions the preoperative biopsy should be performed
to allow therapy planning including therapeutical
surgery and sentinel lymph node biopsy proce- 10.1.5.3
dures after malignancy is proven by percutaneous Vacuum Assisted Needle Core Biopsy
biopsy.
Sampling techniques should be carried out with Vacuum assisted needle core biopsy (VANCB) pro-
respect to the imaging modality carrying the most vides the highest accuracy rates obtained by non-
suspicious features. In general it is most suitable invasive procedures. Negative pressure is used to
to perform sampling under ultrasound control. suck sample tissue into the biopsy port, being cut
Microcalcifications should be sampled by vacuum by a rotating cylinder passing down within the
assisted needle core biopsy. It is regarded consent, probe. VANCB should be performed using 11 G or
that significant architectural distorsions should not 8 G needles to obtain 24 samples within 2 rounds
be sampled by percutaneous biopsy, because associ- of 12 clockwise steps. In case of microcalcifica-
ated malignancy may not be demonstrated. In these tions within the sampled area, the obtained tissue
cases women should primarily undergo open biopsy should be examined by radiography immediately
after preoperative wire localization. after the procedure. The obtained samples provide
higher tissue volumes compared to NCB and allow
defi nitive diagnosis even in case of moderate or
10.1.5.1 low suspicion microcalcification. Moreover asso-
Fine Needle Aspiration Cytology ciated ductal in situ cancer (DCIS) and associated
atypical ductal hyperplasia (ADH) is more often
The accuracy of Fine Needle Aspiration Cytology demonstrated compared to NCB (Burbank 1997).
(FNAC) is highly dependent on the experience of In a few instances, however, VACB is not appli-
the operator and requires a well-trained pathologist cable. These include microcalcifications located
(Wells 1995). Although FNAC is less expensive and adjacent to the mamilla or the pectoral muscle. In
less time consuming than needle core biopsy, some small breasts, the compression thickness may be
substantial drawbacks limit the value of the method. less than two cm, not allowing complete insertion
The reported sensitivity is much lower compared to of the needle.
needle core biopsy (Pisano et al. 1998). Poor cel- The results of any biopsy procedures performed
lularity may cause an inadequate sample rate of by the radiologist and evaluated by the pathologist
10%–15%, especially in case of sclerosing adenosis, should be presented in an multidisciplinary panel.
sclerosed fibroadenoma and invasive lobular car- All benign results have to be correlated with the
cinoma. imaging work-up and the degree of radiological sus-
picion to determine, whether the sample obtained
was representative or not. When imaging findings
10.1.5.2 suspicious of malignancy are inconsistent with his-
Needle Core Biopsy topathological findings, it should be consent, that
the biopsy in case of NCB must be either repeated or
Needle core biopsy (NCB) is the technique of choice complemented by VANCB or open biopsy. Women
for sampling of non-palpable masses providing with benign findings correlating with imaging
high sensitivity (92%–98%) and specificity (100%) work-up should undergo one short term follow-up 6
(Britton et al. 1997; Nguyen et al. 1996). The months after the biopsy procedure.
biopsy should be performed with a needle of at least Performance indicators for biopsy techniques
14 G diameter. Since the sensitivity of the method and initial treatment are listed in Table 10.9.
Oncological Disease: Breast Cancer 191
Table 10.9. Performance indicators for biopsy techniques and initial treatment (European Guidelines, 4th edn)
10.1.6 References
Perspectives
ACR (2003) Breast imaging reporting and data system atlas
(BI-RADS atlas), 4th edn. American College of Radiology,
In recent years full-field digital mammography has Reston, VA
been increasingly used and it may be expected that Britton PD, Flower CD, Freeman AH et al. (1997) Changing to
in the near future this techniques will displace fi lm core biopsy in an NHS breast screening unit. Clin Radiol
mammography. There are substantial advantages of 52:764–767
Burbank F (1997) Stereotactic breast biopsy of atypical ductal
digital mammography in particular for screening hyperplasia and ductal carcinoma in situ: improved accu-
conditions such as image manipulation, electronic racy with a directional, vacuum-assisted biopsy instru-
transmission, retrieval and data display. Worksta- ment. Radiology 202:843–848
tions with automatic hanging protocols, central- Fröhlich CP, Weigel C, Mohr M et al. (2007) Teleradiology
ized server and Dicom shuttles for the exchange of and mammography screening: evaluation of a network
with dedicated workstations for reporting. Fortschr
images are available to simplify both double reading Röntgenstr 179:137–145
at two different sites and possible review by an arbi- Gordon PB (2002) Ultrasound for breast cancer screening
trator (Fröhlich et al. 2007). On-screen magnifica- and staging. Radiol Clin North Am 40(3):431–441
tion is sufficient, obviating the need for additional Laquement MA, Mitchell D, Hollingsworth AB (1999) Posi-
tive predictive value of the breast imaging reporting and
microfocus magnification views. Future technologi- data system. J Am Coll Surg 189:34–40
cal developments may provide further improvement Lehman C, Holt S, Peacock S et al. (2002) Use of the Ameri-
like computer-aided detection and tomosynthesis. can College of Radiology BI-RADS Guidelines by com-
The largest comparative study has shown a possible munity radiologists: concordance of assessments and
benefit in the evaluation of mammograms with very recommendations assigned to screening mammograms.
AJR Am J Roentgenol 179:15–20
dense breast tissue, because monitor reading pro- Liberman L, Abramson AF, Squires FB et al. (1998) The
vides the possibility to adjust the image contrast breast imaging reporting and data system: positive pre-
(Pisano et al. 2005). dictive value of mammographic features and fi nal assess-
Further research considering the different bio- ment categories. AJR Am J Roentgenol 171:34–40
Mandelson MR, Oestreicher N, Porter PL et al. (2000) Breast
logical appearances of breast cancer may allow more
density as a predictor of mammographic detection: com-
individual imaging recommendations with regard to parison of interval- and screen-detected cancers. J Natl
genetic predispositions and patterns of biomarker. Cancer Inst 92:1081–1087
192 K. Hellerhoff, C. Perlet, and T. Schlossbauer
Nguyen M, McCombs MM, Ghandehari S et al. (1996) An Pisano MD, Gatsonis C, Hendrick E et al. (2005) Diagnos-
update on core needle biopsy for radiologically detected tic performance of digital versus fi lm mammography for
breast lesions. Cancer 78:2340–2345 breast-cancer screening. N Engl J Med 353:1773–1783
Perry N, Broeders M, de Wolf C et al. (eds.) (2006) European Thurfjell EL, Lernevall KA, Taube AAS (1994) Benefit of
Guidelines for quality assurance in breast cancer screen- independent double reading in a population-based mam-
ing and diagnosis, 4th edn. Office for Official Publica- mography screening program. Radiology 191:241–244
tions of the European Communities, Luxembourg Wald J, Murphy P, Major P et al. (1995) UKCCCR multicentre
Pisano ED, Fajardo LL, Tsimikas J et al. (1998) Rate of randomised controlled trial of one and two view mam-
insufficient samples for fi ne-needle aspiration for non- mography in breast cancer screening. BMJ 311:1189–1193
palpable breast lesions in a multicenter clinical trial: the Wells CA (1995) Quality assurance in breast cancer screening
Radiologic Diagnostic Oncology Group 5 study. Cancer cytology: a review of the literature and a report on the UK
82:678–688 National Cytology Scheme. Eur J Cancer 31A:273–280
Oncological Disease: Renal Cancer – Ultrasound 193
Oncological Diseases 10
10.2 Renal Cancer – Ultrasound
Dragana Filipas, Sascha Pahernik and Joachim W. Thüroff
D. Filipas, MD
S. Pahernik, MD
Department of Urology, Johannes-Gutenberg-University of
Mainz, Medical School, Langenbeckstraße 1, 55101 Mainz, 10.2.2
Germany The Mainz/Wuppertal Screening Study
J. W. Thüroff, MD
Professor and Chairman, Department of Urology, Johannes-
Gutenberg-University of Mainz, Medical School, Langen- We have conducted a feasibility study on screening
beckstraße 1, 55101 Mainz, Germany for RCC by ultrasonography in two cities over a two-
194 D. Filipas, S. Pahernik, and J. W. Thüroff
year period (Filipas et al. 1999, 2002, 2003). This MRI imaging and – when positive – to surgery. Other
screening program was established in 1996 in Mainz solid tumors which are mostly indistinguishable
(180,000 inhabitants) and Wuppertal (370,000 inhab- from RCC by imaging such as solid transitional cell
itants). Participants were screened by 55 general carcinoma, oncocytoma, angiomyoma, leiomyoma
physicians, 79 internists and 19 urologists in private and lymphangioma were accepted to be included
practice. Overall, 68% of all eligible physicians par- in the group of positive findings. Masses consis-
ticipated in the program. Eligibility of participating tent with angiomyolipomas on ultrasound and/or
physicians was validated for qualification in renal CT were excluded. To compare cases of RCC in the
ultrasonography and state-of-the-art sonographic screened population to those from an unscreened
equipment. Additionally, an active medical practice population, the clinical data on all patients present-
in the already established German screening pro- ing with a renal mass at the departments of Urology
grams was required. In cooperation with different in Mainz and Wuppertal over the study periods were
health insurers, the infrastructure was developed registered and analyzed. The TNM system of tumor
firstly to recruit physicians and secondly the eli- stage classification according to the UICC of 1997
gible study population. The screening program was was used. The results were assessed using descrip-
offered to the citizens of both cities free of charge. tive statistical analyses. The analyzed data were sen-
Inclusion criteria were: age > 40 years (according sitivity, specificity and positive predictive value of
to the inclusion criteria of the already established ultrasonographic screening for RCC.
German screening programs), no urinary symptoms In total, 9959 volunteers (49% men and 51%
with a possible renal origin (e.g. hematuria, flank women) with a mean age of 61 years (range 40–
pain) and no history of renal disease. Informed con- 94 years) participated in the first screening phase.
sent was obtained in writing from all subjects. There The participation rate in the second phase was 79%
were three types of recruitment of subjects for the (7851) of all participants from the first phase. Of all
RCC screening program, firstly exclusive recruit- screened individuals, 49% (4763) participated in the
ment for the RCC screening program, secondly as screening exclusively because of the offered new
participant in one of the other established German program. The remainder was informed about the
screening programs (for skin, colon, breast, cervix program when they visited the physicians office for
and prostate cancer) and thirdly at the occasion of other reasons: 15% (1441) came for other screening
an office visit for other than renal symptoms. Based programs offered by the German Ministry of Health
on data available from German tumor registries on and 38% (3755) presented with other than renal
the reported incidence of RCC and on a previous symptoms.
retrospective abdominal ultrasound study (Kremer Thirteen (0.1%) findings were classified positive
et al. 1984), it was calculated that 10,000 screening in the initial screening ultrasonography. Of these
participants would be necessary to allow statistical 13, 12 subjects were eligible for further diagnostic
analysis of detected cases. evaluation and 6 were histologically confirmed to
The screening was conducted over two consecu- have RCC. Thus, the positive predictive value of a
tive periods of 13 months each. The initial screen- positive screening finding was 50%. In all, 175 (1.8%)
ing started in December 1996 and the second findings were classified as equivocal in the initial
phase in January 1998. The second screening phase screening ultrasonography; 171 of 175 subjects were
offered follow-up ultrasonography to the popula- eligible for further diagnostic evaluation and a renal
tion screened in the first phase. A solid renal mass tumor was confirmed in seven patients. Diagno-
detected on screening was described either as equiv- sis was confirmed by histology in five cases (three
ocal or positive for renal tumor. When an equivo- RCCs, two benign tumors) and by imaging alone in
cal mass was detected, reference ultrasonography at two patients, who were not subjected to furgery. In
each of the two university urology departments was these latter cases, CT was highly suspicious for RCC
offered but was not mandatory. The criterion for an of 2.0 and 2.5 cm diameter. The positive predictive
equivocal finding was a solid renal mass suspicious value of an equivocal screening finding was thus
of RCC, and that for a positive finding a solid mass 4.1% for a solid renal tumor, excluding angiomyo-
typical of RCC. The criterion for a negative result lipomas, and 1.8% for RCC. The positive predictive
was no evidence of tumor. Positive findings and value for both, equivocal and positive screening
equivocal findings which could not be excluded by findings was 7.1% for a solid renal tumor and 4.9%
reference ultrasonography were subjected to CT or for RCC. In the second screening phase, there were
Oncological Disease: Renal Cancer – Ultrasound 195
no additional positive findings. Equivocal findings renal tumor (T1N0M0) was incidentally detected.
were obtained in 64 of 7851 patients (0.8%), none of In the second case, both screening studies were
whom was confirmed to have a renal tumor by refer- negative, when a third abdominal ultrasonography
ence ultrasound, CT or MRI. 6 months after the latest study for other than uro-
Positive and equivocal findings in the first phase logical symptoms revealed a renal mass of 3.8 cm in
of screening ultrasonography were false positive in diameter (pT1N0M0). From these data, the sensitiv-
93% of cases as judged by subsequent imaging stud- ity of ultrasound screening for detecting RCC was
ies. Of all false positive cases, 48% were reclassified 82% as assessed at the 1-year of follow-up of 79% of
negative after reference ultrasonography alone. Of the original cohort. The specificity was 98% in the
all positive and equivocal cases referred to reference first screening phase and 99% in the second phase.
ultrasound before further CT or MRI imaging was Table 10.2.1 lists the data of the first screening
obtained, 62% were reclassified as negative. CT was phase, including ultrasound and CT findings, sur-
obtained in 68 of 9959 subjects who underwent renal gical procedures, histology, tumor stage and size of
ultrasonography in the first screening phase, 40 of detected tumors. RCC was confirmed on histology
68 obtained reference ultrasonography and 28 were in nine cases, six men and three women (mean age
directly referred to CT or MRI by the screening phy- 61.6 years, range 40–85 years). Their age distribution
sicians. Of the latter 28, 4 had been classified posi- is given in Table 10.2. 2. Two benign tumors (patients
tive on ultrasound and 24 equivocal. The false-posi- 10 and 11 in Table 10.2.1) were an oncocytoma and a
tive rate in the second screening phase was 100%. CT leiomyoma. Pre-existing medical comorbidities pro-
was obtained in 32 of 7851 subjects who underwent hibited surgical exploration in two further patients
renal ultrasonography, 23 of 32 without previous ref- (patients 12 and 13 in Table 10.2.1). Of the nine cases
erence ultrasound, even when all of them were clas- with RCC, six had been declared positive and three
sified equivocal on only screening ultrasonography. equivocal for renal tumor in the on initial screening
Two additional cases of RCC (interval cases) were ultrasonography (Table 10.2.1). All but two positive
detected in patients with no evidence of tumor in cases (patients 2 and 6) underwent CT imaging with-
the first screening phase. One participant moved out prior reference ultrasonography.
into another city and had an abdominal ultrasound A total of 482 patients (38% women and 62% men)
for other reasons 13 months after initial screening were admitted to both hospitals with renal tumors
at which occasion a small (2.5 cm) centrally located during the same periods. The screened patients
Table 10.2.2. Detected renal cell cancers and age groups Table 10.2.4. Other pathological fi ndings of renal sonogra-
(n = 9959) phy screening
Age groups [years] RCC [n] Screened population [n] Finding [n]
The participation rate was 68% for all eligible physi- metastasize early at small tumor volumes. For RCC,
cians and 90% for urologists. Almost half (48%) of there is a positive correlation between tumor size
all screened patients participated exclusively in the and the rate of lymph node and distant metastases
RCC screening program, indicating a high accep- (Hermanek and Schrott 1990). However, in our
tance rate. Currently, 14% of the eligible male and first screening of a previously unscreened popula-
34% of the female population comply with the exist- tion, tumor prevalence was determined as compared
ing screening programs offered in Germany. Com- to 1-year tumor incidence, which was determined in
pared with a digital rectal examination for detecting our second screening of the same population. Even
prostate and rectal cancer, and the cervical smear if detection of a tumor by systematic screening (our
for detecting cervical cancer, renal ultrasound is less patients had no symptoms at the time of screening)
invasive and disturbing to the patient. This assump- is by definition ‘earlier’ than detection by symptoms
tion is confirmed by a 79% return rate for the second in the same patients, it does not necessarily mean
screening phase of renal ultrasonography. A total of that ‘earlier’ detection is also at an ‘earlier’ tumor
13 renal tumors were detected, nine of which were stage. PSA screening of prostate cancer resulted ini-
RCCs on histology which is a prevalence of 9/10,000 tially in more frequent detection of prostate cancer
from the first phase of this screening study. Based on of all stages, which led to considerable debate about
older German cancer registry data and abdominal the value of such a screening program (Roberts et
ultrasound screening studies (Kremer et al. 1984), al. 1999; Labrie et al. 1999). For a screening pro-
we expected to find only 3/10000 cases of RCC in gram to be useful, it must lead to a net benefit in
the studied age groups. It cannot be concluded with patient survival. Six cases with low stage (T1 and T2)
any certainty, whether the difference between the tumors in the current cohort are likely to have ben-
observed and expected prevalences can be explained efited from screening by detecting and treating an
by the limitations of the databases from which the organ-confined tumor. Conversely, the two patients
primary estimates were derived, or by a too small with metastases presumably have not benefited from
cohort of our study, or by selection of the study the program, as there is no effective treatment for
population, or by actual early detection through sys- metastatic disease. Furthermore, the two patients
tematic screening as opposed to incidental or symp- with RCC on CT who were no surgical candidates
tom-guided detection. The second screening of the because of poor overall health have suffered psy-
cohort for detection of new cases provides insight chological distress secondary to the screening. They
into the true incidence of RCC in the screened popu- know of their potentially fatal disease but cannot
lation over the time period of follow-up when the be treated.
data of the first screening represent prevalence of The sensitivity in the current study was 82%,
RCC in an unscreened population. The prevalence as judged from the results of the 1-year follow-up
of RCC was similar in abdominal screening studies during which period two interval cases of RCC were
(Spouge et al. 1996; Mihara et al. 1998). In contra- detected after previous negative ultrasonography.
diction to our expectations, we found larger tumors This is based on the assumption, that these tumors
of higher stages in the screened population as com- were present but overlooked at the time of screen-
pared to the incidentally detected group. As a result, ing (false-negatives). Another possibility is that they
fewer tumors were amenable to NSS. Early detec- were present but too small to be detected at the time
tion of RCC by screening did not result in a stage of screening. A third possibility is that these tumors
shift towards lower tumor stages, which was one of truly developed after the last negative screening
the hypotheses of our study. One explanation may (true incidence). In the first case, a 2.5-cm centrally
again be a too small study cohort. Another expla- located tumor almost isoechogenic to normal renal
nation may be that detection at an early stage by parenchyma was detected 13 months after ultra-
screening requires screening at regular, tumor-spe- sound screening. Although considered a false nega-
cific intervals to depict the true incidence of newly tive of screening ultrasonography, the time elapsed
developing tumors. Tumors would be detected at since the first ultrasound, the tumor size and the
early stages when the prevalence of RCC including estimated speed of growth of this stage of the tumor
higher stages had been taken care of with the initial could justify its classification as a newly developed
screening and if the intervals of follow-up screening tumor. In contrast, the second case was most likely
are matched to the incidence of RCC and the speed missed on ultrasonography during the second phase
of tumor growth, provided that most tumors do not of screening, if not also in the first. This peripheral
198 D. Filipas, S. Pahernik, and J. W. Thüroff
tumor was 3.8 cm in diameter and detected 6 months Filipas D, Spix C, Schultz-Lampel D et al. (1999) Pilotstudie
after the second screening ultrasonography. zur sonographischen Fruherkennung des Nierenzellkar-
zinoms. Radiologe 39:350–353
Other pathological findings were detected at a low Filipas D, Fichtner J, Spix C et al. (2000) Nephron-sparing
rate of 13% in both screening phases. This is much surgery of renal cell carcinoma with a normal opposite
less than reported in other studies (Kremer et al. kidney: long-term outcome in 180 patients. Urology
1984; Fuji et al. 1995), which may be related to the 56:387–392
Filipas D, Spix C, Schulz-Lampel D et al. (2002) Sonogra-
fact that a complete abdominal ultrasound was per-
phisches Screening von Nierenzellkarzinomen. Radio-
formed in these studies as opposed to renal ultra- loge 42:612–616
sound only in our study. A further concern of our Filipas D, Spix C, Schultz-Lampel D et al. (2003) Screening
screening study was the initiation of a sequence of for renal cell carcinoma using ultrasonography: a feasi-
costly imaging studies for clarification of equivocal bility study. BJU Int 91:595–599
Fujii Y, Ajima J, Oka K, Tosaka A, Takehara Y (1995) Benign
findings. With reference to the 17810 renal ultra- renal tumors detected among healthy adults by abdomi-
sound studies at both phases of our screening, 100 nal ultrasonography. Eur Urol 27:124–127
CT scans were initiated. Although it was not manda- Guinan PD, Vogelzang NJ, Fremgen AM et al. (1995) Renal
tory in the study protocol, reference ultrasonogra- cell carcinoma: tumor size, stage and survival. Members
phy was efficient for further evaluation of equivocal of the Cancer Incidence and End Results Committee.
J Urol 153:901–903
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sified as negative by reference ultrasound, which tumor, nodes and metastases classification of renal
reduced the incidence of further imaging studies cell carcinoma. J Urol 144:238–241; discussion 241–
by 48%. From this experience, reference ultrasound 242
Jemal A, Murray T, Ward E et al. (2005) Cancer statistics,
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imaging studies are initiated. Cost-effectiveness Kauczor HU, Delorme S, Trost U (1992) Sonographie des Nie-
is a critical issue when evaluating any screening renzellkarzinoms. Radiologe 32:104–113
program. Assessing the cost-effectiveness of renal Konnak JW, Grossman HB (1985) Renal cell carcinoma as an
ultrasonography as a screening tool for RCC in the incidental fi nding. J Urol 134:1094–1096
Kremer H, Dobrinski W, Schreiber MA, Zollner N (1984)
current study is difficult, because there is no infor- Sonographie des Abdomens als Screeningmethode. Ultr-
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RCC and the total prevalence of incurable disease. Labrie F, Candas B, Dupont A et al. (1999) Screening
As for the costs of the screening process alone, the decreases prostate cancer death: fi rst analysis of the
1988 Quebec prospective randomized controlled trial.
relatively low prevalence and incidence of RCC com-
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Matched comparison of radical nephrectomy vs neph-
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Oncological Diseases: Colorectal Cancer 201
Oncological Diseases 10
10.3 Colorectal Cancer
Anno Graser
CONTENTS Part I
CT Colonography in Colorectal Cancer
Screening
Part I CT Colonography in Colorectal Cancer
Screening 201
native screening tests. Although annual fecal occult Muto et al. 1975; Winawer 1999). About 80%–
blood testing (FOBT) has demonstrated a reduction 90% of all cancers of the colon and rectum prob-
in mortality due to colorectal cancer, FOBT does not ably develop like this (Morson 1984; Winawer et
evaluate the colonic mucosa itself (Kronborg et al. al. 2003). Therefore, resection of polyps can reduce
1996). Its sensitivity for colonic polyps is extremely colorectal cancer mortality by over 90%. Besides
low as most polyps, even large adenomas, do not these adenomatous polyps which can be divided
bleed, and occasionally cancers will not bleed either. into three histological subtypes (tubular, tubu-
In addition, there are many false positive results in lovillous and villous), there is a benign subtype
FOBT leading to additional diagnostic tests and costs (hyperplastic). Hyperplastic polyps do not have
(Rockey et al. 1998). Any new alternative screening premalignant potential (Winawer et al. 1993).
test will have to be compared to fiberoptic colonos- The prevalence of adenomatous polyps in an
copy, the current reference standard. High accuracy asymptomatic screening population has been
in detection of polyps and cancers will be required, reported to be about 20% (Ahmed 2003; Kahi and
and at the same time the test has to be accepted by Rex 2004; Weissfeld et al. 2005) and at autopsy
the screening population. up to 60% of men and 40% of women are reported
to have colonic adenomas (Winawer et al. 2003).
This implies that in 4 out of 5 persons undergo-
10.3.1.2 ing noninvasive CRC screening by CT colonogra-
Screening for Colorectal Cancer phy no subsequent colonoscopy and polypectomy
is required. These 80% of persons may benefit
The incidence of colorectal cancer, the second lead- from a non-invasive evaluation of the colon using
ing cause of cancer death in western countries, CT colonography. Studies have shown that many
is estimated to be around 150,000 new cases and small (< 5 mm) polypoid lesions in the colon are
about 50,000 deaths per year in the United States not adenomas and will never progress to become
(Podolsky 2004; Winawer et al. 2003). This high cancer (Macari et al. 2004; Pickhardt et al. 2003;
incidence as well as the fact that most cancers of the Winawer et al. 2003). Nevertheless, there is still
colon and rectum develop from benign precursor controversy about what size of polyps should be
lesions makes screening effective. The benefits of considered clinically significant. In CT colonogra-
CRC screening outweigh the costs associated with phy, this is of key importance as several research-
it, and with CT colonography gaining importance, ers emphasized that small polyps are not reliably
screening may become more acceptable to patients. identified (Cotton et al. 2004; Johnson CD et al.
In general, there is consensus that screening for CRC 2004; Macari et al. 2004; Rockey et al. 2005). One
is justified, and reimbursable options include fecal recent multicenter trial, however, reported high
occult blood testing, sigmoidoscopy, double con- sensitivities for polyps smaller than 6 mm in size
trast barium enema (DCBE) examination, colonos- (Pickhardt et al. 2003). The discrepancy in these
copy, and combinations of these tests (Ransohoff results may be due to differences in CT technique
and Sandler 2002). and image interpretation strategies. The presence
In the colon and rectum the vast majority of of polyps will determine whether a patient has to
cancers develop slowly, over a time period of 10– undergo colonoscopy for resection of polyps or
15 years, from benign precursor lesions, called not.
polyps (Winawer et al. 1993). Due to this slow Results from recent multicenter trials comparing
growth rate, removal of these lesions will lead to CT colonography and conventional colonoscopy in
a reduction of CRC incidence (Jemal et al. 2005; the detection of colonic polyps have made the ongo-
Mandel et al. 1993; Muller and Sonnenberg ing discussion about how to perform screening for
1995; Ransohoff and Sandler 2002; Winawer colorectal cancer more and more animated. In Ger-
et al. 1993; Winawer and Zauber 2001; Winawer many as well as in the United States it is now recom-
2005). In accordance with the adenoma-carcinoma mended that asymptomatic persons at average risk
sequence, any adenomatous polyp can harbour low for CRC should undergo screening starting at age 50
grade dysplasia which will subsequently progress (Ransohoff and Sandler 2002; Schmiegel et al.
to high grade dyplasia as the adenoma keeps grow- 2004). Complete colonoscopy is considered the gold
ing. Finally, there is the possibility of progression standard, and it has been shown to lead to decreases
to invasive cancer (Aldridge and Simson 2001; in morbidity and mortality associated with colon
Oncological Diseases: Colorectal Cancer 203
cancer because it allows detection and removal of its Another recent study on 703 higher-than-average
precursor lesions (Jemal et al. 2005; Mandel et al. risk patients without symptoms, however, showed
1993; Muller and Sonnenberg 1995; Ransohoff low sensitivities of 34%, 32% and 73% for detection
and Sandler 2002; Weissfeld et al. 2005). At pres- of polyps > 10 mm for three different experienced
ent, the only reimbursable means of screening in the readers (Johnson CD et al. 2003). Other recent
U.S. as well as in Germany are FOBT, DCBE, flexible single-institutional studies, on the other hand, have
sigmoidoscopy and colonoscopy. A fundamental shown high sensitivities of over 80% for polyps in
problem is that FOBT and DCBE lack sensitivity this size group (Iannaccone et al. 2003; Yee et al.
and colonoscopy lacks acceptance among patients, 2001). In addition, it has been concordantly reported
requires sedation, and is associated with the risk and accepted by most researchers that CTC reliably
of bleeding and colonic perforation which may and reproducibly identifies almost all lesions larger
have to be treated by laparoscopic or open repair. than 2 cm in size with sensitivities ranging from
Although the risk of these complications is a minor 85% to 100% (Iannaccone et al. 2003; Pickhardt
one if colonoscopy is performed by an experienced et al. 2003) and 95% specificity (Macari et al. 2002),
gastroenterologist, many individuals refrain from and that carcinomas are well depicted (Chung et al.
undergoing the exam. In Germany, overall partici- 2005).
pation in the national colorectal cancer screening In CTC, reader experience and training is essential
programme was as low as 2.2 % or 300,000 persons and leads to marked increases in sensitivity (Spinzi
in 2004. Bearing in mind that in this country alone et al. 2001). Several studies suggest that there is a
there are 20 million people in the age group at risk, learning curve associated with CT colonography:
it is necessary to think about CTC as a reliable alter- In 1997, a study showed 75% sensitivity for polyps
native screening test. 10 mm or larger (Hara et al. 1997). In 2001, a follow-
up trial showed improved sensitivity, which ranged
from 80% to 89% for polyps 10 mm or larger (Hara
et al. 2001). This was also demonstrated in a recent
multiinstitutional study comparing multi-detector
10.3.2 row CT colonography and conventional colonoscopy
Current Role of CT Colonography in (Cotton et al. 2004). In that study, the overall detec-
Colorectal Cancer Screening tion rate for CT colonography for colorectal polyps
10 mm or larger was only 55%. However, analysis of
At the present time, CT colonography could be con- results from those centers that had the most prior
sidered the most important alternative screening experience with CT colonography showed excellent
test, although the three largest recent multicenter sensitivity (approaching 90%) for 10-mm or larger
trials have shown inconsistent results with sensi- polyps.
tivities for the detection of polyps larger than 6 mm CTC particularly benefits from the high resolu-
ranging from as low as 51% (Rockey et al. 2004) to tion of modern multidetector-row CT scanners
as high as 89% (Pickhardt et al. 2003). The larg- and sophisticated 3D volume rendering techniques
est study to date evaluating CT colonography and (Dachman et al. 1998; Hara et al. 2001; Macari et
optical colonoscopy in an asymptomatic population al. 2003; Royster et al. 1997). It is widely accepted
performed by Pickhardt et al. (2003) suggests that that CTC should best be performed on 16- or 64-
CT colonography is almost equal to optical colonos- detector row scanners to achieve highest resolution
copy in the detection of clinically significant polyps in order to reliably depict colonic fi lling defects.
larger than 5 mm in size when state of the art MDCT Furthermore, patient preparation (see Sect. 10.3.3.1)
scanners and 3D visualization methods are used. consisting of either full or reduced colonic cleans-
Remarkably, in this study the sensitivity of CTC for ing is key for high diagnostic accuracy (Lefere et al.
the detection of polyps 10 mm or larger in size was 2004; Macari et al. 2001). To date, most researchers
over 90% and was, in fact, greater than that of con- believe that full bowel preparation is essential for
ventional colonoscopy. Most of the smaller polyps good results (Fletcher et al. 2000; Johnson CD
that were missed turned out to be hyperplastic in and Dachmann 2000; Macari et al. 2001; Yee et al.
nature (Pickhardt et al. 2004). This suggests that 1999), although most patients consider bowel prepa-
benign hyperplastic polyps may be more deformable ration the most cumbersome part of the examina-
then adenomas. tion (Gluecker et al. 2003).
204 A. Graser
a b
Fig. 10.3.1a,b. Endoluminal 3D VRT view (a) and axial soft tissue window CT image (b) of a clean and well-distended
colon. Note extrinsic impression of the colonic wall due to contact of this part of the descending colon to the spleen (arrow).
Diverticula are seen on the endoluminal view (curved arrow)
Oncological Diseases: Colorectal Cancer 205
a b
c d
Fig. 10.3.2a–d. Axial soft tissue window CT images (a,b) and 3D endoluminal views (c,d) demonstrating a fluid level in the
transverse and descending colon (curved arrow) on the supine scan. When the patient is turned over to the prone position,
fluid shifts from the descending colon towards the anterior wall of the transverse colon (straight arrows)
fluid. Occasionally, however, tagged fecal material tagging without bowel cleansing (Callstrom et al.
may obscure polypoid lesions, and the presence of 2001), and in the near future preparation protocols
large amounts of tagged fecal residues may prevent for CT colonography will probably be more patient-
3D endoluminal evaluation of the colonic surface if friendly and less cumbersome, if larger studies are
no electronic subtraction algorithms are used. In able to show consistent results for polyp detection.
the largest multicenter trial to date, Pickhardt et This would possibly make CTC the test of choice in
al. (2003) reported very high accuracy rates in polyp colorectal cancer screening (Rex 2002). Preliminary
detection using optimal cathartic preparation, fecal data suggests that even “prepless” CT colonogra-
and fluid tagging in combination with 3D evaluation phy with administration of tagging agents 48–72 h
of the colon. Furthermore, very good preliminary before the scan may become feasible in the near
results were demonstrated in one study using fecal future (Zalis et al. 2003).
