Download Endocrinological Applications in Nuclear Medicine

Endocrinological Applications in Nuclear Medicine
Hans J. B i e r s a c k a n d Frank G r l 3 n w a l d
Diagnosis and treatment of thyroid diseases have
played a major role in Central European Nuclear Medicine. Since 1950, endocrinological nuclear medicine
has been one of the strengths of this medical discipline. Not only diagnosis but also conservative treatm e n t with thyroid depressants or hormones is performed by the nuclear medicine specialists. Nuclear
medicine also takes part in the diagnosis of other
endocrine diseases. The respective procedures include
imaging of the adrenal gland (cortex and medulla) as
well as of the parathyroid glands. Especially in the
latter diseases, imaging was improved through Tc99m sestamibi scintigraphy. Beyond that, the measurement of bone mineral content contributes to the full
spectrum of endocrinological nuclear medicine. The
development of In-111 octreotide now plays a limited
role in the diagnosis of diseases of the pituitary gland.
NDOCRINOLOGICAL applications play
adolescent group have goiter. 1,2 Because some
20% of the respective population suffers from
goiter, it is obvious that the nuclear medicine
clinician is confronted with a large number of
thyroid patients, mostly with endemic goiter
and normal thyroid function. Nonendemic regions with only sporadic cases of goiter show a
very low percentage of nontoxic goiter) Nonendemic regions include, for example, the United
States, Great Britain, Sweden, and Norway.
Endemic regions are Central Europe, Finland,
and large areas of Central Africa. In the latter
areas, the 24-hour urinary iodine excretion is
less than 50 to 80 txg, leading to an increased
iodine or technetium thyroid uptake test. 3 Apart
from clinical investigations, thyroid-specific
symptoms or diseases have to be evaluated by in
vitro tests and imaging modalities. However,
before these tools are used, a classification of
thyroid diseases according to clinical criteria is
necessary. The classification of thyroid diseases,
as recommended by the thyroid section of the
German Society of Endocrinology, 4 is summarized in Table 1.
E a major role in nuclear medicine, especially in Central Europe because the goiter
prevalence in iodine-deficient regions is 25% to
54%. The most frequent disease in these endemic areas is nontoxic goiter. In many cases,
autonomously functioning thyroid tissue leading to borderline or overt hyperthyroidism is
present. Thyroid imaging is the only procedure
to detect this disease. Because in Europe the
diagnosis and treatment of thyroid disorders is
part of the daily routine work of a Nuclear
Medicine specialist, these issues are discussed
in detail. Another metabolic disease in which
nuclear medicine plays a major role is osteoporosis. A high percentage of bone mineral content measurement is performed by Nuclear
Medicine specialists. Beyond that, imaging of
the adrenal gland (cortex and medulla) contributes to the full spectrum of nuclear medicine. In
cases with hyperparathyroidism, parathyroid
gland imaging was improved by the use of
Tc-99m MIBI instead of Tc-99m/T1-201 subtraction scintigraphy. Furthermore, scintigraphy of
the pituitary gland (In-lll Octreotide) has
gained more importance during the last years.
Indications and results of these procedures are
discussed in this review.
THE THYROID GLAND
C o p y r i g h t 9 1995 by W.B. Saunders Company
NONTOXIC GOITER
The patient usually complains about a lump
in the neck, globus hystericus, swallowing disturbances, dyspnea, intolerance of narrow collars,
and visible or palpable nodules.
The term endemic goiter is used when more
than 10% of the population or 5% of an
HYPERTHYROIDISM
From the Department of Nuclear Medicine, University of
Bonn, Bonn, Germany.
Address reprint requests to Hans J. Biersack, MD, Department of Nuclear Medicine, Un&ersityof Bonn, Sigmund-FreudStrafle 25, D-53127 Bonn, Germany.
Copyright 9 1995 by W..B. Saunders Company
0001-2998/95/2502-0002505.00/0
The leading symptoms of hyperthyroidism
are nervousness, sweating, loss of body weight
and hair, insomnia, tachycardia, etc. It should
be mentioned here that younger patients in
particular may present with the whole spectrum
of symptoms, whereas in older patients, this
disease becomes more and more monosymptomatic. In older patients, differential diagnosis
92
Seminars in Nuclear Medicine, Vol XXV, No 2 (April), 1995: pp 92-110
ENDOCRINOLOGICAL APPLICATIONS
Table 1. Classification of Thyroid Diseases According to
Clinical Criteria
1. Goiter
Diffuse
Uninodular
Multinodular
Dystopic thyroid tissue (intrathoracic,
base of tongue)
Grade 0: not palpable
Grade I" thyroid gland palpable; not visible
Grade I1: goiter palpable and visible with
head in normal position
Grade IIh visible at a distance; criteria of
goiter grade II but with mechanical complications like tracheal obstruction or jugular
vein obstruction
2. Thyroid function: euthyroid, hypothyroid,
hyperthyroid
includes malignant or cardiac diseases. The
clinical investigation comprises measurement of
blood pressure and heart rate as well as physical
inspection. The next step is the differential
diagnosis of toxic nodular goiter, Graves' diseases, and Plummer's disease.
HYPOTHYROIDISM
Many of the patients complain of depression,
cold intolerance, increase of body weight, dry
and rough skin, obstipation, and anemia. The
clinical investigation may show eyelid edema,
connective tissue manifestations such as myxedema, bradycardia, hypotension, and electrocardiogram alterations, such as low voltage.
Sometimes, depression may be the only symptom in older patients. The most important
disease leading to hypothyroidism is chronic
(Hashimoto's) thyroiditis.
INFLAMMATION OF THE THYROID GLAND
The clinical diagnosis is marked by neck pain,
swallowing disturbances, and pain during palpation. A frequent finding is high fever, and the
blood sedimentation rate (BSR) as well as the
white blood cell (WBC) count are increased.
Acute/subacute inflammation may be seen in
connection with a viral upper airway infection.
THYROID CANCER
The same clinical criteria as described in
nontoxic goiter may be present. However, palpation of the neck may show lymph node enlarge-
93
ment. In addition, malignant thyroid nodules
may be adherent to the skin and muscle. All
patients with solid thyroid nodules should undergo thin-needle biopsy.
DIAGNOSIC PROCEDURES IN THYROID
DISEASES~IN VIVO
Ultrasound
Real-time scanners are usually used for the
thyroid investigation. The best results are obtained with a 7.5-MHz frequency of the transducer. 5 The neck region is investigated with the
patient's head in the supine position, with the
cervical spine overstretched. Several longitudinal and transversal sections are documented.
The measurement of the maximal diameters
(length x depth x width x 0.479) allows the
simple calculation of the thyroid volume,6 given
the estimation that the thyroid lobes have the
form of an ellipsoid. The upper normal volume
values in iodine-deficient areas for men are 25
mL and for women 18 mL. 5 The characteristic,
homogeneous echo pattern of the normal thyroid gland may be easily differentiated from the
surrounding tissue. In cases of long-standing
chronic goiter, the echo pattern becomes more
echogenic; in thyroid inflammation and Graves'
disease, it becomes typically echo poor. Nodules
may present with a normal, echogenic, echopoor or echo-free pattern. Echogenic nodules
are mostly of benign origin, whereas echo-poor
nodules must be considered as potentially malignant. However, two thirds of the autonomously
functioning adenomas present with this latter
echo pattern, sometimes with central cysts.
Mixed pattern lesions are frequent in longstanding goiters. Echo-free lesions with increased echo pattern in the dorsal region are
cysts.
Thin Needle Biopsy
The needle is moved several times through
the nodule to obtain enough cells for cytology.
Larger cysts may be sclerosed by injection of, for
example, aethoxysclerol or glucose.
Thyroid Scintigraphy
Currently, thyroid scintigraphy is performed
after intravenous injection of 1 to 2 mCi (35 to
70 MBq) Tc-99m Pertechnetate. 1-131 is only
used for diagnosis in patients with thyroid
94
BIERSACK AND GRONWALD
cancer. The use of 1-123 may be neccessary in
patients with retrosternal goiters or decreased
thyroid uptake caused by contrast media. Thyroid scintigraphy is usually performed with a
gamma camera equipped with a dedicated thyroid collimator and linked to a computer, v,8
Measuring the injected dose and the radioactivity that has accumulated in the thyroid gland
allows an estimation of the percentage of thyroid tracer uptake after 15 to 20 minutes.
Background correction is also neccessary. Because of the regionally different iodine intake,
each thyroid center has to establish its own
range of normal values. Scintigraphy allows the
differentiation of ultrasound-proven lesions into
hot or cold nodules. The prevalence of thyroid
cancer in a cold nodule is between 2% and 5%.
Hot lesions are very frequent in endemic goiter
areas and are caused b y the maladaption to
iodine deficiency. The establishment of unifocal, multifocal, and disseminated autonomously
functioning thyr9id tissue is only possible by
scintigraphy (Fig 1). Thus, this procedure hasto
be performed in all patients with focal lesions in
the ultrasound study. 9 Often, a suppression
scan 1~ is necessary to document compensated
autonomously functioning thyroid tissue. For
this purpose 100 to 150 Ixg L-thyroxine daily for
2 weeks or 100 ~g triiodothyronine daily for 5
days have to be administered. Thyroid uptake
above 1% under suppression is indicative of
autonomy.
DIAGNOSTIC PROCEDURES IN THYROID
DISEASES--IN VITRO
The variety of general laboratory tests that
are of clinical relevance in the diagnosis of
thyroid diseases are not discussed in this report.
Fig 1. Thyroid scan (Tc-99m) in multinodular autonomously
functioning thyroid tissue.
Total and Free Thyroxine
Either total T4 (TT4) or free T4 (FT4) level
estimations should serve as basic tests in suspected thyroid dysfunction. Also, TT4 and FT4
should be used in determining the severity of
thyroid hyperfunction and hypofunction and in
monitoring known thyroid dysfunction, especially under thyrosuppressive or depressive
therapy. Many pitfalls should be considered.