206 A. Graser
2004). Theoretically, in modern multidetector row CD and Dachman 2000; Macari et al. 2000, 2004;
CT scanners even higher doses would be necessary Royster et al. 1997). In this approach, the colon
to compensate for the much thinner collimation. is tracked from the rectum to cecum using axial
However, the very high intrinsic tissue contrast of intermediate window source images. On most com-
more than 1000 Hounsfi eld units between bowel mercially available workstations, supine and prone
wall and gas-fi lled lumen enables low dose scan- images can be linked and scrolled simultaneously in
ning. As absorbed dose and milliampere-seconds order to discriminate between polyps and residual
level are directly proportional, lowering mAs set- fecal matter, and to assess the distribution of fluid.
tings is the easiest way of decreasing radiation dose Coronal, sagittal and endoluminal reformatted
to the patient (Kalra et al. 2004a). Furthermore, images can be obtained if an abnormality is detected.
lowering the tube voltage to 120 or 100 kVp is fea- In order to discriminate stool from polyps, the inter-
sible in normal size patients. The increase in image nal attenuation of a lesion can be used. Internal gas
noise induced by these changes does not seem to or areas of high attenuation suggest that a lesion is
affect polyp detection (Macari et al. 2002). Recent residual stool, while homogeneous attenuation sug-
advances in automatic tube current adaptation to gests polypoid nature (Fletcher et al. 1999; Macari
patient anatomy and dose modulation lead to even and Megibow 2001). Furthermore, morphology of
further reduction in patient exposure (Kalra et al. a lesion helps to determine its nature: geometric or
2004b). A study by Graser et al. (2006) showed that irregular borders are almost always found in resid-
use of an automated dose modulation technique that ual stool. Morphology of a lesion is best assessed on
adjusts tube current in the patient’s x, y, and z-axes 3D endoluminal VRT images. Mobility of a lesion is
leads to a 35% dose reduction in CT colonography. another important criterion that facilitates differen-
The algorithm measures patient attenuation during tiation between residual fecal material and polyps.
the topogram scan and consecutively automatically Stool tends to move towards the dependent surface
adjusts the mAs level to patient anatomy. Using ref- of the colonic mucosa (Macari and Megibow 2001;
erence values of 120 mAs and 40 mAs for supine and Taylor et al. 2003a; Yee et al. 2003), while polyps
prone scans, mean overall radiation dose is going maintain their position. One has to bear in mind
to be 4.8 mSv on a 16-detector row scanner. Pre- that pedunculated polyps can alter their position in
liminary data from the University of Munich suggest relation to colonic folds thereby simulating mobility
similar values for a 64-detector row scanner. (see Fig. 10.3.3). Furthermore, polyps in segments of
When performing CT colonography, extraco- the colon with a long mesentery may appear to be
lonic organs should also be evaluated. One study on mobile because the entire colonic segment changes
250 patients showed extracolonic findings in more its location between supine and prone scans (Laks
than 30% of patients, of which 12.5% were highly et al. 2004).
important and 40% were moderately important One reason for using a primary 2D approach
(Rajapaksa et al. 2004). Too much image noise pre- in reading CT colonography is that in theory the
vents assessment of parenchymatous organs; there- entire colonic mucosa can be visualized with one
fore, image noise should be kept to a minimum. pass. Polyps cannot be hidden behind or in between
folds, and CT density of fi lling defects can be read-
ily assessed. A second reason in favor of 2D inter-
10.3.3.4 pretation is reading time. Several studies showed
Strategies for Data Interpretation in that it should not exceed 15 min if a primary 2D
CT Colonography read is used, as opposed to 20–30 min for primary
3D read (Gluecker et al. 2002; Macari et al. 2002;
Two primary techniques for data interpretation have Yasumoto et al. 2006).
been described in CT colonography, a primary 2D The primary 3D approach relies on visualization
and a primary 3D approach. In each of these tech- of the colonic mucosa in a fashion that is very simi-
niques, the alternative visualization has to be at lar to the familiar view at endoscopy. Most worksta-
hands for problem solving and characterisation of tions create a centerline path for the endoluminal
polyps, residual stool and fluid, and folds. “fly through” from rectum to cecum and vice versa,
Traditionally, most researchers have relied on a which allows for viewing both sides of colonic folds.
primary 2D technique for CTC reading (Dachman Using this approach, contact time between the radi-
et al. 1998; Fenlon and Ferrucci 1997; Johnson ologist’s eye and a lesion will be longer than with
208 A. Graser
a b
c d
Fig. 10.3.3a–d. Endoluminal (a,b) and axial (c,d) views from supine (a,c) and prone (b,d) CT colonography datasets dem-
onstrate a 15-mm pedunculated polyp (arrow) in the sigmoid colon. Positional change of the polyp due to the presence of a
stalk simulates mobility. Note homogeneous soft tissue attenuation of the lesion on axial soft tissue window images (c,d)
quently is the need for reader training. Anecdotally, one of the major drawbacks is the distortion of geo-
a minimum of 50 colonoscopically correlated datas- metric shapes (Johnson KT et al. 2006).
ets has been suggested as number of examinations to In the future, CT colonography will probably play
be read before starting to read CTC in a clinical set- a unique role in colorectal cancer screening, pro-
ting. Recent work suggests that response to training viding noninvasive evaluation of the entire colon
is highly variable amongst individual radiologists, without need for sedation and risk of perforation.
and competence certainly cannot be assumed after Advances in CT protocols, tagging regimens, reader
this number of cases (Taylor et al. 2004). Further- strategies and computer-aided detection software
more, reporting strategies and standards have to be will help ensure that the technique becomes estab-
developed in order to guarantee reproducible results lished as a credible method of colonic investiga-
in CTC. tion.
The reported interreader variability even among
expert readers and the need to evaluate large data
volumes in reasonable time have stimulated the cur-
rent interest in computer-aided diagnosis. Continu-
ing advances in computer technology make the use of Part II
CAD algorithms more and more feasible. Normally, MR Colonography
these algorithms will be used as “second reader”
to the reporting radiologist. With CAD having
been used successfully in mammography and lung 10.3.4
nodule detection, CAD tools are becoming more and Introduction
more sensitive in polyp detection in CTC. Basically,
all CAD algorithms rely on three steps: extraction of While in colorectal cancer screening excellent sen-
the colon from the data volume; detection of polyp sitivities and specificities have been reported for
candidates; and reduction of false positive detection. CT colonography, MR colonography (MRC), first
Analysis of shape and internal CT density of lesions described in 1997 (Luboldt et al. 1997), to date is
are basic principles of polyp detection and classifi- still considered to perform less well. In a screening
cation. Most false positive detections occur because population, MRI would be a perfect imaging tool as
fecal residues, the ileocecal valve, or prominent folds it lacks ionizing radiation. Even if radiation expo-
are inadvertently detected. Preliminary results show sure is kept to a minimum in CTC, there is still a
promising sensitivities of over 90% in the detection stochastic risk of causing radiation-induced malig-
of clinically significant polyps over 6 mm in size nancy. Lifetime attributable risk has been estimated
(Bogoni et al. 2005; Yoshida and Dachman 2005). to be as high as one in 50 patients (Brenner and
Nevertheless, validation of these systems in larger Elliston 2004).
clinical trials is still necessary before they will be In order to perform MRC it is recommended to
accepted as reliable software tools. use a high end multichannel MRI scanner employ-
Latest software developments include tools that ing parallel imaging techniques for fast scanning
visualize “unseen areas” hidden behind colonic and high spatial resolution. Dedicated sequences are
folds on endoluminal evaluation to the radiologist. mandatory in order to obtain sufficient signal-to-
These algorithms guarantee complete evaluation of noise ratio, and to minimize motion artifacts. While
the colonic mucosa. Our preliminary clinical expe- in CT colonography motion artifacts could literally
rience shows that visualization of over 99% of the be eliminated with the introduction of 64-slice scan-
colonic mucosa can be achieved. ners, image quality can be seriously hampered by
In order to evaluate the colonic mucosa with- bowel wall motion at MR colonography. Therefore,
out having to perform endoluminal fly through in intravenous application of spasmolytic drugs like
two directions, novel visualization algorithms are Buscopan is advisable.
being developed including methods of unfolding Generally, MRC can be performed using a dark-
and dissecting the colon or visualizing antegrade lumen technique that relies on an aqeuous enema
and retrograde views at the same time. Although with intravenous administration of a paramagnetic
the approach seems promising, initial results did contrast agent, or in bright-lumen technique that
not show a decrease in image interpretation time employs T2-weighted sequences without intrave-
(Hoppe et al. 2004). Further research is needed, and nous contrast agent.
210 A. Graser
As in CTC, bowel preparation is an important be used for optimum spatial resolution and use
factor that greatly influences MRC image quality and of parallel imaging technique. After intravenous
detection accuracy for colonic polyps. To date, MR administration of 40 mg of scopolamine, the colon
colonography is predominantly being performed can be fi lled with warm tap water using a rectal
at specialized centers, and most patients have been enema tip. At our institution, the enema bag is
examined as part of clinical trials. At the same time, positioned 1–1.5 m above the patient resulting in
dissemination of MRC into clinical practice is under sufficient hydrostatic pressure for distention of the
way, resulting in increasing demand for radiologist entire colon. Proper distention is required because
and technician training. Further research is needed collapsed segments may mimic bowel wall thicken-
to prove that MRC is a reliable tool that can be inte- ing. During application of the rectal enema, single
grated into screening programmes for CRC. shot online monitoring sequences like HASTE
sequences can be acquired. On average, a volume of
2000–3000 mL will be needed to distend the entire
colon. If bowel distention is sufficient, the colon
can be imaged using different sequence techniques
10.3.5 that will result in high contrast between the bowel
Patient Preparation and Examination wall and the colonic lumen. Contrast mechanisms
Technique will then depend on the MR sequences employed
and the intravenous and/or rectal administration
Most studies published to date rely on a full bowel of contrast agents. Different types of sequences
preparation for MR colonography since residual should be acquired. First, a fast T2-weighted single
stool impedes proper evaluation of the colonic shot sequence like HASTE with or without fat sup-
lumen. This can be achieved by oral ingestion of pression or fast imaging with steady state free pre-
3–4 L of a polyethylene glycol solution, or a prepara- cession (TrueFISP) should be acquired in the axial
tion regimen based on magnesium citrate and other and coronal plane. This type of sequence is com-
laxatives. For bright lumen technique, gadolinium parably insensitive to motion, and shows the water
chelate contrast agents can be added to the rectal in the colonic lumen at high signal intensity, while
enema for T1 weighted imaging. Recently, so-called the colonic wall and fi lling defects will be displayed
prepless protocols without bowel cleansing have at low signal intensity (Figs. 10.3.4 and 10.3.5). The
been described in MR colonography in a large single colonic mucosa can be optimally visualized on a high
center study analyzing the performance of MRC in resolution T1-weighted gradient echo sequence (3D
asymptomatic screening patients (Kuehle et al. VIBE, volume interpolated breath hold examina-
2007). No bowel cleansing was applied, and a tag- tion). This sequence should be acquired before and
ging agent based on gadolinium, barium sulfate, and 75 s after intravenous injection of contrast agent.
locust bean gum was administered with each meal Depending on the field strength of the scanner and
within two days prior to MR colonography. In 96% the number of coil elements, up to 128 slices can be
of all colonic segments, fecal tagging was sufficient acquired in one single breath hold. Typically, these
to assess the presence of significant polyps. slices will have a thickness of 1.0–1.6 mm, depend-
For adequate image quality, MR colonography ing on patient diameter and the properties of the
should be performed on a system with a high-per- scanner. The normal colonic mucosa will strongly
formance gradient system and a minimum of 1.5 T enhance, and so will adenomatous polyps. Most
static magnetic field strength allowing for data larger studies published to date agree that MRC is
acquisition confined to one single breath hold. Prior unable to detect hyperplastic polyps as these do
to MRI scanning, possible contraindications like not take up contrast agent (Hartmann et al. 2006).
presence of cardiac pacemakers, metallic implants Furthermore, a T1-weighted axial FLASH sequence
in the central nervous system, or claustrophobia should be acquired for assessment of extracolonic
have to be excluded. fi ndings with high image quality. After acquisition
MRC should be performed with the patient in of these sequences, the enema bag can be placed on
the prone position in order to minimize breath- the floor to allow for drainage of the water from the
ing artefacts. A combination of a multi-channel patient’s bowel.
surface coils, ideally 32-channel coils covering the Image analysis should be performed on a dedi-
entire abdomen, and the spine array coil should cated workstation integrating 2D and 3D display
Oncological Diseases: Colorectal Cancer 211
a b
Fig. 10.3.4a,b. Axial (a) and coronal (b) bright lumen image of the sigmoid colon showing a 1.5-cm pedunculated polyp in
a 50-year-old male patient. TrueFISP sequence acquired on a 3 T magnet (Magnetom Trio TIM, Siemens Medical Solutions,
Erlangen, Germany) using a 32-element abdominal coil
a b
Fig. 10.3.5a,b. Axial (a) and sagittal (b) dark lumen image of the same pedunculated polyp as in Fig. 10.3.4. A 3D VIBE
sequence acquired 75 s after intravenous administration of gadolinium chelate (Multihance, Bracco) shows strong enhance-
ment of the normal colonic mucosa as well as the adenoma
capabilities. Various software systems allow for strongly enhance. Enhancement is only detectable
three-dimensional endoluminal rendering of the on reformatted 2D images. High resolution 3D VIBE
colon (3D “fly through”, as described in CT colo- datasets should be used to localize clinically sig-
nography). This technique will help to detect small nificant polyps, as they enable visualization of the
(< 6 mm) polyps at high sensitivity, as well as visual- colon in all three orthogonal planes. Comparison
ize larger lesions. Primary 2D reading is even more between pre- and post contrast images is manda-
popular in MRC than in CTC, because adenomas tory for discrimination of stool from residual fecal
212 A. Graser
material. Residual stool does not enhance, while racy, requiring further research for validation. Inte-
true colorectal lesions, predominantly the ones that gration of MRC in clinical routine will also depend
have precancerous potential, always show contrast on reimbursement strategies and patient acceptance.
agent uptake. As a radiation-free screening tool, it would be per-
fectly suitable for triageing between persons without
significant polyps and patients needing to undergo
optical colonoscopy for polyp resection.
10.3.6
Diagnostic Performance of
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Congenital Pediatric Diseases: Pre- and Postnatal Kidney Screening 215
11.1.1 Practical Aspects and Results of Postnatal Organ category Mainz 1996–2003
Kidney Screening 215
Musculoskeletal system 181
11.1.2 Value of Prenatal Screening for Internal urogenital system 169
the Detection of Malformations with
High Morbidity and Mortality 217 Cardiovascular system 141
Digestive system 71
11.1.3 Outcome Improvement by Early Postnatal
Diagnosis of Renal Malformations 2184 Central nervous system 60
Chromosome aberrations 65
References 2195
External urogenital system 39
Facial clefts 39
Eye 4
11.1.1
Ear 7
Practical Aspects and Results of Postnatal
Kidney Screening Population based cohort 1996–2003: 22,070 infants and
fetuses; 1460 (6.2%) major malformations
Major congenital malformations are diagnosed
in 4%–6% of all infants and fetuses (Lynberg
and Edmonds 1992). About one third of them are To estimate the value of pre- and postnatal ultra-
the leading cause for infant mortality or morbid- sound screening of the internal urogenital tract we
ity (Grandjean et al. 1999). Malformations of the analyzed the population-based birth cohort of the
internal urogenital system are diagnosed in about Mainz Model. Prevalence rates and percentage of
1% of all infants and account for approximately 20% prenatally or postnatally detected malformations
of all congenital malformations, thus being one of are given. Sensitivity rates are calculated and mal-
the three most frequent birth defects (Table 11.1.1). formations with high morbidity and/or mortality
Therefore a pre- and/or postnatally performed ultra- are defined. In addition, the improvement of the
sound screening for malformations of the internal outcome by early postnatal diagnosis of renal mal-
urogenital system should be part of the routine to formations is evaluated.
reduce perinatal mortality and morbidity. The reli- The major aim of a screening program is to detect
ability and value of ultrasonographic screening for treatable diseases in a population as early as possi-
congenital malformations is the subject of ongoing ble. For valuable screening programs the existence
discussions. of preventive or curative interventions is required;
poor prognosis and limited treatment options may
mean lack of adequate possibilities to improve the
G. Stolz, MD
Birth Registry Mainz Modell, Universitätskinderklinik der
infants life (Queisser et al. 2001). It is demonstrated
Johannes-Gutenberg-University of Mainz, Langenbeck- that these criteria are fulfilled by the routinely per-
strasse 1, 55101 Mainz, Germany formed ultrasound scan of the kidneys.
216 G. Stolz
In the population-based birth cohort of the Mainz Table 11.1.2. Number of urinary malformations and prena-
Model (January 1996 – December 2003) 22,070 new- tal detection rate, 1996–2003
borns 0.55% (121) stillbirths, 1.1% (235) abortions
Diagnosis 1996– Prenatally %
and 0.6% (128) induced abortions were registered. 2003 detected
The surveillance covers the region of Rheinhessen
and monitors 89% of all infants born and living in Supernumerary kidney 91 15 16
this area. Nearly all newborns (99%) underwent a Megaureter 65 28 43
postnatal ultrasound screening of the kidney. A mal- a 55 26 47
Hydronephrosis
formation of the urogenital tract was diagnosed in
1.7% (n = 373) of all neonates, findings to be reinves- Reflux 47 12 25
tigated in more detail in 2.1% (Fig. 11.1.1). The most Pyelo ureteral junction 44 15 34
common diagnoses (Table 11.1.2) were supernumer- obstruction
ary kidney (21%) (Fig. 11.1.2), megaureter (15%) Multicystic kidney disease 23 10 43
(Fig. 11.1.3) and hydronephrosis (13%). Infants with
Unilateral renal agenesis 22 6 27
multiple malformations have birth defects in differ-
ent organ systems, infants with complex malforma- Horseshoe kidney 25 7 28
tions have two or more malformations within the Potter-sequence 11 7 64
same organ system (e.g. supernumerary kidneys, Polycystic kidney disease 10 4 10
vesico-renal reflux, megaureter). A single malforma-
Solitary kidney cyst 8 1 12
tion of the urogenital tract was diagnosed in 41.2%
of the infants with malformations of the urinary Vesico ureteral junction 3 0 0
tract, multiple malformations in 11% and complex obstruction
malformations in 49% of these newborn. Urethral valve 6 4 66
Ureterocele 7 1 14
Malformation of urethra 5 2 40
Malformation of ureter 8 5 45
Exstrophy of bladder 3 2 66
Aplasie of bladder 9 4 44
Total 442 149 34
Fig. 11.1.1. Findings in need of further evaluation Fig. 11.1.2. Supernumerary kidney and vesico-renal reflux
(dilated renal pelvis: 9 mm) (postnatal scan)
Congenital Pediatric Diseases: Pre- and Postnatal Kidney Screening 217
11.1.3
Outcome Improvement by Early Postnatal
Diagnosis of Renal Malformations
11.2.1
Summary
11.2.2
Sonographic hip screening has led to a significant The Clinical Picture of Hip Dysplasia and
decrease in inpatient treatments of congenital Hip Dislocation
(= developmental) dislocation /dysplasia of the hip
(DDH). In recent years, prognosis for this disor- The terms congenital dysplasia and dislocation of
der has notably improved owing to early diagnosis the hip encompass a spectrum of abnormal ana-
and accordingly earlier initiation of treatment – by tomical changes of the hip unfolding in various peri-
simple therapeutic measures quite often. By inter- ods of growth. In both the American and European
national comparison, this undisputed success was literature, these terms have therefore been replaced
by “developmental dysplasia of the hip” (DDH).
We distinguish the following degrees of anatomi-
D. Weitzel, MD
Professor, Department of Pediatrics and Adolescent Medicine,
cal severity:
German Diagnostic Clinic, Aukamm-Allee 33, 65191 Wiesbaden, • Displaced hip: the head of femur is located out-
Germany side the acetabulum.
222 D. Weitzel
• Displaceable hip: the head of femur can be shifted ment of the acetabulum are asynchronous as strain
from the acetabulum by flexion with synchro- is increasing strain due to progressing motor devel-
nous adduction, and can also be returned to the opment.
acetabulum by flexion and adduction. We may thus conclude that normal hip devel-
• Semiluxated hip: the head of femur is only partly opment does not only depend on regular skeletal
in contact with the acetabulum, i.e. it is decen- development per se, but also on the concordance of
tered. skeletal and neuromuscular development. Faulty
• Semiluxable hip: there is normal contact between development of the skeletal system and disturbed
head of femur and acetabulum in the resting posi- neuromuscular development are likely to result in
tion, the head of femur, however, can be decen- malformation of the hip. Sonography as an imaging
tered by external maneuvers. procedure can merely demonstrate the anatomy of
• Dysplasia: abnormal anatomy and/or defective the hip joint, meaning the shape of the acetabulum
growth of the acetabulum. and its relation to the femoral head, besides showing
the proportion of the osseous acetabular segment to
Prognosis for dislocation /dysplasia of the hip the chondral segment. It cannot visualize the forces
depends on: acting on the hip joint that may have a detrimental
• The time of onset of defective development: impact on hip maturation.
• Embryonic: teratologic displacement of the
hip
• Fetal: breech position, genetic disposition
• Infantile: imbalance between osteochondro-
genesis and motor development 11.2.3
• The time when the diagnosis is made, since the Incidence of the Disorder
growth rate is exponentially declining during the
first year of life. This sets a time limit to growth- Data on the incidence of this disorder vary greatly.
guiding treatment. This might for once be due to the different defini-
tions used – as we pointed out earlier – since the
Teratologic hip displacement is the most severe terms displacement/dislocation and/or dysplasia
form of the disorder, and it is subdivided into a form of the hip (DDH) include a spectrum of disorders
generating approximately during the 12th week of with differing therapeutic and prognostic conse-
gestation, and into a form materializing approxi- quences.
mately in the 18th week of gestation. In the 12th On the other hand, the origin of the studies is play-
week, the fetal leg will also rotate in medial direction. ing a part as well, since the genetic disposition for the
Defective development during this period involves development of disease is not universal but may be
any part of the hip joint. The muscular system of the varying from country to country, which is making
hip starts to develop in week 18. Malformations at for the differences in the epidemiologic incidence.
that time will likewise result in complete displace- The methods and the quality of diagnostic workup
ment and are frequently associated with neuromus- are another reason for the greatly diverging data on
cular abnormalities, e.g. myelomeningocele, arthro- the incidence. In Austria for instance, the rate of
gryposis. treatment used to be 11.92% in the presonographic
During the last 4 weeks of pregnancy (fetal phase), era, and could be reduced to 6.57% within 7 years
acetabular development is impaired by a particular after the introduction of sonographic hip screen-
form of breech presentation in which the legs are ing Müller (1995). This reduction in treatments
folded upward. cannot be explained by fewer cases of disease; it
The increased incidence in girls and the familial has to be attributed to improved diagnostics alone.
disposition are suggestive of genetic factors involved The rate nevertheless continues to be significantly
in developmental dislocation/dysplasia of the hip higher than the average figures of 0.15–2% quoted
(DDH). by Bialik et al. (1999) in their survey.
Postnatal hip displacement occurs when osteo- All studies maintain that the teratologic form of
chondrogenesis of the acetabulum and neuromus- hip dislocation is a rare disorder.
cular development do not coincide, i.e. when, in the Whether at all, and if so to what extent develop-
course of growth, ossification and gradual develop- mental displacement/dysplasia of the hip (DDH)
Congenital Pediatric Diseases: Sonographic Screening of the Infant Hip 223
can be related to arthrosis of the hip joint in adult Of all children with congenital displacement/dys-
years, has been controversially discussed. A caus- plasia of the hip (DDH), 60% do not present with risk
ative relation is hard to establish owing to the large factors (Patel 2001). Within the context of our pilot
span of years between hip dysplasia in infancy and study and based on 7198 neonate screening exami-
arthrosis of the hip joint in adulthood. A connec- nations, we were able to prove that risk-selective
tion with early arthrosis was corroborated only for screening will at most catch 40%–50% of the infants
hip displacements operated after the third month of in need of therapy. At least 20% of the newborns
life. Longterm studies are lacking with regard to the ought to be tested because of their risk factors.
development of dysplasias left untreated or conser- The problem is that prospects for a favorable out-
vatively managed in infancy. come of treatment are greater when the infant is still
very young, whereas clinical diagnostics are more
reliable the older the infant is getting. The neces-
sity of earliest possible sonographic screening has
thus been postulated. Such screening has a double
11.2.4 function: it detects disorders manifest already and
Diagnostic Workup Based on Risk Selection it identifies the risks of faulty development. Since it
cannot provide for diagnosis by exclusion, it has to
The place-value of risk factors in the diagnostic be supplemented by follow-up on the clinical course,
workup of DDH had been high, especially in the the expressiveness of which will be more weighty the
presonographic era. Breech position and familial dis- older the infants are.
position used to be an indication for pelvic survey at
the age of 3–6 months. Approximately 3%–5% of the
babies are delivered from a breech position. About
20%–30% of those will develop dislocation /dyspla-
sia of the hip (DDH). The highest risk is encountered 11.2.5
with the legs placed to the trunk, i.e. bent in the hips Sonographic Examination of the Hip by
and stretched in the knees. The lowest risk is found Graf’s Technique
in children who have been in the squatting position,
as commonly seen in twin pregnancies. By the description of imaging elements, Graf suc-
Data on heredofamilial features are difficult to ceeded in defining a reproducible cut surface in the
assess, for the grade of relatedness and the inci- craniodaudal as well as in the lateromedial plane
dence of hip disorders are variables to be consid- (Graf 1980, 1985; Graf et al. 1987). This cut surface
ered. 15%–20% of the newborns do have a relative goes precisely through the center of the hemispher-
who had been affl icted with hip disease in infancy. ical joint. Recognition of acetabular development
Heredity of this disorder is still not fully elucidated; was facilitated by the accurate presentation of the
there seem to be several forms of hereditary trans- fibrochondral acetabular labrum, the hyalinochon-
mission. In our group of 247 children who had a drally preformed roof of acetabulum as well as of the
fi rst-grade relative with DDH, 67 (27%) required bony part of the acetabulum reaching to the y-joint
treatment in infancy. (Fig. 11.2.1a). Steepness of the osseous acetabulum
Although DDH has meanwhile been generally will increase with normal hip development, while
accepted to be a developmental disorder, there the width of the chondrally preformed part of the
are but a few studies relating clinical findings to roof of acetabulum decreases as ossification goes
age (Mau and Michaelis 1983; Pfeil et al. 1988; on; the shape of acetabulum is turning more concave
Schuler and Rossak 1984). Inhibited abduction, (Fig. 11.2.1b).
for instance, is shaping up as a risk factor for hip Standardization of the cut surface moreover per-
defects as motor development advances. Risk selec- mits quantitative processing of the developmental
tion by clinical examinations is possible at increas- process by angle measurements. A base line can be
ing infant age. This is supported by the results of defined due to the horizontal presentation of the
preventive clinical checkups. According to Patel’s iliac bone. The acetabular line runs from the lower
survey, the rate of surgical treatments went down margin of the acetabular part of the iliac bone to the
by more than 50% to a level of 0.2–0.7/1000 (Patel bony rim. The so-called acetabular angle D is thus
2001) owing to preventive clinical checks alone. made up by the base line and the acetabular line. The
224 D. Weitzel
a b
Fig. 11.2.1a,b. Presentation of normal hip anatomy of a neonate and of a 3 month-old infant (Graf´s standard plane)
11.2.6
Neonatal Hip Screening
0–< 2 weeks 2–< 6 weeks 6–< 10 weeks 10–14 weeks > 14 weeks
n = 15.794 n = 250 n = 967 n = 682 n = 770
P1 45 50 52 55 57
P5 50 52 55 57 60
P 10 52 54 56 58 60
P 25 55 56 58 60 61
P 50 58 60 61 62 63
P 95 63 69 69 69 68
P 99 65 74 73 73 74
(Table 11.2.2). We are convinced that a child without shaky grounds, initial diagnostics are first of all
a conspicuous history or clinical abnormality should unreliable, and second the solid measuring base for
only be followed if angle D were below percentile 5. diagnostic follow-up is lacking. Delayed ossification
At any rate, precise measurement of angle D will in the course of development can only be quantified
be absolutely essential. It depends on the accurate when we have correct baseline values to compare
adjustment of the cut surface as well as on an ade- with. So we frequently found an implausible dete-
quate scale. One should also mind that the size of a rioration of angle D in our study, when the opening
neonate’s hip joint is only about thumbnail. Precise examination was carried out with a device set to a
measurements are impossible on a 1:1 scale. On such 1:1 scale.
Congenital Pediatric Diseases: Sonographic Screening of the Infant Hip 227
Table 11.2.3. Answering behavior of parents in correspondence with hip type distribution in neonatal screening (patient-
related, the worse hip taking the lead)
Table 11.2.4. Percentage of treatments per neonatal hip types and percentage of neonatal hip types in treatments
tion based on parameters from history and clinical expected to amount to 2.6/1000. Just by implement-
picture is possible in due course. ing the study and by data processing, this figure was
In addition we polled office-based pediatricians decreased to 1.3/1000.
to learn that merely three children had inpatient Niethardt et al. (2000) gave a first account of
treatment. One infant did not participate in the the results of nationwide hip screening performed
screening. The other two children, who had been between the 4th and 6th week of life. This screen-
enrolled in the screening, were taken to follow-up ing had been introduced in Germany on January 01,
too late. This reveals an inpatient treatment rate of 1996. The expectation to lower the follow-up rate
3/11,629 corresponding with 0.26/1000. This figure is by choosing a later time for screening was not met.
lower by factor 8 than the one obtained by Melzer The follow-up rate was indeed 23.7%, albeit having
(1994) in his Hessian study (2/1000). defined the need for follow-up only from angle D
Rosendahl et al. (1994) conducted the only 56q – contrary to Graf’s model. Taking Tauscher’s
study comparing a general sonographic screen- maturation curve (mean value minus simple stan-
ing (n = 3613), a risk-selective screening (n = 4388) dard deviation) or our percentiles (percentile 25),
and a purely clinical screening (n = 3924) with each and the limit set like this, this follow-up rate should
other, and following all children screened over a not come as a surprise. There are no data as to the
mean period of 42.4 months (24 months minimum). number of repeated follow-ups.
These researchers investigated the effect of a gen- In a separate poll it was assessed whether the
eral screening on the primary diagnosis, on the maternity clinics had been following the guidelines
management and incidence of later forms of con- as to risk-selective screening within the framework
genital/developmental dislocation /dysplasia of the of U1/2. This revealed that some centers did not per-
hip (DDH). It turned out that 3.4% of the infants form any hip screening at all, others attended to risk
in the general screening group received treatment, selection merely in part or just focused on general hip
which held true for only 2.0% in the risk-selective screening. According to the resulting computer pro-
group and 1.8% in the group left unscreened. Later jection, approximately 50% of the neonates under-
forms of DDH were found in the general screen- went hip sonography already when still in the mater-
ing group at a ratio of 0.3/100, in the risk-selective nity ward (Stoll 2001). These infants were likely to
group at 0.7/1000, and in the unscreened group at be screened again then within the scope of U3. The
1.3/1000. Of the untreated children, 13% were fol- effective costs, in fact, would thus not differ much
lowed in the screening group, and 3% in the risk- from the costs incurred by a general screening of
selective group. Treatment on account of ultrasonic neonates plus a general follow-up screening at a later
criteria was applied to just 3% of all the children date. A cost-benefit analysis would have to include
followed. The authors thus infer that the incidence the aspect that in number of the children requiring
of later forms of developmental dislocation /dys- treatment as a result of U3 screening, therapy had
plasia of the hip (DDH) will at most be marginally been delayed, which is making for higher costs in
reduced by general sonographic screening while the end. Stoll points out that 25% of the extension
the diagnostic expenditure is at the same time sig- treatments were carried on in the first trimester
nificantly increased. One side effect of this study is (Stoll 2001). This indicates that those infants had
obvious: Based on the data available from the period had been diagnosed and treated too late, since soft
before the study was started, late forms of DDH were tissue atrophy had already been setting in.
Congenital Pediatric Diseases: Sonographic Screening of the Infant Hip 229
Niethart found out that 23.5% of the pediatri- they were younger than 10 weeks and 27 because
cians, 38.9 % of the orthopedists and 21.6% of they were older than 5 years, when the first opera-
other medical specialists did not comply to the tive procedure was performed.
screening guidelines. Pediatricians went beyond The fact that 55% of the infants receiving inpa-
the recommendations for follow-up and treat- tient treatment had been screened in due time and
ment in every 5th case, whereas orthopedists did 45% had either a negative ultrasound screening or
so in every 3rd case. Only in every 20th case less delayed or no ultrasound screening leaves us with
was actually done than provided for by the guide- the following questions:
lines. Investigation is called for as to why these 1. What about the appropriateness of the technical
guidelines are not being adhered to. The rate of equipment used and/or the quality of examina-
treatment was 6.7%, which is very high by inter- tion?
national comparison. 2. Had there been malpractice?
The effect of ultrasound screening on the rate 3. Would this treatment have been avoidable if
of first operative procedure for developmental hip screening had taken place during the neonatal
dysplasia in Germany was published by von Kries period?
et al. (2003). Cases who had had operations were 4. What about parent compliance?
identified through active surveillance from May 5. Is congenital dislocation /dysplasia of the hip
1997 to April 2002, by use of the German paediatric (DDH) so complex a disorder that a certain per-
surveillance unit (ESPED, Table 11.2.5). From 1887 centage of inpatient treatments is going to be
returned questionnaires only 535 meet the criteria inevitable despite early diagnosis and adequate
for inclusion. 608 children were excluded, because medical procedures?
Table 11.2.5. Children with first operative procedures by the time of sceening and screening result (von Kries et al. 2003)
Table 11.2.6. Prevalence of inpatient and surgical treatments of developmental dysplasia/displacement of the hip (DDH)
by international comparison (from Stoll 2001). FDR = Federal Republic of Germany (West Germany) and GDR = German
Democratic Republic (East Germany) before the 1990 unification
First measure
Inpatients total 1.32 5.78 0.385 0.4 0.202
Surgery only - 0.78 0.092 0.15 0.152
Most serious measure
Inpatients total 1.97 7.7 0.264
Surgery only 0.129
a Godward and Desateux (1998)
b Chan et al. (1999)
230 D. Weitzel
gelenken aus einem neonatalen Screening. Monatsschr Szöke N, Kühl L, Heinrichs J (1988) Ultrasound examina-
Kinderheilkd 138:664–669 tion of congenital hip dysplasia in newborns. J Pediatr
Rosendahl K, Markestad T, Lie RT (1994) Ultrasound screen- Ortop 8:12–16
ing for developmental dysplasia of the hip in the neonate: Tönnis D, Storch K, Ulbrich H (1990) Results of newborn
the effect on treatment rate and prevalence of late cases. screening for CDH with and without sonography and cor-
Pediatrics 94:47–52 relation of risk factors. J Pediatr Orthop 10:145–152
Schuler P, Rossak K (1984) Sonographische Verlaufs- Tschauner C, Klapsch W, Baumgartner A, Graf R (1994) „Rei-
kontrollen von Hüftreifungsstörungen. Z Orthop fungskurve“ des sonographischen Alpha-Winkels nach
122:136–140 GRAF unbehandelter Hüftgelenke im ersten Lebensjahr.
Sellier T, Alaiyan H, Zell J, Stolz W (1987) Erfahrungen mit Z Orthop 132:502–504
dem sonographischen Hüftscreening bei Neugeborenen. von Kries R, Ihme N, Oberle D, Lorani A, Stark R, Alten-
Buchreihe für Orthopädie und orthopäd. Grenzgebiete, hofen L, Niethard FU (2003) Effect of ultrasound screen-
Bd 14. ML-Verlag, Uelzen, S 169 ing on the rate of fi rst operative procedures for devel-
Stein V, Merk H, Weicker H (1988) Neugeboreneen-Hüft- opmental hip dysplasia in Germany. The Lancet; Dec. 6,
screening mit Hilf der Sonographie. Beitr Orthop Trau- 362(9399):1883–1887
matol 35:137–142 Weitzel D, Schneider R, Oberman B (1994) Sonographische
Stoll S (2001) Betrachtung des hüftsonographischen Screen- Befunde in einem flächendeckenden neonatalen Hüft-
ings als Bestandteil der dritten Krankheitsfrüherken- screening: Ist die Grafsche Typeneinteilung der Hüftso-
nungsuntersuchung für Kinder (U3) in der BRD. Disser- nogramme korrekturbedürftig? Monatsschr Kinder-
tation, München heilkd 142:425–431
Magnetic Resonance Imaging in Prevention of Alzheimer´s Disease 233
CONTENTS 12.1
Introduction
enlarged cerebrospinal fluid spaces than f increas- patient mental decline. Beside structural analyses,
ing accumulation of this protein in cerebral tissue however, functional neuroimaging methods allow
(Näslund et al. 2000; Schröder et al. 1997). an even more detailed view into the pathophysi-
Neurofibrillary bundles are composed of a smaller ologic changes associated with the development of
precursor protein, W-protein. Due to pathological dementia.
hyperphosphorylation, tau protein can no longer
fulfi l its function of stabilising microtubules. In
turn, hyperphosphorylation of tau protein contrib- 12.3.2
ute indirectly to neuronal destruction due to desta- Neuroanatomical Findings in Structural Imaging
bilisation of the axonal cytoskeletal structure with
subsequent disturbance of axonal transport and Structural imaging is an integral part of the rou-
increasing metabolic impairment (Blennow and tine diagnostic procedure to exclude secondary,
Hampel 2003). Thus W-protein is released. While in particular treatable causes of dementia. Pre-
increased W-protein concentrations are character- vious studies revealed about 1%–10 % of clinical
istic although not specific for AD, values obtained relevant imaging findings in patients with mental
in MCI typically show a wide range between those decline. Hejl et al. 2002 reported on 1000 consecu-
determined in AD and those measured in otherwise tive memory clinic patients of whom 89% had cross
healthy controls. Longitudinal studies indicate that sectional imaging, mainly CT. Of 891 patients that
this heterogeneity of W-values correspond to the risk had a scan, 42 (almost 5%) had an identifiable lesion
of developing AD in the near future (Schröder, per- (tumour or hydrocephalus) that altered the diagno-
sonal communication). sis and required acute or subacute treatment. About
the same percentage was reported for the work-up
of demented patients (n = 432) with 4% having a
12.3.1 lesion. In their series they found significant findings
Imaging in Dementia in about 3% of submitted cases (Fig. 12.1).
The amount of cerebrovascular findings is even
In the past years there has been an increasing use of higher. Massoud et al. (2000) found clinically
neuroimaging in the diagnostic work-up of individ- unsuspected cerebrovascular disease in 26% of their
uals suffering from mental decline. Both computed sample by routine imaging. Beyond those findings
tomography (CT) and Magnetic Resonance Imag- cross sectional imaging is able to detect classical
ing (MRI) are used to rule out secondary demen- morphologic changes in patients with dementia.
tias (which refer to somatic disorders other than According to Braak and Braaks’ staging scheme
neurodegenerative diseases) or concomitant condi- of AD (Braak et al. 1993), it would be expected that
tions that may be associated with the dementing the earliest morphological changes affect the tran-
disorder. This includes in particular the diagnosis sentorhinal cortex, including parts of the parahip-
of treatable conditions like chronic subdural hema- pocampal gyrus (Fig. 12.2). With clinical manifesta-
toma, tumors, infections, or normal pressure hydro- tion of the disease, the hippocampus and amygdala
cephalus as well as the exclusion of concomitant are also affected; other neocortical areas such as the
neurovascular changes (Schröder et al. 1997). frontal and temporal cortices are involved later in
Beside the exclusion of these secondary causes the course. These changes can be identified most
the detection of subtle changes in the early stages of sensitively and precisely with MRI (Fig. 12.2).
dementia, including the investigation of the under- Using volumetric MRI (Pantel et al. 2003) the
lying pathophysiology, has gained more and more early diagnostic values of parahippocampal gyrus
interest. Accurate diagnosis and prognosis is not and hippocampus volume reduction as predilec-
only of great importance for the patient himself but tive sites of entorhinal and limbic atrophic change,
also for the developing new therapeutic concepts respectively, have been investigated (Fig. 12.3) in
including preventive strategies. Since the different 21 healthy subjects, 22 MCI patients as well as 12
pathological processes that produce cerebral dys- patients with mild AD as an additional control
function at a cellular level also produce macroscopic group. All subjects except the AD patients were
effects which may be detected with imaging, struc- recruited within the “Longitudinal Study of Adult-
tural neuroimaging plays an important role, and is hood” (ILSE) from the general population of the Pal-
regarded as a major part of the investigation of a atine. Patients with MCI showed a significant right
Magnetic Resonance Imaging in Prevention of Alzheimer´s Disease 237
a b c
Fig. 12.2a–c. Progressive temporal atrophy according to Braak and Braak. Temporal lobe morphology in three subjects
at the age of 70. (a) Normal morphology of the medial temporal lobe. With increasing atrophy a shrinking of the medial
aspects and an enlagement of the basal cisterns can be observed (b). With increasing atropy (c) the changes also affect the
cap of the temporal lobe with pronounced enlargement of the basal cystern, the insula and the temporal horn of the lateral
ventricles
238 M. Essig and J. Schröder
4000,0
right parahippocampal gyrus right
righthippocampus
hippocampus
3500,0
3000,0
2500,0
2000,0
1500,0 1000,0
a Volunteers MCI AD Volunteers MCI AD b
Fig. 12.3a,b. Volumetric fi ndings in the right hippocampus and right parrahipocampal gyrus in age matched healty volun-
teers, minor cognitive impairment and Alzheimer´s disease (according to Pantel et al. Am J Psych. 2003). Subjects with
MCI showed significant right parahippocampal gyrus volume reduction compared to healthy controls. These changes were
more pronounced in patients with manifest AD, whilst individuals with MCI took an intermediate position. Hippocampal
changes were only demonstrable in patients with manifest AD
Fig. 12.4a–c. Corpus callosum changes in MCI and mild AD. Five anatomic areas have been evaluated (a). While manual
tracing demonstrated atrophy for the more rostral parts (b), voxel based morphometry only confi rmed the more pronounced
alterations in manifest AD (c)
with volume reduction of up to 20% typically found involve the more rostral parts of the corpus callo-
in the early stages of AD (Jack et al. 1999; Convit et sum in both, MCI and AD. In contrast, by using a
al. 1997; Kaye et al. 1997). voxel-based approach, significant changes could
Although these atrophic changes primarily only be demonstrated in AD but not in its preclini-
involve cortical structures, interhemispheric fiber cal state suggesting a greater sensitivity of manual
connections are also compromised by Wallerian tracing.
degeneration. Through this process the respec- Neuropathological changes – i.e. neurofibrillary
tive segments of the corpus callosum become atro- tangles – primarily develop in the entorhinal cortex,
phic, a finding which can be typically visualized on but extend to the entire limbic circuit including
mid-sagittal slices (Fig. 12.5). As demonstrated by the hippocampus in the second stage of the disor-
manual segmentation, these changes particularly der. While initial pathology can be compensated
Magnetic Resonance Imaging in Prevention of Alzheimer´s Disease 239
Fig. 12.5. Microangiopathic changes in a patient with mental decline. Three consecutive slices of a 65-year-old patient with
mental decline. Anamnestic a hypertension and diabetes have been documented. FLAIR imaging shows multiple conflu-
encing white matter lesions periventricular. Involved are primary the white matter tracks with involvement of the cortical
structures at a later stage of the disease
for by large and thus involving only mild cognitive tive indices were assessed in 52 patients with MCI
deficits, limbic and hippocampal changes typically or AD and healthy controls on the basis of the static
lead to more pronounced neuropsychological defi- T1-weighted 3D-data sets. The method proved to be
cits in particular involving the declarative memory fast and rater independent. Qualitative ventricular
domain. The term hippocampal dementia has been inspections using surface rendering shading could
coined by Ball et al. (1985) to address this associa- uncover atrophic processes with enlargement of the
tion and the clinical importance of mnestic deficits. whole and especially temporal horn volume. The
Subsequently, neuropathological changes extend to authors found a significant difference between both
the entire neocortex except the sensorimotor and the temporal horn volume and index of AD patients
visual cortices resulting into severe dementia. compared to MCI subjects and controls (p < 0.005).
In the later stages of AD the degenerative process THV and THI of both MCI subjects and controls did
leads to progressive loss of brain volume that is sig- not differ significantly (p > 0.05). In their study they
nificantly greater in AD patients as compared to age- found also a significant negative correlation between
matched controls or subjects with MCI (Schröder the neuropsychological performance and both THI
et al. 2004) and strongly correlates with the rate of and THV (p < 0.01). Although the study used MRI
cognitive deterioration (Pantel et al. 2002). The data, the used method should also work with CT
assessment of the medial temporal lobe structures data in which the intensity of water and brain tissue
are limited on CT; however there are some newer can be clearly differentiated.
techniques which may overcome this problems by In MRI the technical requirements for a volumet-
the use of indirect measurements of the medial tem- ric analysis are at least 3-mm or thinner slices ori-
poral lobe volume. ented parallel to the medial temporal lobe and skil-
Giesel et al. (2006) proposed an indirect mea- ful handling of the caliper.
surement of the temporal lobe atrophy by volumet- In our series using volumetric analyses (Pantel
ric analysis of the temporal horn of the ventricular et al. 2003) we achieved sensitivity values up to 95%
system. The new methodology is based on an “Inter- in differentiating AD patients from controls with a
active Watershed Transform” (IWT) which allows specificity up to 90%.
a fully automated segmentation of the temporal The prognostic significance of hippocampal atro-
horn volume (THV) and a temporal horn index phy in MCI is still under investigation. Accumulat-
(THI) which is defined as the ratio of temporal horn ing the evidence from quantitative MRI studies we
volume to lateral ventricular volume. The respec- can suspect that hippocampal or parahippocampal
240 M. Essig and J. Schröder
atrophy is already present before dementia onset the temporal pole, the parahippocampal gyrus and
(Johnson et al. 2000; Saykin et al. 1999; Prvulovic the lateral temporal gyri that could be helpful in
et al. 2002; Kato et al. 2001; Rombouts et al. 2000) distinguishing AD from semantic dementia as the
and dramatically increases with conversion to clini- semantic dementia group has significantly more
cally apparent disease (Small et al. 1999). atrophy in all these regions in both hemispheres.
However, in most studies no significant correla- Boccardi et al. (2003) performed a discriminant
tion between the clinical status and the volumetric function on a set of AD and FTD patients, showing
changes was found. In a large prospective study of that including the asymmetry values of frontal and
MCI patients, Jack et al. (1998) found a fourfold temporal regions one could separate fronto-tempo-
increase in the percentage of individuals convert- ral dementia from AD with a 90% sensitivity and
ing to dementia within 5 years when hippocampal a 93% specificity.
size was two standard deviations below age- and They concluded that a pattern of atrophy is more
sex-defined norms. Similar findings were noted in useful than atrophy of single regions in the differ-
a second study, although memory scores were also ential diagnosis. Chan et al. (2001) showed that, in
significant predictors (Jack et al. 2000). addition to asymmetry, a marked anterior to pos-
These findings may support the utility of ana- terior gradient of atrophy within the temporal lobe
tomical brain imaging in MCI to predict a conver- also suggests a diagnosis of fronto-temporal demen-
sion to AD within the near future (Whitwell and tia rather than AD.
Jack 2005). Importantly, future work from popula- Vascular dementia is the second most common
tion-based studies (e.g. the Heidelberg ILSE study) cause of dementia, following Alzheimer disease
will be helpful in clarifying the utility of anatomical (Erkinjuntti 2002; Roman et al. 2002). The
imaging in the early diagnosis of AD for populations diagnosis of vascular dementia requires a decline
in which clinical definitions of MCI are less predic- in memory and intellectual ability that causes
tive (Pantel et al. 2003). impaired functioning in daily living, associated
with evidence of cerebrovascular disease demon-
strated by either history, or clinical examination,
12.3.3 and brain imaging. Therefore modern neuroimag-
Differentiation of Other Forms of Dementia ing is required for confi rmation of cerebrovascular
disease in vascular dementia and provides infor-
In order to be able to diagnose a mental decline mation about the topography and severity of the
as AD or to predict the disease, the process needs vascular lesions. Both CT and MRI are suitable in
to be differentiated from other forms of dementia, the diagnostic workup of vascular lesions with a
especially from the fronto-temporal lobar degen- clear advantage for MRI (Guermazi et al. 2007).
eration. The clinical criteria of frontal dementia Absence of vascular lesions on brain CT or MRI
have been described by Neary et al. (2005) who rules out probable vascular dementia and repre-
also differentiated frontal and temporal atrophy as sents the most important element to distinguish
supportive diagnostic features for fronto-temporal Alzheimer disease (Roman 2002). Since there are
dementia, while. However, the absence of one or the no pathognomonic CT or MR fi ndings of vascular
other does not rule out the diagnosis. Asymmetric, dementia, the correlation with the clinical evidence
predominantly left-sided perisylvian atrophy char- is mandatory. The sensitivity of MRI to vascular
acterises progressive nonfluent aphasia and asym- pathology (Fig. 12.5) has allowed a substantially
metric anterior temporal lobe atrophy is diagnostic better differentiation between Alzheimer disease
of AD. With progression of the disease and over and other forms of dementia, especially the vas-
time, atrophy becomes more widespread in both cular forms. However, there are possible overlap
diseases but usually remains asymmetric in AD. syndromes between the two disorders, and opera-
A study by Galton et al. (2001) focused on MRI tional defi nitions for “mixed” dementia, indicating
of fronto-temporal dementia, including patients the presence of both Alzheimer disease and VaD,
with semantic dementia and the frontal variant are still lacking (Scheltens et al. 2002).
of fronto-temporal dementia (fvFTD). In a study With the use of modern MRI or CT angiographic
consisting of 30 patients with AD, 17 with seman- techniques it is also possible to assess non-inva-
tic dementia, 13 with fvFTD and 18 controls, the sively the vascular situation of both the supraaortic
authors used a new visual scale based on atrophy of and intracranial vessels in a single exam.
Magnetic Resonance Imaging in Prevention of Alzheimer´s Disease 241
12.4
Vascular Imaging in Cognitive Decline
While perfusion MRI is already an established coverage and common EPI artifacts have been limi-
method in the assessment of subjects with neuro- tations in the past. With the use of parallel imaging
cognitive changes, diffusion MRI and fMRI are techniques the method might be improved substan-
still considered as investigative procedures and are tially.
therefore not described in detail. At a field strength of 1.5 T the main approaches to
assess brain tissue perfusion are dynamic contrast
enhanced techniques (DCE-MRI): T2* perfusion
12.5.1 MRI and tracer kinetic MRI.
Perfusion MRI in Psychiatric Diseases T2* perfusion MRI is based on a rapid contrast
media injection and the evaluation of the signal
Perfusion is physiologically defined as the steady intensity time curve with spin-echo or gradient-
state delivery of blood to an element of tissue. The echo EPI sequences. The dynamic data is used to
term “perfusion” is also used to emphasize contact calculate the regional cerebral blood volume (rCBV)
with the tissue, or in other words capillary blood and regional cerebral blood flow (rCBF) (Fig. 12.7).
flow. Because perfusion and blood volume is dis- Perfusion MRI is routinely used in the diagnostic
turbed in many disease processes, monitoring of work-up of cerebral ischemia and cerebral tumors
this key physiological parameter can often provide (Essig et al. 2004). In the diagnostic process of demen-
insight into disease. Consequently, the measure- tia there are only limited data available (Maas et al.
ment of perfusion for medical purposes has been 1997; Harris et al. 1998; Bozzao et al. 2001; Alsop
performed in almost all organs using many tech- et al. 2000). Previous perfusion studies using PET
niques (Barbier et al. 2001). have shown alterated rCBV and rCBF values in both
During the last decade several methods have been grey and white matter. Perfusion imaging with MRI
described to measure perfusion non-invasively with has been applied to this problem as well, with early
magnetic resonance imaging. Most effort has been studies indicating similar results to those of PET and
made in the perfusion imaging of the brain with two SPECT. These early studies indicate that rCBV map-
major approaches: contrast-enhanced techniques ping may have a sensitivity and specificity similar to
based on tracer kinetic models (Rempp et al. 1994) that of nuclear medicine approaches for the diagnosis
and non-enhanced techniques based on arterial of AD.
spin-labeling (Wong et al. 1998). Vascular causes of dementia have also been stud-
While the contrast-enhanced techniques are well ied with perfusion MRI. Several studies have shown
established, the non-enhanced techniques are of that these patients present with a generally decreased
increasing interest with the use of high field MR sys- cerebral perfusion. The white matter changes are
tems. Especially in the latter the limited anatomic more pronounced than in patients with AD. As in
ing, However, there is a need for the assessment as compensatory effects – while decreased activa-
of the neuronal functionality beside the morpho- tions described by others (Dickerson et al. 2005)
logic changes. A new promising technique that may are assumed to refer to atrophic changes. Interpre-
be used for this is to measure local brain activa- tation of the respective effect which were primarily
tion using functional magnetic resonance imaging described in mesial temporal structures is further
(fMRI), since functional loss predates structural compromised by methodological issues, in particu-
loss of brain tissue. Functional MRI was recently lar the question whether patients were trained before
used to examine activation associated with aging the examination or not. This point is further under-
and dementia (Buckner et al. 2000; Johnson et al. lined by the results of fMRI studies under repetitive
2000; Saykin et al. 1999). motor tasks or working memory tasks which yielded
Johnson et al. (2000) correlated the effect of atro- a decrease of activation values at an increased per-
phy with the MRI signal. In their study they first formance following practice (Fig. 12.9).
described a compensatory recruitment of cortical
units in cases of Alzheimer`s disease.
Newer studies focus on the effects of pathologic
ageing and the findings in minor cognitive impair-
ment subjects. 12.7
Studies in MCI and early AD addressed activa- Discussion and Conclusion
tion changes under declarative memory tasks, since
the latter refer to the core symptoms of the disease. The assessment of atrophic changes is well estab-
However, results appear to be somewhat conflict- lished in the assessment of subjects with mental
ing. Some studies (Machulda et al. 2003) reported decline. The most likely future use of imaging, how-
increased activation values – generally interpreted ever, will be the identification of patients at risk
Fig. 12.9. Functional MRI during a working memory task in healthy controls. At baseline, execution of the task led to
an activation of fronto-parietal cortices as described in previous studies. While the respective regions showed activation
increases with improved performance after the initial 2 weeks of training. The activation values decreased at the time of
consolidation of performance gains after 4 weeks
Magnetic Resonance Imaging in Prevention of Alzheimer´s Disease 245
for Alzheimer’s disease or suffering from preclini- The 3D data postprocessing and the volumetric
cal Alzheimer’s disease, most likely mild cognitive analysis should also be standardized and com-
impairment. For imaging this will mean focusing pared with previous data. The postprocessing
on those areas that are affected earliest in the dis- should be fast and reliable.
ease, i.e. entorhinal cortex and hippocampus, using 3. Contrast enhanced MRA of the supraaortic ves-
high-resolution structural or functional MR imag- sels including the carotid arteries and the intra-
ing methods. Work from different groups has shown cerebral vessels. Multiphasic acquisition to eval-
that moderate medial temporal lobe atrophy, as mea- uate both the arterial and venous system. MRA
sured qualitatively or quantitatively may serve as a enables a better analysis of the vascular compo-
prediction of development of AD. With the ability nent, e.g. to rule out vessel stenoses or vasculitic
to rapidly acquire high contrast, high spatial resolu- changes.
tion, three-dimensional brain images, a number of 4. Spin-labelling or contrast enhanced MR perfu-
laboratories are experimenting with sophisticated sion measurements allowing an absolute quanti-
brain-mapping algorithms. This process allows an fication of the cerebral blood flow and volume.
individual MRI to be compared to an ‘average’ or Postprocessing using a standardized software
‘ideal’ brain, enabling the detection of anatomical solution.
differences at one point in time as well as change in 5. Diffusion Tensor MRI with quantification of the
anatomical structure over repeated observations. fractional anisotropy. Postprocessing using a
In an evidence based evaluation, however, standardized and reader independent software
Wahlund et al. (2005) recently summarized that solution.
only at specialized settings does the MRI based
evaluation of atrophy of medial temporal structures
contribute to the diagnostic accuracy. However,
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Osteoporosis 249
Osteoporosis 13
Andrea Baur-Melnyk and Holger Boehm
USA in 1995 (Ray et al. 1997). Annual expenditures ography and bone mineral density measurements).
for osteoporotic fractures exceeded all health care Secondary reasons for osteoporosis and osteomala-
expenditures for breast and gynaecological cancers cia need to be excluded (Fig. 13.1). Patient‘s history
combined, only being surpassed by costs related to should explore risk factors, genetical disposition
cardiovascular disease (Hoerger et al. 1999). In the (mother) and recent fractures in clinical history. It
industrialized nations, medical expenditures are has to be recorded whether or not the patient has
rising faster than the rate of inflation. The prevalence already suffered a fracture in the past, whether
of osteoporosis is so great that the decision whether significant loss of body height has occurred or the
or not to treat the individual patient will have tre- patient complains about back pain. Since 2/3 of fra-
mendous economic impact. For instance, treating the gility fractures are clinically inapparent, as a mini-
whole population of postmenopausal women in the mum requirement, lateral X-ray fi lms of the tho-
US (35 million) with hormone replacement therapy
at just $430 per year would total nearly $15 billion
annually, reaching the direct medical expenditures
for treatment of the fractures themselves (Melton
2002). How best to balance the benefits of treatment
with these potentially ruinous treatment costs is the
subject of ongoing discussions. Cost effectiveness
of treatment is extremely difficult to ascertain. On
the other hand, using costs and criteria applicable
to the US, pharmacological treatment that aims at
the reduction of hip fracture risk has been shown to
be cost effective in high-risk individuals (Eddy et al.
1998; Jönsson et al. 1999). Widespread use of expen-
sive drugs for prevention of fractures may not be
affordable in many countries where effective drugs Fig. 13.1. A 54-year-old female with severe osteomalacia. In
are not reimbursed by government health insurance contrast to osteoporosis the structure of the trabeculae is
plans even for patients at high risk of fractures. blurred. Note also the bilateral insufficiency fractures of the
pubic bones
racic and lumbar spines ought to be obtained at first nia is detectable) have been poor (Lachmann and
presentation. Clinical examination focusses on the Whelan 1936; Doyle et al. 1967; Wagner et al.
identification of spinal deformities (kyphosis) and 2005). Typical radiological signs of osteoporosis are
height measurements. Testing the sense of balance increased radiolucency of bones, accentuation of the
is essential because of its great impact on the inci- vertebral end-plates and accentuated trabeculae of
dence of falls, which is itself a dominant risk factor the principal tensile and compressive group of the
for hip fractures. The radiologist plays a key role hip (Figs. 13.2 and 13.3).
in the diagnostic process by detection of fractures
as well as by assessment of bone mineral density
(BMD) for base-line and follow-up examinations.
BMD measurement represents the only method
to determine osteopenia and osteoporosis prior to
fracture (Table 13.1).
13.3
Imaging Methods for Osteoporosis
13.3.1
Conventional Radiography
Conventional radiography is of limited use in detect- Fig. 13.2. An 80-year-old female with severe osteoporosis
ing osteoporosis prior to fracture but plays a cen- of the pelvis. Increased radiolucency and accentuation of
trabeculae of the femur
tral role in the assessment of the fracture status of
the osteoporotic patient. Furthermore, radiographs
serve to exclude differential diagnoses, such as osteo-
malacia, hyperparathyroidism, renal osteodystro-
phy, malignant bone marrow disorders, as well as
local bone or soft tissue conditions which may lead to
significant errors in bone mineral measurements.
In the appendicular skeleton, radiographs readily
allow to identify osteoporotic fractures. The presence
of a fragility fracture – after exclusion of all other
possible causes of the fracture – justifies the diagno-
sis of osteoporosis. A fragility fracture is a fracture
that occurs inappropriately at minimal mechanical
impact (e.g. fall on the hip from standing position,
coughing, bending over). The primary goal is to
detect osteoporosis before a fracture occurs rather
than identify fracture-associated deformities.
Many semi-quantitative indices have been devel-
oped to assess indirectly BMD from radiographs,
e.g. trabecular quantification or combined cor-
tical thickness quantification (Chen et al. 1994;
Veenland et al. 1994; Buckland-Wright et al.
1994; Millard et al. 1998). Due to inherent vari-
ability concerning image quality in standard radio-
Fig. 13.3. Lateral projection radiograph of the spine in a 76-
graphs, sensitivity and reproducibility of radio- year-old female with severe osteoporosis (T-value: –4,4 SD).
graphic techniques (a reduction of bone mineral Increased radiolucency and accentuation of end-plates. Note
in excess of 20%–40% is required before osteope- also wedge shape deformity of L2
252 A. Baur-Melnyk and H. Boehm
Normal
(Grade 0)
Mild deformity
(Grade 1)
Moderate deformity
(Grade 2)
Severe deformity
(Grade 3)
Fig. 13.8. Example for densitometric evaluation of the lumbar spine by DXA. The patient’s lumbar bone density is compared
to reference populations. The “T-score” is calculated as the standard deviation (SD) variance of the patient’s BMD compared
to a healthy young-adult reference population. The reference population may vary according to the manufacturer and there-
fore also mean SD of the reference population is variable. Comparison of serial DXA studies should therefore always relate
to absolute BMD values expressed in g/cm 2 , and should not be based on T-scores. The “Z-score” is the standard deviation
(SD) variance of the BMD compared to an age- and sex-matched reference population, and should not serve for diagnosis of
osteoporosis. It is calculated according to the same formula as the T-score, with the exception of the reference population
being age- and sex-matched instead of young-adults. In this case, due to degenerative spondylarthrosis, the BMD value of L4
is significantly higher than the BMD for L1-3. This vertebra should be excluded from T-score evaluation. Thus, the T-score
for this patient (L1-L3) is –2.6 indicating osteoporosis
damage accumulation (e.g. micro-fractures) and and positioning of ROIs (Fig. 13.8). Several limit-
matrix composition and as such is not as trivially ing factors and conditions are associated with AP
accessible by diagnostic methods as bone density. lumbar measurements, though inter-individual
BMD obtained from DXA is a good predictor of frac- anatomic variability in vertebral size may lead to
ture risk and measurements can be performed at or a bias in the sense that larger vertebrae with larger
close to the site of interest, i.e. at the spine, the proxi- transverse diameters result in higher BMD values.
mal femur and the distal radius. However, there is A major disadvantage in AP examinations is the
considerable overlap in the BMD results between relevance of errors caused by calcifications of sur-
individuals who have fractured and those who have rounding soft tissue and degenerative alterations
not. The anatomic sites that are routinely and most of the spine. The posterior vertebral elements fre-
frequently studied using DXA are the lumbar spine quently involve osteoarthritic changes (i.e. facet
and the hip. Whole body acquisition and BMD mea- sclerosis, degenerative disc disease, osteophytes)
surement at the distal radius and the calcaneus may – particularly in the elderly – which may lead to an
also be obtained. over-estimation of bone mineral density. The same
AP examination of the lumbar spine is typically is true for aortic calcifications if superimposed onto
conducted for L1-L4 and has an in vivo precision of the ROIs, or deformed vertebrae which must not be
1% and a high accuracy of 4%–10% (Pacifici et al. included in the evaluation of BMD. Lateral lumbar
1988; Glüer et al. 1990; Mazess et al. 1989). The DXA which assesses solely the vertebral bodies is
scans are evaluated using automatic segmentation less affected by the above factors but measurements
256 A. Baur-Melnyk and H. Boehm
have lower precision and involve higher doses of high precision measurements. However, all stan-
radiation (Larnach et al. 1992; Rupich et al. 1992). dardized therapy regimens and diagnosis of osteo-
Osteopenia fi rst and most severely affects the porosis based on BMD measurements rely solely on
trabecular bone compartment. Therefore, trabecu- DXA T-values, and therefore QCT measurements
lar bone is considered the most reliable indicator should be reserved for special circumstances: sus-
of overall metabolic integrity. Today, quantitative pected BMD loss despite normal DXA values, metal
computed tomography (QCT) is the only com- implants in the spine, severe scoliosis and expected
mercially available technique allowing volumetric false negative DXA measurements (massive athero-
measurement of the trabecular interior of bone sclerosis of the aorta, severe scoliosis, degenerative
(Fig. 13.9). All other densitometric techniques alterations of the lumbar spine, metal implants).
evaluate a combination of both trabecular and the
overlying cortical bone. QCT is the most accurate
modality to measure bone density being two to three 13.3.6
times more sensitive than DXA in detecting loss of Screening
bone mineral. In vivo precision of up to 1.3% can be
achieved for trabecular BMD in the spine (Lang et Costs of screening vary corresponding to the tech-
al. 1999). QCT can be performed on standard clini- nique and average reimbursement rates in 2000 in
cal scanners, which are equipped with a calibration the U.S. were $133 for DXA and $34 for ultraso-
phantom and specialized software allowing for nography (National Physician Fee Schedule
Payment Amount File 2000).
If 10,000 women 65–69 years of age underwent
DXA of the femoral neck, 12% would be identified
as high-risk (T-score d2.5). The number of women
in this age group needed to screen to prevent 1 hip
fracture in 5 years would be 731, and the number of
women with low bone density needed to treat for
benefit would be 88 (Nelson et al. 2002).
Abnormal ultrasonography results may require
a confirmatory DXA before treatment is initiated
because clinical trials are based on DXA as entry
criteria. Patients would require follow-up tests over
several years before receiving a diagnosis of osteo-
porosis and leaving the screening population.
13.3.7
Follow-Up BMD Measurements
change in BMD is considered to be a good response, respect to the presence of osteoporotic fractures of
a significant decrease of BMD is worrisome. In situa- the spine (in vivo) or correlated with biomechani-
tions where a rapid change in BMD can be expected, cal strength (in vitro). Fairly well established are
e.g. initiation of high dose glucocorticoid therapy, linear structural measures in 2D based on standard
a baseline test is recommended, with a follow-up histomorphometry (trabecular spacing, trabecular
study in intervals of 6 months until a stable level volume, connectivity).
is reached. Micro-CT- or HRMRI-based microstructural
computer models of trabecular bone can be exam-
ined by finite element analysis (FEA), thus pro-
13.3.8 viding additional and relevant information about
Radiation Exposure anisotropy and mechanical properties in a direct
and non-destructive way (Ulrich et al. 1998; van
Radiation exposure in DXA ranges from 1 to Rietbergen et al. 1998). Due to the complexity of
50 µSv depending on the location of the measure- natural bone, the computational effort is extremely
ment (axial/peripheral skeleton) and the tech- high and – at present – only available at specialized
nique (pencil beam/fan beam scanner) (Link and centers.
Majumdar 2003) Effective doses associated with Recently, non-linear techniques for structural
QCT are quoted as 60–500 µSv for the lumbar spine analysis of trabecular bone in 3D have been devel-
and about 1 µSv for the distal radius. Quantitative oped, which proved to be superior to both the stan-
ultrasound is a test that does not utilize ionizing dard measures and BMD in predicting bone strength
radiation and therefore does not contribute to radia- and fracture risk. The new parameters are based
tion exposure. on the scaling index method (SIM), the Standard
Hough Transform, and the Minkowski functionals
(Boehm et al. 2003a,b, 2005). Although the results
13.3.9 of structural analysis are very promising further
Trabecular Imaging development in hardware and software are required
to make these new techniques available for clinical
Bone densitometry is based on the absorption of practice.
photons passing through the tissue but (unfortu-
nately) does not consider the underlying architec-
tural features of bone which strongly influence the 13.3.10
biomechanical properties. Various of studies have Therapy
shown that micro-structure and BMD are widely
independent contributing factors to bone strength Osteoporosis is a disease which is not only underdi-
(Genant et al. 1996; Ulrich et al. 1997). agnosed but also undertreated. The aim of treatment
Recently, imaging techniques have become avail- should be to prevent fractures. By preference the
able allowing to depict individual trabeculae (Link occurrence of the first fracture should be prevented
et al. 1999). In this context high-resolution magnetic in patients at high risk for osteoporotic fractures. In
resonance imaging (HR-MRI) has received consid- patients with a previous fracture, treatment should
erable attention both as a research and as a clinical be initiated soon after the fracture has occurred.
tool. Since the MR signal corresponds to the proton Therapy challenges the patient in terms of measures
content of a particular tissue – due to the surround- in life style and the doctor in terms of selecting the
ing marrow and fat – bone is represented as a nega- ideal medication.
tive image. Depending on the field strength, coil Live style recommendations include avoiding risk
design, and the choice of the specific pulse sequence factors such as smoking, alcohol abuse, adequate
and imaging parameters HR-MRI can be used for calcium and vitamin D intake by food and physical
in vitro as well as in vivo situations. Anatomic sites activity. In older patients fall prevention exercises
which have successfully been studied in human and training of body balance, can reduce the risk
subjects using HR-MRI are the phalanges, the distal of falling. Hip protectors decrease the incidence for
radius, the proximal femur and the calcaneus. hip fractures. In patients with solely osteopenia,
From the image data, micro-structural features life style recommendations in combination with
obtained by quantitative measures are analysed with a daily dose of calcium and vitamin D are recom-
258 A. Baur-Melnyk and H. Boehm
mended. In patients with osteoporosis, with or with- Women may benefit from pharmacologic treatment
out a fracture, further medication has to be initiated if T-score is –2.5 or below, if T-score is –1.5 and
(Geusens 2003). below and risk factors are present, or if non-phar-
Bisphosphonates are the treatment of choice for macologic preventive measures are ineffective (bone
the prevention and treatment of fragility fractures. loss continues or low trauma fractures occur). In
At present, three types of bisphosphonates are used Germany, according to the new DVO guidelines,
clinically in both postmenopausal and glucocorti- treatment start point has been changed recently.
coid-induced osteoporosis, namely cyclic etidro- Treatment is dependent on T-scores in combination
nate, alendronate and risedronate. According to with age and five risk factors (peripheral fracture,
several studies the incidence of vertebral fractures hip fracture of a relative, nicotine abuse, multiple
and hip fractures can be reduced by 50%–70% after falls, immobilisation). This new more complicated
the use of bisphosphonates. The optimal duration of scheme was introduced in order not to overtreat
bisphosphonate therapy has not been established. patients only because of low DXA levels and to limit
A number of oral and transdermal hormone costs for treatment.
replacement preparations are licensed for the pre- Several organizations have developed helpful
vention of postmenopausal osteoporosis. However, guidelines for initiation of pharmacologic therapy.
in spite of the epidemiologic evidence of a protective All patients should be advised about non-pharma-
effect of hormone replacement on osteoporosis and cologic therapy, such as physical exercise, fall pre-
the incidence of fractures, no anti- fracture effect vention, calcium, vitamin D, and lifestyle modifi-
in the spine has been documented in a randomised cations such as avoidance of smoking and alcohol
controlled trial. Furthermore the role of long term abuse. Some may benefit from additional interven-
hormone replacement therapy is discussed contro- tions, such as balance training or hip protectors.
versially since the results of the “women`s health ini- The main aspect is to consider the T-score values in
tiative” study were released. A 26% relative increase conjunction with the patient’s clinical profi le and to
of invasive breast cancer in the combined hormone have a good working understanding of the risks and
replacement group as well as an increased risk of benefits of the therapeutic options.
cardiovascular and cerebrovascular incidents was
observed causing more harm than benefits.