These pitfalls are described elsewhere, la Abnormal protein binding of thyroid hormones is in
particular one of the reasons for false-positive
or false-negative test results.
Total and Free Triiodothyronine
Total T3 (TT3) and free T3 (FT3) assays
should be used either in cases of suspected
hyperthyroidism, even when the T4 assay registers still normal concentrations, and in suspected abnormal carrier protein concentrations. Because of the minimal affinity of the T3
molecule to carrier proteins, the FT3 assay does
not provide a significant advantage over the
TT3 assay. The results of both TT3 and FT3
assays are influenced (altered) by severe general diseases, eg, low T3 syndrome.
Reverse Triiodothyronine
Clinical applications in which the use of the
reverse T3 (rT3) assay is informative include
the diagnosis and follow-up of the so-called low
T3 syndrome. This condition is characterized by
a low T3 serum concentration with normal T4,
FT4, and thyroid-stimulating hormone and without clinical evidence of thyroid hypofunction.
Thyroxine-Binding Globulin
Today, the use of the thyroxine-binding globulin assay should be limited to conditions such as
familial dysproteinemia. In the past, it was used
to establish a T4/TBG ratio to exclude abnormal T4 binding to carrier proteins. This disadvantage has been overcome by the availability of
FT4 determination with assays that directly
measure FT4.
Antibodies Against Microsornes
The reference value for antibodies against
microsomes (MAB) has been found to be 40
U/L. Recently, the determination of thyroidal
peroxidase (TPO), which represents a micro-
ENDOCRINOLOGICAL APPLICATIONS
somal antigen, became available and will probably replace the MAB assay. Increased values
may be found in Hashimoto's and Graves'
disease.
Antibodies Against Thyroglobulin
The reference value for these antibodies
(TAB) is also about 40 U/L. An increased TAB
concentration combined with increased MAB is
found in autoimmune thyroiditis and in its
atrophic form. Fibrotic courses of Hashimoto's
thyroiditis are often characterized by increased
TAB with low MAB levels. Also, low levels of
TAB and MAB may be found in patients with
Graves' disease, healthy normal subjects, and
even younger patients with autoimmune thyroiditis.
Antibodies Against Thyroid Stimulating
Hormone Receptors
The determination of TSH receptor antibodies (TRAB) enables the differentiation between
Graves' disease and disseminated autonomous
thyroid dysfunction. However, a normal TRAB
concentration does not exclude Graves' disease,
especially in younger patients.
Thyroid-Stimulating Hormone ( TSH)
Today, supersensitive immunoradiometric assays (TSH-IRMAs) that use monoclonal TSHspecific antibodies (coated on the test tube) and
a second, labeled TSH-specific antibody (tracer)
are used. 12A3
The supersensitive TSH assay permits somewhat reliable discrimination between subnormal and normal TSH concentration, which is
not possible using the former RIA method.
Usually, the TSH in the normal range (0.5 to 4
mU/L) virtually excludes hyperthyroidism. Thus,
subnormal concentrations (in our laboratory
less than 0.1 mU/L) of unstimulated TSH
suggest hyperthyroidism. However, under questionable conditions (basal TSH between 0.1 and
0.3 and 0.5 mU/L), the TRH test (TSH concentration after injection of 0.2 mg thyrotropinreleasing hormone [TRH]) still remains the
most reliable tool to discriminate hyperthyroidism from euthyroidism. 14 Subnormal TSH concentrations can also be seen in patients with
euthyroid stages of Graves' disease or toxic
goiter; in patients treated for hyperthyroidism,
95
even though they are biochemically not hyperthyroid; and in patients on L-thyroxine therapy.
Furthermore, one has to consider that subnormal TSH concentrations may be observed in
patients treated with steroids or dopamine, in
depressed patients without treatment, or in
critically ill patients. Reasons for test alterations were described in detail elsewhere. 11
Human Thyroglobulin (h TG)
Used as a tumor marker in thyroid cancer for
more than 2 decades, 15 hTG is a major protein
that originates exclusively from the thyroid gland
and thyroid tissue, including thyroid cancer and
its metastases, hTG is a very sensitive tumor
marker. Although the clinical usefulness of
hTG has been proven in patients with thyroid
cancer, 16 recent work showed that hTG is also
helpful in other conditions. 17,18 New IRMAs
allow the detection of values less than 0.1
ng/mL. Thus, serum hTG is an excellent marker
for residual thyroid tissue, for local relapse of
thyroid cancer, and for the detection of distant
metastases that may occur later in the course of
the disease. The hTG assay also allows the
monitoring of L-thyroxine therapy of goiter. In
this group of patients, the hTG value (supressed
by L-thyroxine or iodine) allows monitoring of
treatment.
THE TREATMENT OF THYROID DISEASES
Endemic Nontoxic Goiter
The so-called endemic goiter is characterized
by a nonmalignant and noninfectious thyroid
enlargement without alteration in hormone production caused by the iodine deficiency. The
goiter incidence in Germany is estimated to be
approximately 30% in girls and 15% in boys of
the same age. 19The thyroid volume in German
children of this age is twice as high compared
with those living in a nonendemic area such as
Sweden. 19 The majority of goiters develop before the patient reaches 20 years of age. The
clinical investigation is followed by an ultrasound study, rendering possible the estimation
of thyroid volume as well as proof of nodules.
The in vitro diagnosis depends on the estimation of TT4 (FT4), TT3 (FT3), and TSH concentrations as measured supersensitively by IRMA
or T R H challenge. Solitary, cold, echopenic
nodules more than 1 cm in diameter in a
96
normally sized thyroid gland should be immediately removed surgically, unless there are significant contraindications. On the other hand, in
multinodular goiters, the incidence of a carcinoma within a nodule is less frequent.
The conservative treatment of endemic goiter
requires the long-standing application of
L-thyroxine or a combination of L-thyroxine
and iodine. The dosage should be augmented
slowly to 100 to 150 Ixg L-thyroxine daily. A
follow-up should be performed after 8 to 10
weeks under thyroid hormone treatment. 2~Suppression scintigraphy should be performed to
rule out autonomously functioning thyroid tissue when ultrasound-proven lesions are present
at the initial investigation. Some clinicians in
Germany strongly endorse suppression scintigraphy and renounce a baseline scintigraphic
study if no nodules are present. 9 The long-term
treatment with combinations of L-thyroxine and
iodine showed superior results when compared
with monotherapy. 18 In endemic goiter without
nodules after 1 to 2 years of therapy, the
L-thyroxine (iodine) therapy may be replaced
by 200 txg iodine per day. 18,21Follow-up investigations during iodine treatment alone did not
show any significant difference of thyroid volume or hTG levels when compared with the
respective findings under L-thyroxine treatment. Juvenile goiters are usually treated with
100 to 200 Ixg iodide per day. Surgery and
radioiodine therapy are confined to patients
with the development of nodules under
L-thyroxine therapy or with mechanical complaints that do not respond to conservative
therapy.
Autonomously Functioning Thyroid Tissue
(UninodularAnd Multinodular, Disseminated)
In populations with normal or high iodide
intake, autonomously functioning thyroid nodules are a rare finding, 22 whereas in iodinedeficient areas, this disease is relatively frequently seen and represents one end stage of
long-lasting goiter. 23 It is estimated that, in
Germany, 3.5 million people suffer from this
disease. In iodine-deficient areas such as Germany, autonomously functioning thyroid tissue
(AFTT) is a consequence of an autoregulatory
maladaption to decreased alimentary iodine
BIERSACK AND GRONWALD
intake that probably results from long-term
stimulation by TSH.
Usually, AFTT secretes more T3 than T4 as
an adaption to iodine deficiency, although the
T4 level may be low or normal. Later in the
course of the disease, TSH is suppressed by the
autonomously produced thyroid hormones. At
the beginning of the disease, the autonomous
production of thyroid hormones is masked by
the surrounding normal thyroid tissue, because
the Volume of the AFTT is relatively small.
These autonomous areas increase with age and
size of goiter, so this disease may be considered
to be latent hyperthyroidism. The fate of thy,
roid autonomy is related to the iodine intake. 23
As long as iodine deficiency is present, the
disease is usually compensated. However, iodine excess leadS to overt hyperthyroidism, a
finding that has been well known since the
iodine prophylaxis in Tasmania. AFTT may
appear compensated (the diagnosis only being
established by suppression scintigraphy), partially decompensated (warm nodule), or decompensated (hot nodule), as shown on a scintigram. The diagnosis of AFTT involves the
anamnesis, clinical findings, laboratory test results, sonogram, and, most importantly, scintigraphy. The necessary laboratory tests comprise
TT3 (FT3), TT4 (FT4), and supersensitive TSHIRMA or TRH challenge. In many cases with
AFTT, normal T3 and T4 values may be obtained in the presence of supressed TSH. The
suppression scan is especially useful to detect
masked AFTT.
AFTT without hyperthyroidism does not necessarily require therapy, and the patient should
be advised to avoid iodide exposure. However,
especially in older patients, prophylactic therapy
should be performed because this disease does
not usually show spontaneous remission. In
younger patients, a cystic degeneration of toxic
adenomas may sometimes be observed, thus
leading to its self-healing, a very rare event. If
AFTT is present in endemic goiter, L-thYroxine
therapy cannot be administered because it would
lead to a factitious hyperthyroidism caused by
its inability to suppress hormone production.
Thyrostatic drugs cannot be applied for longterm tre~itment because spontaneous remissions do not occur. Thus, AFTT requires definitive therapy with radioiodine or surgery. 23
ENDOCRINOLOGICAL APPLICATIONS
Because of positive results and negligable side
effects, radioiodine therapy is being used increasingly, even in younger patients. Radioiodine
therapy uses high-target doses of 200 Gy (300 to
400 Gy) and greater. Because iodine deficiency
is the most common reason for AFTT, a sufficient iodine intake is required after therapy.