Raloxifene, a selective estrogen receptor modu-
lator (SERM), a non hormonal substance, is used
for the treatment and prevention of osteoporosis in 13.4
postmenopausal women. It has a spectrum of effects Summary
when binding to the estrogen receptor, with agonist
effects on bone and antagonist effects on the breast. With the development of highly effective drug thera-
It has been shown to reduce the incidence of verte- pies osteoporosis has become a potentially treatable
bral fractures. No relevant effect was observed for disease. If diagnosed at an early stage the worst of
non-vertebral fractures. complications – osteoporotic fractures – may be pre-
vented. The central – but limited – role of conven-
tional radiography is the assessment of the patient’s
13.3.11 fracture status which bears a strong correlation with
Initiation of Drug Therapy the individual fracture risk. Once osteoporotic frac-
tures have occurred there is a high risk for future
The T-score cutoff points for defining osteoporo- fractures. The standard clinical parameter for osteo-
sis and osteopenia are not the same as the T-score porosis today is bone mineral density, upon which
thresholds for initiating drug therapy. The WHO the WHO definition of osteoporosis is based and
cut-off for defining osteoporosis is –2.5. The Fed- which can readily be assessed by standard DXA
eral Drug Administration (FDA) approves starting techniques. High resolution imaging modalities in
medications, such as bisphosphonates or calcito- conjunction with advanced image processing tools
nin, for the treatment of osteoporosis, in women allow to evaluate the micro-architecture of trabecu-
if the T-score is below –2.0 with no risk factors, lar bone quantitatively which, in the future, will help
T-scores below –1.5 with one or more risk factors, to improve the prediction of the patient´s fracture
or in patients with a prior vertebral or hip fracture. risk and assessment of therapeutic effects.
Osteoporosis 259
Mueller D, Isbary M, Boehm H, Bauer J, Rummeny E, Link T Ulrich D, Rietbergen B, Laib A, Ruegsegger P (1998) Mechan-
(2004) Recognition of osteoporosis related vertebral frac- ical analysis of bone and its microarchitecture based on
tures on chest radiographs in postmenopausal women. in vivo voxel images. Technol Health Care 6:421–427
RSNA, Chicago, p 305 van Rietbergen B, Majumdar S, Pistoia W, Newitt DC, Koth-
National Physician Fee Schedule Payment Amount File ari M, Laib A, Ruegsegger P (1998) Assessment of cancel-
(2000) lous bone mechanical properties from micro-FE models
Nelson HD, Helfand M, Woolf SH, Allan JD (2002) Screen- based on micro-CT, pQCT and MR images. Technol
ing for postmenopausal osteoporosis: a summary of the Health Care 6:413–420
evidence Ann Intern Med 137(6):529–541 Veenland JF, Grashuis JL, Gelsema ES et al. (1994) Texture
Pacifici R, Rupich R, Vered I et al. (1988) Dual energy radi- analysis of trabecular bone in radiographs to detect oste-
ography (DER): a preliminary comparative study. Calcif oporosis. Symposium for Computer Assisted Radiology,
Tissue Int 43:189–191 pp 77–82
Praemer A, Furner S, Rice DP (1992) Musculoskeletal condi- Wagner S, Baur-Melnyk A, Sittek H, Stäbler A, Bonel, H,
tions in the United States. American Academy of Ortho- Laeverenz G, Reiser MF (2005) Diagnosis of osteoporo-
paedic Surgeons, Park Ridge sis: visual assessment of conventional and digital radi-
Ray NF, Chan JK, Thamer M, Melton LJ III (1997) Medical ography in comparison with dual X-ray absorptiometry
expenditures for the treatment of osteoporotic fractures (DEXA) of the lumbar spine. Osteopath Intl 16:1815–
in the United States in 1995: report from the National 1822
Osteoporosis Foundation. J Bone Miner Res 12:24–35 WHO (1994) Technical Report: Assessment of fracture risk
Rupich RC, Griffi n MG, Pacifici R et al. (1992) Lateral dual- and its application to screening for postmenopausal oste-
energy radiography: artifact error from rib and pelvic oporosis: a report of a WHO study group. World Health
bone. J Bone Miner Res 7(1):97–101 Organization, Geneva, Switzerland
Ulrich D, Hildebrand T, van Rietbergen B, Muller R, Rueg- Yuh WTC, Zachar CK, Barloon TJ, Sato Y, Sickels WJ, Hawes
segger P (1997) The quality of trabecular bone evaluated DR (1989) Vertebral compression fractures: Distinction
with micro-computed tomography, FEA and mechanical between benign and malignant causes with MR Imaging.
testing. Stud Health Technol Inf 40:97–112 Radiology 172:215–218
Exogenous Exposition: Asbestos 263
Exogenous Exposure: 14
Occupation and Environment
14.1 Asbestos
Roger Eibel and Dennis Nowak
et al. 2001) and malignant mesothelioma (Goldberg Bystander (those working near insulation install-
and Luce 2005). ers, for example)
In the United States, the initial exposure limit was Environmental (naturally occurring sources)
established in 1971 at 5 fibers per cubic centimetre, (Fig. 14.1.2)
reduced to 2 fibers in 1976, to 0.5 fibers per cubic
centimetre in 1983, and to 0.1 in 1994 (Brownson Frequently the diagnosis of asbestos-related dis-
1998). eases must be made in a particular person without
Because of difficulties in quantifying exposure, the aid of pathology. That is, asbestosis must often
the variable persistence of asbestos fibers in tissue, be diagnosed on clinical grounds by the use of (Ross
differences in elapsed time from first exposure to 2003):
the manifestations of asbestos-related disease, and Appropriate exposure/history
interindividual differences in susceptibility to dis- Latency
ease, the existence of “safe” exposure level remains Signs and symptoms
highly questionable (Cugell and Kamp 2004). But Chest radiograph and CT scan
low-level exposure, as encountered in public build- Lung function tests
ings, probably does not represent a measurable
additional health hazard beyond what is incurred Every point has its drawbacks. For example, the
breathing outdoor air (Health Effects Institute chest radiograph is problematic when trying to
1991; Mossman et al. 1990). diagnose minimal or mild disease. A lot of workers
Asbestos fibers enter the body either by inhala- were unaware that they were exposed 30 and more
tion, ingestion, or skin contact. But for the public at years ago.
large, asbestos is harmless if swallowed. Essentially It is therefore extremely important:
all adverse effects on health are due to inhalation To take a very detailed and gapless exposure his-
(Fig. 14.1.1). Chrysotile fibers are less harmful than tory covering the time since leaving school
the amphiboles, in part because they are broken To refer to trade names of various asbestos prod-
down and removed from the lung (Roggli and ucts (e.g., Eternit, Marinite, Navelite), since work-
Sanders 2000). Short asbestos fibers can be success- ers are frequently unaware that their working
fully phagocytized and incorporated into lysosomes. material contained asbestos
This phenomenon may explain in part why long thin To show pictures of particular working condi-
fibers, i.e., > 8 µm in length, are more carcinogenic tions where asbestos contamination was typical
after inhalation or injection into the pleura or peri- but frequently unknown
toneum of rodents (Mossman et al. 1990; Kamp and
Weitzman 1999).The different types of exposure Restriction in lung function testing is too non-
have been categorized as: specific to be used as a sole diagnostic tool and is
Primary (occupational) relatively insensitive for the detection of mild fibro-
Household (family members of the occupation- sis.
ally exposed) (Sider et al. 1987) Asbestos-related diseases can be summarized as
follows:
Pleura
– Pleural effusion
– Pleural plaques, circumscribed, with / without
calcification
– Diffuse pleural thickening and diffuse pleural
fibrosis
– Mesothelioma
Lung parenchyma
– Fibrosis (asbestosis)
Lung cancer
Laryngeal cancer
a b
c d
e f
Fig. 14.1.2. a Asbestos milling. b Spraying of asbestos cement with extremely high fiber concentrations. c Asbestos exposure
in the construction industry. d Textile asbestos exposure in the textile industry. e Asbestos exposure in the construction
industry. f Asbestos exposure in a car repair shop while cleaning brake pads (courtesy of Ernst Hain, Hamburg-Harburg)
266 R. Eibel and D. Nowak
14.1.2
Special Entities
14.1.2.1
Pleural Effusions
a b
Fig. 14.1.4. a Same patient as in Fig. 14.1.3. Calcified and non-calcified pleural plaques at the lateral and mediastinal (arrows)
parietal pleura. b Calcified and non-calcified pleural plaques (chest wall and diaphragmatic pleura) (arrows)
Limited or circumscribed pleural plaques have be classified. Nevertheless, with CT the detection of
no clinically significant adverse impact on pulmo- these pleural abnormalities has a better sensitivity
nary function (Jones et al. 1988). Furthermore, and specificity and nowadays, a CT classification
plaques do not increase the cancer risk, but plaques system had been introduced for the description of
are markers of asbestos exposure, and asbestos is a pleural findings (Hering et al. 2004).
recognized carcinogen (Cugell and Kamp 2004). In
other words, the risk of lung cancer is not restricted
to workers with pleural plaques (Welch 2003). 14.1.2.4
Mesothelioma
Epitheloid (50%)
Sarcomatous or mesenchymal (16%)
Mixed (34%)
Fig. 14.1.7. Same patient as in Fig. 14.1.3. HRCT. Fine sub- 14.1.2.6
pleural lung fibrosis not reversible in prone position (not
shown here). Please note the ground-glass appearance adja-
Lung Cancer
cent to the pleural plaques (arrows)
Overall, the Nicholson study projected that nearly
500,000 workers would die from asbestos related
of these lesions, with CT reserved for problem solv- cancers between 1967 and 2030; deaths from asbes-
ing (Aberle and Balmes 1991). In former years, tosis are above and beyond this number. The poor
both the expense and the time required to perform prognosis of lung cancer (5-year survival 12%) is
CT of the entire thorax have made this examination attributable to the lack of efficient diagnostic meth-
impractical for examining large asbestos-exposed ods for early detection and the inability to cure meta-
populations (McLoud 1988). In addition, typical static disease. By contrast, when detected at an early
chest CT protocols have been associated with rela- stage (I–II) as radically resectable disease, the 5-year
tively high radiation doses to patients, which have survival can be as high as 50%–70% (Flehinger
raised concern about the potential for induced et al. 1992; Nesbitt et al. 1995; Strauss 1998). All
malignant disease, particular in screening settings major types of lung cancer are caused by asbestos.
(Remy-Jardin et al. 2004). Numerous studies show that there is a dose-response
The introduction of low-radiation-dose scan- relationship between exposure to asbestos and the
ning techniques has facilitated renewed interest in risk of lung cancer, with increasing exposure leading
270 R. Eibel and D. Nowak
to increasing risk of disease. Asbestosis is a sur- lar, occupational programs are designed to detect
rogate measure of exposure, but it is important to work-related disease at an early stage, when treat-
know that asbestosis is not a necessary intermedi- ment or removal from exposure can improve the
ary for development of asbestos related lung cancer outcome of that disease. Three types of prevention
(Welch 2003). can be differentiated:
The Helsinki Criteria establish an exposure level Primary prevention is reduction or elimination
of 25 fiber-years, or the equivalent exposure using of hazardous exposures.
an occupational history, as a level of exposure that Screening is called secondary prevention, when
significantly increases the risk of lung cancer. Sev- hazardous exposures have not been eliminated.
eral European countries have established this or a Tertiary prevention is essentially medical care
similar level of exposure as the criterion to be used and rehabilitation of disease, when it cannot be
for compensation of lung cancer in asbestos exposed reversed after diagnosis.
workers (Welch 2003).
Smoking and asbestos multiply the lung cancer Some key principles should underlie all medical
risk conferred by the other: screening programs:
Non-smoking asbestos workers were five times The test used should be selective, and chosen to
more likely to die from lung cancer. identify a specific disease.
Smokers not exposed to asbestos were approxi- There must be some effective action that can be
mately 10 times more likely to die from lung taken if the screening test is positive, such as
cancer. removal from exposure or medical treatment.
Asbestos workers who smoked were more than 50 Adequate follow-up is critical, and further diag-
times more likely to die from lung cancer. nostic tests must be available, accessible, and
Asbestos workers who stopped smoking demon- acceptable to the individual screened. Follow-
strated a sharp decrease in lung cancer mortal- up also entails action to reduce or eliminate the
ity. hazard.
Individuals who have been screened should
receive test reports and interpretations of those
14.1.2.7 results.
Screening The screening tests used should have good reli-
ability and validity.
In the USA, from 1940 to 1979, 27.5 million work- The benefits of the screening program should
ers were occupationally exposed to asbestos in outweigh the costs (Welch 2003).
shipyards, manufacturing operations, construc-
tion work and a wide range of other industries and The screening for asbestosis has several clear
occupations, 18.8 million of these having high levels public health and medical benefits:
of exposure. As a result hundreds of thousands of Identification of occupations and industries
workers and their family members have suffered or where excess exposure still occurs, so that expo-
died from asbestos-related cancers and lung disease, sure reduction can occur.
and more than a million more cases are expected. Implementation of smoking cessation programs.
Because of the long lag between exposure and the Identification of individuals at heightened risk
development of cancer or other asbestos diseases, from other occupational exposures (Welch
the worldwide asbestos disease epidemic has not 2003).
reached its peak, and will be with us for decades
(Welch 2003). However, screening is only conducted as a pre-
In 2000, the Association of Occupational and liminary step in determining the presence of asbes-
Environmental Clinics (AOEC) developed criteria tos-related disease. Therefore AOEC supports the
for medical screening programs for asbestosis and following statements:
related asbestos-related diseases; these principles Screening on the basis of CR and work history
apply equally also to screening for silicosis and alone identifies possible cases but does not itself
related diseases. Medical screening is defined as a provide sufficient information to make a firm
search for previously unrecognized disease, when diagnosis, to access impairment or to guide
finding the disease can lead to a benefit. In particu- patient management.
Exogenous Exposition: Asbestos 271
An appropriate screening program for asbestos- on an early repeat CT within 30 days in tumours as
related lung disease includes: small as 5 mm.
– Properly chosen and interpreted CR To mention briefly the cost-effectiveness, Miet-
– A complete exposure history tinen (2000) found out that CT-based screening for
– Symptom review lung cancer, suitably specified, can be presumed to
– Standardized spirometry save lives at a cost lower than the 10,000 USD per
– Physical examination saved life-year and can be effective enough, to jus-
Programs should also include: tify its cost. If diagnostic algorithms are used which
– Smoking cessation interventions have been applied in published feasibility studies,
– Evaluation for other malignancies the mean percentage of invasive diagnostic mea-
– Evaluation for immunization against pneumo sures revealing benign lesions is about 34% and thus
coccal pneumonia below those obtained in, e.g., breast cancer screen-
– Timely physician disclosure of results to the ing trials. Currently, randomized controlled studies
patient involving low dose CT in about 100,000 subjects are
– Appropriate medical follow-up on the way. Around the year 2010 we will be able to
– Patient education (Welch 2003) define whether or not lung cancer screening in high
risk populations including new techniques and stan-
So far, screening using conventional methods dardized algorithms yields a decrease in mortality
like CR and sputum cytology has mostly been con- (Nowak et al. 2005).
sidered ineffective; randomised trials have failed
to show a significant reduction in mortality rate.
This is most probably due to methodological prob- 14.1.2.8
lems and to the inadequacy of conventional CR Conclusions and Recommendations
as a screening technique (Fontana et al. 1986;
Melamed et al. 1984). However, recent studies Despite international and national actions, occu-
using low-dose spiral CT techniques report more pational exposure to asbestos in industrialized
encouraging results: the cancer detection rate countries continues to be a major cause of mor-
varied from 0.35% to 2.7%, with most tumours bidity and mortality from both lung cancer and
being small, radically resectable, peripheral ade- mesothelioma. Furthermore, benign asbestos-
nocarcinomas (stage I–II) (Henschke et al. 1999; related diseases can result in loss of work ability,
Sone et al. 1998; Kaneko et al. 1996). Tiitola et loss of years of healthy life and quality of life for
al. (2002) conducted a CT screening for lung cancer workers and their families.
in a high-risk population. A total of 602 workers Screening for asbestos-related diseases with
(38–81 years, 97% smokers) with asbestos-related respect to imaging studies refers to the visual-
occupational disease were screened using spiral ization of different benign pleural and pulmo-
CT and chest radiography and they detected suspi- nary abnormalities and the above mentioned two
cious lung nodules in 18.4% of the study popula- malignancies. And as a consequence, a method
tion. Five lung cancers and one peritoneal meso- has to be chosen, that can detect pleural effusion,
thelioma were found. Kaneko et al. (1996) found pleural plaques, small pulmonary nodules as well
abnormalities in 17% of their study population, the as well as fine lung fibrosis and mesothelioma.
ELCAP-study (Henschke et al. 1999) in 23%, and Currently, only thin-section spiral CT (slice thick-
Yoshimura et al. (1999) in 22%. Recently, Das et ness of 1–2 mm, 120 kV, 120 mA but low-dose
al. (2007) reported on a prevalence of 4.28% (i.e. 8 seems to be possible, two window settings, and
in 187) lung cancer in a high-risk asbestos-exposed matrix of 512 pixels) has an acceptable sensitivity
cohort using low-dose MDCT. for all these abnormalities. MRI, PET and ultra-
On the other hand, the great number of false posi- sound can be worthy to answer special questions,
tive findings is a fundamental problem in lung cancer but cannot be recommended as screening tools.
screening. An international standard for follow-up CR is commonly used to monitor for pneumoco-
examinations would be beneficial. Henschke et al. niosis among workers exposed to asbestos. In gen-
(1999) classified nodules as benign, if no growth was eral, its benefit for the early identification of lung
noted over 2 years. According to Yankelevitz et al. cancer has not been demonstrated due to its low
(1999), however, malignant growth can be detected sensitivity and specificity (Tossavainen 2000).
272 R. Eibel and D. Nowak
Medical screening: periodic use of standard on Nonoccupational Health Risks of Asbestiform Fibers,
sputum cytology has been evaluated for the mass Board of Toxicology and Environmental Health Hazards,
National Research Council. National Academics Press,
screening for lung cancer and was shown to be of Washington DC, pp 24–29
limited value. Bronchoscopy, including autofluo- Connelly RR et al. (1987) Demographic patterns for mesothe-
rescence endoscopy, is impractical as a screen- lioma in the United States. J Natl Cancer Inst 78:1053–
ing tool because of its cost, availability, and low 1060
Copley SJ et al. (2001) Functional consequences of pleural
patient acceptance because of the invasiveness of
disease evaluated with chest radiography and CT. Radiol-
the procedure (Tossavainen 2000). Additional ogy 220:237–243
use of serum markers such as mesothelin-related Copley SJ et al. (2007) Asbestos-induced and smoking-
peptides (Scherpereel et al. 2006) and osteo- related disease: apportioning pulmonary function deficit
pontin (Pass et al. 2005) seems promising. by using thin-section CT. Radiology 242:258–266
Cugell DW, Kamp DW (2004) Asbestos and the pleura: a re-
Controlled screening programs for high-risk
view. Chest 125:1103–1117
asbestos-exposed workers should take into con- Das M et al. (2007) Asbestos surveillance program Aachen
sideration the following known risk factors or (ASPA): initial results from baseline screening for lung
risk markers of lung cancer: cancer in asbestos-exposed high risk individuals using
– Cumulative exposure to asbestos of any fiber low-dose multidetector-row CT. Eur Radiol 17:1193–
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Exogenous Exposition: Heavy Smokers: CT Screening for Lung Cancer for High-Risk People 275
Exogenous Exposition 14
14.2 Heavy Smokers
14.2.1 CT Screening for Lung Cancer for High-Risk People
Claudia I. Henschke, Matthew Cham, and David F. Yankelevitz
CONTENTS 14.2.1.1
Background
14.2.1.1 Background 275 Screening for lung cancer in high-risk people has
been widely accepted for those exposed to asbestos
14.2.1.2 Screening for a Cancer: Its Essence 275
in the United States, Germany, France, and Finland
14.2.1.3 Evaluation of CT Screening for Lung (Straif and Silverstein 1997; Koskinin et al.
Cancer 276 1996; Frimat et al. 1999). The recommendations
thus far have been for screening with chest radi-
14.2.1.4 Diagnostic Performance 277
ography, although computed tomography (CT) is
14.2.1.4.1 Proportion Having a Positive Result of
the Initial CT Test 278 also being considered. In 2000, the Finnish Insti-
14.2.1.4.2 Proportion of Screen-Diagnosed tute of Occupational Health sponsored a meeting
Cases 281 to discuss the updating of these screening recom-
14.2.1.4.3 Proportion of Cases by Relevant mendations (Finnish Institute of Occupational
Prognostic Indicators 281
14.2.1.4.4 Proportion of Cases Resulting in a Health 2000). They invited the lead author of the
Diagnosis of Malignancy after a research study of 1000 high-risk people started in
Biopsy 281 the United States (Henschke et al. 1999, 2001) and
14.2.1.4.5 Summary of Diagnostic a mass screening study in Japan (Sone et al. 1998,
Performance 281
2001) to present their results. These two studies
14.2.1.5 Genuineness of Diagnoses 281 showed that CT is markedly superior to chest radi-
ography in detecting small, early lung cancers and
14.2.1.6 Prognostic Performance 282 it has long been established that resection of early
small lung cancers markedly improves the cure rate
14.2.1.7 Indication for Screening 282
over that of late stage lung cancer (Mountain 1997;
14.2.1.8 Summary 283 Inoue et al. 1998). Since then several studies in high-
risk occupationally exposed people have found CT
References 283 screening to be useful (Tiitola et al. 2002; Minniti
et al. 2005; Muravov 2005).
In this chapter we present the ELCAP paradigm
for the evaluation of the usefulness of CT screening
for a disease and the results to date.
asymptomatic person and to think that this testing ing regimen at issue are genuine; and even the man-
is supposed to reduce mortality from the cancer. agement of the diagnosed cases presupposes the
The diagnostic test is viewed as an ‘intervention,’ understanding of those matters, as in the end, the
and it is supposed to have ‘effectiveness’ in that it ultimate usefulness – and adverse consequences – of
should prevent the cancer’s fatal outcome. In our the screening depend on how these cases are actu-
view, it is this viewpoint and its consequent meth- ally managed. Specifically, we need to address the
odology to screening research that has led to much genuineness of the screen-diagnosed cancer, that is
of the controversy surrounding screening, not only whether it would lead to death if not resected, partic-
in screening for lung cancer but for other cancers as ularly in cases of Stage I. Next we need to determine
well (Jackson 2002; Miettinen et al. 2002a,b). how often such a genuine case is curable. In other
At variance with this view, the researchers of the words, insofar as Stage I (pre-spread detection) is
Early Lung Cancer Action Project (ELCAP) hold that achieved and early intervention is applied, we need
a sharp distinction is to be made between diagnos- to determine how frequently death from an other-
tic testing and the subsequent intervention which wise fatal cancer is avoided; and on the community
follows upon the early diagnosis (Henschke et al. level, by how much the mortality from the cancer is
1994, 2002). A diagnostic test provides informa- reduced by such screening-and-intervening.
tion about the person undergoing it but without an Recommendation for or against screening requires
associated intervention, the test has no effect on the knowledge inputs beyond the central one, the gain
subsequent course of health. An intervention, by in curability of lung cancer considered above – or
contrast, is intended to change the course of health its corresponding reduction in case-fatality rate.
for the better, to have effectiveness. For example, the Principal among these further considerations are
use of chest radiography did not change the typical the two that have critical bearing on the definition
course of pulmonary tuberculosis; rather, the inter- of the indication for the screening: the person’s risk
vention with streptomycin did (Hill 1990). for lung cancer (in the near future), and his/her life
The ELCAP viewpoint defi nes screening as the expectancy (when spared of death from lung cancer).
pursuit of early diagnosis, which starts with an These two inputs bear on when, if ever, to begin the
initial test and proceeds along a well-defi ned path screening on a given person; and insofar as it has
(screening regimen) to the diagnosis of cancer. The been initiated, when to discontinue it, including its
diagnosis which results from this pursuit is early cost. Indeed, the decision about screening for lung
in the meaning that, at the time of diagnosis, the cancer requires consideration of its benefits specific
cancer is still in the latent, asymptomatic phase of to a particular person at a particular time.
its course, and also it is hoped that it is still local-
ized and, thereby, curable. Ultimately, the aim is
to determine whether early intervention following
early diagnosis provides the hoped-for greater cura-
tive effectiveness relative to later intervention upon 14.2.1.3
prompting of symptoms, or to determine how often Evaluation of CT Screening for Lung Cancer
the pursuit of early diagnosis leads to the prevention
of the cancer’s fatal outcome. To us, the real issue is, The ELCAP report on baseline CT screening for
thus, the quantitative determination of the number lung cancer (Henschke et al. 1999) led to consid-
of deaths that can be prevented. We call the ELCAP erable public (Grady 1999) and professional inter-
study design a ‘diagnostic-prognostic’ design as it is est in the practice of CT-based screening for lung
not simply a ‘cohort’ or ‘observational’ design but a cancer. Suddenly, screening for lung cancer became
trial with two distinctive components, the diagnos- a hot topic with researchers initiating projects to
tic one and the interventive one, each component study it, the public demanding it, and medical insti-
to be evaluated separately. As for the interventive tutions offering it. The demand for information
component, alternative designs, including random- on screening led us to hold the First International
ized ones can be used, depending on the questions Conference on Screening for Lung Cancer in 1999,
which need to be answered. to which all those already performing screening
Understanding of the ultimate usefulness of CT or wishing to start it were invited (I-ELCAP 1999).
screening requires understanding whether the vari- These conferences were an outgrowth of the already
ous subtypes of diagnoses resulting from the screen- extensive role of ELCAP in helping other investiga-
Exogenous Exposition: Heavy Smokers: CT Screening for Lung Cancer for High-Risk People 277
14.2.1.4.1
Proportion Having a Positive Result of the Initial
CT Test
a b
Fig. 14.2.1.4a,b. CT of a nonsolid nodule (a), also shown in Figure 14.2.1.1 which changed into a part-solid (b) one after
4 years. This was resected and classified as an adenocarcinoma, mixed subtype
a b
Fig. 14.2.1.5a,b. CT showing growth of a nonsolid nodule. a The initial image. b The nodule 4 years later. Diagnosis upon
resection was adenocarcinoma, mixed subtype
On repeat screenings, again, the first concern with solid, or appearance of a solid component if previ-
the initial CT is to identify all non-calcified nodules, ously nonsolidI-ELCAP protocol – website: http://
but now regardless of size, and with special regard www.IELCAP.org. The result of the initial, low-dose
for the nodules(s), if any that produced a semi-posi- CT test is positive if at least one such nodule is iden-
tive result on the initial CT at baseline; and now the tified.
focus, among these, is on those that are showing Using these updated definitions, it occurred in
growth since the previous screen, of overall size or less than 15% of screenees on baseline and less than
the size of the solid component if previously part- 6% on annual repeat screening.
280 C. I. Henschke, M. Cham, and D. F. Yanekelvitz
a b
c d
Fig. 14.2.1.6a–e. Contiguous high-resolution CT (HRCT) images are obtained of the small solid nodule in the left upper
lobe at the time of detection (a), and three months later (b). c,d The three-dimensional (3D) axial, sagittal, and coronal
views of the nodule. e Provides axes for comparison purposes and more clearly demonstrates growth. The calculated volume
doubling time was 120 days. Subsequent fi ne needle aspiration biopsy resulted in a diagnosis of adenocarcinoma, mixed
subtype. and this was confi rmed by histologic diagnosis at the time of resection
Exogenous Exposition: Heavy Smokers: CT Screening for Lung Cancer for High-Risk People 281
14.2.1.4.2 14.2.1.4.5
Proportion of Screen-Diagnosed Cases Summary of Diagnostic Performance
Screen-diagnosed cases are classified as baseline The diagnostic performance of the I-ELCAP regimen
or annual repeat cancers according to the screen- of screening demonstrated that further work-up can
ing cycle in which the nodule is first identified, be limited to a reasonable percentage of the cases and
regardless of when the diagnosis is actually made. result in 80% or more being of clinical Stage I and
A screening cycle starts with the performance of the that by following the regimen of screening, 94% of the
initial test including any diagnostic work-up and recommended biopsies resulted in a malignant diag-
ends before the next routinely scheduled rescreen- nosis. A key performance parameter of the screening
ing. Any case of cancer diagnosed outside the regi- regimen is the proportion of Stage I diagnoses, and
men is called an interim-diagnosed cancer and is this proportion may be as high as 90% depending on
attributed to the cycle of screening during which it the adherence to the regimen of screening.
is diagnosed. We also demonstrated that among cases of lung
The proportion of screen-diagnosed cases was cancer diagnosed in asymptomatic persons by CT
more than 95% in the baseline cycle and 98% in screening, there is a strong relationship between
repeat cycles of screening. tumor size and lymph-node status (I-ELCAP 2006).
14.2.1.4.3
Proportion of Cases by
Relevant Prognostic Indicators 14.2.1.5
Genuineness of Diagnoses
The frequency distribution of the cases by relevant
prognostic factors (e.g., stage, size, histology) are When a person with a screen-diagnosed case of lung
important performance measures. In terms of stage, cancer dies of some other cause before having clini-
the critical determination as to treatment depends cal manifestations of lung cancer, the case is said to
on the pre-surgical stage, typically based on CT and be an ‘overdiagnosed’ case of lung cancer; and so is a
PET results, so it is the proportion of pre-surgical screen-diagnosed case that is so slow-growing that it,
Stage I diagnoses that is of particular interest. We even if left untreated, would not pose a risk for sur-
found that more than 80% of all lung-cancer diag- vival. While both are important topics to be addressed
noses, interim cases included, were of pre-surgical in the context of screening, only the latter represents
Stage I on baseline and annual repeat screening. overdiagnosis for us, the former being an issue of com-
Also, as expected, the median tumor size was larger peting causes of death. We address both topics, first
at baseline than on annual repeat. the proportion of screen-diagnosed cancers that are
genuine, that is, leading to death if not treated, and
secondly the issue of competing causes of death.
14.2.1.4.4 Potentially detracting from the apparent benefit
Proportion of Cases Resulting in a of CT screening is the possibility that a proportion
Diagnosis of Malignancy after Biopsy of the screen-diagnosed cases of lung cancer are free
of manifest metastases because they are growing so
Among the recommended biopsies according to the slowly as to not lead to death if not resected. Protec-
regimen of screening, 94% resulted in a diagnosis tion against this was built into the regimen by requir-
of malignancy. No lobectomies were performed for ing assessment of growth prior to biopsy of nodules
benign disease. Thus the screening regimen turned less than 15 mm in diameter and by pathologic
out to be quite successful in avoiding undue invasive review by a panel of expert pulmonary pathologists.
procedures, complications, and cost. On the other To supplement this, we also determined the propor-
hand, none of the biopsies performed outside of the tion of genuine clinical Stage I cases diagnosed as
regimen’s recommendation resulted in diagnosis of a result of baseline screening as these are the most
lung cancer. suspect for being slow-growing. Among the cases
282 C. I. Henschke, M. Cham, and D. F. Yanekelvitz
presenting as solid nodules, all had doubling times ment of screen-diagnosed cancer thus has a good
of less than 400 days, except for a carcinoid tumor opportunity to be life-saving.
and the cases presenting as part-solid nodules and
nonsolid nodules, the percentage was 90% and 67%,
respectively (Henschke et al. 2006). It should be
noted that a cancer of 10 mm with a doubling time
of 400 days would lead to death from it in approxi- 14.2.1.6
mately 10 years. In the repeat cycles, the cancers are Prognostic Performance
typically aggressive ones as growth since the pre-
vious screen is integral in the concept of positive The proportion of deaths that can be prevented by
result. For example, a newly-seen nodule of 3 mm CT screening can be estimated by the (proportion
means that it has grown since the prior screen when of pre-surgical Stage I cases)×(cure rate of genuine
it was not visible. Assuming it had a diameter just Stage I cases). This is a conservative estimate as it
under the visibility threshold of 2 mm on the prior assumes that all screen-diagnosed cases of higher
screen, its slowest doubling time would be 200 days. stage die. The estimated cure rate of genuine Stage I
As newly seen nodules on repeat screening are typi- cases of lung cancer is 95% and 96%, respectively for
cally 3 mm or larger in diameter when first identi- baseline and repeat screening. Thus, the estimated
fied, this means that these cancers are rapidly grow- deaths that can be prevented are 87% × 95% = 83%
ing, aggressive, genuine cancers. and 85% × 96% = 82%, respectively for baseline and
Further evidence was provided by the Pathology annual repeat screening (I-ELCAP 2005). Using,
Review Panel review of the pathologic specimens; very conservatively, the lower 95% confidence limits
all diagnoses were confirmed to be genuine lung for both of these two proportions, the correspond-
cancers. Ultimately, evidence against overdiagno- ing estimates for the probability of preventing an
sis is provided by the untreated cases of lung cancer otherwise fatal outcome of cancer for baseline and
(Henschke et al. 2003; Flehinger et al. 1992; Sobue annual repeat cycles are 76% and 68%, respectively
et al. 1992) or those in whom the recommended – still high when contrasted with the 5% (1–163,
biopsy and/or treatment was delayed. To date, all 510/172,570) or so (American Cancer Society
those cases for which treatment was delayed, pro- 2005) in the absence of screening.
gressed, and those which were not treated, died.