Graves' Disease (Immunogenic Hyperthyroidism,
Basedows' Disease)
Graves' disease is a genetically determined,
autoimmune disease. 24 The thyroid cells are
stimulated by TSH-receptor autoantibodies,
which leads to an increased production of thyroid hormones. The clinical diagnosis comprises
endocrine ophthalmopathy and pretibial myxedema (which is now very rare). The diagnosis
of Graves' disease is more likely in younger
patients, patients without goiter, patients with
only a small goiter, and patients with diffuse
goiter without nodules. 25 Sonography usually
shows a typically diffuse, echopenic pattern, as
in Hashimoto's thyroiditis. The thyroid scan
shows an increased Tc-99m uptake and usually
a homogeneous pattern of activity distribution
throughout the gland (Fig 2). In addition, the
lobus pyramidalis may be visualized.
The laboratory tests (increased T4, T3, and
suppressed TSH levels) help to establish the
diagnosis of hyperthyroidism. The differential
diagnosis against AFT/" may be made in the
case of increased TRAB, with the latter finding
being more frequent in older patients, whereas
Fig2. Thyroid scan (Tc-99m) in Graves" disease with homog.
enous tracer uptake.
97
younger patients may present without increased
antibody levels. 25 The distinction between
Graves' disease and AFTT is a prerequisite for
choosing the appropriate therapy. Only with
Graves' disease can definitive therapeutic success be achieved in about 60% of patients using
thyroid depressants. 26 Thyrostatic therapy in
AFTT and toxic adenoma should only be used
to maintain a euthyroid status until definite
therapy, such as with radioiodine or surgery,
takes place.
Thyrostatic therapy in Graves' disease should
be performed over a time period of at least 12
months. It should be initiated with relatively
high doses (30 to 40 mg carbimazole daily, 100
to 300 mg propylthiouracil daily, or 20 to 30 mg
thiamazole daily). The maintenance dose will
be reached within 2 to 3 weeks (approximately 5
mg thiamazole and carbimazole daily or 50 mg
propylthiouracil daily). This low-dose monotherapy produces almost no side effects such as
agranulocytosis, pruritus, or exanthema. For
patients who develop side effects, lithium
therapy (450 to 900 mg/d) may be administered.
The dose must be titrated carefully to maintain
serum lithium concentrations between 0.7 and
1.4 mU/L. 26 Especially large goiters do not
respond well to antithyroid drugs; thus, surgery
is the therapy of choice. In cases of relapse after
12 to 18 months, radioiodine therapy should be
taken into consideration. During pregnancy, a
low-dose thyroid depressant therapy (eg, 5 mg
Carbimazol [Henning, Berlin, Germany] daily)
should be administered. 27Hyperthyroidism usually shows improvement during pregnancy, most
probably because of the increased binding of
thyroid hormones to increased TBG levels.
Even in the first 3 months of pregnancy, lowdose thyroid depression therapy does not lead
to teratogenic effects.
If endocrine ophthalmopathy (EO) occurs,
treatment should be performed as soon as
possible, because after 6 months, increasing
fibrosis leads to an irreversible condition. Frequently, EO exhibits regression during thyroid
depressant therapy, when the hormone values
are in the normal range. If this is not the case,
cortisol therapy should be initiated, beginning
with 100 mg prednisone administered daily. The
dose is decreased by 10 mg/d every week. When
the 10 mg/d dose is reached, the dose should be
98
reduced by 2.5 mg/d every week. If cortisol
treatment is not successful, radiation therapy of
the orbital apex (10 to 14 Gy) is necessary and
should be performed in association with prednisone therapy. 28
Inflammations of the Thyroid Gland
Acute (bacterial) inflammation is marked by
neck pain, swallowing disturbances, and pain
during palpation. A frequent finding is high
fever, and the BSR level as well as the WBC
count are increased. Sonography may show an
inhomogeneous, partly echopenic pattern, sometimes with an abscess. The Tc-99m uptake is
usually significantly decreased, and the thyroid
hormone may be increased because of necrosis
of the follicles. Therapy requires the application
of anti-inflammatory drugs and antibiotics.
Acute/Subacute Inflammation. Acute/subacute inflammation is more frequent in iodineexcess areas, may present with the same clinical
features, and may sometimes be misdiagnosed
as bacterial inflammation. Subacute thyroiditis
may be differentiated from acute bacterial thyroiditis by increased levels of a2-globulin as well
as by the absence of leukocytosis. Again, sonography presents with an inhomogenous echopenic pattern. A scintigram shows a decreased, or
even absent, tracer uptake. The final diagnosis
may be established by thin-needle biopsy, showing a typical cytological pattern of giant cells.
The concentration of thyroid hormones may be
increased in the early course of the disease
because of the necrosis of cells. Later on,
hypothyroidism may arise. Thyroid autoantibodies may be present only in the minority of cases.
Mild inflammation may be cured by antiinflammatory drugs, whereas the severe forms
require the application of prednisone, beginning with 40 to 60 mg/d. The dosage should
again be decreased by 10 mg/d every week and
then continued with about 10 mg/d for 2 to 3
weeks. An L-thyroxine supplement with 100 Ixg
daily should be administered later, after the
initially increased T4 and T3 values are again
within the normal range. In some rare cases
with frequent inflammation, irradiation of the
thyroid gland by 1-131 therapy may be necessary.
Chronic Inflammation. Chronic inflammation is most probably caused by Hashimoto's
BIERSACK AND GRLINWALD
thyroiditis. The disease is clinically silent, so
that only the end stage of hypothyroidism may
be diagnosed: The sonography study presents
the typical echopenic pattern, whereas a scintigram usually shows a decreased Tc-99m uptake.
The diagnosis is based on the results of laboratory tests. Both TAB and MAB exhibit high
titers, the TSH level is increased, and T3 and T4
are decreased, findings indicative of hypothyroidism. The therapy is the same as for hypothyroidism (discussed below) and necessitates the lifelong application of thyroid hormones.
A rare disease is fibrous-invasive thyroiditis
(Riedel's disease), which presents with a goiter
that invades the soft tissue of the neck. Because
the differential diagnosis includes thyroid cancer, these patients often undergo surgery. Treatment again requires long-term application of
thyroid hormones to suppress the TSH activity.
Hypothyroidism
The cause of hypothyroidism covers a wide
spectrum of diseases. The congenital form may
be caused by aplasia of the thyroid gland,
thyroid dysplasia, and ectopic thyroid tissue (eg,
at the base of the tongue). 29 Another inborn
error is characterized by disturbed iodine use
(Pendred's Syndrome).3~ Other diseases include peripheral thyroid hormone resistance or
secondary hypothyroidism caused by TSH deficiency. All these afflictions are irreversible and
have to be differentiated from intrauterine hypothyroidism caused by iodine deficiency, iodine
excess, thyroid depressant drugs, and sometimes radioiodine therapy in undiagnosed pregnancy. Hypothyroidism of adults is marked by
depressive syndromes (especially in elderly patients, in whom it is sometimes the only syndrome), memory and concentration impairment, increase of body weight, obstipation, lack
of drive, and edema. Arthralgia in hypothyroidism may also be misdiagnosed as rheumatic
disease.
The diagnosis of clinically suspected hypothyroidism is centered around laboratory tests
(decreased T4 and T3 in combination with
increased TSH) and thyroid scintigraphy (ectopic tissue). Hypothyroid T3 and T4 values in
combination with a low or normal TSH level
suggest secondary (pituitary) hypothyroidism. A
subgroup of hypothyroidism is subclinical hypo-
ENDOCRINOLOGICAL APPLICATIONS
thyroidism, a disease in which the TSH activity
is increased and a pathological TRH test is
seen, despite normal or borderline low T3 and
T4 levels. 31 This situation may remain unchanged for years; thus, therapy is not necessary
unless the patient suffers hypothyroid symptoms. However, a follow-up every 6 to 12 months
should be performed because subclinical hypothyroidism may end in overt hypothyroidism.
Therapy of hypothyroidism requires administration of L-thyroxine. In case of longerstanding hypothyroidism, the dosage should be
augmented slowly, beginning with 25 ~g/d and
then increasing the dose by 25 Ixg/d every week
until reaching a dose of 100 to 150 p.g/d. The
optimum dose can be correlated with a normal
TSH level (1 to 3 U/L). The dose for children is
25 to 50 ~g/d during the first 6 months and 50 to
75 I~g/d for the next 6 months. Between years 2
and 5, the dosage is usually between 75 and 100
Ixg; after years 6 and 12, the dosage is 100 to 150
~g/d. During pregnancy and breast feeding,
higher doses may be necessary.
Thyroid Tumors
We will focus here on selected important
features because thyroid cancer would fill more
than one article. 32-4~Thyroid cancer contributes
to 0.5% to 1% of all malignancies; only 2% of
thyroid nodules in unselected patients from a
thyroid clinic are malignant. Benign thyroid
tumors are cysts, follicular adenomas, or nodular hyperplasia. All thyroid nodules greater than
1 cm in diameter, as well as nodules not responding to thyroxine therapy, should be sampled by
thin-needle puncture. Thus, diagnosis of thyroid cancer is initially a matter of palpation,
sonography, scintigraphy, and fine-needle biopsy. Some 80% of all malignant tumors are
well-differentiated follicular (approximately
40%) or papillary (approximately 40%) carcinomas. In areas of sufficient iodine uptake, the
rate of papillary carcinomas is increased,
whereas that of follicular carcinomas is decreased. The number of anaplastic tumors varies between 5% and 15% according to the area,
and 5% are medullary cancer. 41 The oncocytic
variant has a poorer prognosis, most probably
because of the decreased radioiodine uptake.
Special interest should be given to solitary
nodules developing in patients who had re-
99
ceived irradiation to the neck during childhood.
There are a variety of more or less agressive
treatment concepts, including hemithyroidectomy, total or subtotal thyroidectomy, and radioiodine therapy, as well as percutaneous radiation therapy. However, it should be stressed
that an optimal follow-up, including a wholebody scan with 1-131 and hTG determinations is
only possible if the thyroid is eliminated by
radioiodine therapy. 33 In recent years, imaging
with TI-201 and Tc-99m sestamibi (MIBI) has
gained increasing clinical interest, especially in
patients with metastases not accumulating radioiodine.
Prerequisites of each follow-up investigation
are anamnesis and clinical investigation, including palpation of the neck and lymph nodes,
followed by an ultrasound exploration of the
neck. If the patient's thyroid is irradiated, an
annual whole-body scan with 1-131 may be
performed during the first 3 years. The frequency may be decreased by using Thallium or
MIBI scintigraphy. Supersensitive hTG investigations are performed every 6 months during
the first 3 years, once a year up to 5 years, and
every second year thereafter. The optimal thyroid hormone substitution is evaluated at 10
weeks and 6 months after completion of therapy.
The L-thyroxine dosage is augmented until the
patient has a negative T R H test result or
suppressed TSH-IRMA. Thereafter, the laboratory tests include evaluation of T4 and T3 as
well as of TSH, the normal value of the latter
being less than 0.1 U/L.
The combination of whole-body scanning and
evaluation of hTG serum concentration seems
to be necessary, because there are either patients with a negative 1-131 scan but positive
hTG results or with positive whole-body scan
and a negative hTG result.
Anaplastic Thyroid Cancer
The majority (80% to 90%) of patients die
within 1 year. Because of the lack of iodine
accumulation, only (unspecific) tumor scintigraphy (TI-201, MIBI) may be performed in addition to sonography, computed tomography (CT),
or magnetic resonance imaging (MRI). Sometimes tumor markers such as carbinoembryonic
antigen (CEA) and alteplase recombinant
100
BIERSACK AND GRONWALD
(TPA) may be helpful to monitor the course of
disease.
Medullary Cancer
In patients with medullary cancer, multiple
endocrine neoplasia (MEN) has to be ruled out.
Investigations include CT and sonography study
of the adrenals, as well as scintigraphy with
metaiodobenzyl guanadine (MIBG). The family
must be screened for MEN II. After surgery,
the pentagastrin test (thyrocalcitonin before
and after application of pentagastrin) is most
useful in the early detection of cancer remnants
or metastaseS. This procedure has to be performed every 3 months for 1 year and every 6
months within the next 2 years. CEA and TPA
may be helpful as additional tumor markers. In
a case of suspected metastasis, tumor scintigraphy using T1-201, MIBI, or dimercaptosuccinate
should be performed.
PARATHYROID GLAND
The diagnosis primary hyperparathyroidism
(pHPT) is assessed with an increasing rate in
the course of routine screening examinations
because autoanalyzers are measuring serum
calcium and inorganic phosphorus. Therefore,
progressive stages of this disease, including
changes of the skeleton (eg, osteodystrophia
fibrosa cystica42) and complications regarding
the central nervous system, have become rare in
civilized countries. Renal complications (most
often nephrolithiasis) can be observed frequently; arterial hypertension is also an early
sign of hyperparathyroidism. 43 But many patients (about 30%) are asymptomatic when the
diagnosis pHPT is proven by increased serum
calcium and parathyroid hormone levels. Although malignancy is the most frequent cause of
hypercalcemia, the second most frequent reason is pHPT. In about 80% to 90% of cases, a
benign solitary adenoma of the parathyroid
gland is the cause for HPT, whereas a hyperplasia of all 4 glands occurs in about 10% to 15% of
all cases. Rare causes of a HPT are the MEN II
syndrome and carcinomas of the parathyroid
gland.
The surgical removal of a benign adenoma of
the parathyroid gland, which is more frequently
localized in the caudal glands, is not associated
with high risks and should be performed be-
cause complications can occur very rapidly and
are partly irreversible (eg, demineralization of
bone and destruction of renal parenchyma after
obstruction). Surgical intervention should include the inspection of all four parathyroid
glands because, particularly in older patients,
multiple adenomas should be considered, in
addition to hyperplasia. During the first operation, the diseased glands are detected in more
than 90% of all cases by the surgeon. Ectopic
adenomas, which are the main source of persisting HPT after surgery, can be localized within
the thyroid gland, the carotid sheath, the tracheal-esophageal groove, the thymus, or the
mediastinum.
SCINTIGRAPHY
Imaging using Se-75-1abeled methionine,
which was introduced in the early 1960s, 44 has
been replaced by TI-201/Tc-99m and, recently,
by Tc-99m-MIBI scintigraphy.
IMAGING TECHNIQUES
Tl-201 / Tc-99m-Pertechnetate Scintigraphy
Initially, 74 MBq (2 mCi) of T1-201 chloride,
which accumulates in the thyroid and parathyroid glands, is injected intravenously. Immediately after the tracer administration, imaging
for about 15 minutes should be started using a
gamma camera equipped with a pinhole collimator, if available. Sequential studies have the
advantage of motion artifacts that can be corrected easier after the acquisition. At the end of
the first acquisition, 74 MBq (2 mCi) of Tc-99mpertechnetate, which accumulates only in the
thyroid gland, is injected. Alternatively, 1-123
can be used, but no superiority of the latter
isotope has been proven. Imaging for another
15 minutes can be started about 5 minutes after
the second injection. Because motion correction between both studies is difficult and cannot
replace an exactly performed study, it should be
emphasized that the second acquisition is performed in the identical position of the patient.
Thereafter, the second image is subtracted from
the first one to obtain a parathyroid scintigram.
The normalization procedure (subtracting the
correct amount of count density) is important
for the interpretation of the results and requires
an experienced observer. It is essential to include imaging of the mediastinum to avoid
ENDOCRINOLOGICAL APPLICATIONS
missing the ectopic parathyroid tissue. It is also
possible to perform the technetium (or iodine)
imaging before the thallium imaging. Using the
latter procedure, a scatter correction also has to
be performed by acquiring an additional image
in the thallium energy window before the T1
injection.
Tc-99m-MIBI Scintigraphy
A total of 555 to 750 MBq (15 to 20 mCi) of
the tracer is injected intravenously. An early
scan should be performed about 15 minutes
postinjection (PI) to obtain an anatomical reference image for the thyroid gland localization
(Fig 3). Thyroid gland and parathyroid gland
initially accumulate the tracer. In the second
scan, which should be performed about 3 hours
PI, the uptake within normal thyroid tissue is
low, whereas parathyroid adenomas or hyper-
101
plastic glands show a significant retention of the
substance. In cases possibly having mediastinal
ectopic tissue, a single photon emission computer tomography (SPECT) acquisition of the
mediastinum should be performed. Geatti et
a145 combined sestamibi scintigraphy with Tc99m-pertechnetate subtraction and achieved a
very high sensitivity of more than 90%. A
combination of MIBI with 1-123 scintigraphy
has also been described. 46
CLINICAL APPLICATION OF SCINTIGRAPHY
Sensitivity and specificity of both scintigraphic procedures are in the same range (70%
to 90%) as other imaging techniques. 47-56 Patient selection influences the sensitivity. If only
symptomatic patients with markedly increased
calcium and parathyroid hormone values are
studied, sensitivity can reach more than 90%.
Fig 3. Bilateral parathyroid adenomas, Scintigraphy with Tc-99m MIBI 15 minutes PI (A) and 3 hours PI; {B) Sonography shows
nodules in the left (C} and right (D} thyroid lobe.
102
The dependence of the sensitivity on the
adenomas size is not as great as in morphological techniques, because the amount of tracer
uptake, which is influenced by several factors
(eg, cellularity, vascularity, and mitochondria
content 56) plays an important role in the sensitivity of scintigraphic detection. An adenoma of
only 60-mg weight has been visualized by T1-201/
Tc-99m scintigraphy. 57 The normal threshold
for scintigraphic detection is suggested to be
about 0.3 to 0.5 g by the majority of the
investigators. In comparison with other methods, one major advantage of scintigraphy is that
previous surgery does not decrease specificity or
sensitivity to a significant extent. This finding is
important because the preoperative imaging is
of much more clinical value before the second
intervention. During the first operation, all four
glands are inspected by the surgeon in almost all
cases. A disadvantage of TI-201 and Tc-99m
MIBI is the accumulation of both tracers in
circumscribed thyroid structures as well (eg,
adenomas, carcinomas, and Hodgkin's lymphoma). 52-6~Particularly in metastatic tumors,
which can be associated with hypercalcemia,
false-positive results must be considered because of TI-201 (or Tc-99m-MIBI) uptake in
neck metastases. 59 The nonspecific uptake in
circumscribed thyroid lesions, which can vary
interindividually and is not useful in distinguishing malignant from benign thyroid diseases, 6~
markedly decreases specificity in patients with
thyroid nodules. Therefore, if hot spots are
detected in the MIBI image, which cannot be
clearly separated from the thyroid gland, thyroid scintigraphy using Tc-99m-pertechnetate
or 1-123 should also be performed to exclude,
eg, a toxic adenoma. In patients with brown
tumors, TI-201 uptake in these bone structures 61,62 must be considered to cause falsepositive results, if it is localized, eg, in the
sternum or clavicula. 62 Sensitivity of scintigraphic techniques is remarkably influenced by
the localization of an adenoma. 63Because lower
pole tumors are frequently beneath the thyroid
gland, whereas upper pole tumors lay behind
the thyroid gland in most cases, sensitivity has
been described to be markedly higher for lower
pole adenomas by Corstens et al. 63 In contrast,
Sandrock et a156did not observe any correlation
between detection rate (using TI-201/Tc-99m
BIERSACK AND GRONWALD
scintigraphy) and age, sex, adenoma versus
hyperplasia, anatomic localization (upper/
lower pole, left/right), serum parathormone
levels, and prior surgery. Most investigators
found sensitivity to be markedly higher for
primary HPT than for secondary or tertiary
HPT. Adenomas can be detected more accurately than hyperplastic glands. 48,64-66In a small
series of patients, Adalet et a148found a sensitivity of only 25% for hyperplastic glands in
patients suffering from renal failure.