Any decision about screening for a cancer needs
to consider the person’s risk of dying from causes
other than lung cancer. This is particularly relevant
for lung-cancer screening as smokers and former 14.2.1.7
smokers are also at higher risk of death from other, Indication for Screening
competing causes, cardiovascular diseases in par-
ticular. To shed some light on the frequency of death We performed a traditional cost-effectiveness anal-
from a competing cause among persons who enter ysis using the actual hospital costs of the original
into CT screening for lung cancer, we determined ELCAP baseline screening and subsequent work-up,
the 5- and 10-year rates of death from causes other it was found that CT screening is highly cost-effec-
than lung cancer in a high-risk older cohort of 2141 tive, around $2500 per life-year saved, for smokers
smokers and former smokers who had enrolled for and former smokers 60 years and older with a history
CT screening for lung cancer from 1993 to 2004 of at least 10 pack-years of smoking (Wisnivesky
(Henschke et al. 2005); they were aged 60–75 years et al. 2003; ). Others using actual data have found
and had a history of 30–100 pack-years of cigarette similar results (Marshall et al. 2001a,b; Chirikos
smoking. Using Kaplan-Meier analysis, we found et al. 2002), except for one model-based analysis
that the 5- and 10-year survival rates conditional on (Mahadevia et al. 2003) using unrealistic assump-
not dying from lung cancer were 96% (95% CI: 95%– tions (e.g., a very high rate of overdiagnosis).
97%) and 91% (95% CI: 88%–93%), respectively. The decision about screening is really an indi-
Based on this analysis, older, high-risk smokers and vidual decision and thus should be based on the
former smokers seeking and receiving CT screening benefit and risks to a specific person for a particu-
for lung cancer have quite a low 10-year risk of dying lar round of screening. Once this benefit and risks
from causes other than lung cancer, and early treat- is known, the individual then has to weigh the cost
Exogenous Exposition: Heavy Smokers: CT Screening for Lung Cancer for High-Risk People 283
of the screening (typically $300) with its benefit in Carter D, Vazquez M, Flieder DB, Brambilla E, Gazdar A,
potentially not dying of lung cancer. Noguchi M, Travis WD, Kramer A, Yip R, Yankelevitz
DF, Henschke CI, ELCAP and NY-ELCAP Investigators
The survival benefit of any contemplated round (Submitted) CT screening for lung cancer: comparison
of screening is determined by the product of the of pathologic fi ndings of baseline and annual repeat can-
following four probabilities: the probability P1 that cers. Submitted
the round of screening will result in the diagnosis Chirikos TN, Hazelton T, Tockman M et al. (2002) Screening
for lung cancer with CT: a preliminary cost-effectiveness
of lung cancer, the probability P2 that of not dying
analysis. Chest 121:1507–1514
from some other cause in a sufficiently long period Diederich S, Wormanns D, Semik M, Thomas M, Lenzen H,
of time, the probability P3 that the diagnosed case, Roos N, Heindel W (2002) Screening for early lung cancer
should there be one, would be genuine and of stage I with low-dose spiral CT: prevalence in 817 asymptomatic
at the time of diagnosis and, finally, the probability smokers. Radiology 222:773–781
Finnish Institute of Occupational Health (2000) Finland
P4 that such a genuine case of lung cancer would be National Screening Seminar, Helsinki, Finland, Feb 10,
curable by early treatment. The first of these prob- 2000
abilities are specific to the individual at the time Flehinger BJ, Kimmel M, Melamed MR (1992) Survival from
while the last two depend on the regimen of screen- early lung cancer: implications for screening. Chest
ing, rather than the individual’s characteristics. 101:1013–1018
Frimat P, Paris C, Letourneux M, Catilina P, Sobaszek A
Using the I-ELCAP database, we are estimating (1999) Screening of diseases associated with asbestos.
these probabilities (I-ELCAP 2005). On-going activities, synthesis [French]. Rev Mal Respir
16(6 Pt 2):1350–1355
Grady D (1999) CAT scan process could cut deaths from lung
cancer. Small tumors detected. New York Times, July 9
1999, p 1
Henschke CI, McCauley DI, Yankelevitz DF, Naidich DP,
14.2.1.8 McGuinness G, Miettinen OS et al. (1999) Early Lung
Summary Cancer Action Project: overall design and fi ndings from
baseline screening. Lancet 354:99–105
Henschke CI, Miettinen OS, Yankelevitz DF, Libby D, Smith
Critical for determination of the effectiveness of JP (1994) Radiographic screening for cancer: new para-
screening is assessment of the diagnostic perfor- digm for its scientific basis. Clin Imag 18:16–20
mance of the regimen of screening and the con- Henschke CI, Naidich DP, Yankelevitz DF, McCauley DI.
sequent curability of the screen-diagnosed cases. McGuinness G, Smith JP, Libby DM, Pasmantier MW,
Koizumi J, Vazquez M, Flieder D, Altorki NK, Miettinen
Assessment of these performance measures provides
OS (2001) Early Lung Cancer Action Project: initial fi nd-
the information as to the proportion of deaths that ings on repeat screening. Cancer 92:153–159
can be prevented by the screening. Henschke CI, Shaham D, Yankelevitz DF, Kramer A, Reeves
Based on the results of CT screening efforts AP, Vazquez DF, Miettinen OS (2006) CT screening for
throughout the world, it is clear that CT screening lung cancer: significance of diagnoses in its baseline
cycle. Clin Imag 30:11–15
provides for a significantly higher proportion of Henschke CI, Wisnivesky JP, Yankelevitz DF, Miettinen OS
Stage I diagnoses than screening using chest radi- (2003) Screen-diagnosed small Stage I cancers of the
ography and thus also provides for a significantly lung: genuineness and curability. Lung Cancer 39:327–
higher cure rate. 330
Henschke CI, Yankelevitz DF, Mirtcheva R, McGuinness G,
McCauley D, Miettinen OS (2002) CT screening for lung
cancer: frequency and significance of part-solid and non-
solid nodules. AJR 178:1053–1057
Henschke CI, Yankelevitz DF, Naidich D, McCauley DI,
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Exogenous Exposition 14
14.2 Heavy Smokers
14.2.2 Characterization of Lung Nodules Using Radiological Imaging
Christian Fink and Frank Berger
References 291
14.2.2.2
Morphological Characterization
malignant non-solid pulmonary nodules are adeno- 1996), and may be present in up to 55% of bronchio-
carcinoma and bronchioalveolar carcinoma. loalveolar cell carcinomas (Zwirewich et al. 1991).
Mixed nodules are characterized by a non-solid The assessment of the size of a pulmonary nodule
ground glass opacity combined with a solid compo- is of major importance as the size of a nodule cor-
nent of soft tissue density. According to Yoon et al. relates with the probability of cancer. Pulmonary
(2005) 90% of mixed nodules with a ground glass nodules measuring less than 5 mm only will be
component measuring 10 mm or less are malignant, malignant in 0.1%–1% of all cases. The prevalence of
whereas only 30% of solid nodules of the same size malignancy ranges between 1% and 30% for nodules
are malignant. measuring 5–10 mm and 30%–80% for nodules sized
One of the most important imaging features that over 10 mm (Winer-Muram 2006). If a pulmonary
can be used to distinguish benign pulmonary nod- nodule shows no detectable growth over a period
ules from cancer is calcification. However, up to of 2 or more years this is commonly accepted as a
13% of lung cancers may show some calcification, reliable indicator for benignity. As a consequence
but this is true in only 2% of lung cancers smaller serial follow-up studies are commonly performed
than 30 mm in diameter (Grewal and Austin in incidentally detected nodules to rule out malig-
1994; Mahoney et al. 1990). Eccentric calcification nancy. Especially in small nodules, however, manual
should especially be considered as suspicious for measurements are not very reliable (Jennings et
malignancy. A typical benign pattern of calcifica- al. 2004). Another problem is that tumor growth
tion is a diffuse calcification which is typical for may be underestimated on two-dimensional mea-
old granulomatous disease. But also metastasis surements. For example, if the diameter of a pul-
from sarcomas, such as osteosarcoma or chondro- monary nodule increases by 26% this corresponds
sarcoma may be entirely calcified. Popcorn calci- to a volume increase of 100%. As a consequence
fication is typical feature of hamartoma. Unfor- computer assisted diagnosis (CAD) tools with auto-
tunately, calcification is often not useful, as about mated volumetry should preferably be used to assess
45% of benign nodules are not calcified (Winer- nodule growth (Marten et al. 2005) (Fig. 14.2.2.1).
Muram 2006). A limitation of these algorithms is that adjacent
The presence of fat within a pulmonary nodule is non-tumorous densities, such as inflammatory
another indicator for a benign lesion and suggests changes, atelectasis, or scars may be included in the
the diagnosis of hamartoma. However, occasionally measurement, thus resulting in an overestimation of
also malignant lesions, such as a metastasis from the nodule size. On the other hand, the ground-glass
liposarcoma or renal cell carcinoma, may contain component of a partly solid nodule, which has a high
fat (Muram and Aisen 2003). frequency of malignancy, may not be detected by the
The assessment of nodule margins is another processing algorithm. For serial examinations of
criterion which can be used for the differentiation tumor growth it has also to be taken into account
between benign and malignant lung nodules. A well- that tumors may undergo necrosis or cavitation, any
defined nodule with smooth and regular margins is of which may decrease their size.
more likely a benign lesion. However, about 20% of
malignant nodules may have well-defined and regu-
lar margins, the majority being pulmonary metas-
tasis (Erasmus et al. 2000). In contrast, irregular,
ill-defined or spiculated margins are more likely 14.2.2.3
malignant, although several benign lesions, such as Characterization of Pulmonary Nodules
organizing pneumonia may have a similar appear- Using Dynamic Imaging
ance (Beigelman-Aubry et al. 2007).
Cavitation of a pulmonary nodule is more fre- 14.2.2.3.1
quently a sign of malignancy, but may also be seen Dynamic Contrast-Enhanced CT
in benign lesions, such as abscesses. Benign cavita-
tions tend to have more regular and thinner walls Due to tumor angiogenesis, blood flow and contrast
than malignant lesions (Woodring et al. 1980). enhancement is usually greater in malignant than
Air bronchograms or bronchiolograms are more in benign pulmonary nodules. Therefore, dynamic
commonly observed in malignant nodules than in contrast-enhanced CT of nodule enhancement has
benign nodules (Zwirewich et al. 1991; Kui et al. been proposed for nodule differentiation.
Exogenous Exposition: Heavy Smokers: Characterization of Lung Nodules Using Radiological Imaging 287
Fig. 14.2.2.1. Volumetry of a suspicious lung nodule of the right upper lobe using a dedicated computer-aided diagnosis
software tool (Lung Care, Siemens Medical Solutions, Forchheim, Germany)
the microvessel density. Neither the tumor enhance- compared using a dynamic snapshot gradient-echo
ment, nor VEGF or microvessel density showed a (GRE) sequence and a conventional T1-weighted SE
correlation with the tumor size. Lymph node posi- sequence. Malignant pulmonary nodules showed a
tive lung cancers showed a higher peak enhance- significantly higher enhancement on the dynamic
ment, VEGF-expression and microvessel density snapshot GRE images than benign lung nodules.
than lymph node negative cancers. In contrast, static T1-weighted failed to show any
The correlation of angiogenesis, vascularization, significant difference of the enhancement between
and contrast-enhancement can furthermore be uti- benign and malignant lung nodules.
lized for the assessment of tumor response to anti- In a more recent study Ohno et al. (2002) inves-
angiogenic therapy (Fig. 14.2.2.2). tigated the value of dynamic contrast-enhanced
MRI for the characterization of pulmonary nodules
using a 3D dynamic MRI technique. Concordant
14.2.2.3.2 to previous studies, malignant nodules showed a
Dynamic Contrast-Enhanced MRI significantly higher and faster enhancement than
benign nodules. Similar to the study of Hittmair et
Apart from CT, dynamic contrast-enhanced MRI al. (1995) the highest and fastest enhancement was
has also been evaluated for the characterization found in active inflammatory lung nodules. Over-
of indeterminate pulmonary nodules. Potential all, their technique had a sensitivity, specificity, and
advantages of dynamic MRI over CT are the excel- accuracy of 100%, 70%, and 95%, for distinguish-
lent contrast resolution, which may allow the detec- ing the malignant and active inflammatory nodules
tion of very discrete nodule enhancement, and the from benign nodules.
smaller contrast agent bolus. In an early feasibil- Schäfer et al. (2004) evaluated 2D dynamic
ity study, Hittmair et al. (1995) showed a stronger contrast-enhanced MRI examinations in non-cal-
and faster enhancement of malignant nodules than cified and fat-free solitary pulmonary nodules in
benign neoplastic nodules using a 2D T1-weighted 58 patients. In contrast to the study by Ohno et
spoiled gradient echo sequence (2D FLASH), which al. (2002), both, the wash-in and wash-out char-
was acquired before, during and up to 15 min after acteristics of pulmonary nodules were evaluated.
injection of Gd-DTPA. However, similar to studies Malignant nodules showed a stronger enhancement
using dynamic CT also a strong enhancement was with a higher peak enhancement and a faster slope.
found in inflammatory or fibrous lesions. Significant washout (i.e. > 0.1% decrease of signal
In a subsequent study by Guckel et al. (1996) the intensity per second) was found only in malignant
enhancement patterns of pulmonary nodules was lesions (Fig. 14.2.2.3). Sensitivity, specificity, and
Fig. 14.2.2.2. Dynamic contrast-enhanced CT of pulmonary and mediastinal metastases from renal cell carcinoma. The
color-coded permeability map (right) shows a strong vascularization of the metastasis
Exogenous Exposition: Heavy Smokers: Characterization of Lung Nodules Using Radiological Imaging 289
14.2.2.4
Positron Emission Tomography (PET)/CT
and PET
insufficient for detecting malignant subcentimeter ever, nodule enhancement remains useful due to its
nodules. Regarding radiologists` interpretation of higher negative predictive value and lower costs, and
and management decision for these nodules, short- taking the above described morphological criteria
term follow-up with length of intervals depending for malignancy into account additionally improves
on the likelihood of malignancy is recommended sensitivity.
(Munden and Hess 2001). Apart from FDG, other tracers might be of poten-
Fluorine-18 FDG PET yields false-negative results tial interest for the characterization of pulmonary
in about 5% of all stage T1 lung cancers, but in only nodules. As the interest in antiangiogenesis therapy
3% of stage T1 lung cancers greater than 5 mm in is growing, the need for tumor perfusion measure-
diameter (Lee et al. 2004). ments is rising. In addition to the CT-or MRI based
The long-term survival of patients with a negative techniques, measurement of tumor perfusion using
PET scan for lung cancer suggests that these tumors positron emission tomography and H215O poten-
behave more indolently. tially is such a technique. When information of a
In a comparison of Fluorine-18 FDG PET and perfusion status of a tumor is needed, water labeled
nodule enhancement in CT, Christensen et al. with oxygen H215O may be used. Initial PET oncol-
(2006) found in a series of 42 examined nodules ogy studies using H215O were performed in brain
a sensitivity and specificity of 100% and 29% for tumors (Mineura et al. 1986). In tumors outside the
nodule enhancement CT vs 96% and 76% in FDG- central nervous system, only a few studies have been
PET. Due to its much higher specificity and only reported using a variety of different techniques. The
slightly reduced sensitivity, it must be concluded aim of the study of Hoekstra et al. (2002) was to
that FDG-PET is preferable to nodule enhancement assess whether it is feasible to measure perfusion in
CT in indeterminate pulmonary nodules. How- vivo in non-small cell lung cancer (NSCLC) using
Exogenous Exposition: Heavy Smokers: Characterization of Lung Nodules Using Radiological Imaging 291
H215O and positron emission tomography. A total Nevertheless, 18F-FDG PET/CT is an established
of 15 dynamic H215O and [(18)F]2-fluoro-2-deoxy- technique in the characterization of lung nodules.
D-glucose ((18)FDG) studies were performed in 10 Studies utilizing tracers to determine perfusion or
patients with stage IIIA-N2 NSCLC. Blood flow data hypoxia of these tumors are still in an experimental
were correlated with simplified methods of analysis stage, but might proof useful in the future to guide
(tumor:normal tissue ratio and standardized uptake antiangiogenic or conventional therapy.
value) and with glucose metabolism. FDG data were
required for accurate definition of tumor and medi-
astinal lymph node metastases. There was large
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Exogenous Exposition: Screening for Endometrial Cancer in Asymptomatic Patients Receiving Tamoxifen Therapy 293
Exogenous Exposition 14
14.3 Screening for Endometrial Cancer in Asymptomatic Patients
Receiving Tamoxifen Therapy
Sandra A. Polin, Sandra J. Allison, and Susan M. Ascher
CONTENTS 14.3.1
Introduction
References 306
14.3.2
Background
14 months ahead of schedule when initial results tamoxifen exposure (Machado et al. 2005). The
showed a 49% reduction in the development of breast incidence is higher in women treated with tamoxi-
cancer in women at high risk who were randomly fen than in untreated women: 8%–36% vs 0%–10%
assigned to receive tamoxifen (20 mg/day), as com- (Lahti et al. 1993; Cheng et al. 1997; Kedar et al.
pared with women at high risk who received a placebo 1994; Cohen et al. 1994; Barakat 1996; Corley et
(Fisher et al. 1998). Based on these findings, on Sep- al. 1992; Schlesinger et al. 1998). Although these
tember 2, 1998, the Food and Drug Administration polyps may cause abnormal uterine bleeding, most
advisory committee unanimously voted to recom- women are asymptomatic.
mend approval of tamoxifen to reduce women’s risk of In the general population, endometrial polyps
developing breast cancer (Kolata 1998). The implica- typically measure 0.5–3.0 cm in diameter, and,
tions of the Breast Cancer Prevention Trial and Food microscopically, contain a mixture of three ele-
and Drug Administration decisions are underscored ments in varying degrees: (a) stroma of dense
by the fact that according to their criteria, more than fibrous tissue, (b) thick-walled vascular chan-
10 million U.S. women qualify for breast cancer che- nels, and (c) endometrial glands (Schlesinger et
moprevention (Freedman et al. 2003). al. 1998; Corley et al. 1992). Tamoxifen-related
polyps tend to be larger (mean diameter 5 cm)
and differ in their microscopic composition: a
combination of proliferative activity (cystic glan-
dular dilatation), aberrant epithelial differentia-
14.3.3 tion (metaplasia), and focal periglandular stromal
Mechanism of Action condensation (Schlesinger et al. 1998; Corley et
al. 1992; Ismail 1994). The importance of the peri-
Tamoxifen is a nonsteroidal antiestrogen agent that glandular stromal condensation is unknown, but it
binds to estrogen receptors. This results in both anti- has been postulated that it may be associated with a
estrogen action on breast tissue, as well as weak estro- form of Müllerian adenosarcoma (Ismail 1994). In
gen agonist effect in endometrial tissue, leading to a addition, extensive stromal reaction (i.e., fibrosis)
spectrum of associated endometrial abnormalities The may account for difficulties in resecting tamoxi-
abnormalities can be categorized into benign alterations fen-related polyps at hysteroscopy. Tamoxifen-
including endometrial polyps, endometrial hyperplasia, associated polyps have a reported increased rate
endometrial cystic atrophy, adenomyosis, and uterine of malignant change. Cohen reported malignant
fibroid growth, as well as malignant transformation into change in 3% of tamoxifen-treated women who
endometrial carcinoma, uterine sarcoma, and malig- had postmenopausal breast cancer, compared with
nant mixed tumor of the uterus (De Muylder et al. 1991; 0.48% in controls (Cohen et al. 1999). Schlesinger
Neven et al. 1990; Gal et al. 1991; Fornander et al. 1989; et al. reported a 10.7% rate of malignant change in
Lahti et al. 1993; Cheng et al. 1997; Kedar et al. 1994; polyps of tamoxifen treated patients (Schlesinger
Cohen et al. 1994; van Leeuwen et al. 1994; Fisher et al. 1998).
et al. 1994; Uziely et al. 1993; Ismail 1994; Barakat
1996; Cohen 1997; Corley et al. 1992). Tamoxifen also
exerts complex effects via mechanisms unrelated to the 14.3.4.2
estrogen receptor (Mourits et al. 2001). Endometrial Hyperplasia
basis of microscopic findings of a morphologically Several studies found that most cases of endome-
abnormal proliferative-type endometrium. Some trial cancers occurring in tamoxifen treated patients
authors insist that, in addition, there must be an were of low grade and stage, with no differences in
abnormal increase in endometrial volume (Kurman stage, grade, or histologic subtype compared to
1994). non-treated patients (Mignotte et al. 1998; Fisher
Endometrial hyperplasia can be divided into et al. 1994; van Leeuwen ea1994; Peters-Engl et
hyperplasia with cytologic atypia and hyperplasia al. 1999; Barakat et al. 2000). However, other stud-
without cytologic atypia. These categories are fur- ies have found endometrial cancers in postmeno-
ther subdivided into simple or complex depending pausal patients treated with tamoxifen to be more
on the extent of glandular complexity and crowd- advanced with poorer prognoses than in non-treated
ing. The nomenclature has prognostic significance: patients (Magriples et al. 1993; Wilder et al. 2004;
In up to 23% of patients with atypical hyperplasia, Deligdisch et al. 2000; Narod et al. 2001; Bergman
the hyperplasia progresses to carcinoma, com- et al. 2000; Lasset et al. 2001). These studies have
pared to only 2% in those without atypia (Kurman shown an increase in unfavorable histologies (sar-
1994). comas and Müllerian mixed tumors) resulting in
advanced stage at time of diagnosis and worse sur-
vival (Bergman et al. 2000; Cohen 2004; Narod et
14.3.4.3 al. 2001; Wickerham et al. 2002). Some studies have
Endometrial Carcinoma found the endometrial cancer mortality rate among
tamoxifen treated patients significantly higher com-
Tamoxifen chemotherapy or prophylaxis increases pared to non-treated patients due to the unfavor-
the relative risk of developing endometrial cancer able histology of the endometrial malignancy and
(Osborne 1998; Fisher et al. 1994, 1998; van advanced stage at diagnosis (Bergman et al. 2000;
Leeuwen et al. 1994; Andersson et al. 1991; Uziely Cohen 2004; Narod et al. 2001; Deligdisch et al.
et al. 1993). Studies have reported a 1.3- to 7.5-fold 2000; Magriples et al. 1993; Ragaz and Coldman
increase in the relative risk of developing endome- 1998).
trial cancer (Osborne 1998; Fisher et al. 1994, 1998;
van Leeuwen et al. 1994; Ismail 1994; Barakat
1996), with data from major clinical studies indi- 14.3.4.4
cating tamoxifen use results in an approximately Other Uterine Changes
twofold increase in the incidence rate of endome-
trial cancer (Early Breast Cancer Trialists’ Other uterine changes reported in association with
Collaborative Group 1998; Curtis et al. 1996; tamoxifen treatment include “tamoxifen” mucosa or
Assikis et al. 1996). This slight increase in endo- endometrial cystic glandular atrophy, adenomyosis,
metrial cancer risk led the International Agency for and leiomyomas (Varras et al. 2003; Neven et al.
Research on Cancer (IARC) to classify tamoxifen as 1998; Cohen et al. 1994, 1995; Ugwumadu et al.
an endometrial carcinogen (IARC 1996). 1993).
The risk of developing endometrial cancer At hysteroscopy, endometrial cystic atrophy is
increases with duration of treatment and cumula- described as smooth, white, hypervascularized,
tive tamoxifen dose as well as with prior estrogen and atrophic, with scattered protuberances that
replacement therapy, obesity, hypertension, and represent cystic atrophy (Neven et al. 1998). This
the presence of endometrial pathologic conditions “tamoxifen” mucosa with its protuberances differs
before the initiation of tamoxifen (Fisher et al. 1998; macroscopically from the atrophic mucosa seen
Osborne 1998; van Leeuwen et al. 1994; Barakat in postmenopausal women who are not receiving
1996; Ismail 1994; Vosse et al. 2002; Berliere et tamoxifen. In the latter, the mucosa is characterized
al. 1998; Fong et al. 2003). The Early Breast Cancer as pale, thin, and without protuberances (Gompel
Trialists’ Collaborative Group reported the inci- 1994).
dence of endometrial cancer in patients treated Endometrial cystic atrophy is diagnosed his-
with tamoxifen approximately doubled in trials tologically when multiple cystic spaces lined by
of 1 or 2 years and approximately quadrupled in atrophic endometrium are present within a dense
trials of 5 years (Early Breast Cancer Trialists’ fibrous stroma (McGonigle et al. 1998). In patients
Collaborative Group 1998). treated with tamoxifen, the exact location of the
296 S. A. Polin, S. J. Allison, and S. M. Ascher
cysts is controversial. Some investigators report eral authors have concluded that there is no sig-
that the cysts extend to the endometrial-myometrial nificant benefit to screening asymptomatic women
junction but clearly reside within the endometrium; treated with tamoxifen for endometrial cancer.
others have placed the cysts in the subendome- Neven reported that decreasing mortality from
trial location (McGonigle et al. 1998; Goldstein endometrial cancer in tamoxifen users is unlikely
1994; Achiron 1995). This is further complicated as most tamoxifen-associated endometrial lesions
by the fact that endometrial glands that extend into are benign polyps without premalignant change and
the myometrium may also be called adenomyosis. the risk of developing endometrial cancer is small
Whether the apparent increased incidence of adeno- (Neven and Vergote 1998). After reviewing the
myosis in women treated with tamoxifen is a true literature, Cardosi and Fiorica (2000) determined
separate phenomenon or represents a spectrum of that routine endometrial surveillance is not war-
tamoxifen-associated cysts („adenomyosis-like ranted in asymptomatic postmenopausal women
changes“) is unknown (Cohen et al. 1995). Regard- taking tamoxifen for the following reasons: the
less of their location, the cysts seen in women treated majority of women with premalignant and malig-
with tamoxifen do not appear to be premalignant nant endometrial lesions are symptomatic, random
(McGonigle et al. 1998). endometrial sampling has a very low yield, and
The leiomyomas observed in women treated screening sonography will lead to additional diag-
with tamoxifen do not differ histologically from nostic procedures in more then 50% of women. Fung
those found in untreated women (Dilts et al. 1992; et al. (2003) found a positive predictive value of only
Lumsden et al. 1989). However, the presence of leio- 1.4% when using an endometrial thickness of 9 mm
myomas, adenomyosis, and polyps may contribute as the cutoff for detecting endometrial carcinoma.
to the larger uterine volume reported in women They concluded that routine screening in asymp-
treated with tamoxifen (Cohen et al. 1995; Cheng et tomatic women on tamoxifen was not useful. In a
al. 1997; Fornander et al. 1989; Lahti et al. 1993). cost-benefit analysis of screening tamoxifen-treated
patients, Bakarat reported the decrease in mortality
for screening asymptomatic women on tamoxifen
14.3.4.5 for endometrial cancer would be only 0.03% of all
Paradoxical Effects tamoxifen-treated patients (Barakat et al. 2000).
Since approximately 80,000 women begin tamoxi-
Interestingly, tamoxifen has apparent paradoxical fen annually, the cost of screening for endometrial
effects at the uterine level. Some portions of the cancer in women taking tamoxifen was felt to be
endometrium may be stimulated by tamoxifen, prohibitive (Barakat et al. 2000).
while others undergo the effects of a more accel- Other authors have concluded that there may be
erated menopause. As a result, coexistent atrophy a benefit to screening asymptomatic women. Uziely
and adenomyosis have been described in postmeno- et al. (1993) studied 95 patients with breast cancer
pausal women treated with tamoxifen (Cohen et al. treated with tamoxifen who underwent endovaginal
1994, 1995). These seemingly contradictory findings US followed by endometrial biopsy. Histopathologic
can be explained, in part, by the existence of more changes were observed in 14 patients, 13 of whom
than one population of uterine receptors respond- had been treated for more than 12 months and all
ing to tamoxifen and/or the possibility that growth of whom had an endometrial thickness of more
sites may lose their sensitivity to the antiestrogenic than 5 mm. These changes included polyps in four
effects of tamoxifen after an initial stimulatory patients, hyperplasia in three patients, dysplasia
response (McGonigle et al. 1998). in three patients, and carcinoma in three patients.
The authors found a statistically significant corre-
lation between long-term tamoxifen administration
and endometrial proliferation and therefore rec-
ommended that women treated with tamoxifen for
14.3.5 more than 12 months undergo annual endovaginal
Screening Review US and endometrial biopsy. Sinawat (2002) stud-
ied 37 asymptomatic postmenopausal breast cancer
The main purpose of a screening program is to patients who had taken 20 mg/day of tamoxifen for
detect disease at an early more curable stage. Sev- at least 6 months. He found the prevalence of endo-
Exogenous Exposition: Screening for Endometrial Cancer in Asymptomatic Patients Receiving Tamoxifen Therapy 297
metrial cancer to be 5.26% and suggested a reliable Some of the studies that found no significant
surveillance method for endometrial abnormality benefit to screening asymptomatic patients noted
should be offered to all asymptomatic postmeno- that endometrial cancers occurring in breast cancer
pausal breast cancer patients undertaking long term patients were of similar stage and prognosis as those
tamoxifen treatment. occurring in women who had not undergone tamox-
Some authors have attempted to identify a subset ifen treatment. Because endometrial cancer in the
of patients who are at high risk for developing general population has a generally good prognosis,
tamoxifen related endometrial pathology in whom the authors concluded early detection would prob-
screening may prove to be beneficial. In a prospec- ably not improve outcome significantly (Barakat
tive study by Berliere et al. (1998), 264 women with et al. 2000). However, as previously discussed, addi-
breast cancer were evaluated for endometrial abnor- tional studies are suggesting that endometrial can-
malities before initiating tamoxifen therapy. Women cers occurring in tamoxifen treated patients have
with endometrial thickness > 4 mm underwent out- more aggressive histologies, with higher mortality
patient hysteroscopy with endometrial biopsy. Of the rates, raising the possibility that there may indeed
264 women, 46 (17.4%) had asymptomatic baseline be a benefit to screening (Cohen 2004; Bergman et
endometrial lesions. Of these 46 women, one had al. 2000).
atypical hyperplasia and one had endometrial ade- Adding to the controversy is a lack of consensus
nocarcinoma in situ. The other 44 women had endo- on the means to carry out surveillance. Endometrial
metrial polyps, submucosal myomas, and hyperpla- biopsy, a safe but invasive procedure, is generally not
sia without atypia. After 3 years, the authors found recommended in asymptomatic women on tamoxi-
an equal incidence of benign endometrial lesions fen due to its low yield. This is because tamoxifen
but a significantly higher incidence of hyperplasia induced endometrial lesions are usually subepithe-
with atypia and adenocarcinoma in the group with lial and focal in nature resulting in false negatives
baseline abnormalities (11.7% vs 0.7%). The authors (Suh-Burgmann and Goodman 1999; Marconi
concluded that they had prospectively identified a et al. 1997; Hann et al. 2003; Barakat et al. 2000).
group of women at high risk of developing endo- Hysteroscopy is superior to blind endometrial sam-
metrial cancer on tamoxifen treatment. They also pling but is too aggressive for screening asymptom-
observed a high percentage of asymptomatic lesions atic women on tamoxifen (Develioglu et al. 2004).
and they recommended that regular endometrial Screening with endovaginal US, an inexpensive,
surveillance of tamoxifen treated women, even in readily available, noninvasive method, is limited by
the absence of symptoms, should be performed. a significant false positive rate and lack of consensus
In breast cancer patients, the adverse effect of on the appropriate cutoff for normal endometrial
developing endometrial cancer is outweighed by thickness in women treated with tamoxifen.
improved survival and lower incidence of contra- Additionally, there is no consensus on the dura-
lateral breast cancer (Jaiyesimi et al. 1995; Early tion of and interval for screening. While studies
Breast Cancer Trialists’ Collaborative have found that endometrial thickening returns
Group 1998). However, the risk/benefit ratio from to normal after cessation of tamoxifen treatment
tamoxifen as a preventive therapy against breast (Gerber et al. 2000; Love et al. 1999), some authors
cancer is unclear. Data from the Breast Cancer Pre- assert that the risk of endometrial carcinoma may
vention Trial suggest that the benefits of tamoxi- remain after cessation of therapy (Bergman et al.
fen therapy outweigh the real, but small 2.5-fold 2000).
increased risk of developing endometrial cancer Currently, the American College of Obstetricians
(Fisher et al. 1998). However, when stratified by age, and Gynecologists does not recommend screening by
the risk of endometrial cancer increased to four- endometrial biopsy or transvaginal ultrasound for
fold in women over 50 years of age (Early Breast asymptomatic women. They recommend all women
Cancer Trialists’ Collaborative Group 1998; undergo annual gynecologic exam and that women
Ferrazzi and Leone 2004). After reviewing the be educated about their increased risk of endome-
literature, Machado et al. (2005) felt that screen- trial cancer. Women are encouraged to promptly
ing asymptomatic women may be appropriate in (a) report any abnormal uterine bleeding. Any abnor-
all patients on tamoxifen as chemoprophylaxis, to mal vaginal symptoms should then be investigated
improve the risk/benefit ratio in these patients and (ACOG 2001). The American College of Obstetricians
in (b) long-term users of tamoxifen. and Gynecologists also states the use of tamoxifen
298 S. A. Polin, S. J. Allison, and S. M. Ascher
for chemoprevention should be limited to 5 years (78.7%). Kedar et al. (1994) reported that endome-
(ACOG 2002). However, physician surveys have indi- trial thickness greater than 8 mm on ultrasound
cated that physicians favor surveillance of asymp- had a 100% positive predictive value for endome-
tomatic breast cancer patients treated with tamoxi- trial disease. A study by Franchi et al. (1999) found
fen. One study of breast cancer patients showed that the proportion of women with abnormal histo-
that 42% of tamoxifen users reported regular sur- logic findings was higher among those with endo-
veillance for uterine abnormalities (Althuis et al. metrial thicknesses greater than 9 mm, compared
2000). Therefore, radiologists must become familiar with those with endometrial thickness 9 mm or less
with the imaging features of the uterus in women (60% vs 6.1%). A study by Ito et al (2001) also advo-
receiving tamoxifen and the relative strengths and cated 9 mm as the optimal cutoff for endometrial
weaknesses of the various imaging modalities with thickness. A retrospective study by Develioglu
respect to evaluation of the uterus. et al. 2004 reported the optimal cutoff of endo-
metrial thickness at ultrasonography was 9.5 mm
with a sensitivity of 89% and specificity of 78% for
endometrial pathology. Gerber et al. (2000) recom-
mended a 10-mm cutoff to try to reduce the false
14.3.6 positive rate of ultrasonography and the resulting
Imaging Review unnecessary aggressive tests.
These statistics should be interpreted with cau-
14.3.6.1 tion. Positive histologic findings (e.g., endometrial
Endovaginal Ultrasound proliferation and simple hyperplasia) may be clini-
cally unimportant. Moreover, a thicker endometrium
US is the first-line imaging modality for evaluation on the US image does not necessarily correlate with
of the endometrium. The normal postmenopausal specific pathologic endometrial findings (Cohen et
endometrium appears as a single echogenic line al. 1993). Additionally, while using a lower cut-off
and should not exceed 5 mm as a bilayer thickness value for endometrial thickness should improve the
(Goldstein et al. 1990; Granberg et al. 1991). In sensitivity of endovaginal US for detecting endo-
general, women undergoing tamoxifen treatment metrial carcinoma, achieving 100% sensitivity is
have a thicker endometrium as compared with still limited. In a case report, Renard et al. (2002)
that in control subjects (9–13 mm vs 4.0–5.4 mm) noted a case of endometrial cancer in an asymptom-
(Cheng et al. 1997; Lahti et al. 1993; Kedar et atic patient with breast cancer with an endometrial
al. 1994; Cohen et al. 1994). In postmenopausal thickness of 3 mm.
women undergoing estrogen replacement therapy, Regardless of the cutoff value for detecting endo-
the normal endometrium may measure up to 8 mm metrial abnormalities, the most common endome-
in thickness. However, the upper limit for normal trial transvaginal US pattern seen in women treated
endometrial thickness on endovaginal US in asymp- with tamoxifen is a thickened endometrium with
tomatic women receiving tamoxifen remains con- cystic spaces described as a “Swiss cheese” pattern
troversial (Fong et al. 2003; Levine et al. 1995). (Fig. 14.3.1) (Lahti et al. 1993; Cheng et al. 1997;
Various authors have recommended cut-off Kedar et al. 1994; Uziely et al. 1993; Cecchini et
values ranging from 4 to 10 mm. In a prospective al. 1996; Hulka and Hall 1993; Hann et al. 1997;
study, using an endometrial thickness of 5 mm as Atri et al. 1994; Love et al. 1999; Mourits et al.
the upper limit of normal, Cohen et al. (1993) found 1999). The findings of a thickened endometrial com-
the sensitivity of endovaginal US in relation to posi- plex, with or without cystic changes, is often non-
tive histologic findings was 91%, and the specific- specific and may be caused by endometrial polyps,
ity was 96%. In a prospective study by Fong et al. submucosal leiomyoma, cystic atrophy, endometrial
(2001, 2003), an endometrial thickness of 6 mm hyperplasia, or carcinoma (Fong et al. 2003). Cer-
was found to be the optimal endometrial thickness tain sonographic findings may improve specificity.
for diagnosing endometrial abnormalities with a A distinct hyperechoic line partially or completely
sensitivity of 85.1% and specificity of 55.7%. The surrounding the endometrial complex favors a focal
combination of transvaginal ultrasound and hys- intracavitary process such as a polyp or submucosal
terosonography further increased the specificity to fibroid (Fong et al. 2003; Baldwin et al. 1999). Sub-
77.1% without a significant decrease in sensitivity mucosal fibroids may be hypoechoic or heterogenous
Exogenous Exposition: Screening for Endometrial Cancer in Asymptomatic Patients Receiving Tamoxifen Therapy 299
and often demonstrate acoustic attenuation (Atri et pathologic conditions and to resolve discrepancies
al. 1994; Fong et al. 2003). Sonographic findings of between endometrial thickening on endovaginal US
adenomyosis include uterine enlargement, asym- images and insufficient material or nondiagnostic
metric thickening of the anterior or posterior uter- results at endometrial biopsy (Wolman et al. 1996;
ine wall, increased myometrial echotexture, het- Cohen et al. 1993; Dubinsky et al. 1997; Shipley et
erogeneous poorly circumscribed areas within the al. 1994; Langer et al. 1997; Lev-Toaff 1996; Cul-
myometrium, and myometrial or subendometrial linan et al. 1995). Specifically, hysterosonography
cysts. These findings can result in a false-positive is an attractive adjunct to endovaginal US because
appearance of thickened endometrium at trans- it more clearly defines endoluminal lesions that are
vaginal ultrasound (Fong et al. 2003). Endometrial pedunculated or sessile and can be used to better
carcinomas are often either diffusely or partially determine whether an abnormality is endometrial
echogenic (Atri et al. 1994; Fong et al. 2003). While or subendometrial (Fig. 14.3.2).
poorly defined endometrial thickening is usually The potential utility of hysterosonography in
suggestive of malignancy, this is not a helpful diag- imaging of tamoxifen-related changes was noted
nostic feature in women treated with tamoxifen due in a 1994 case report (Bourne et al. 1994) in which
to underlying adenomyosis (Fong et al. 2003). a patient treated with tamoxifen was described as
having an atrophic endometrium at endometrial
biopsy despite a thickened endometrium (1.9 cm)
14.3.6.2 on endovaginal US images. Hysterosonography
Hysterosonography demonstrated a large polyp, which was confi rmed
and excised at hysteroscopy. Later, Goldstein
Hysterosonography has increasingly been used (1994) described five women with a thick, “irregu-
to improve the ability to diagnose intrauterine lar, bizarre, heterogeneous” endometrium on endo-
300 S. A. Polin, S. J. Allison, and S. M. Ascher
a c
b d
Fig. 14.3.2a–d. Hysterosonography as adjunct to endovaginal ultrasound. a Sagittal endovaginal ultrasound demonstrates
a thickened endometrium. b Sagittal hysterosonogram shows an endometrial polyp accounting for the endometrial thicken-
ing. c In the same patient, a small fibroid (calipers) abuts the endometrium and a submucosal component cannot be excluded.
d Hysterosonogram shows the fibroid (calipers) is intramural without a submucosal component
endometrial thickness of more than 8 mm at trans- round structures arising from the myometrium,
vaginal ultrasound. Hysterosonography revealed commonly with wide attachment to the myome-
hyperechoic or polypoid masses in 22 patients, trium, although they are occasionally peduncu-
and histologic results confi rmed the presence of lated (Fong et al. 2003). Hysterosonographic fea-
benign endometrial polyps (12 patients), polyps tures of adenomyosis include small cysts which
with simple or complex hyperplasia (4 patients), appear in the inner myometrium (Fong et al. 2003).
leiomyomas (2 patients), and no tissue obtained Diffuse smooth thickening of the endometrium
(4 patients). In the remaining 46 patients, hystero- suggests hyperplasia, however, hyperplasia may
sonography did not reveal any intracavity pathol- also appears as irregular asymmetric endometrial
ogy. Correlative hysteroscopy and biopsy revealed thickening (Laifer-Narin et al. 1999). An irregu-
complex hyperplasia (2 patients), simple hyperpla- lar heterogenous mass or irregular focal thicken-
sia (5 patients), and atrophic endometrium or no ing of the endometrium is suggestive of endome-
tissue (39 patients). There were no false negative trial carcinoma (Fong et al. 2003).
hysterosonographic diagnoses. The authors con-
cluded that hysterosonography has high sensitivity
(100%) and a high positive predictive value (95.5%) 14.3.6.3
in patients receiving tamoxifen who have an endo- Doppler
metrial thickness of more than 8 mm at endovagi-
nal US. In an attempt to increase the specificity of sonogra-
In a retrospective study of 51 patients treated phy for detecting endometrial pathology, Doppler
with tamoxifen, Hann et al. (2003) found a sig- studies of the endometrium of women on tamoxifen
nificantly higher sensitivity of hysterosonography have been performed. Several studies have shown
(100%) versus endometrial biopsy (4%) for the diag- lower impedance of the uterine and endometrial
nosis of endometrial polyps. She concluded that flow compared with control groups (Achiron et al.
sonohysterography should be considered for evalu- 1995; Kedar et al. 1994; Sladkevicius et al. 1994;
ation of abnormal uterine bleeding or thickened Develioglu et al. 2004). However, in the majority
endometrium even if endometrial biopsy results of these studies Doppler indices have been unable to
are negative. differentiate between benign and pathologic etiolo-
At hysterosonography, polyps appear as gies (Achiron et al. 1995; Sladkevicius et al. 1994;
smoothly marginated echogenic masses with or Develioglu et al. 2004). In certain cases, color Dop-
without cystic areas. Polyps often have a narrow pler US can improve the specificity of sonography by
attachment to the endometrium but may be broad- showing the feeding artery in the pedicle of a polyp
based (Fig. 14.3.3). Submucosal fibroids appear as (Atri et al. 1994) (Fig. 14.3.4).
a b
Fig. 14.3.6. a Sagittal T2-weighted fast spin-echo MR shows significantly thickened endometrium with heterogeneous signal
intensity. b The corresponding sagittal gadolinium-enhanced spoiled gradient-echo MR image shows latticelike enhance-
ment travsersing the endometrial canal and was found to represent a benign endometrial polyp. The corresponding ultra-
sound is shown in Fig, 14.3.1a. (Reprinted with permission from Silva et al. 1998)
304 S. A. Polin, S. J. Allison, and S. M. Ascher
a
b
a
Fig. 14.3.8. a Saittal endovaginal ultrasound shows a thickened
hetrogenous endometrium (calipers). b T2-weighted fast spin-
echo MR image shows a heterogeneous mass distending the
endometrial canal. The junctional zone remains intact allowing
exclusion of deep myometrial invastion. At hysterectomy, superfi-
cal endometrial carcinoma was found without evidence of myo-
metrial invasion b
Exogenous Exposition: Screening for Endometrial Cancer in Asymptomatic Patients Receiving Tamoxifen Therapy 305
b c
spurious endometrial thickening on endovaginal US also noted that most cases of endometrial cancers
scans. The authors (Ascher et al. 1995) concluded occurring in tamoxifen treated patients were of
that both modalities are sensitive for the detection similar prognosis to non-treated patients. However,
of endometrial abnormalities, although neither is other studies are finding that endometrial cancer
very specific. mortality rates among tamoxifen treated patients
are significantly higher compared to non-treated
patients due to an increase in unfavorable histolo-
gies (Bergman et al. 2000; Cohen 2004; Narod et
al. 2001; Deligdisch et al. 2000; Magriples et al.
14.3.7 1993; Ragaz and Coldman 1998). In light of these
Conclusion findings, further studies may be necessary to evalu-
ate if screening may be able to improve the mortality
Significant controversy still exists regarding appro- in this population.
priate surveillance for endometrial cancer in asymp- In breast cancer patients undergoing tamoxi-
tomatic women treated with tamoxifen. fen treatment, it is clear that the adverse effect of
Earlier studies which concluded there is no sig- developing endometrial cancer is outweighed by
nificant benefit to screening asymptomatic women improved survival and lower incidence of contra-
306 S. A. Polin, S. J. Allison, and S. M. Ascher
lateral breast cancer (Jaiyesimi et al. 1995; Early Acknowledgement. The authors acknowledge Aki
Breast Cancer Trialists’ Collaborative Kido, for assisting with the images.
Group 1998). However, in healthy women, the risk/
benefit ratio from tamoxifen as a preventive therapy
against breast cancer is unclear. Authors have sug-
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Genetic Disposition: Breast Cancer – Screening in Women with an Inherited Risk 311
Genetic Disposition 15
15.1 Breast Cancer – Screening in Women with an Inherited Risk
Thomas Schlossbauer, Karin Hellerhoff, and Claudia Perlet
CONTENTS 15.1.1
Introduction
15.1.1 Introduction 311 Although all women are at high risk for breast
cancer, various studies have demonstrated that
15.1.2 Women at Increased Risk –
Standardized Risk Evaluation 312 certain subgroups have a significantly increased
15.1.2.1 Patient’s Perspective 312 probability of developing this disease compared
15.1.2.2 Family History 312 to their same-age counterparts. In the early 1990s,
15.1.2.3 BRCA1 and BRCA2 Testing 312 two genes (BRCA1 and BRCA2) have been identi-
15.1.2.4 Clinical Relevance of Breast Cancer
fied in which mutations are associated with an up
Susceptibility Gene Detection 314
15.1.2.5 Additional Risk Factors 314 to 85% lifetime risk for developing breast cancer. It
15.1.2.6 Radiation Exposure in Screening and is estimated that more than 50% of BRCA1 muta-
Radiation Therapy 314 tion carriers have already developed the disease by
age 50 (Easton et al. 1995). In addition, BRCA1
15.1.3 Radiological Screening in High Risk
Populations 314 and BRCA2 genes are associated with an increased
15.1.3.1 Who Should Participate in Intensified risk for ovarian cancer. Other genetic predisposi-
Screening Programs? 314 tions for breast cancer might exist, but have not
15.1.3.2 Intensified Radiological Screening 315 yet been discovered. Therefore, evaluation of family
15.1.3.3 MRI Screening 315
history for breast and ovarian cancer is of signifi-
15.1.3.4 High-frequency Ultrasound 318
cant importance for the detection of individuals at
15.1.4 Breast Biopsy 318 moderate or high risk. Mammography is the cur-
rent standard screening method for early diagnosis
15.1.5 Primary Preventive Measures 320 of breast cancer. However, women at high-risk tend
15.1.5.1 Bilateral Preventive Mastectomy 320
15.1.5.2 Preventive Salpingo-Ovaraectomy 320
to develop cancer at a younger age, when their tissue
is more dense and the detection of small in-situ and
15.1.6 Summary 320 invasive cancer is more challenging. In this context,
additional imaging modalities and shorter screen-
References 321 ing intervals might contribute a potential benefit.
Nevertheless, in this age group, breast tissue shows
an increased sensibility for radiation. Different
recent studies support the application of contrast-
enhanced MRI in high-risk screening. The diagnos-
tic value of high-frequency ultrasound is currently
under evaluation. Besides imaging, an adapted
clinical surrounding is of significant importance
T. Schlossbauer, MD for intensified care of high-risk individuals. Radiol-
K. Hellerhoff, MD ogy and gynaecology departments should establish
C. Perlet, MD
Department of Clinical Radiology, University Hospitals –
intensive interdisciplinary cooperation and should
Grosshadern, Ludwig-Maximilians-University of Munich, consult a human genetics specialist for individu-
Marchioninistrasse 15, 81373 Munich, Germany alized risk assessment. Mammography-, ultra-
312 T. Schlossbauer, K. Hellerhoff, and C. Perlet
Table 15.1.1. Criteria for classification of women into moderate and high risk for developing breast cancer. Guidelines of
the National Institute of Clinical Excellence
One fi rst degree relative diagnosed with breast cancer Two fi rst, or one fi rst + one second degree relative both
< 40 years diagnosed with breast cancer < 50 years
One fi rst degree relative + one second degree relative or Three fi rst degree + second degree relatives diagnosed
two fi rst degree relatives diagnosed with breast cancer < 60 years
at any age Four fi rst + second + third degree relatives diagnosed
Two second degree paternal relatives with breast cancer at any age
Three second degree relatives maternal relatives diag- One ovarian + one breast cancer diagnosed < 50 years
nosed with breast cancer at any age Two ovarian and one breast cancer at any age
One fi rst degree male relative diagnosed with breast One ovarian + two breast cancers < 60 years
cancer at any age One bilateral breast cancer case both sides < 50 years
One fi rst degree relative with bilateral breast cancer Male breast cancer at any age + breast cancer < 50 years
One fi rst or second degree relative with breast cancer + or two breast cancer cases under 60 years
one fi rst or second degree relative with ovarian cancer at Close family members Ashkenazi Jewish families with
any age (one must be fi rst degree) breast cancer < 40 years or ovarian cancer
Family patterns including Li-Fraumeni or hereditary
non-polyposis colonic carcinoma
These genes show an autosomal dominant mode of Table 15.1.2. Increased probability of BRCA 1/2 mutation in
inheritance (Parmigiani et al. 1998). Mutations of respective family histories
BRCA1 and BRCA2 genes are associated with an Two or more relatives with breast or ovarian cancer
increased risk for breast and ovarian cancer and
Breast cancer occurring before age 50 in an affected rela-
are widely spread in the general population (Miki
tive
et al. 1994; Wooster et al. 1995). Certain specific
BRCA mutations are clustered among ethnic groups, Relatives with both, breast and ovarian cancer
such as Ashkenazi Jews, and generally in the popu- One or more relatives with two cancers (breast and ovarian
lations of Belgium, the Netherlands, Iceland, and cancers or two independent breast cancers)
Sweden. Genetic testing should be considered in Male relatives with breast cancer
patients with suspicious family histories. Family
A family history of breast or ovarian cancer and Ashkenazi
history characteristics that suggest a genetic breast Jewish heritage
cancer risk are summarized in Table 15.1.2 (Isaacs
et al. 2000). The diagnostic value and drawbacks of
genetic testing have to be discussed in detail with
the affected person and only those who have signed cancers. Other genes, maybe with multi-factorial
informed consent should be enrolled. heredity, have not yet been identified.
Genetic risk can be inherited equally from mater- The American Society of Oncology (ASCO)
nal and paternal side. There may be no apparently has provided an update on its general guidelines
affected first-degree relatives. Any woman with a for genetic testing for cancer (ASCO 1996). These
BRCA1 or BRCA2 mutation should be considered guidelines help to determine who would ben-
at high risk. If mutation testing is not available, or efit from testing and recommendations have been
has been done but is non-informative, or if testing accepted by those who provide genetic counselling
was refused by the affected individual, family his- and testing services. Risk assessment is likely to
tory (Table 15.1.1) characteristics have to be used for offer the greatest benefit for women aged less than
genetic risk evaluation. Individuals with pedigree 40. Patient education should consist of a compre-
high-risk criteria should be enrolled in intensified hensive discussion of the benefits, limitations, and
screening, even if genetic testing gives a negative risks of undergoing genetic testing. To date, there
result. BRCA1 and BRCA2 mutations are likely to be is a lack of information regarding post-test disclo-
responsible for only about half of hereditary breast sure. The optimal manner in which the post-test
314 T. Schlossbauer, K. Hellerhoff, and C. Perlet
tive BRCA1 or BRCA2 test result, the test is classi- lesion. Routine annual MRI screening (Fig. 15.1.1e–
fied “non-informative”, and the individual risk for g) shows a round, well-defined retromamillar lesion
developing breast cancer will be calculated from in the right breast. Histological evaluation after sur-
pedigree criteria. The threshold to include patients gical excision of the lesion confirmed an invasive
into an intensified screening program is determined ductal carcinoma.
between 15% to 30% lifetime risk, according to Based on an analysis among 192 BRCA mutation
different international criteria. Software tools for carriers, recommendations for intensified screen-
standardised risk evaluation based on individual ing in high-risk populations were provided (Kuhl
analysis of family history are available (“Cyrillic”, et al. 2000). A significantly increased sensitivity and
“BRCA-PRO”). Risk assessment should be performed equal specificity of contrast-enhanced breast MRI
by a human genetics specialist. compared to mammography was found. Results jus-
tify annual MRI screening within high-risk popu-
lations. Similar studies were conducted in differ-
15.1.3.2 ent countries (including the U.S. and Canada), and
Intensified Radiological Screening study results could be reproduced several times.
Sensitivity for the detection of breast cancer is
Different imaging modalities could potentially be approximately twice as high in MR screening com-
included into an intensified screening process, e.g. pared to mammography. Based on these findings,
mammography, high-resolution ultrasound, and intensified screening in high-risk groups includes
contrast-enhanced breast MRI. Recommendations annual mammograms starting at an age of 30 years,
for specific imaging techniques and screening inter- annual contrast-enhanced MRI, and periodic high-
vals are predominantly based on incidence analyses frequency ultrasound once every 6 months.
at different age groups. Women at increased risk
might benefit from additional screening strategies
beyond those offered to women at average risk. The 15.1.3.3
evidence currently available is insufficient to justify MRI Screening
strict recommendations for a specific modality or
screening interval (Smith et al. 2003). Based on the Screening MRI is not recommended for women at
limited available information and expert opinion, average risk. In these individuals, MRI is recom-
general recommendations have been developed by mended solely for generally accepted indications,
the ACS in 2003 (Smith et al. 2006). These guidelines e.g. staging in patients with known malignancy, his-
include the fact that women at increased risk should tory of breast cancer and postoperative scarring, and
talk with their doctors about the benefits and limi- searching for cancer of unknown primary. The high
tations of starting mammography checks earlier, sensitivity of the method would lead to the detection
having additional tests (for example, breast ultra- of a large number of false positive lesions which sub-
sound, or MRI), or having more frequent exams. sequently require invasive evaluation. However, in
Screening in each individual should be based on individuals with an increased risk for breast cancer,
shared decision-making after a review of poten- MRI represents a valuable screening method. In
tial benefits, limitations, and dangers of different these populations, sensitivities for the detection of
screening strategies and the degree of uncertainty cancer between 71% and 100% have been reported
about each. Generally, in patients with elevated risk, (Lehmann 2006). The relatively low detection rates
screening should be initiated at the age of 30 (or of mammography (sensitivities between 0% and
5 years prior to the first cancer episode in family 40%) and ultrasound (sensitivities between 13% and
history) and intervals should not exceed 1 year. 40%) in high-risk populations underline the value of
In cases of a documented high-risk situation (e.g. MRI in this particular surrounding. During a clini-
mutation carriers, high-risk family history), inter- cal evaluation conducted with BRCA1 and BRCA2
vals should not exceed 6 months (Pichert et al. mutation carriers, 9.3% of women developed in situ
2003). Figure 15.1.1a–d shows mammograms of a or invasive cancer within a 36 months period under
65-year-old high-risk patient (BRCA2, father with observation. Figure 15.1.2a,b shows right mammo-
breast cancer) who had breast-conserving therapy grams of a 40-year-old high-risk patient (BRCA1)
(left side) because of an invasive ductal carcinoma with mastectomy because of left breast invasive
3 years ago. Mammograms do not show a suspicious breast cancer 4 years ago. No suspicious lesion
316 T. Schlossbauer, K. Hellerhoff, and C. Perlet
a b c d
e f g
Fig. 15.1.1. a–d Digital mammograms of a 65-year-old patient 3 years after breast conserving therapy. Residual parenchyma
in anterior localisation. No suspicious lesion could be detected. Corresponding 3D T1-weighted fast low-angle shot sequence.
e Pre-contrast image. f Fourth repetition after contrast injection (0.1 mmol/kg) shows a round-shaped retromamillar lesion
with homogenous enhancement. g Subtraction
could be detected. Additional routine MR screen- malignancy has been reported (Warner et al. 2001).
ing (Fig. 15.1.2c,d) depicts two focal lesions with Similar results were found regarding sensitivity of
pronounced contrast enhancement. Subsequent MRI screening. MRI findings in each patient need
histological evaluation confirmed a bifocal invasive to be compared with previous studies and findings
ductal cancer. from clinical evaluation, mammography, and ultra-
The positive predictive value of suspicious con- sound in order to improve diagnostic accuracy. The
trast-enhancing lesions in MRI depends on the expe- MR-mammographic detection of in-situ carcinoma
rience of the reader. A high correlation of the experi- is particularly challenging. Typical signs of malig-
ence of readers and the positive predictive value for nancy, like intense contrast enhancement and signal
Genetic Disposition: Breast Cancer – Screening in Women with an Inherited Risk 317
a b
c d
Fig. 15.1.2. a,b Mammograms of the right breast of a 40-year-old patient with previous mastectomy of the left breast because
of ductal invasive cancer. Mammograms show dense parenchyma (ACR3) and no focal lesion. c,d Corresponding contrast-
enhanced dynamic MRI (subtraction images) shows two suspicious lesions with an intense homogenous enhancement in
the right breast. Histological evaluation confi rmed a bifocal ductal invasive carcinoma
intensity time curves with a washout phenomenon cancer. Excision biopsy was made 1 year ago because
in the post-initial phase are missing in 40%–60% of of a palpable lesion 12 months ago. There was an
in-situ lesions. Of in-situ carcinomas, 10% do not additional excision biopsy 9 months ago, again
show the contrast enhancement pattern character- because of a palpable lesion. Both lesions showed a
istic for malignant tumors, but a delayed enhance- benign histology. In mammography, besides post-
ment with a spotty, linear, segmental or ductal shape operative changes, no focal lesion was visible. Cur-
(Hwang et al. 2003). rent MRI shows a small lateral round-shaped lesion
Figure 15.1.3 displays the sinistral breast MRI of a (Fig. 15.1.3a,b). Histological evaluation after MR-
58-year-old high-risk patient with previous left side guided biopsy showed an invasive ductal carcinoma
breast conserving therapy because of ductal invasive (Fig. 15.1.3c).
318 T. Schlossbauer, K. Hellerhoff, and C. Perlet
a b c
Fig. 15.1.3a–c. Sinistral breast MRI of a 58-year-old high-risk patient with previous left side breast conserving therapy
because of ductal invasive cancer. Excision biopsy 1 year ago because of a palpable lesion 12 months ago. Additional exci-
sion biopsy 9 months ago, again because of a palpable lesion. Both lesions showed a benign histology. In mammography,
besides postoperative changes, no focal lesion was visible. Current MRI shows: a,b a small lateral round-shaped lesion; c
histological evaluation after MR-guided biopsy showed an invasive ductal carcinoma
Figure 15.1.4a–d shows mammograms of a 45- the shortcomings of mammography, and it causes
year-old patient with known BRCA1 mutation. In a substantial number of false positive diagnoses.
the left breast extensive polymorphic microcalci- A combination of MRI and mammography screen-
fications are present in the inner quadrants. MRI ing with ultrasound does not result in a substan-
(Fig. 15.1.4e–g) shows a homogenous enhancement tial improvement of diagnostic accuracy. However,
of the parenchyma of the left breast which affects high-frequency ultrasound is recommended as the
all four quadrants. The right breast does not show imaging modality of choice every 6 months to close
a substantial enhancement. Histological evaluation the gap between the annual mammography and MRI
confirmed a ductal in-situ carcinoma with invasive screening intervals in high-risk individuals. To date,
components. a substantial diagnostic outcome, i.e. earlier detec-
tion of interval-carcinomas, has not been reported.
15.1.3.4
High-frequency Ultrasound
a b
c d
Fig. 15.1.4. a–d Polymorph microcalcifications in the inner quadrants (see text). e–g Corresponding MRI study. Ductal
carcinoma in situ with invasive components. Homogenous contrast enhancement in sinistral residual parenchyma. 3D T1-
weighted fast low-angle shot sequence. e Pre-contrast image. f Fourth repetition after contrast injection. g Subtraction
true positive findings in image-guided biopsy, ade- for histological evaluation and the sampling error
quate planning of subsequent surgical procedures is reduced. For MR-guided and mammography-
can be achieved. Techniques in use include fine- guided interventions, vacuum-assisted techniques
needle aspiration cytology, core-needle biopsy, and should be preferred (Perlet et al. 2002). Its main
vacuum-assisted core-biopsy (Vargas et al. 2000). advantage concerns the acquisition of a larger tissue
For guiding the biopsy, the imaging method should volume. This allows one to reduce sampling error,
be employed in which the target lesion is most read- which is important for the histopathologic diagnosis
ily detected. Compared to core-needle and vacuum- of small in situ malignancies or borderline lesions.
assisted biopsy, fine-needle aspiration techniques Furthermore, tissue shift by bleeding is avoided by
have become less important, as the first mentioned continuous suction and errors due to tissue shift
methods provide more representative specimens may be compensated by removing a sufficiently large
320 T. Schlossbauer, K. Hellerhoff, and C. Perlet
area of tissue (1.5–2 cm in diameter). Finally, cor- Table 15.1.3. Outcome measures for prophylactic mastec-
rect biopsy can be proven by direct visualization of tomy (PM) according to EUSOMA
lesion removal on the postinterventional images. Final cosmetic result of the reconstructed breast follow-
MR-guided vacuum-assisted biopsy in high-risk ing PM should be excellent (with complete satisfaction on
patients has a high diagnostic value and allows to behalf of the woman), in at least 75% of cases
greatly reduce the number of surgical interventions Minor complications (e.g. infection, persistent pain, lim-
(Perlet et al. 2006; Viehweg et al. 2006). In 97 ited skin necrosis, etc.) should be expected in less than 10%
cases, only 24% of focal enhancing lesions showed of cases
a malignant histology. In MR-guided interventions, Asymmetry of the breast with modification in shape (and
success rates of up to 98% have been reported. MRI consistency) and contracture of peri-prosthetic capsula
guided biopsy should be conducted between days 7 should occur in less than 20% and 10%, respectively
and 15 after the fi rst day of menstrual cycle in order Of women undergoing PM, 100% should be completely
to avoid hormone induced contrast enhancement. informed by the plastic surgeon, of the type of operation,
Additionally, hormone replacement therapy should they are undergoing and the possible complications should
be interrupted approximately 4 weeks prior to each be explained in detail
breast MRI. By now, several biopsy devices for MR- Of women undergoing PM, 95% should be followed up with
guided intervention have been developed and most an annual physical examination carried out by a breast and
aids available provide medial and lateral access. plastic surgeon
Similar to MR-guided interventions, there is no When the correct positioning of the implant is to be
technical difference in performing mammography assessed, ultrasound examination should be adopted in
and ultrasound-guided biopsies between high-risk 100% of cases
and average-risk populations. If initial ultrasound If a possible rupture of the implant is suspected, MRI
did not show a pathologic finding, but subsequent should be prescribed in 100% of cases
MRI evaluation leads to the detection of a suspi-
cious lesion, ultrasound should be repeated. In cases
which finally show a morphologic correlate under and procedures for diagnostic evaluation to ensure
the knowledge of the MRI result, ultrasound-guided quality of treatment are summarized in Table 15.1.3.
biopsy should be performed. Potential advantages Follow-up examinations should include ultrasound
of ultrasound-guided biopsy include lower costs, if implant dislocation is suspected. MRI should be
higher acceptance by affected individuals, and a performed for the evaluation of implant rupture.
less time consuming procedure compared to MRI-
guided biopsy.
15.1.5.2
Preventive Salpingo-Ovaraectomy
in high-risk individuals. MRI should be part of the ASCO (1996) Statement of the American Society of Clinical
annual breast cancer screening in these patients. Oncology: Genetic testing for cancer susceptibility. J Clin
Oncol 14:1730
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situ carcinomas) which frequently do not fulfi l the functioning. Patient Educ Couns 53:79–86
standard MRI criteria of malignancy. Assessment Easton DF, Ford D, Bishop DT (1995) Breast and ovarian
cancer incidence in BRCA1-mutation carriers. Breast
of suspicious lesions should be performed without
Cancer Linkage Consortium. Am J Hum Genet 56:265–
delay in order to minimize psychological distress 271
of patients. Compared to surgical evaluation, ultra- Hwang ES, Kinkel K, Esserman LJ, Lu Y, Weidner N, Hylton
sound-, mammography-, or MR-guided biopsy rep- NM (2003) Magnetic resonance imaging in patients diag-
resent cost-effective and time-saving alternatives nosed with ductal carcinoma-in-situ: value in the diagno-
sis of residual disease, occult invasion, and multicentric-
with comparable diagnostic accuracies. Screening of ity. Ann Surg Oncol 10(4):381–388
high-risk individuals should be embedded into a spe- Isaacs CJ, Peshkin BN, Lerman PB (2000) Evaluation and
cialized clinical surrounding with close cooperation management of women with a strong family history of
of radiologist, gynaecologist, and human genetics breast cancer. In: Harris LMJR, Morrow M, Osborne CK
specialist. Each of the screening methods has limita- (eds) Diseases of the breast, 2nd edn. Williams & Wilkins,
Lippincott, Philadelphia pp 237–254
tions, and there are potential harms associated with Kauff ND, Satagopan JM, Roson ME et al. (2002) Risk-reduc-
false-positive findings. Women should be informed ing salpingo-oophorectomy in women with BRCA1 or
about the benefits and limitations of screening. Mul- BRCA2 mutation. N Engl J Med 346:1609–1615
tiple international studies have demonstrated that Kirova YM, Stoppa-Lyonnet D, Savignoni A et al. (2005)
Risk of breast cancer recurrence and contralateral breast
MRI is a powerful tool for the early detection of cancer in relation to BRCA1 and BRCA2 mutation status
breast cancer in high-risk individuals. Results could following breast-conserving surgery and radiotherapy
be independently reproduced. However, to date, the (for the Institut Curie Breast Cancer Study Group). Eur
impact of intensified screening on survival remains J Cancer 41:2304–2311
unclear. Further studies need to be conducted to Kuhl CK (2006) Familial breast cancer: what the radiologist
needs to know. Fortschr Röntgenstr 178:680–687
evaluate if the earlier detection of malignant lesions Kuhl CK, Schmutzler RK, Leutner CC et al. (2000) Breast MR
finally leads to higher survival rates. imaging screening in 192 women proved or suspected to
The authors of this section support annual mam- be carriers of a breast cancer susceptibility gene: prelimi-
mography and breast MRI, and additional high-fre- nary results. Radiology 215:267–279
Kuhl CK, Schrading S, Leutner CC, Morakkabati-Spitz N,
quency ultrasound every 6 months in patients who
Wardelmann E, Fimmers R, Kuhn W, Schild HH (2005)
fulfi l high-risk criteria. Screening should be initi- Mammography, breast ultrasound, and magnetic reso-
ated approximately 5 years prior to the first case in nance imaging for surveillance of women at high familial
family history (e.g. mother diagnosed with breast risk for breast cancer. J Clin Oncol 23(33):8469–8476
cancer at the age of 35, daughter starts screening at Lehman CD (2006) Role of MRI in screening women at high
risk for breast cancer. J Magn Res Imaging 24:964–970
30 years of age). Lerman C, Schwartz MD, Miller SM, Daly M, Sands C, Rirner
BK (1996) A randomized trial of breast cancer risk coun-
seling: interacting effects of counseling, educational
level, and coping style. Health Psychol 15:75–83
Liede A, Karlan BY, Narod SA (2004) Cancer risks for male
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view of the literature. J Clin Oncol 22:735–742
American College of Radiology (1993) Breast Imaging Lynch HT, Watson P, Conway T, Fitzsimmons ML, Lynch
Reporting and Data System (BI-RADS) American College J (1988) Breast cancer family history as a risk factor
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Reporting and Data System (BI-RADS) American College Meijers-Heijboer H, van Geel B, van Putten WL et al. (2001)
of Radiology, Reston, VA Breast cancer after prophylactic bilateral mastectomy in
Antoniou AC, Gayther SA, Stratton JF, Ponder BA, Easton women with a BRCA1 or BRCA2 mutation. N Engl J Med
DF (2000) Risk models for familial ovarian and breast 345:159–164
cancer. Genet Epidemiol 18:173–190 Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harsh-
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of breast and ovarian cancer associated with BRCA1 and the breast and ovarian cancer susceptibility gene BRCA1.