Mediastinal ectopic parathyroid tissue (1.5-cm
diameter), stimulated by abnormalities in calcium and vitamin D metabolism caused by renal
failure, has been successfully detected with
T1-201 scintigraphy. 67 The major advantage of
Tc-99m sestamibi compared with T1-201/Tc99m is the higher radiation energy of Tc-99m,
which renders possible an improved detection
of posteriorly or mediastinal located adenomas
and additional SPECT imaging. Some investigators found a higher sensitivity for sestamibi. 45,51
In contrast to the T1-201/Tc-99m scintigraphy,
the Tc-99m sestamibi imaging is not so susceptible to motion artifacts because no image
subtraction is needed, and an acquisition can be
repeated without difficulties if patient motion
has been recognized. Tc-99m sestamibi has
been shown to be able to visualize also ectopic
autotransplanted tissue in the forearm. 68 An
increased uptake of Tc-99m sestamibi in hyperthyroidism 69 must be considered in patients
suffering from both diseases. Nevertheless,
Bockisch et al 7~ showed a very high specificity
for Tc-99m-sestamibi imaging; the study also
included some patients with selected thyroid
diseases. A small study directly comparing T1201/Tc-99m and Tc-99m-sestamibi imaging 47
showed both techniques to be equivalent. Tc99m-sestamibi scintigraphy needs less acquisition (camera) time (about 20 minutes) than
TI-201/Tc-99m scintigraphy (about 50 minutes), but the total time is higher (3 hours from
injection until the end of the second scan).
Radiation exposure is lower using Tc-99m sestamibi than T1-201/Tc-99m. The costs of sestamibi imaging are not higher if the study is
performed together with cardiac studies in other
patients on the same day.
ENDOCRINOLOGICAL APPLICATIONS
CONCURRENT METHODS
Ultrasonography
Normal parathyroid glands cannot be imaged
ultrasonographically in most cases because they
are only a few millimeters in diameter. Adenomas, hyperplastic glands, and carcinomas are
typically homogenously hypoechoic or anechoic. 71 Because many thyroid nodules also
show reduced echo, the differentiation between
thyroid and parathyroid adenomas is often difficult using only ultrasonography, particularly in
the detection of intrathyroidally localized parathyroid adenomas. Ultrasound has the highest
sensitivity for adenomas at the lower pole of the
thyroid gland, the area that is easiest to explore
surgically. Sensitivity of ultrasound depends on
the lesion's side, more than of scintigraphy. The
technique is inferior to other imaging procedures in the detection of retrotracheal, retroesophageal, substernal, or mediastinal adenomas.
103
MRI is about 70% in the neck and 85% in the
mediastinum. There is no clearcut threshold
volume for the detection with MRI. 72 Particularly in the detection of intrathoracic parathyroid tissue, MRI is markedly superior to the
other imaging techniques and is the method of
choice if intrathoracic adenomas are suspected.
Because of the high costs of this technique, it is
not routinely performed before initial surgery.
Angiography and Selective Venous
Blood Sampling
This method has the disadvantage of being
invasive and it has not an a priori superior
sensitivity compared with other methods. Therefore, it is not used before the first operation. But
before reoperation, it becomes important, particularly if the other imaging techniques have
not successfully visualized the tumor, because
the second surgical intervention is associated
with a higher risk.
FDG-PET
CT Scan
Normal-sized glands cannot be visualized
under normal conditions with CT scanning. For
retrosternal, mediastinal, or retroclavicular adenomas, CT scanning is particularly useful,
whereas in the evaluation of the neck, bone and
swallowing artifacts can decrease its sensitivity.
Accuracy can be improved by the use of contrast
media, to reliably distinguish vessels from other
structures, eg, parathyroid adenomas. Some
adenomas (about 25%) show contrast enhancement, depending on the tumor's size. 72 The
adenoma's size has the highest influence on the
sensitivity of the CT scan. 73
MR/
Even using surface coils normal parathyroid
glands can hardly be detected by MRI, as seen
with the other imaging techniques. The typical
pattern of a parathyroid adenoma is a signal
similar to that of the thyroid gland or muscle in
the Tl-weighted image and similar or higher
than fat on the T2-weighted image. 74 But other
patterns also can occur, particularly in parathyroid hemorrhage. The use of contrast media
(Gd-DTPA) and the inclusion of T1- and T2weighted images improves the sensitivity of
MRI. 74,75 In recurrent HPT, the sensitivity of
Recently, sestamibi-SPECT imaging has been
compared with FDG-PET, 76showing PET to be
the more sensitive technique.
CONCLUSION
In conclusion, the best sensitivity and specificity can be achieved by combining various imaging procedures, eg, scintigraphy with ultrasonography. Adenomas, the most frequent cause for
primary HPT, can be detected in more than
90% of all cases with the combination of scintigraphy and ultrasonography. Preoperative localization using imaging techniques should be
routinely performed because it is useful to
optimize surgical strategy and can markedly
reduce operation time if combined with intraoperative PTH measurement. 77 In recurrent/
persistent HPT or ectopic parathyroid tissue,
imaging is essential. Scintigraphy is most important in recurrent HPT after previously unsuccessful surgery because its sensitivity is not decreased significantly by previous surgery.
THE ADRENAL CORTEX
Conn 's and Cushing's Syndromes
In Conn's and Cushing's syndrome, CT or
sonography and scintigraphy together allow a
diagnosis of an enlarged adrenal that is function-
104
BIERSACK AND GRI~INWALD
ally active. In many cases, adrenal vein catheterization as an invasive technique can be avoided.
The findings in Cushing's syndrome are usually
more clearcut, and scintigraphy can contribute
to the diagnosis of bilateral hyperplasia as a
consequence of primary or ectopic ACTH production. In Cushing's adenoma, the tumor produces excessive cortisol, which suppresses pituitary corticotropin production, and, thus, tracer
uptake by the contralateral normal adrenal is
suppressed. In adrenogenital syndrome, both
glands show high uptake because of bilateral
renal hyperplasia. The sensitivity and specificity
for detecting an adenoma is more than 95%; for
detecting bilateral adrenal hyperplasia it is about
80%. 78,79 Adrenal cortical carcinoma causing
Cushing's syndrome usually shows no uptake.
Only rare cases of well-differentiated carcinoma
show uptake, s~ A large mass on CT that shows
no uptake should be considered as potentially
malignant. Conn's syndrome is usually produced by an adenoma (70% to 80%) or idiopathic bilateral hyperplasia (20% to 30%). Rare
causes of this disease are carcinomas. The
diagnosis is established by the proof of increased renal potassium excretion, increased
aldosterone, decreased renin, and associated
hypokalemic alkalosis. Further procedures include US and CT. Sensitivity for an adenoma
producing Conn's syndrome is more than
95%.78, 79
In conclusion, scintigraphy of the adrenal
cortex has a high level of accuracy that can
guide the surgeon as the majority of the patients
have to undergo operation.
with 2 mg of dexamethason daily (starting 2 days
before the injection) may improve the results.
SPECT is only necessary in equivocal results.
Some investigators sl advocate the use of Se-75
selenocholesterol (200 txCi [8 MBq]), which is
taken up by the adrenal gland to a slightly
greater extent than iodocholesterol. Above that,
the gamma-ray characteristics are better for the
conventional gamma camera. 81 Imaging with
Se-75 selenocholesterol is performed 1 and 2
weeks after the injection.
THE ADRENAL MEDULLA AND
PARAGANGLIOMA
The main diagnostic indication for the use of
MIBG is the proof of pheochromocytoma and
paraganglioma in patients presenting with hypertension. Another indication is an incidental
finding of an adrenal mass on CT. For pheochromocytoma, the conventional history of palpitations and episodic hypertension may be absent,
but urinary catecholamine metabolites are usually increased. In neuroblastoma, carcinoid, and
medullary carcinoma of the thyroid, the indication for imaging is not so much for diagnosis but
in preparation for the possibility of MIBG
therapy, sl
Ninety percent of pheochromocytomas are
benign, only 10% are malignant. Ninety percent
of the tumors are localized in the adrenal
marrow or the plexus of the sympatic nerve
system of the abdomen. Ten percent of pheochromocytomas are bilateral in heriditary diseases (MEN).
SCINTIGRAPHY
SCINTIGRAPHY
Usually, 1-131 (aldosterol [I-131-6-iodmethyl19-norcholesterol]) is injected (adults, 0.5 mCi
[19 MBq]; children, 20 ixCi [740 kBq]/kg). In
some cases, allergic side effects are observed.
To block the thyroid iodine uptake, 1 day before
the injection and the following 7 days 3 • 30
drops of perchlorate are administered. Images
are obtained from days 3 to 5 PI in anterior and
posterior projection. Whole-body scans are necessary, if ectopic lesions are expected. All patients receive a laxative. On day 5, a scan with
0.5 mCi Tc-99m DMSA should be performed
for better landmarking, If aldosterol-producing
tumors are suspected, suppression scintigraphy
Usually, I-131-benzylguanidine is injected (0.5
to 1 mCi [18.5 to 37 MBq]) in adults and in
children (0.2 to 0.4 mCi [7.4 to 15 MBq]). sl
Reserpine and tricyclic psychopharmaceuticals
may interfere with the uptake and should be
stopped 1 week before the investigation. Side
effects may be heartpain, tachycardia, transient
hypertension, and abdominal sensations. In some
cases, allergic reactions with exanthema and
hypotension may occur. The thyroid iodine
uptake should be suppressed by 3 x 30 drops
(60 mg) of potassium iodide 1 day before and 7
days after the injection. Scans in anterior and
posterior projection are obtained after 24, 48,
and 72 hours and after 7 days, including the
ENDOCRINOLOGICAL APPLICATIONS
abdomen and the pelvic region as well as thorax,
head, and neck. Bone and kidney scans may
serve for better landmarks.
Alternatively, 1-123 MIBG may be used: 5
mCi (185 MBq) for adults and 2.5 mCi (92.5
MBq) for children. Images are taken 24 and 48
hours PI. Mozley et a182 concluded that 1-123
MIBG may be the most sensitive screening test
available for the diagnosis of phaeochromacytoma.
1-131 MIBG scintigraphy has a high sensitivity of about 80% and greater than 90% specificity (Fig 4). 83,84 False-negative results can be
obtained in cystic and hemorrhagic tumors, in
addition to small lesions. 84
Paragangliomas can be detected with a high
sensitivity scintigraphy (> 90%) using the somatostatin analogue In- 111 octreotide.85
Recently, Shulkin et a186 developed a radiopharmaceutical for PET imaging in pheochromocytomas. C-1 l-labeled hydroxyephedrine has
been shown to accumulate rapidly in pheochromocytomas, rendering possible a tumor visualization as early as 5 minutes after tracer injection. In the patients studied in this series, all
those with 1-131-MIBG identified tumors were
also detected with PET using hydroxyephedrine. Image quality was superior with PET
imaging.
1-131 MIBG THERAPY
Moderate therapeutic success was achieved
in malignant pheochromacytoma, as well as in
childhood neuroblastoma. This therapy was also
used in paragangliomas, carcinoid tumors, and
medullary carcinoma of the thyroid. 87For therapeutic purposes, 200 to 300 mCi (8 to 12 GBq) is
usually administered in adults. In intensive
malignant bone marrow involvement, aplastic
syndromes should be considered. Particularly in
childhood neuroblastoma, better results may be
achieved when MIBG therapy is used before
chemotherapy, because well-differentiated tumor (which may show high-MIBG uptake) converts to relatively undifferentiated forms. Both
completed remissions and partial remissions
were obtained, but the therapy is palliative
rather than curative. In some cases, several
doses up to 400 mCi (16 GBq) may be required.
105
BONE MINERAL CONTENT (BMC)
The measurement of BMC is now performed
using quantitative CT (QCT) or dual energy
x-ray absorptiometry (DEXA). National health
insurances no longer pay for dual photon absorptiometry (GD-153) evaluation as of January
1995. Although the market is relatively small, a
controversial discussion has started in Europe
whether national health insurances should pay
for this procedure. Most of the bone densitometry procedures are performed by orthopedic
and internal medicine specialists or radiologists.
However, most of the nuclear medicine institutions and specialists in private practices do
investigate some patients. Recently, a multicenter European study on the standardization
of bone densidometry procedures was published, as Twenty-six European centers participated in this research. The present results
obtained with an internationally accepted European spine and forearm phantom can now serve
to stimulate the manufacturers to improve the
comparability of bone measurement systems.
The trial used QCT and DEXA equipment.
The main group of patients who may benefit
from bone densitometry may be postmenopausal women. Many trials have proven a positive effect of an estrogen prophylaxis in postmenopausal women with low BMC. 89 Other
diseases that require bone densitometry are
cases with long-term cortisone treatment and
G N R H treatment. Beyond that, BMC measurement may be used to check fluoride or magnesium treatment of osteoporosis. Because longitudinal investigations are necessary in these
cases, DEXA offers a superior reproducibility
of 0.9% compared with DPA. With respect to
the regular annual BMC loss of 2% (after the
age of 35 years), BMC measurements should be
performed only every second year. Early diagnosis and precise monitoring of osteopenia are
medically useful, if a respective treatment is
available. This is true for bone mineral loss
caused by deficiency of androgens, estrogens,
vitamin D metabolites, or excess of parathyroid
hormone, glucocorticoids, or thyroid hormones.
In all of these circumstances, successful treatment is possible. Thus, in these patients the
measurement of bone density is useful, 9~ especially when used in presymptomatic stages of
the disease.
106
BIERSACK AND GRONWALD
ease. All other forms of pituitary tumors are
very rare. The neuropeptide somatostatin (somatotropin-release-inhibiting factor [SRIF])
was identified in the early 1970s in the hypothalam u s . 92 Somatostatin receptors have been identified in vivo and in vitro on the cell surface of
various tissues (eg, neuroendocrine tissue and
intracranial tumors). 93-95Somatostatin has been
proven to be effective in the suppression of GH
secretion and tumor size reduction. Somatostatin has the disadvantage of a very short half
life (2 to 3 minutes). Recently, a long-acting
(half-life of about 2 hours) somatostatin analogon, octreotide, has been developed that is
more potent than somatostatin and is used in
the medical treatment of GH- and TSHsecreting pituitary tumors. 96 Prolactinomas or
ACTH secreting tumors cannot be treated sufficiently with octreotide. The GH responses to
octreotide are dependent on the somatostatin
receptor status. 96
Fig 4. Malignant pheochromocytoma. Scintigraphy with
1-131-mlBG 3 days PI; multiple lesions in the region of the left
kidney caused by recidivation of malignant pheochromocytoma and nephrectomy left (posterior projection).
PITUITARY
Tumors of the pituitary are most often benign
adenomas, whereas carcinomas occur only
rarely. Seventy-five percent of the pituitary
adenomas are endocrine active tumors, whereas
25% are inactive.9~Among the endocrine active
tumors, prolactinomas are the most frequent
forms of tumors (35%); the second most frequent are growth hormone (GH)-producing
adenomas (20%).91 Nonfunctioning microadenomas (diameter < 10 mm) are often asymptomatic for a long time. They are detected when
causing neurological or ophthalmological symptoms (bitemporal hemianopsia, caused by chiasmal compression). Prolactinomas present with
secondary amenorrhea in women, libido decrease in men, and symptoms of pituitary insuffiency in macroprolactinomas. GH-producing
adenomas present clinically as acromegaly. In
some cases, a cosecretion of prolactin and GH
by pituitary adenomas exists. Paraneoplastic
GH-releasing hormone (GH-RH) occurs only
rarely. ACTH-secreting adenomas account for
about 10% of all benign pituitary adenomas,
and become clinically evident as Cushing's dis-
SCINTIGRAPHY
Nonspecific imaging with Tc-99m-pertechnetate or Tc-99m-DTPA depends on the tumor
vascularity and is nowadays replaced by other
techniques. [I-123-Tyr3]-octreotide scintigraphy was introduced in the late 1980s and has
been useful in the in vivo imaging of somatostatin receptors. 97,98 [In-lll-DTPA-D-PheI] octreotide has the advantage of a longer effective half-life99 and has mainly replaced
scintigraphy with radioiodinated octreotide in
various fields. 1~176176
As it could be expected from
in vitro studies and from therapeutic experiences, sensitivity of octreotide scintigraphy was
high in GH-secreting adenomas of the pituitary.
A visualization of the pituitary tumor with
octreotide seen in Fig 5 is predictive of good
response to therapeutic administration of octreotide. l~ Scheidhauer et aP ~ did not observe a
correlation between endocrine activity of the
tumors and scintigraphic visualization. But nonfunctioning adenomas also can present with an
increased tracer uptake. 98,99 Ga-67/Ga-68[DFO]-octreotide is a potential tracer for PET
imaging of somatostatin receptor-positive tumors. 1~ Prolactinomas can also be detected by
1-123 iodobenzamide, which is used to visualize
cerebral dopamine-Dz receptors (eg, in Wil-
ENDOCRINOLOGICAL APPLICATIONS
107
Fig 5. Adenoma of the pituitary. Scintigraphy with In-111
octreotide shows increased somatostatin receptor density of
the tumor.
son's disease and under therapy with typical and
atypical neuroleptics).
IMAGING TECHNIQUE
For the octreotide scintigraphy, the gamma
camera should be equipped with a medium
energy parallel-hole collimator. Both In-111
windows (172 keV and 245 keV) should be used
for the acquisition. The study should include a
dynamic acquisition, started immediately after
injection of 111 to 185 MBq (3 to 5 mCi)
In-lll--octreotide. Four and 24 hours after
tracer injection, a SPECT study of the head
should be performed in addition, including a
semiquantitative evaluation. The SPECT study
should be acquired using 60 or 64 projections
(at least 30 seconds each) with a 64 x 64 matrix.