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Hum Genet 72:1117–1130 risk assessment and BRCA mutation testing for breast
322 T. Schlossbauer, K. Hellerhoff, and C. Perlet
and ovarian cancer susceptibility: systematic evidence Smith RA, Saslow D, Andrews Sawyer A, Burke W, Cos-
review for the U.S. Preventive Service Task Force. Ann tanza ME, Evans WP, Foster RS, Hendrick E, Eyre HJ,
Intern Med 143:362–379 Sener S (2003) American Cancer Society guidelines for
NICE Guidelines (2004) Familial breast cancer. The clas- breast cancer screening: update 2003. CA Cancer J Clin
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BRCA1 and BRCA2. Am J Hum Genet 62:145–158 Acta Obstet Gynecol Scand 85(1):93–105
Perlet C, Heinig A, Prat X, Casselman J, Baath L, Sittek H, Struewing JP, Lerman C, Kase RG, Giambarresi TR, Tucker
Stets C, Lamarque J, Anderson I, Schneider P, Taourel P, MA (1995) Anticipated uptake and impact of gentic test-
Reiser M, Heywang-Köbrunner SH (2002) Multicenter ing in hereditary breast and ovarian cancer families.
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106(5):982–990 Viehweg P, Bernerth T, Kiechle M, Buchmann J, Heinig A,
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mastectomy for women at high risk of breast cancer (on MR-guided intervention in women with a family history
behalf of EUSOMA). Eur J Cancer 38:23–26 of breast cancer. Eur J Radiol 57(1):81–89
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ian cancer risk. Ann Oncol 14:9–19 and ultrasound for surveillance of women at high risk for
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Genetic Disposition: Practical Aspects and Results of Screeening for Medullary Thyroid Carcinoma 323
Genetic Disposition 15
15.2 Practical Aspects and Results of Screeening for
Medullary Thyroid Carcinoma
Friedhelm Raue and Stefan Delorme
F. Raue, MD
Professor, Endocrine Practice, Brückenstrasse 21, 69120 15.2.3
Heidelberg, Germany Therapeutic Modalities
S. Delorme, MD
Professor, Department of Radiology, German Cancer Research
Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, To date, the only established treatment modality
Germany is surgical removal of the thyroid and regional
324 F. Raue and S. Delorme
measured with specific and sensitive two-site assays. cious for MTC, more than 200 pg/ml indicate MTC
This procedure allows early diagnosis and early sur- in nearly 100%. This procedure allows the preopera-
gery of MTC, reducing the significant mortality asso- tive diagnosis of unsuspected MTC at a relative early
ciated with this malignant tumour. It is well known, stage where the tumor is limited to the thyroid and a
that basal plasma Calcitonin can also be elevated definitive cure by surgical treatment is possible.
during normal childhood and pregnancy in differ-
ent malignant tumors, Hashimoto’s thyroiditis and
chronic renal failure. Patients with these conditions,
however, usually have blunted or absent stimulatory
responses to Calcitonin secretagogues. Provocative 15.2.6
Calcitonin stimulation tests thus help to sort out these RET Mutations in MEN 2 Patients
false-negative and false-positive conditions. There
are a number of other substances, including carcino- The MEN 2 gene was localised to centromeric chro-
embryonic antigen (CEA), PDN-21 (katacalcin), chro- mosome 10 by genetic linkage analysis in 1987. Point
mogranin A, neurone-specific enolase, somatostatin, mutations of the RET proto-oncogene were iden-
ACTH, that are produced by MTC and which may tified in 1993 in MEN 2A, MEN 2B and FMTC in
help to differentiate it from other tumors. six closely located exons (Kouvaraki et al. 2005).
Routine Calcitonin measurement has been sug- Analysis of RET in families with MEN 2A and
gested for the work-up of patients with thyroid nod- FMTC revealed that only affected family members
ular disease (Fig. 15.2.1), followed by a pentagastrin had germline missense mutations. This has brought
stimulation test in all cases of detectable basal Cal- major advances in our understanding of the molecu-
citonin levels more than 30 pg/ml. Stimulated calci- lar genetic basis of medullary thyroid cancer and
tonin levels of more than 100 pg/ml is highly suspi- has significantly changed the clinical management
of these families with hereditary tumors.
Thyroid nodule The RET gene has 21 exons and encodes a recep-
tor tyrosine kinase that appears to transduce growth
Serum calcitonin determination and differentiation signals in several developing tis-
sues including those derived from the neural crest. It
is expressed in cells, such as C-cells, the precursors
normal elevated
<10 pg/ml >10 pg/ml
of medullary thyroid carcinoma, and in pheochro-
mocytomas. The RET gene codes for a receptor that
pentagastin stimulation test has a large extracellular cysteine-rich domain which
is involved in ligand binding, a short transmembrane
stimulated Calcitonin domain, and a cytoplasmic tyrosine kinase domain
which is activated upon ligand-induced dimerization.
30-100 pg/ml >100pg/ml
Recent studies have provided evidence for an
re-evaluate after suspected MTC
activating effect of receptor mutations associated
6 months with MEN 2/FMTC. It was demonstrated that muta-
tion of the extracellular cysteine at codon 634 causes
total thyroidectomy spontaneous receptor dimerization, enhanced
phosphorylation, and cell transformation without
histologically confirmed MTC
ligand binding (autophosphorylation). Mutation of
the intracellular tyrosine kinase (codon 918) has no
RET- gene analysis
effect on receptor demerization but causes enhanced
Negative positive phosphorylation of a different set of substrate pro-
SporadicMTC MEN 2 /familial MTC teins and also results in cellular transformation.
Point mutations in the RET proto-oncogene have
been identified in 92%–100% of MEN 2 and FMTC
Family screening with
families in exon 8, 10, 11, 13–16 (Berndt et al. 1998;
specific RET-mutation
Frank-Raue et al. 1996; Kouvaraki et al. 2005). In
Fig. 15.2.1. Screening for sporadic and familial medullary the majority of these families, germline point muta-
thyroid carcinoma (MTC) tions are found tightly clustered in five cysteine
326 F. Raue and S. Delorme
15.2.8
Conclusion
Frank-Raue K, Buhr H, Dralle H, Klar E, Senninger N, Weber correlation in hereditary medullary thyroid cancer and
T, Rondot S, Höppner W, Raue F (2006) Long-term out- associated endocrine tumors. Thyroid 15:531–544
come in 46 gene carriers of hereditary medullary thyroid Leboulleux S, Baudin E, Travagli JP, Schlumberger M (2004)
carcinoma after prophylactic thyroidectomy: impact of Medullary thyroid carcinoma. Clin Endorinol 61:299–
induvidual RET genotype. Europ J Endocrinol 155:1–9 310
Gimm O, Sutter T, Dralle H (2001) Diagnosis and therapie Machens A, Nicolli-Sire P, Hoegel J, Frank-Raue K, van
of sporadic and familial medullary thyroid carcinoma. Vroonhoven TJ, Roeher HD, Wahl RA, Lamesch P, Raue
J Cancer Res Clin Oncol 127:156–165 F, Conte-Delvox B, Dralle H (2003) Early malignant pro-
Hoegerle S, Altehoefer C, Ghanem N, Brink I, Moser E, gression of hereditary medullary thyroid cancer. New
Nitzsche E (2001) 18F-DODO positron emission tomograp- Engl J Med. 349:1517–1525
ghy for tumour detection in patients with medullary thy- Raue F, Frank-Raue K (2005) Diagnosis of medullary thyroid
roid carcinoma and elevated calcitonin levels. Eur J Nucl carcinoma. In: Biersack H-J, Grünwald F (eds) Thyroid
Med 28:64–71 cancer, 2nd edn. Springer, Berlin Heidelberg New York,
Karges W, Dralle H, Raue F, Mann K, Reiners C, Grussendorf pp 297–309
M, Hüfner M, Niederle B, Brabant G (2004) Calcitonin Saller B, Moeller L, Görges R, Janssen OE, Mann K (2002)
measurement to detect medullary thyroid carcinoma in Role of conventional ultrasound and color doppler sonog-
the nodular goiter: German evidence-based consensus raphy in the diagnosis of medullary thyroid carcinoma.
recommendation. Exp Clin Endocrinol Diabetes 112:52– Exp Clin Endocrinol Diabetes 110:404–407
58 Vitale G, Caraglia M, Ciccarelli A, Lupoli G, Abbruzzese A,
Kouvaraki MA, Shapiro SE, Perrier ND, Cote GJ, Gagel RF, Tagliaferri P, Lupoli G (2001) Current approaches and
Hoff AO, Sherman SI, Lee JE, Evans DB (2005) RET Proto- perspectives in the therapy of medullary thyroid carci-
Onkogene: a review and update of genotype-phenotype noma. Cancer 91:1797–1800
Predisposing Diseases: Chronic Hepatitis and Liver Cirrhosis 329
Predisposing Diseases 16
16.1 Chronic Hepatitis and Liver Cirrhosis
Gerald U. Denk and Ulrich Beuers
16.1.10 Non-alcoholic Steatohepatitis 333 Hepatitis B is one of the most frequent infections
world-wide. According to the World Health Orga-
16.1.11 Chronic Liver Disease and Hepatocellular
nization two billion people have been infected and
Carcinoma 333
more than 350 million suffer from chronic infec-
References 334 tion. In the Western world transmission of the
hepatitis B virus mostly occurs via sexual contact
and intravenous drug abuse. Pre- and perinatal
transmission of the hepatitis B virus from infected
Liver cirrhosis is the final stage of a chronic hepato- mothers to the embryo is very common with up
pathy characterized by widespread fibrosis, nodule to 95% of cases worldwide, but is not a frequent
formation and destruction of the lobular and vas- route of infection in the Western world. Between
cular architecture of the liver. Alcohol abuse and 5% and 10% of infected adults and 90% of infected
chronic viral hepatitis are the main causes of liver newborns become chronic carriers of the virus
cirrhosis. Other less frequent causes are inherited with an increased risk for developing cirrhosis and
(e.g., hemochromatosis, Wilson’s disease, α1-anti- hepatocellular carcinoma. According to the Robert
trypsin deficiency) and autoimmune disorders (e.g., Koch Institute (Berlin, Germany) the risk for devel-
oping cirrhosis in HBe antigen positive carriers is
8%–10% per year and 2%–5.5% per year in HBe
G. U. Denk, MD
Department of Medicine II , University Hospitals – Grosshadern, antigen negative carriers. The risk for developing
Ludwig-Maximilians-University of Munich, Marchionini- hepatocellular carcinoma is increased by a factor
strasse 15 , 81377 Munich, Germany of 100 in patients with chronic infection with the
U. Beuers, MD hepatitis B virus with an incidence of 0.5% per year
Professor, Department of Gastroenterology and Hepatology,
Academic Medical Center, University of Amsterdam,
and 2.5% per year in case of known cirrhosis in
Meibergdreef 9, P.O. Box 22700, 1100 DE Amsterdam, comparison with the normal population (Bruix
The Netherlands and Sherman 2005).
330 G. U. Denk and U. Beuers
Also the hepatitis D virus (HDV) is prevalent all deficiency virus. Pre- and perinatal transmission
over the world. An infection with this virus is pos- of the hepatitis C virus from infected mothers to
sible only in the presence of the hepatitis B virus. the fetus/newborn occurs in less than 5% of cases
Both, simultaneous infection with hepatitis B and is dependent on the viral load of the mother.
virus and hepatitis D virus (coinfection) as well So far six genotypes of the hepatitis C virus have
as sequential infection of chronic carriers of the been described with varying geographic distribu-
HBs antigen (superinfection) may occur. Coinfec- tion. The natural course of hepatitis C is character-
tion presents clinically like an acute infection with ized by a high rate of chronification in up to 85% of
hepatitis B virus; the risk for developing chronic cases. Spontaneous elimination of the virus is rare.
hepatitis is not increased. In contrast, superinfec- Liver cirrhosis is expected in 20% of patients with
tion is associated with a more progressive course chronic infection after 20–30 years. The risk for
with an increased risk for developing liver cirrho- developing hepatocellular carcinoma is between 2%
sis. Besides standard liver biochemistry, serologi- and 8% per year in patients with manifest cirrhosis
cal markers are essential for the diagnosis of hep- (Bruix and Sherman 2005). Anti-HCV antibodies
atitis B and D. Acute infection with the hepatitis B and HCV-RNA in serum are diagnostic markers of
virus is characterized by anti-HBc IgM, HBs anti- chronic and acute infection with the hepatitis C
gen, and HBV-DNA in serum. Persistence of HBs virus, respectively. In case of chronic infection, i.e.
antigen and HBV-DNA for more than 6 months is after more than 6 months, serum HCV-RNA should
indicative of chronification of the infection. Acute be quantified and the genotype of the virus should
infections with the hepatitis B virus are not treated be determined. In chronic hepatitis C, pegylated
specifically because of the low frequency of chroni- interferon α in combination with ribavirin for 48
fication in symptomatic patients. Only in fulminant weeks (genotype 1) or 24 weeks (genotype 2, 3) is
hepatitis B with liver failure, that occurs in less than the standard therapy resulting in sustained virus
1% of cases, lamivudine should be administered. control – i.e. no detection of HCV-RNA in serum
For treatment of chronic hepatitis B, several thera- for more than 6 months after therapy – in 50%
peutic options are currently available and experts of the treated patients. While successful elimina-
differ in their view of primary drug therapy. Inter- tion of the hepatitis C virus is achieved in only
feron α can be used successfully for the treatment 40%–50% of cases with genotype 1, HCV elimina-
of high-replicative HBe antigen-positive patients tion is observed in more than 80% of cases with the
with a sustained response, defi ned as sustained genotypes 2 and 3. Treatment of acute hepatitis C
loss of HBe antigen, in 30%–40% of patients. In is controversially discussed. An immediate start
addition, pegylated interferon α has been licensed with pegylated interferon and ribavirin and start
for the treatment of chronic hepatitis B since 2005 after observation for 3 months both revealed high
and has recently been shown to be superior to lami- sustained rates of viral clearance. A comparison of
vudine in HBe antigen-positive patients. Alterna- these treatment strategies is currently the subject
tively, lamivudine or – in case of lamivudine resis- of a large randomized multicenter study (Dienstag
tance – adefovir can also be used successfully for and McHutchison 2006).
the treatment of HBe antigen-positive patients.
Further treatment options are awaited in the near
future (Perrillo 2005).
16.1.3
Hemochromatosis
involve the genes for hemojuvelin, hepcidin, the of the mostly young patients reflect liver damage
transferrin receptor 2, and ferroportin 1 (hemo- and/or neurological and psychiatric involvement.
chromatosis type 2a, 2b, 3, and 4) (Pietrangelo In about 5%, Wilson’s disease presents with acute
2004). Having developed liver cirrhosis, patients liver failure and hemolysis. Wilson’s disease can be
with hemochromatosis have a markedly increased diagnosed when two of the following four condi-
risk (20-fold) for hepatocellular carcinoma with an tions are fulfi lled: (1) a Kayser-Fleischer corneal
annual incidence of 3%–4% (Bruix and Sherman ring, (2) reduced coeruloplasmin serum level (less
2005). Typical symptoms for patients with advanced than 0.2 g/L), (3) increased urine copper excretion
hemochromatosis are fatigue, skin pigmentation, (more than 100 µg in urine collected over 24 h), and
impotence, amenorrhoea, arthralgia, abdominal (4) markedly elevated copper content of the liver
pain, and diabetes. In men, first symptoms typi- (more than 250 µg copper per g dry liver tissue).
cally occur after the age of 40, in women after the In addition, total copper in serum that is 95% coe-
menopause. Patients typically present with elevated ruloplasmin-bound in healthy persons is reduced
serum liver enzymes and elevated blood glucose. in patients with Wilson’s disease in the presence
Serum iron is an insensitive parameter that is not of often elevated transaminases. In contrast, the
necessarily elevated. When a transferrin saturation serum alkaline phosphatase level can be reduced
> 50% and a serum ferritin > 300 ng/mL (> 200 ng/ down to undetectable levels in acute liver failure
mL in women) are observed, molecular genetic test- in Wilson’s disease. Life-long medical therapy is
ing for HFE gene mutations (Cys282Tyr homocygos- indispensible and consists in: (1) increasing the
ity, Cys282Tyr/His63Asp compound heterocygosity) urine copper excretion by chelator substances like
is recommended. Native magnetic resonance imag- D-penicillamine or trientine until total body copper
ing of the liver, the pancreas and the cardiac muscle is normalized (< 60 µg copper in urine/24 h), and (2)
is a useful and non-invasive technique for detection impairing intestinal copper uptake by administra-
of abnormal iron storage in these organs confirm- tion of zinc acetate or zinc sulfate after total body
ing the diagnosis. Liver histology with quantitative copper has normalized (regular control of urinary
determination of hepatic iron and determination copper excretion!). Acute liver failure is treated by
of the hepatic iron index is helpful in patients older high urgency liver transplantation (Brewer and
than 40 and with the suspicion of liver cirrhosis Askari 2005).
and/or serum ferritin higher than 1000 ng/mL for
assessing the individual prognosis. Lifelong ther-
apy consists of regular phlebotomy (Hb > 10 g/dL)
to keep the serum ferritin lower than 50 ng/mL.
In the first 1–2 years when phlebotomies (500 ml) 16.1.5
are needed at weekly intervals, serum ferritin and α1-Antitrypsin Deficiency
transferrin saturation should be controlled every
3 months, thereafter at least once a year when 4–12 α1-Antitrypsin deficiency is an inherited autoso-
phlebotomies are performed per year. Patients with mal co-dominant disorder (prevalence 1/2000 to
cirrhosis have a high risk for hepatocellular car- 1/5000) with more than 100 known alleles. Typical
cinoma and should undergo regular surveillance signs and symptoms include early-onset emphy-
(see below). sema, pulmonary infections, and indicators of liver
disease. α1-Antitrypsin is a protease inhibitor that
protects the lung against proteolysis by neutrophilic
elastase and that is synthesized predominantly in
the liver. The most frequent mutation affects the
16.1.4 SERPINA1 gene and gives rise to the Z allele. In
Wilson’s Disease homocygotes for this mutation, one aminoacid
substitution in the α1-antitrypsin molecule causes
Wilson’s disease is a rare (prevalence 3/100,000) its retention in the hepatocytes. This may fi nally
autosomal-recessive disorder characterized by an lead to cirrhotic transformation of the liver. The
impaired transport of copper from the liver into concomitant lack of α1-antitrypsin in serum pre-
bile resulting in copper accumulation in liver, brain disposes to emphysema of the lung (Stoller and
and other tissues. The major signs and symptoms Aboussouan 2005).
332 G. U. Denk and U. Beuers
16.1.6 16.1.7
Autoimmune Hepatitis Primary Biliary Cirrhosis
Autoimmune hepatitis (AIH) is an infrequent type Primary biliary cirrhosis (PBC) is the most common
of chronic hepatitis (prevalence 17/100,000) which cholestatic liver disease with a prevalence of 25–
leads to progressive inflammatory destruction 42 per 100,000 (Kaplan and Gershwin 2005). Of
of liver tissue. AIH affects mainly women (80%). the patients, 90% are female, mostly middle-aged.
Before immunosuppressive treatment was estab- The underlying pathomechanisms seem to be of
lished, up to 50% of patients died within 3 years. autoimmunological character. The natural course
The diagnosis of AIH is based on the presence of of PBC is characterized by a chronic progressive
elevated serum transaminases, elevated immuno- portal inflammation of interlobular and septal bile
globulin G, characteristic histologic fi ndings of a ductules resulting in complete biliary cirrhosis after
moderate to severe “interface hepatitis” with dense 10–15 years without treatment. Typical symptoms
lymphocellular portal and periportal infi ltrates and comprise pruritus, fatigue, and sicca syndrome. In
piecemeal necroses, autoantibodies, and exclusion addition to elevated markers of cholestasis, most
of other viral, toxic, metabolic, or autoimmune liver patients present with antimitochondrial antibodies
diseases (Krawitt 2006). Based on the serum auto- (AMA, subclass M2) and elevated immunoglobulin
antibody profi le, two types of autoimmune hepa- M levels in serum. The only established conservative
titis are distinguished. The more frequent type 1 therapy is oral administration of ursodeoxycholic
(> 80% of cases) affects patients at all ages and is acid, the therapy of decompensated liver cirrho-
characterized by the presence of antinuclear (ANA), sis consists in liver transplantation (Kaplan and
anti-smooth muscle (ASMA) and/or soluble liver Gershwin 2005). The incidence of hepatocellular
antigen (SLA) antibodies in serum. Type 2 mainly carcinoma in patients with advanced primary bili-
affects girls and young women and is characterized ary cirrhosis (stages III and IV) is comparable with
by the presence of liver kidney microsomal (LKM1) patients suffering from cirrhosis due to chronic
antibodies. Insufficient treatment response is more hepatitis C (Caballeria et al. 2001).
often observed in AIH type 2 than AIH type 1
(Krawitt 2006).
Patients with AIH typically present with distinctly
elevated serum transaminases and increased immu-
noglobulin G levels. Clinical signs and symptoms 16.1.8
are nonspecific (fatigue, anorexia, nausea, jaundice, Primary Sclerosing Cholangitis
hepatosplenomegaly). AIH is associated with extra-
hepatic autoimmune disorders like autoimmune Primary sclerosing cholangitis (PSC) is a rare chronic
thyreoiditis, rheumatoid arthritis, or coeliac disease cholestatic disorder of unknown origin affecting
in 30%–50% of cases. intra- and extrahepatic bile ducts (Withington et
The established therapeutic concept consists in al. 2005). Its prevalence is 9–13 per 100,000 with
immunosuppressive treatment with corticosteroids a preference of the male gender (2:1). The disease
and azathioprine. Initially, prednisolone (up to is associated with chronic inflammatory bowel
60 mg daily) is administered for the fi rst 2 weeks. disease, especially ulcerative colitis (70%–90% of
An adequate treatment response is expected, oth- all patients), and the typical age of manifestation
erwise the diagnosis of AIH should be questioned. is between 25 and 40 years. PSC carries a risk of
Subsequently, azathioprine (1–1.5 mg/kg daily) developing cholangiocellular carcinoma of 1.5% per
is added and corticosteroids are reduced slowly year. Clinical symptoms are nonspecific similar to
every week down to an individual maintenance PBC. Patients with PSC present with elevated serum
dose (titration in dependence on disease activity). markers of cholestasis, atypical antineutrophilic
Therapy with azathioprine and low-dose corticoste- cytoplasmatic antibodies with perinuclear fluores-
roids or monotherapy with azathioprine (or pred- cence pattern (atypical pANCA; in 70% of patients),
nisolone) should be continued for at least 4 years. In and onion skin fibrosis around the bile ducts in liver
most cases, however, life-long treatment is needed biopsy specimens. The established diagnostic gold
(Krawitt 2006). standard is endoscopic retrograde cholangiography
Predisposing Diseases: Chronic Hepatitis and Liver Cirrhosis 333
(ERC) which reveals irregular strictures and dilata- tease inhibitors, steroids, or tamoxifen. Diagnosis
tions of the intra- and/or extrahepatic bile ducts. is based on exclusion of active alcohol abuse, pres-
High quality Magnetic Resonance Cholangiopan- ence of elevated serum transaminases, an enhanced
creaticography (MRC) is increasingly replacing ERC echogenicity in liver ultrasonography, and typi-
as a diagnostic procedure. Ursodeoxycholic acid has cal liver histology with balloon-like degeneration
been shown to improve serum liver tests and liver of hepatocytes, nuclear vacuoles, Mallory bodies,
histology and to decrease the risk of colon and chol- and inflammatory infi ltration. Therapy consists in
angiocellular cancer in PSC and is, therefore, rec- weight reduction and adequate treatment of diabe-
ommended at daily doses of 15–20 mg/kg. In addi- tes or hyperlipidemia. Potentially hepatotoxic drugs
tion, high-grade stenoses are treated by endoscopic should be avoided. The natural course of non-alco-
dilatation. Liver transplantation must be considered holic steatohepatitis is not well-known, the inci-
in late stage disease when cirrhosis has developed dence of cirrhosis is estimated to be up to 30% of
(Rust and Beuers 2005). cases (Göke et al. 2005).
16.1.9 16.1.11
Alcoholic Liver Disease Chronic Liver Disease and Hepatocellular
Carcinoma
Alcoholic liver disease is one of the leading causes of
chronic hepatopathy and comprises alcoholic fatty Hepatocellular carcinoma (HCC) is the third most
liver (up to 90% of alcoholics), alcoholic hepatitis common cause of cancer-related death and the
(up to 10%–35%), and alcoholic liver cirrhosis. It fifth most common cancer worldwide. The annual
is known that there is a correlation between the incidence of HCC has been rising in the Western
amount of the alcohol daily consumed and the risk world during the last decades with 10–30 new cases
of developing alcoholic liver cirrhosis but no exact per 100,000 citizens (Spangenberg et al. 2004).
threshold is known. Typically, only a relatively small Chronic viral hepatitis, alcoholic liver disease, and
portion of alcoholics, drinking daily > 60 g of alco- hemochromatosis represent the main risk factors
hol in men and > 20 g in women, will develop alco- for developing HCC. In addition, any chronic hepa-
holic liver cirrhosis (Willner and Reuben 2005). topathy and liver cirrhosis is accompanied by an
Alcoholic liver cirrhosis is an established risk factor increased risk for this tumor. The risk rate depends
for developing hepatocellular carcinoma (Bruix and on etiology, duration, and activity of the respective
Sherman 2005). In a study by Hassan et al. (2002) hepatopathy. The risk to develop HCC is highest in
alcoholic liver disease was the risk factor for 32% of patients with cirrhosis due to chronic hepatitis C
all hepatocellular carcinomas. (60% life-time risk, LR), chronic hepatitis B (50%
LR), hemochromatosis (40% LR), and alcoholic liver
disease (30% LR) (Spangenberg et al. 2004). Early
diagnosis of HCC is crucial: potentially curative
therapeutic strategies like surgical resection, liver
16.1.10 transplantation, and percutaneous ablation can suc-
Non-alcoholic Steatohepatitis cessfully be applied only in early stages of HCC.
Surveillance for HCC is recommended in patients
Non-alcoholic steatohepatitis is a hepatopathy of with liver cirrhosis due to chronic hepatitis B and C,
unknown origin that is histopathologically very alcohol abuse, genetic hemochromatosis, and pri-
similar to alcoholic hepatitis despite absent alco- mary biliary cirrhosis (Bruix and Sherman 2005).
hol abuse. The typical age of manifestation is In addition, cost-efficacy analyses led to the recom-
40–60 years. Women are affected more often than mendation of regular surveillance in hepatitis B car-
men. Risk factors for non-alcoholic steatohepatitis riers without cirrhosis who are: (1) Africans above
include disorders of the metabolic syndrome com- 20 years, (2) Asian males above 40 years, (3) Asian
plex (obesity, diabetes mellitus, hyerlipidemia) and females above 50 years, (4) with a family history
certain drugs such as amiodaron, diltiazem, pro- of HCC. In addition, hepatitis B carriers with high
334 G. U. Denk and U. Beuers
HBV-DNA levels and ongoing hepatic inflammation can be made. In case of a nonspecific pattern or con-
remain at risk to develop HCC. Patients with cirrho- flicting results, a biopsy should be obtained.
sis due to α1-antitrypsin deficiency, non-alcoholic Lesions < 1 cm should be followed with ultra-
steatohepatitis, and autoimmune hepatitis may also sound at intervals of 3–6 months. In case the lesion
be at an increased risk to develop HCC. However, does not grow over a period of up to 2 years, it is
there are insufficient published data available so far improbable that the nodule represents a HCC. The
to recommend regular surveillance in these cases patient can then return to routine surveillance
(Bruix and Sherman 2005). (Bruix and Sherman 2005).
Serum α-fetoprotein (AFP) has long been used as
a diagnostic test for HCC although its sensitivity and
specificity are limited. At serum levels above 20 ng/mL,
sensitivity for HCC is only 60% (Trevisani et al.
2001). Thus, AFP alone should not be used for screen- References
ing unless ultrasound is not available (Bruix and
Sherman 2005). AFP levels above 200 ng/mL can be Brewer GJ, Askari FK (2005) Wilson’s disease: clinical man-
agement and therapy. J Hepatol 42(Suppl 1):S13–21
helpful in patients with a lesion in a cirrhotic liver. Bruix J, Sherman M (2005) Management of hepatocellular
Surveillance for HCC should be performed carcinoma. Hepatology 42:1208–1236
using ultrasonography (Bruix and Sherman Caballeria L, Pares A, Castells A et al. (2001) Hepatocellular
2005). Abdominal ultrasound achieves a sensitivity carcinoma in primary biliary cirrhosis: similar incidence
to that in hepatitis C virus-related cirrhosis. Am J Gastro-
between 65% and 80% and a specificity greater than enterol 96:1160–1163
90% for detection of HCC when used as a screening Dienstag JL, McHudchison JG (2006) AGA technical review
tool (Bruix and Sherman 2005). However, nodu- on the management of hepatitis C. Gastroenterology
lar cirrhosis often makes differentiation of hepatic 130:231–264
lesions by ultrasound difficult, and ultrasonography Göke B, Kolligs F, Rust C (2006) Interner Klinikleitfaden
Gastroenterologie, Hepatologie, Endokrinologie, Stoff-
is an operator-dependent technique. Screening at 6- wechsel. Eigenverlag, München
to 12-month intervals has been recommended based Hassan MM, Hwang LY, Hatten CJ et al. (2002) Risk fac-
on tumor doubling times, and a 6-month interval is tors for hepatocellular carcinoma: synergism of alcohol
used by most experts (Bruix and Sherman 2005). with viral hepatitis and diabetes mellitus. Hepatology
36:1206–1213
Contrast-enhanced MRI of the liver represents the
Kaplan MM, Gershwin ME (2005) Primary biliary cirrhosis.
gold standard for detection and differentiation of N Engl J Med 353:1261–1273
hepatic masses in liver cirrhosis, but has not yet Krawitt EL (2006) Autoimmune hepatitis. N Engl J Med
been accepted as a routine screening procedure due 354:54–66
to its enormous costs. Besides diagnostic imaging Perrillo RP (2005) Current therapy of chronic hepatitis B:
benefits and limitations. Sem Liver Dis 25(Suppl 1):
and serum AFP, histopathology is helpful for the 20–28
diagnosis of HCC. Pietrangelo A (2004) Hereditary hemochromatosis – a new
The diagnostic workup depends primarily on the look at an old disease. N Engl J Med 350:2383–2397
size of a hepatic lesion detected. Lesions > 2 cm in Rust C, Beuers U (2005) Medical treatment of primary bil-
iary cirrhosis and primary sclerosing cholangitis. Clin
diameter in cirrhotic livers with typical features of
Rev Allerg Immunol 28:135–145
HCC such as hypervascularity and washout in the Spangenberg HC, Thimme R, von Weizsäcker F et al. (2004)
portalvenous phase in dynamic imaging or an ele- Hepatozelluläres Karzinom. Internist 45:777–785
vated serum AFP above 200 ng/mL do not have to Stoller JK, Aboussouan LS (2005) Alpha1-antitrypsin defi-
be biopsied for diagnosis of HCC. However, biopsy ciency. Lancet 365:2225–2236
Trevisani F, D´Intino PE, Morselli-Labate AM et al. (2001)
should be performed if the vascular profi le on imag- Serum alpha-fetoprotein for diagnosis of hepatocellu-
ing is not characteristic or if the lesion is detected in lar carcinoma in patients with chronic liver disease:
a non-cirrhotic liver. inf luence of HBsAg and anti-HCV status. J Hepatol
Lesions 1–2 cm in diameter detected in cirrhotic 34:570–575
livers should be analyzed by two dynamic imaging Willner IR, Reuben A (2005) Alcohol and the liver. Curr Opin
Gastroenterol 21:323–330
techniques such as MRI, dynamic CT, or contrast Worthington J, Cullen S, Chapman R (2005) Immunopatho-
enhanced ultrasonography. When the lesion pres- genesis of primary sclerosing cholangitis. Clin Rev
ents with typical signs of HCC, the diagnosis of HCC Allergy Immunol 28:93–103
Predisposing Diseases: Autoimmune Disease, AIDS and Transplanted Patients 335
Predisposing Diseases 16
16.2 Autoimmune Disease, AIDS and Transplanted Patients
Johannes R. Bogner and Michael Fischereder
16.2.2
Autoimmune Disease
Table 16.2.1. Autoimmune diseases with potential benefit from radiological screening
in combination. The pattern of organ involvement were 2.5, 5.1 and 11.5 for patients respectively.
and comorbidity are as complex as is the underlying (Smedby et al. 2006).
pathophysiology. For the purpose of this chapter, it Systemic corticosteroid therapy is known to
appears most reasonable to use rather a pragmatic reduce bone mineral density BMD (Sambrook 2005;
than pathophysiologic approach. As most of these Blake and Fogelman 2002). Since various different
diseases are rather rare, little evidence based recom- treatment regimens are available, the identification
mendations on the utility of screening are available. of patients at risk appears warranted. Randomized
Table 16.2.1 summarizes co-morbid conditions, the studies on the utility are also missing, but expert
detection of which may either aid in the diagnosis opinion, which has also been incorporated in guide-
of the autoimmune disease (such as serositis in sys- lines suggests BMD measurement especially if risk
temic lupus or granulomas in vasculitis) or which factors such as:
represent a potentially fatal complication of a spe- ● Oestrogen deficiency
cific autoimmune disease. ● Corticosteroid therapy > 7.5 mg/day
● Maternal family history of hip fracture
● Body mass index < 19 kg/m²
16.2.2.1 ● Anorexia nervosa
General Recommendations ● Malabsorption syndrome
● Primary hyperparathyroidism
Some general recommendations can be given for ● Chronic renal failure
radiological screening examinations that apply to ● Post transplantation
the entire group of patients. Foremost, prior to the ● Hyperthyroidism
institution of immunosuppressive therapy, active ● Cushing syndrome
infection, past exposure to tuberculosis or malig- ● Radiologic evidence of osteopenia
nant disease has to be ruled out. ● Previous osteoporotic fracture
From this point of view obtaining a screen- ● Thoracic kyphosis are present (Blake 2002 and
ing chest X-ray at the time of diagnosis is recom- Fogelman)
mended. The utility for the reduction of symptom-
atic pulmonary infections has been well evaluated
in patients with rheumatoid arthritis (Carmona et 16.2.2.2
al. 2005). During treatment with a biological agent, Disease Specific Screening Recommendations
i.e. a TNF-antagonist, the risk for reactivation of
tuberculosis risk was fourfold higher vs treatment As summarized in Table 16.2.1, a number of autoim-
without a TNF-antagonist (Askling et al. 2005). mune diseases are associated with an increased risk
Likewise the incidence of adverse events also cor- of malignancy:
related with the intensity of immunosuppressive ● Hashimoto’s thyroiditis is associated with thyroid
therapy in these patients and SIR for lymphomas lymphoma (Pedersen and Pedersen 1996).