REFERENCES
1. G~irtner H: Pathophysiologie und Definition des
Krankheitsbildes, in K6bberling J, Pickardt CR (eds):
Struma. Berlin, Germany, Springer, 1990, pp 7-13
2. Stanbury JB, Hetzei BS: Endemic goiter and endemic
cretinism. New York, NY, Wiley, 1980
3. Ermans AM: Endemic Goiter, in Ingbar SH, Braverman LE (eds): Werner's the Thyroid--A Fundamental and
Clinical Text (ed 5). Philadelphia, PA, Lippincott, 1986, pp
705-721
4. Kriiskemper AL, Joseph K, KObberling J, et al: Klassifikation der Schilddriisenkrankheiten. Neue Fassung der
"Empfehlungen der Sektion Schilddriise der Deutschen
Gesell-schaft ftir Endokrinologie." Int Welt 8:47-49, 1985
5. G~irtner H: Sonographie in: K~bberling J, Pickardt Cr
(eds): Struma. Berlin, Germany, Springer, 1990, pp 65-73
6. Brunn J, Block U, Rough G, et al: Volumetric der
Schilddriisenlappen mittels Real-Time-Sonographie. Dtsch
Med Wochenschr 106:1338-1340, 1981
7. Joseph K: Statische, dynamische und quantifizierte
Schilddriisen-szintigraphie. Nuklearmediziner 2:83-101,1979
8. Mahlstedt J: Statische und dynamische Schilddriisenszintigraphie. Nuklearmediziner 9:15-26, 1986
9. Schicha H, Emrich D-. Schilddriisenszintigraphie--ist
sic noch zeitgemiiB? Dtsch Arzteb187:4024-4030, 1990
10. Shimmins J, Alexander WD, McLarty DG: 99m-Tc
pertechnetate for measuring thyroid suppressibility. J Nucl
Med 12:51-54, 1971
11. Biersack H J, Hotze AL: The clinician and the thyroid. Eur J Nucl Med 18:761-778, 1991
12. Bayer MF: Performance criteria for appropriate characterization of "(highly) sensitive" thyrotropin assays. Clin
Chem 33:630-631, 1987
13. Tort AD: Thyroxine replacement treatment: Clinical
judgement or biochemical control? Br Med J 291:233-324,
1985
14. Bockisch A, Grfinwald F, Ruhlmann J, et al: Bestimmungen des basalen TSH-Spiegeis mit einem supersensi-
108
tiven IRMA--diagnostische Aussagekraft im VergIeich mit
dem TRH-Test. Nucl Compact 19:19-26, 1988
15. Herle Van AJ, Uller RP, Matthews NL, et al:
Radioimmunoassay for measurement of thyroglobuiin in
human serum. J Clin Invest 52:1320-1327, 1973
16. Schlumberger M, Travagli JP, Fragu P, et al: Follow-up of patients with differentiated thyroid carcinoma,
Experience at Institut Gustave-Roussy, Villejuif. Eur J
Cancer 24:345-350, 1988
17. Hiifner M, Reiners C (eds): Thyroglobulin and Thyroglobulin Anti-Bodies in the Follow-Up of Thyroid Cancer
and Endemic Goiter. Stuttgart, Germany, Thieme, 1987
18. Hotze A, Bockisch A, Briele B, et al: Therapie der
Jodmangelstruma mit Levothyroxin und einer Kombination
aus Jodid und Levothyroxin. Nucl Compact 20:166-170,
1989
19. Gutekunst R, Smolarek H, W/ichter W, et al: Strumaepidemiologie. IV. Schilddriisenvoluminabei deutschen und
schwedischen Schulkindern. Dtsch Med Wochenschr 109:5054, 1985
20. Biersack HJ, Albrecht W, Oehr P, et al: Ermittlung
der optimalen L-Thyroxin-Dosis zur Behand!ung der Nanden Struma. Dtsch Med Wochenschr 108:1269-1273, 1983
21. Hintze G, K6bberling J: Iodine vs thyroxine. A
changing concept Of therapy in endemic goiter? Klin
Wochenschr 65:583-59L 1987
22. Hamburger JI: Solitary autonomously functioning
thyroid lesions. Diagnosis, clinical features and pathogenetic considerations. Am J Med 58:740-749, 1975
23. Joseph K: Allgemeines zur funktionellen thyreoidalen Autonomie, in B6rner W, Weinheimer B (eds): Schilddrtise 1989--Prim~ire Diagnostik und Verlaufskontrolle der
Struma. Berlin, Germany, De Gruyter, 1991, pp 174-201
24. Woeber KA: Graves' disease--General considerations, in Ingbar SH, Braverman LE (eds): Werner's the
Thyroid--A Fundamental and Clinical Text (ed 5). Philadelphia, PA, Lippincott, 1986, pp 982-986
25. Schicha A, Emrich D: Immunogene und nichtimmunogene Hyperthyreose. Dtsch Med Wochenschr 108:6,
11, 1983
26. Solomon DH: Treatment of Graves' hyperthyroidism, in Ingbar SH, Braverman LE (eds): Werner's the
Thyroid--A Fundamental and Clinical Text (ed 5). Philadelphia, PA, Lippincott, 1986, pp 987-1014
27. Pfannenstiel P, Colbow B: Schilddriisenkrankheiten
in der Schwangerschaft. Gyn~ikologe 23:47-52, 1990
28. Pinchera A, Bartalena L, Chiovato L, et al: Radiotherapy of Graves' ophthalmopathy, in Gormann CA, Waller
RR, Dyer JA (eds): The Eye and Orbit in Thyroid Disease.
New York, NY, Raven, 1984, pp 301-311
29. Hehrmann R: Allgemeines Vorgehen mit Verlaufskontrolle bei Struma mit Hyperthyreose, in BOrner W,
Weinheimer B (eds): Schilddrfise 1989--Prim~ire Diagnostik und Verlaufskontrolle der Struma. Berlin, Germany, De
Gruyter, 1991, pp 407-416
30. Friedman JM, Fialkow P: Genetic factors in thyroid
disease, in Ingbar SH, Braverman LE (eds): Werner's the
Thyroid--A Fundamental and Clinical Text (ed 5). Philadelphia, PA, Lippincott 1986, pp 634-650
31. Evered D: Subclinical hypothyroidism, in Ingbar SH,
Braverman LE (eds): Werner's the Thyroid--A Fundamen-
BIERSACK AND GRONWALD
taI and Clinical Text (ed 5). Philadelphia, PA, Lippincott,
1986, pp 1439-1444
32, Beierwaites WH: Carcinoma of the thyroid: Radionuclide diagnosis, therapy and follow-up, Clin Oncol 5:23-31,
1986
33. Biersack HJ, Winkler C: Neue Aspekte in Diagnostik
und Therapie des Schilddl'fisenkarzinoms. Stuttgart, Germany Schattauer, 1982
34. B6rner W, Reiners C: Schilddrtisenmalignome-Diagnostik, Therapie und Nachsorge: Stuttgart, Germany,
SchattaUer, 1987
35. Schelhout LJD, Creutzberg CL; Hanning JF, et al:
Multivariate analysis of survival in differentiated thyroid
cancer: The prognostic Significance of the age factor. Eur J
Cancer 24:331-337, 1988
36. Simpson WJ, Panzarella T, Carruthers JS, et al:
Papillary and follicular thyroid cancer: Impact of treatment
in 1587 patients. Int J Radiat Oncol Biol Phys 14:1063-1075,
1988
37. Mazzaferri EL: Treatment Of carcinoma of follicular
epithelium; in tngbar SH, Braverman LE (eds): Werner's
the Thyroid--A Fundamental and Clinical Text (ed 5).
Philadelphia, PA, Lippincott, 1986, pp 1329-1348
38. Melvin KE: Medullary carcinoma of the thyroid, in
Ingbar SH, Braverman LE (eds): Werner's the Thyroid--A
Fundamental and Clinical Text (ed 5). Philadelphia, PA,
Lippincott, 1986, pp I349-1362
39. Walfish PG: Miscellaneous tumors of the thyroid, in:
Ingbar SH, Braverman LE (eds): Werner's the Thyroid--A
Fundamental and Clinical Text (ed 5). Philadelphia, PA,
Lippincott, 1986, pp 1363-1376
40. Zimmermann D, Hay ID, Gough IR, et al: Papillary
thyroid carcinoma in children and adults: Long-term follow-up of 1039 patients conservatively treated at our institution during three decades. Surgery 104:1157-1166, 1988
4 L Hedinger C, Williams ED, Sobin LH: The WHO
histolog!cal claSsification of thyroid tumors: A commentary
on the second edition. Cancer 63:908-911 1989
42. Sch0mburgA, Griinwald F Menzel Ch, e t al: Regression Qf bone Scan lesions in hyperparathyroidism resembling
osseous metastases. Radiol Diagn 34:48-52, 1993
43. Hesch RD: Hyperparathyreoidismus, in Hesch (ed):
Endokrinologie, vol 4. Miinchen, Germany, Urban und
Schwarzenberg, 1989
44. DiGuilio W Beierwaltes WH: Parathyroid scanning
with selenium 75 labeled methionine. J Nucl Med 5:417-427;
1964
45. Geatti O, Shapiro B, Orsolon PG, et al: Localization
of parathyroid enlargement: Experience with technetium99m methoxyisobutylisonitrile and thallium-201 scintigraphy, ultras0nography and computed tomography. Eur J
Nucl Med 21:17-22, 1994
46. Burke GJ, Wei JP, Binet EF: Parathyroid scintigraphy with iodine-123 and Tc'99m-sestamibi: Imaging findings. Am J Roentgenol 161:1265-1268, 1993
47. Wilson M, Shinners P, Rowe B, et al: Tl-201/Tc99m04 subtraction scintigraphy is stil! the gold standard in
parathyroid localization. J Nucl Med 35:164, 1994 (abstr)
48. Adalet I, Hawkins T, Clark F, et al: Thalliumtechnetium-subtractionscintigraphy in secondary hyperparathyroidism. Eur J Nucl Med 21:509-513, 1994
49. Fogelman I, McKillop JH, Bessent RG, et al: Success-
ENDOCRINOLOGICAL APPLICATIONS
ful localisation of parathyroid adenomata by thallium-201
and technetium-99m subtraction scintigraphy: Description
of an improved technique. Eur J Nucl Med 9:545-547, 1984
50. Sandler MP, Patton JA: Multimodality imaging of the
thyroid and parathyroid glands. J Nucl Med 28:122-129,
1987
51. Taillefer R, Boucher Y, Potvin C, et al: Detection
and localization of parathyroid adenomas in patients with
hyperparathyroidism using a single radionuclide imaging
procedure with technetium-99m-sestamibi (double-phase
study). J Nucl Med 33:1801-1807, 1992
52. Ferlin G, Borsato N, Camerani M, et al: New perspectives in localizing enlarged parathyroids by technetiumthallium subtraction scan. J Nuci Med 24:438-441, 1983
53. Winzelberg GG, Hydovitz JD: Radionuclide imaging
of parathyroid tumors: Historical perspectives and newer
techniques. Semin Nucl Med 15:161-170, 1985
54. Potchen EJ: Parathyroid imaging---Current status
and future prospects (editorial). J Nucl Med 33:1807-1809,
1992
55. Miiller-G/irtner WH, Montz R, Schneider L, et al:
Lokalisationsdiagnostik vergrfBerter Nebenschilddriisen: die
TI-201/Tc-99m-Subtraktionsszintigraphie im Vergleich zur
5 MHz-Sonographie. Fortschr Roentgenstr 142:543-547,
1985
56. Sandrock D, Merino M J, Norton JA, et al: Ultrastructural histology correlates with results of thallium-201/
technetium-99m parathyroid subtraction scintigraphy. J Nucl
Med 34:24-29, 1993
57. Basarab RM: The evolving role of parathyroid seintigraphy. Clin Nucl Med 14:58-60, 1989
58. Griinwald F, Bollmann R, Schmitz P, et al: Falschpositives Thallium-201/Technetium-99m Subtraktionsszintigramm zur Darstellung der Nebensehilddriise bei einem
fetalen Schilddriisenadenom. Nucl Compact 21:195-196,
1990
59. Punt CJA, De Hooge P, Hoekstra JBL: False-positive
subtraction scintigram of the parathyroid glands due to
metastatic tumor. J Nucl Med 26:155-156, 1985
60. F61des I, Levay A, Stotz G: Comparative scanning of
thyroid nodules with technetium-99m pertechnetate and
technetium-99m methoxyisobutylisonitrile. Eur J Nucl Med
20:330-333, 1993
61. Durak H, Aras T, Sungur C, et al: TI-201 uptake in
brown tumors of hyperparathyroidism. Clin Nucl Med
12:931-935, 1991
62. Yang CJC, Seabold JE, Gurll NJ: Brown tumor of
bone: A potential source of false-positive thallium-201
localization. J Nucl Med 30:1264-1267, 1989
63. Corstens F, Ticheler C, de Boer H, et al: Low
sensitivity of parathyroid scintigraphy for upper pole adenomata and a new subtraction method to improve their
detectability. J Nucl Med 30:885, 1989 (abstr)
64. Borsato N, Zanco P, Camerani M, et al: Scintigraphy
of the parathyroid glands with TI-201: Experience with 250
operated patients. Nucl Med 28:26-28, 1989
65. Joseph K, Welcke U, HOffken H, et al: Lokalisation
von Parathyroidea-Adenomen mit Tc-99m-Sestamibi. Nucl
Med 33:A48, 1994 (abstr)
66. Beierwaltes WH: Endocrine imaging: Parathyroid,
adrenal cortex and medulla, and other endocrine tumors.