Predisposing Diseases: Autoimmune Disease, AIDS and Transplanted Patients 337
● Primary sclerosing cholangitis carries a 10%– tion. These studies comprise a plain chest X-ray
15% lifetime risk of cholangiocarcinoma (Rosen and an ultrasound examination of the abdominal
et al. 1991). organs (liver, spleen, kidneys and exclusion of large
● In primary Sjogren syndrome (SS) a 5.8% NHL perivascular lymph node mass). The rationale for
prevalence has been reported. The SIR is increased this type of baseline screening is derived from three
to 18.8. In 19 of 21 patients with lymphomas these arguments:
were located in the head or neck (Tonami et al. ● HIV-patients show an increased incidence of pneu-
2003; Smedby et al. 2006; Zintzaras et al. 2005). monia in case of deterioration of their immune
● There is a moderate risk of lymphoma in patients system and even those who are under HAART
with SLE with a SIR of 7.4 (Smedby et al. 2006). may have higher incidence of bacterial disease as
● A mildly elevated risk of lymphoma was observed compared to the general age matched population.
in patients with rheumatoid arthritis, i.e. a SIR of In order to assess the presence of new infiltrates or
3.9 (Smedby et al. 2006). changes in hilus pattern it is important to compare
a film with previous studies (Hopewell 1988).
However, no studies are available to demonstrate ● HIV-patients develop pulmonary hypertension
an improvement in clinical outcome with the intro- significantly more frequently (Pellicelli et al.
duction of radiological screening. Therefore, despite 2004). In this scenario it is also of help if there
the increased malignancy rates general screening is a study that was performed months or years
has not been advocated thus far. before the onset of symptoms.
● HIV-patients have a higher risk to develop non-
Hodgkin’s lymphoma (NHL) and other malig-
nant diseases in the regions of chest or abdomen.
These could be timely found by a screening study.
16.2.3 Again, comparison with a baseline study greatly
AIDS facilitates this task.
of pulmonary diseases that occurred were similar or white matter lesions occurred in patients with
in the subjects with normal and abnormal screen- CD4 counts less than 200/µl. The authors’ conclu-
ing radiographs. The authors conclude that serial sion is that performing CT of the head in patients
screening chest radiography in asymptomatic HIV- with CD4 counts equal to or greater than 200/µl is of
infected adults is unwarranted because the diagnos- questionable value considering the low prevalence
tic yield is too low (Schneider et al. 1996). of positive CT findings (Graham et al. 2000).
A direct comparison of CCT and MRI reveals higher
sensitivity for MRI; Post et al. (1988) performed a
16.2.3.3 comparison of CCT and MRI in 22 patients: MRI was
Abdominal Disease more sensitive in detection of demyelinating lesions.
In another study 119 MRI studies were evaluated in
In asymptomatic HIV disease a typical immunologic a multicentric design. 95 patients were asymptomatic
finding on histology is the hyperplasia of germinal cen- and 24 were symptomatic. The results were correlated
tres in lymphatic organs, e.g. lymph nodes or spleen. with clinical data. MR images regarded as positive
Enlargement of lymph nodes or spleen therefore is a included those showing atrophy and/or white matter
typical sign of HIV infection. However, at late stages lesions. On the basis of these criteria, 96 subjects had
when most of the germinal centres are destroyed, normal MR images and 23 had abnormal images.
lymphatic organs become lymphocyte-depleted. In There was a significant difference (p < 0.001) between
parallel, spleen size returns to normal or small. Sple- the asymptomatic group (12 of 95 [13%] with abnor-
nomegaly or hepato-splenomegaly are indicative of an mal scans) and the symptomatic group (11 of 24 [46%]
opportunistic infection or opportunistic tumour if it with abnormal scans). In the asymptomatic group,
is encountered in a patient in the stage of immuno- positive MR images showed fewer, smaller, and/or less
logic destruction and depletion (e.g. stage Centers of extensive abnormalities. The researchers concluded
Disease Control (CDC) “3”, e.g. less than 200 CD4/µl). that MR imaging can show indirect evidence of HIV
Thus, imaging studies with ultrasound and/or CT of infection early in the disease, but abnormalities will
the abdomen contribute to the question of spleen size be minor and seen only in a small minority of neuro-
(Gerber and Hohlfeld 2003). logically asymptomatic subjects. Another conclusion
was that the appearance of clinically recognizable
neurological disease correlates with the MR imag-
16.2.3.4 ing findings of increasingly severe brain atrophy and
Central Nervous System white matter lesions (Post et al. 1991). However, MRI
may be negative despite neurological disease. The
The central nervous system (CNS) is afflicted by results of this study indicate that routine screening
HIV infection in two forms: HIV can result in HIV with cranial MR imaging of neurologically asymp-
encephalopathy as a direct effect of CNS-infection tomatic HIV-seropositive individuals would yield a
and replication. On the other hand, opportunistic very low number of positive findings.
infections and tumours are indirect manifestations However, all studies on imaging in HIV patients
of HIV due to low T-cell immune function (Castillo are affected by the problem, that studies performed
1994; Lizerbram and Hesselink 1997). in the pre HAART era may not be valid nowadays.
The question whether cerebral CT is of use in HIV This is due to the fact that the spectrum of disease
patients who present with headache and no other manifestations has been changing since 1995 (intro-
neurological symptoms or signs was evaluated by duction of saquinavir as the first protease inhibi-
Graham and co-workers. They reviewed 204 CT scan tor) and a new differential diagnosis called immune
results and CD4 counts in 178 patients with this con- reconstitution syndrome has become prevalent after
stellation. For analysis, scans were considered posi- the commencement of HAART.
tive or negative and were grouped according to CD4
counts of less than 200/µl, 200–499/µl, and equal to
or greater than 500/µl. Of the scans, 128/204 (62.7%) 16.2.3.5
were negative, and 76/204 (37.3%) were positive. Of Bone Disease
the positive scans, 58 (76.3%) showed atrophy only
and 18 (23.7%) showed mass lesions or white matter Also adding to the complications of HIV infection
lesions. All cases that were positive for mass lesions under treatment there is a number of reports on
Predisposing Diseases: Autoimmune Disease, AIDS and Transplanted Patients 339
osteoporosis and aseptic bone necrosis (Miller et 1990; Santin et al. 1995; Tatsch et al. 1988, 1990).
al. 2002). Whether a screening with plain X-ray fi lms Gallium-scanning was sensitive and predictive in
or a routine bone densitometry would be cost effec- localisation and differential diagnosis of opportu-
tive is still not clear. In a series of 339 asymptomatic nistic infections like atypical mycobacterioses, PcP
patients, 4.4% showed osteonecrosis of the femoral and other parasitic diseases.
head on MRI scans (Miller et al. 2002). The screening recommendations for patients with
Besides the radiological imaging techniques are summarized in Table 16.2.2.
based on X-ray and magnetic resonance imaging,
scans based on the use of radioisotopes have been
studied and used in the screening of symptomatic
HIV patients.
16.2.4
Transplanted Patients
16.2.3.6
Fever of Unknown Origin 16.2.4.1
General Considerations
In patients with symptoms suggestive of systemic
disease like night sweats, prolonged fever and Over the past decades, the half-life of organ trans-
weight loss, in whom localization of the underly- plants has substantially increased, mostly due to
ing pathological process is not accomplished with more sophisticated pharmacologic therapy. This
conventional radiological imaging, positron emis- results in longer exposure to more potent immu-
sion tomography (PET) is a useful diagnostic tool nosuppression. Clinical consequences are a pre-
(Lorenzen et al. 2001; O’Doherty et al. 1997). disposition to infections, malignant tumours and
In one study PET use was investigated in 80 HIV osteoporosis. The management of potential allograft
patients: in patients with NHL localisation the recipients includes therefore screening procedures
extent of the disease could be determined more prior to transplantation in order to detect preexist-
precisely. In patients with opportunistic infections ing diseases that prohibit transplantation as well as
(Cryptococcus neoformans, Pseudomonas aerugi- screening after the procedure.
nosa, Mycobacterium tuberculosis, Mycobacterium Although infections are more prevalent, they
avium intracellulare) PET was successful in finding usually can be either suspected on clinical grounds
a suitable site for taking biopsy or microbiologic or are detected during routine preoperative evalua-
samples (O’Doherty et al. 1997). tion. Therefore, the potential benefit of radiological
Moreover, PET was suggested for use in patients screening has not been proven for the management
with fever of unknown origin (without HIV infec- of infectious complications so far.
tion) (Lorenzen et al. 2001). The increased malignancy rate observed in trans-
In contrast, gallium-scanning, which was mainly plant recipients is certainly of multifactorial aetiol-
used in the late 1980s and 1990s is no longer recom- ogy. For one, it is influenced by standard risk factors
mended, PET and MRI not being widely available such as smoking, exposure to ultraviolet radiation,
(Gomez et al. 1996; Lee et al. 1999; Moser et al. certain viral infections, gender and age. Further-
more, transplant specific issues, e.g. the degree and mended examinations also cover the detection of
duration of immunosuppressive therapy, use of clinically relevant infection, namely previous tuber-
agents with a higher risk of secondary malignan- culosis, and are summarised in Table 16.2.3.
cies, e.g. cyclophosphamide, calcineurin inhibitors However, the diagnosis of malignancy or infec-
or lymphocyte depleting antibodies, or preexisting tion does not necessarily preclude solid organ trans-
malignancy are relevant (Morath et al. 2004). As plantation. After identification and appropriate
a consequence, current recommendations for radio- therapy of such tumours, patients can be accepted
logical screening of transplanted patients are based on the waiting list provided freedom from cancer or
on the general population and are extended with infection has been demonstrated. This approach has
some specific additions highlighted below. resulted in a total of 1297 renal allograft recipients
Although world wide the numbers of organ trans- transplanted with preexisting tumours who had
plants are increasing, one has to keep in mind that been reported to an international registry by 1997
the field of transplantation is still relatively young (Penn 1997). The recurrence rates of the respective
and total patient numbers are rather low, especially cancer after transplantation were
if specific organs are considered. Thus, evidence ● Breast cancer 23%
from large, randomised studies on the benefit of ● Renal cancer 27%
various screening strategies is rather limited. By far ● Sarcoma 29%
the largest number of patients has received a renal ● Bladder cancer 29%
transplant and most of the information presented in ● Skin cancer 53%
this chapter is based on experiences in this cohort or ● Myeloma 67%
adapted from general recommendations for screen- ● Thyroid cancer 8% (Penn 1997)
ing examinations. However, organ-specific recom-
mendations are included when available. Results from the Australian and New Zealand reg-
istry, ANZDATA, of 11894 renal transplant recipients
indicate that 210 recipients had a history of cancer
16.2.4.2 prior to transplantation and in only 11, i.e. 5%, did
Preexisting and Recurrent Malignancy a recurrence occur. Similar to the results from the
international registry, the recurrence was more
When increased rates of cancer following solid organ likely for renal cancer (2/37), bladder cancer (1/24)
transplantation are discussed, it must not be over- and prostate (1/5). As expected, the recurrence rate
looked that a fair number of patients have malig- for melanoma was also rather high (2/19), whereas
nant disease before or when they are evaluated for breast cancer (0/23) and colon cancer (0/23) did not
the transplant waiting list. This is due to the fact recur (Chapman et al. 2001). However, it has to be
that solid organ transplantation may be a valuable kept in mind that these patients were subjected to
therapy for certain tumours, e.g. hepatoblastoma or selection bias, reflected in the lower prevalence com-
hepatocellular cancer as well as the general preva- pared to the dialysis population. Most likely these
lence of malignancy in this age group. Most com- data are also influenced by reporting bias. Thus, in
monly, cancers are detected either in the intestine, an individual patient, the risk of recurrence may be
breast or urinary system. Overall, 3% of dialysis higher, depending on tumour stage and grade.
patients developed cancer during a follow-up of On the other hand, recurrence rates per se give little
2.5 years (Maisonneuve et al. 1999). In other words, information on the clinical relevance of such a recurrent
a large number of patients is affected and up to 9% of cancer. This is nicely illustrated by the clinical course
patients on dialysis carry a diagnosis of malignancy of prostate cancer after transplantation. In 19 of 90
at initiation of dialysis. transplant recipients (17.7%) prostate cancer recurred
Unless transplantation is intended to treat a after transplantation but mortality due to recurrent
tumour, freedom from malignancy and infection at carcinoma was low: PCA related death rate was 7.8%,
the time of transplantation is of greatest importance overall mortality 28.8% (Woodle et al. 2005).
in order to avoid accelerated clinical deterioration Not surprisingly, recurrence rates are higher if
due to the decreased immunosurveillance. This pre- transplantation is performed for the treatment of
requisite results in current recommendations for the cancer. In 135 children, liver transplantation was
screening of potential transplant candidates prior performed for hepatoblastoma and in 41 children
to their acceptance on a waiting list. These recom- for hepatocellular carcinoma. Respective 1-, 5-, and
Predisposing Diseases: Autoimmune Disease, AIDS and Transplanted Patients 341
10-year patient survival was 79%, 69%, and 66% for nant disease, i.e. 39 Kaposi sarcoma, 38 lymphopro-
hepatoblastoma and 86%, 63%, and 58% for hepa- liferative diseases and 95 carcinomas (17 renal cell
tocellular carcinoma. The primary cause of death cancer, 11 non-basalioma skin cancer, 10 colorectal
for both groups was metastatic or recurrent disease, cancer, 8 breast cancer, 7 gastric cancer, 7 lung cancer,
accounting for 54% of deaths in the hepatoblastoma 6 bladder cancer, and 3 mesothelioma) (Pedotti
group and 86% in the hepatocellular carcinoma et al. 2003). This observation is confirmed when
group (Austin et al. 2006). standardised incidence ratios, SIR, are calculated
Although such registries supply valuable infor- (Table 16.2.4) (Kasiske et al. 2004). The highest rela-
mation on tumour recurrence in the post-transplant tive increase is present in skin and renal cancer with
course of these high risk patients, the actual preva- an almost 90-fold increase in incidence. Except for the
lence of preexisting malignancy in transplant recip- high relative increase in renal cancer, the frequencies
ients can not be extracted. The prevalence of malig- of de novo malignancies following other solid organ
nancy in transplant recipients was addressed in a transplants are comparable (Fung et al. 2001). As
cross-sectional study which evaluated 380 patients in the general population, bronchogenic carcinoma
evaluated for renal transplantation. In this cohort, is associated rather with a history of smoking than
10% of patients had a preexisting malignancy. 20 with any particular for of transplant (De Perrot et
of 45 tumours were located in the urinary system al. 2003). While skin or oral cancer is readily identi-
(Fischereder and Jauch 2005). fied on routine physical examination, renal cancer
This observation is supported by another study requires a more sophisticated screening strategy.
of 260 renal transplant recipients who underwent
unilateral nephrectomy at the time of transplanta- 16.2.4.3.1
tion. In these patients, abnormalities detected were Kidney Transplantation
acquired renal cystic disease, a condition frequently
associated with renal cell cancer, in 85 kidneys On rare occasions, renal cell cancer may also arise
(33%), renal adenomas in 35 kidneys (14%) and renal from the transplant. A survey among 27 German
cell cancer in12 patients (4%) (Denton et al. 2002) transplant centres including 10.997 recipients of
the years 1990–1998 identified 16 cases of de novo
renal cell cancer (0.15%) within the graft. The
16.2.4.3 latency since transplantation was 3–12 years, the
De Novo Malignancy tumour size at diagnoses ranged from 2 to 2.8 cm
(Wunderlich et al. 2001). The Cincinnatti Tumor
The state of decreased immunosurveillance, as well Register has compiled 31 cases up to 1996 with a
as specific side effects of immunosuppressive drugs, latency of 9–258 months. Most cases were identified
result also in a dramatic increase of certain de novo on routine ultrasound screening of the transplant
tumours after transplantation. A survey among which should be performed at least once annually
transplant centres in Northern Italy found that 172 (Kasiske et al. 2000). Treatment was either trans-
out of 3521 renal transplant patients developed malig- plant nephrectomy or partial nephrectomy (Lamb et
342 J. R. Bogner and M. Fischereder
Table 16.2.4. SIR of malignant tumours in solid organ transplant recipients. Standardized incidence rates are given for
various tumours expressed as cases per 100,000 patients (for the general population) and year or cases per 100,000 patient
years (transplant recipients). Data based on Kasiske et al. 2000 unless stated
al. 2004; Roupret et al. 2004; Siebels et al. 2000). In (Ishikawa et al. 2004). This underlines the prob-
order to qualify for nephron sparing resection early lems frequently encountered in ultrasound imaging
diagnosis is crucial. of the native kidneys in renal transplant recipients.
By far more common are neoplasms arising from Due to increasing echogenicity of the renal paren-
the native kidneys. Frequently this is heralded by the chyma the kidneys eventually may appear indistin-
development of secondary cysts during the process guishable from the surrounding structures. A more
of scarring. Since such acquired cystic disease has subtle diagnosis of cyst morphology, e.g. detection
been reported in up to 20% of patients and can read- of complicated cysts, appears exceedingly diffi-
ily be identified (Fig. 16.2.1), renal ultrasound should cult. Imaging technologies, such as CT-scan or MRI
also be performed at least once annually after trans- result in superior visualisation of such scarred kid-
plantation (Denton et al. 2002). The benefits of early neys and the acquired cysts contained therein. This
detection have been highlighted by a cohort study is nicely illustrated in one patient who was found to
comparing the outcome of renal cancer in dialysis have acquired cystic disease on ultrasound and was
patients with renal cell cancer either detected on then evaluated by MRI (Figs. 16.2.1 and 16.2.2).
screening or due to symptoms. As expected, tumours Subsequent nephrectomy confirmed a pT1/G1
detected on screening were smaller and exhibited tumour of the right kidney.
lower histologic grading while tumour stages were The utility of prospective renal ultrasound and
not different. The median survival was 119 months the additional benefit of MRI scanning was also
for 721 cancers detected by screening and thus sig- shown by Heinz-Peer et al. (1998). In 840 transplant
nificantly longer compared to 80 months in 76 symp- recipients, prospective renal ultrasound examina-
tomatic patients (Ishikawa et al. 2004). After adjust- tions were performed. A total of 169 patients were
ment for age and duration of dialysis, screening diagnosed with ACKD, seven of those were found to
conferred a survival benefit of 57 months for surgi- have renal cell cancer. Among 46 patients who were
cally treated patients. As the average life expectancy additionally examined with MRI complex renal
of transplant recipients is longer than for dialysis cysts were identified in 17 more patients.
patients, an even greater benefit of screening has to In summary, annual renal ultrasound should be
be assumed for transplanted patients. performed in all patients with advanced renal fail-
Although not specifically evaluated in this study, ure and additional imaging with CT or MRI should
it is of note that 381 cancers were detected using renal be instituted in case of technical problems or com-
ultrasound and 340 cancers with abdominal CT-scan plex cysts.
Predisposing Diseases: Autoimmune Disease, AIDS and Transplanted Patients 343
a
Fig. 16.2.1. a Ultrasound of a native kidney with acquired cystic kidney disease. Note the increased echogenicity of the
renal cortex which is almost identical to the surrounding tissues. Various intrarenal cysts can be visualized but further
classification is not possible. b Descriptive sketch for a. The renal border is depicted with a dotted line, cysts are depicted
with solid circles
a b
Fig. 16.2.2. a MRI of native kidneys with acquired cystic kidney disease (T2 weighted image, fat saturated). The patient
with ACKD detected on renal ultrasound underwent MRI. The cysts in both kidneys are well visualized due to the bright
signal. Note the difference of the lesion in the right kidney. b MRI of native kidneys with acquired cystic kidney disease (T1
weighted, fat saturated, after Gadolinium). Note the contrast enhancement of the renal cancer. (Courtesy Dr. M. Treitl)
post transplantation. Survival after this diagnosis cancer). They should undergo routine follow-up for
was dismal. Of note 5 patients with early stages Ia the underlying cancer as recommended elsewhere.
and IIa who were detected on annual chest X-ray were
found to have a better prognosis (Potaris et al. 2005).
An even higher incidence of 6.8% bronchogenic car- 16.2.4.4
cinoma was reported by Rosenbaum et al. (2005). Complications at the Site of Anastomosis
Again, the progosis of patients with resectable cancer
was superior to patients ineligible for surgery. Early dysfunction of solid organ transplants is fre-
Based on these observations, it appears advisable quently due to acute rejection, disturbed perfusion
to perform screening chest radiographs annually in or primary non-function. In renal transplantation,
cardiac transplant recipients with a greater than 10 obstruction of the transplant ureter and in hepatic
pack year history of smoking. The additional value transplantation bile duct complications are addi-
of low-dose chest CT in individuals with a high risk tional differential diagnoses. Since ultrasound with
of lung cancer has previously been shown for oth- colour Doppler technology is readily available and
erwise healthy volunteers (Henschke et al. 1999). detects most problems arising from the arterial,
If this strategy is applied to heart transplant recipi- venous, ureteral or biliary anastomosis, routine
ents, all tumours detected on CT were resectable postoperative ultrasound of the renal, hepatic or
compared to only 38% of tumours found on chest cardiac graft in the early postoperative period is rec-
X-ray, arguing for a screening strategy with CT in ommended (Friedewald et al. 2005; Uzochukwu
high risk heart transplant recipients (Rosenbaum et al. 2005). Supplementary use of microbubble con-
et al. 2005). trast media enhanced US or CT- or MRI-angiogra-
phy constitute other valuable methods for selected
16.2.4.3.3 patients with e.g. those at a high risk of anastomotic
Liver Transplantation thrombosis (Karani et al. 2005). In a series of 110
adult liver transplant recipients, ultrasonographic
As already discussed for heart transplant recipients, screening 24 and 48 h post surgery detected seven
tobacco use prior to transplantation is associated patients (6.4%) with vascular complications, includ-
with a substantial increase in lung cancer. Liver ing two (1.8%) hepatic artery and two (1.8%) hepatic
transplantation (OLT) is also increasingly offered vein stenoses, one (0.9%) hepatic vein thrombosis,
to patients with cirrhosis due to alcohol abuse, pro- two (1.8%) portal vein thromboses, and one (0.9%)
vided patients are abstinent prior to placement on thrombosis and two (1.8%) stenoses of the infe-
the waiting list. Alcohol abuse is frequently coin- rior vena cava (IVC). In 19 patients (17.3%), bili-
cident with tobacco use. Possibly due to this cir- ary complications included anastomotic strictures
cumstance, a significant increase in lung cancer and leaks 1 week to 18 months after transplanta-
after transplantation has recently been reported tion. In 11 patients (10%), large hematomas detected
(Jimenez et al. 2003; Oo et al. 2005). Without effec- by US required surgical evacuation (Uzochukwu
tive screening strategies, such neoplasms are usually et al. 2005). Patients with vascular complications
detected at advanced stages and little therapeutic had significantly lower mean main, right, and left
options are available. Median survival in a cohort hepatic artery resistive index values of 0.52 ± 0.18
of 15 OLT recipients is 5.3 months, clearly underlin- (SD), 0.49 ± 0.17, and 0.47 ± 0.19, respectively com-
ing the necessity of adequate screening protocols pared to patients without vascular complications
(Jimenez et al. 2003). Although not prospectively 0.72 ± 0.17, 0.72 ± 0.19, and 0.72 ± 0.17, respectively.
evaluated with respect to survival benefit or cost- Of 27 patients with hepatic artery resistive indices
effectiveness, routine screening with chest CT as for less than 0.6, six had vascular complications and
heart transplant recipients should be considered. only one patient with multiple vascular complica-
tions had a RI of greater 0.6 (Uzochukwu et al.
16.2.4.3.4 2005). Although anastomotic complications at the
Stem Cell Transplantation site of anastomosis are overall infrequent, screening
is warranted due to the therapeutic consequences.
Worthy of specific consideration in stem cell trans- MRI angiography may be of additional value once
plantation are patients in whom this treatment venous or arterial complications are suspected, is
is performed for malignant disease (e.g. breast however often compromised due to suboptimal
Predisposing Diseases: Autoimmune Disease, AIDS and Transplanted Patients 345
image quality (Ishigami et al. 2005) if no sophisti- tion from acute tubular necrosis. Due to the sub-
cated examination technique is employed. stantial overlap between acute rejection and acute
tubular necrosis, the authors concluded that the use
of duplex scanning is greatly limited.
16.2.4.5 In conclusion, transplant biopsy still has to be
Immunological Rejection considered the gold standard for the diagnosis of
acute rejection.
For quite a while it has been an intriguing idea
to detect rejection of kidney or heart transplants
non-invasively through colour Doppler ultrasound. 16.2.4.6
Although some prediction can be made from such Osteoporosis
studies, one has to keep in mind that the diagnosis
of acute transplant rejection usually results in modi- Exposure to corticoid therapy and, in renal trans-
fication of the immunosuppressive therapy which plant recipients preexisting hyperparathyroidism,
carries the risk of over-immunosuppression. Any predispose transplant recipients to a loss of bone
diagnosis of solid organ rejection should therefore mineral density, BMD, resulting in osteoporosis and
be based on a definitive diagnosis. Results of state- osteonecrosis. One-third of the patients’ bone loss
of-the-art ultrasound examinations have been com- occurs during the first year after renal transplanta-
pared with biopsy results in various studies. tion but accelerated resorption more than one year
A total of 48 transplant recipients were evaluated post renal transplantation has also been reported
with Doppler and Doppler tissue imaging assess- (Cayco et al. 2000; Marcen et al. 2005). Following
ment along with catheter-measured pulmonary cap- bone marrow transplantation, BMT, a significant
illary wedge pressure (PCWP) at the time of endo- decline of previously normal BMD of lumbar spine
myocardial biopsy. Although propagation velocity and hip was reported after 12 and 24 months of treat-
(Vp), mitral E-wave velocity (E)/Vp, and E/annular ment with cyclosporine A, prednisolone and metho-
mitral E-wave velocity were significantly associated trexate (Kashyap et al. 2000). Likewise, within 10
with rejection and an elevated PCWP was associated years after cardiac transplant osteoporosis occurred
with rejection, the sensitivity of these tests for the in 13 of 32 patients, and vertebral fractures were
prediction of acute rejection was poor (Eun et al. present in seven of these patients (Glendenning et
2005). al. 1999). After renal transplantation, 193 patients
For renal transplant recipients, this question was with > 6 months post transplantation exhibited a
addressed by Sharma et al. (2004) who performed significantly increased number of fractures which
6017 serial ultrasound examinations in 614 patients. occurred in 17% of patients. Interestingly, trans-
Pulsatile index and Resistive index had a sensitiv- plant recipients with diabetes experienced 40% frac-
ity of 78% and 60% respectively, and a specificity of tures, compared to a fracture rate of 11% without
78% and 90% for the discrimination of acute rejec- diabetes mellitus (Nisbeth et al. 1999). Other fac-
tors affecting bone loss include total steroid dose, Eun LY, Gajarski RJ, Graziano JN et al. (2005) Relation of
age, PTH level and duration since transplantation left ventricular diastolic function as measured by echo-
cardiography and pulmonary capillary wedge pressure
but exhibit a high degree of variability and make a to rejection in young patients (< or = 31 years) after heart
precise prediction of osteoporosis for the individual transplantation. Am J Cardiol 96:857–860
patient problematic (Caglar and Adeera 1999). Fischereder M, Jauch KW (2005) Prevalence of cancer history
The protective effects of bisphosphonate therapy prior to renal transplantation. Transpl Int 18:779–784
Friedewald SM, Molmenti EP, Friedewald JJ (2005) Vascu-
on bone mineral density are established, although
lar and nonvascular complications of renal transplants:
not for fracture rate (Palmer et al. 2005). Neverthe- sonographic evaluation and correlation with other imag-
less, screening of transplant recipients within the ing modalities, surgery, and pathology. J Clin Ultrasound
first 6 months after transplantation for osteoporo- 33:127–139
sis appears prudent and less costly compared to Fung JJ, Jain A, Kwak EJ et al. (2001) De novo malignancies
after liver transplantation: a major cause of death. Lab
bisphosphonate prophylaxis of all patients. Invest 7(Suppl 1):S109–S118
As in the general population, the DEXA method Gerber S, Hohlfeld P (2003) Screening for infectious dis-
is the recommended method of osteoporosis eases. Childs Nerv Syst 19:429–432
screening. Glendenning P, Kent GN, Adler BD et al. (1999) High preva-
For transplanted patients the screening recom- lence of osteoporosis in cardiac transplant recipients
and discordance between biochemical turnover mark-
mendations are summarized in Table 16.2.5. ers and bone histomorphometry. Clin Endocrinol (Oxf).
50:347–355
Gomez MV, Gallardo FG, Cobo J et al. (1996) Identification
of AIDS-related tuberculosis with concordant gallium-67
and three-hour delayed thallium-201 scintigraphy. Eur J
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Subject Index 349
Subject Index
A B
P Q
PACS 92 QA, see quality assurance
Papanicolaou 3, 17 QCT, see quantitative computed tomography
parahippocampal gyrus 236 quality
parallel – assurance (QA) 6, 10, 101
– acquisition technique (PAT) 53, 82 – control 101
– imaging 82 QUS, see quantitative ultrasound
– MRI 82
parenchymal band 268
part-solid nodule 5.0 278 R
PAT, see parallel acquisition technique
paternalism 141 radiation
perfusion measurement, contrast-enhanced 245 – dose consideration 206
– MRI 242 – exposure 54, 89, 92, 118, 314
peripheral arterial occlusive disease 30, 177 – radiation-induced carcinogenesis 43
PET, see positron emission tomography – therapy 20, 178
phase-encoding direction 78 radiofrequency (RF)
plaque 89, 159, 179 – ablation (RFA) 20, 121
– classification 174 – electromagnetic field 78, 133
– disruption 47 radiography, conventional 251
– morphology 175 radiological vertebral index 252
– texture 173 radiolucency, increased 251
pleura/pleural 264
RAM 81
– effusion 266
RCC, see renal cell carcinoma
– mesothelioma 268
real-time trueFISP 81
– plaque 263, 266, 267
recall rate 105
– thickening 267
pneumonia 337 receiver coils 56
polyethylene glycol 93 RECIST 66
polyp 93, 202, 203, 211 recording 103
polyp, flat 16 rectosigmoidoscopy 16
positive predictive value 7 reimbursement 69
positron emission tomography (PET) 31, 113, 241, 289, 339 rejection 345
post-menopausal 249 relative risk 30
– patient 302 renal
– – breast cancer patient 294 – cell 42
postnatal – cell carcinoma (RCC) 193–198
– hip displacement 222 – transplant recipient 345
– kidney screening 215 – ultrasonography 197, 198
prenatal ultrasound scan 218 repeat screening 277
preventive reproduction 103
– mastectomy 320 RES 134
– salpingo-ovaraectomy 320 respiratory distress 20
primary retrospective ECG gating 90
– prevention 270, 320 RFA, see radiofrequency ablation
PROCAM 160 rheumatoid arthritis 337
processing 103 risk
progression 41 – factor 162, 250
progressive temporal atrophy 237 – ratio 145
propagation 41 risk-benefit analyse 132
prostacyclin 46 rounded atelectasis 266, 268
prostate cancer 14, 17
pseudo-disease 7
pulmonary S
– disease 337
– hypertension 337 salivary gland 118
– lesion 119 salpingo-ovaraectomy 320
– nodule 92, 285, 286, 288, 289, 291 sample size calculation 6
– – malignant 287 sampling perfection with application-optimized contrast
– – characterization 286 using (SPACE) 85
pulse sequence 77 sarcoma 268
Subject Index 355
X
V
X-ray 4
vacuum-assisted needle core biopsy 190
VANCB 190
vascular Z
– dementia 240
– malformation 155 Z-score 255
List of Contributors 357
List of Contributors
Christoph R. Becker, MD
Department of Clinical Radiology Gunnar Brix, PhD
University Hospitals – Grosshadern Professor, Federal Office for Radiation Protection
Ludwig-Maximilians-University of Munich Department of Medical Radiation
Marchioninistrasse 15 Hygiene and Dosimetry
81377 Munich 85764 Neuherberg
Germany Germany
358 List of Contributors
123
Oncologists’ Responses to 40 Histories Current Treatment Concepts
Edited by A. R. Kagan with the Edited by W. A. Alberti, G. Richard,
Assistance of R. J. Steckel and R. H. Sagerman