Part II. J Nucl Med 32:1627-1639, 1991
109
67. Lossef SV, Ziessman HA, Alijani MR, et al: Multiple
hyperfunctioning mediastinal parathyroid glands in a patient with tertiary hyperparathyroidism. Am J Roentgenol
161:285-286, 1993
68. Diaz M, Bockisch A, Hahn K, et al: Radionuclide
imaging with Tc-99m-sestamibi in atypically localized parathyroid adenomas. Nucl Med 33:42-45, 1994
69. Kao CH, Wang SJ, Liao SQ, et al: Quick diagnosis of
hyperthyroidism with semiquantitative 30-minute technetium-99m-methoxy-isobutyl-isonitrile thyroid uptake. J Nucl
Med 34:71-74, 1993
70. Bockisch A, Walgenbach S, Meyer G, et al: Evaluation of the specificity of Tc-99m-MIBI-scanning in the
detection of parathyroidal adenomas--A kinetic study. J
Nucl Med 35:A162, 1994 (abstr)
71. Reading C, Charboneau JW, James EM: High resolution parathyroid sonography. Am J Roentgenol 139:539546, 1982
72. Stark DD, Gooding GAW, Moss AA, et al: Parathyroid imaging: Comparison of high-resolution sonography.
Am J Roentgenoi 141:633-638, 1983
73. Stark DD, Moss AA, Gooding GAW, et al: Parathyroid scanning by computed tomography. Radiology 148:297299, 1983
74. Higgins CB, Auffermann W: MR imaging: Parathyroid gland, in Higgins CB, Auffermann W (eds): Endocrine
Imaging. Stuttgart, Germany, Thieme, 1994
75. Stevens SK, Chang JM, Clark OH, et al: Detection of
abnormal parathyroid glands in postoperative patients with
recurrent hyperparathyroidism. Am J Roentgenol 160:607612, 1993
76. Neumann DR, Esselstyn CB, MacIntyre WJ, et al:
Comparison of FDG PET and double-phase sestamibi
SPECT in the preoperative evaluation of primary hyperparathyroidism. J Nucl MOd 35:P68, 1994 (abstr)
77. Sfakianakis G, Foss J, Georgiou M, et al: The role of
preoperative SPECT-99mTc-sestamibi imaging and intraoperative PTH measurement in parathyroidectomy. J Nucl
Med 35:P68, 1994 (ahstr)
78. Shapiro B, Britton KE, Hawkins LA, et al: Clinical
experience with Se-75 Selenomethyl-cholesterol adrenal
imaging. Clin Endocrinol 15:19-27, 1981
79. Reschini E, Catania A: Clinical experience with
adrenal scanning agents iodine 131-19-iodocholesterol and
selenium 75-6 Selenomethylcholesterol. Eur J Nucl Med
18:817-823, 1991
80. Reschini E, Peracchi M: Uptake of Se-75-selenocholesterol by an adrenal carcinoma and its metastases. Eur J
Nucl Med 9:291-293, 1984
81. Britton KE: The Badgastein lecture--Nuclear endocrinology, in H6fer R, Bergmann H (eds): Radioaktive
Isotopen in Klinik und Forschung (Gastein International
Symposium). Vienna, Austria, Egermann 1992, pp 2-14
82. Mozley PD, Chun KK, Mohsin J, et al: The efficacy of
Iodine-123-MIBG as a screening test for pheochromocytoma. J Nucl Med 35:1138-1144, 1994
83. Sasaki Y, Kubo A, Kusakabe K, et al: The assessment
of clinical usefulness of 1-131-MIBG scintigraphy for localization of tumors of sympathetic and adrenomedullary
origin--A report of multicenter phase III clinical trials.
Kaku Igaku 29:1083-1098, 1992
84. Tsuji A, Shimomura O, Tomiguchi S, et al: Diagnosis
110
of phaeochromocytoma using 1-131-MIBG scintigraphy.
Kaku igaku 30:241-247, 1993
85. Kwekkeboom D J, van Urk H, Pauw BK, et al:
Octreotide scintigraphy for the detection of paragangliomas. J Nucl Med 34:873-878, 1993
86. Shulkin BL, Wieland DM, Schwaiger M, et al: PET
scanning with hydroxyephedrine: An approach to the localization of phaeochromocytoma. J Nucl Med 33:1125-1131,
1992
87. H0efnagel CA: Radionuclide therapy revisited. Eur J
NUcl Med 18:408-431, 1991
88. Dequeker J, Reeve J, Paerson J, et al: Multicentre
European COMAC-BME study on the standardisation of
bone densitometry procedures. Technol Health Care 1 !127131. 1993
89. Grady D. Rubin SM, Petitt DB: Hormone therapy to
prevent disease and prolong live in postmenopausal woman.
Ann Intern Med 117:1016-1037, 1992
90. Neer RM: The utility of single-photon absorptiometry and dual-energy x-ray absorptiometry. J Nucl Med
33:170-171. 1992
91. Gr/if KJ: Endocrinology: Pituitary, in Higgins CB.
Auffermann W (eds): Endocrine Imaging. Stuttgart. Germany, Thieme. 1994
92. Brazeau P, Vale W, Burgus R. et al: Hypothalamic
polypeptide that inhibits the secretion of immttnoreactive
pituitary growth hormone secretion. Science 129:77-79,
1982
93. Reubi JC. Lang W, Maurer R, et al: Distribution and
biochemical characterization of somatostatin receptors in
tumors of the human central nervous system. Cancer Res
47:5758-5764, 1984
94. Lamberts SWJ. Krenning EP. Bakker WH. et al:
Somatostatin receptor imaging in the diagnosis of pituitary
and parasellar tumors, in Melmed S. Robbins RJ (eds):
Molecular Advances in Pituitary Disorders. Oxford, UK.
Blackwell, 1991, pp 285-292
95. Krenning EP. Bakker WH, Breemann WAP. et al:
Localisation of endocrine-related tumours with radioiodinated analogue of somatostatin. Lancet ii:242-244. 1989
BIERSACK AND GRONWALD
96. Reubi JC, Landolt AM: The growth hormone responses to octreotide in acromegaly correlate with adenoma
somatostatin receptor status. J Clin Endocrinol Metab
68:844-850, 1989
97. Bakker WH, Krenning EP, Breeman WA, et al: In
vivo use of a radioiodinated somatostatin analogue: Dynamics, metabolism, and binding to somatostatin receptorpositive tumors in man. J Nucl Med 32:1184-1189, 1991
98. Faglia G, Bazzoni N, Spada A, et al: In vivo detection
of somatostatin receptors in patients with functionless
pituitary adenomas by means of a radioiodinated analog of
somatostatin ([I-123]SDZ 204-090). J Clin Endocrinol Metab
73:850-856, 1991
99. Krenning EP, Kwekkeboom D J, Bakker WH, et al:
Somatostatin receptor scintigraphy with [In-111-DTPA-DPhel] - and [I-123-Tyra]-octreotide: The Rotterdam experience with more than 1000 patients. Eur J Nucl Med
20:716-731, 1993
100. Luyken C, Hildebrandt G, Scheidhauer K, et al:
Diagnostische Wertigkeit der S0nlatostatin-RezeptorSzintigraphie bei Patienten mit intrakraniellen Raumforderungen. Nuklearmediziner 16:3i7-324, 1993
101. Rieker O, Hotze AL, Briele B, et al: Rezeptorszintigraphie mit Somatostatin-Analoga. Ein neues bildgebendes
Verfahren in der Nuklearmedizin. Endoscopy 4:262-266,
1992
102. Lamberts SWJ, de Herder WW, Kwekkeboom DJ,
et al: Current tools in the diagnosis of pituitary tumours.
Acta Endocrinol 129:6-12, 1993 (suppl 1)
103. Scheidhauer K, Hildebrandt G, Luyken C, et al:
Somatostatin receptor scintigraphy in brain tumors and
pituitary tumors. Horm Metab Res 27;59-62, 1993 (suppl)
104. Smith-JoneS PM, Stolz B, Bruns C, et al: Gallium-67/
Gallium-68-[DFO]-octre0tide--A potentia ! radiopharmaceutical for PET imaging of sornatostatin receptor-positive
tumors: Synthesisand radiolabeling in vitro and preliminary
in vivo studies. J Nucl Med 35:317-325, 1994