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Endocrine scintigraphy with hybrid SPECT/CT

June 2014
Endocrine Reviews 35(5):er20131030

June 2014
35(5):er20131030

DOI:10.1210/er.2013-1030

Source
PubMed

Authors:

Ka Kit Wong

University of Michigan

Youssef Ehab

Misr International University

Alice Ferretti

Azienda ULSS 5 Polesana

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Nuclear medicine imaging of endocrine disorders takes advantage of unique cellular properties of endocrine organs and tissues that can be depicted by targeted radiopharmaceuticals. Detailed functional maps of bio-distributions of radiopharmaceutical uptake can be displayed in 3D-tomographic formats, using single photon emission computed tomography (SPECT), that can now be directly combined with simultaneously acquired cross-sectional anatomic maps derived from computed tomography (CT). The integration of function depicted by scintigraphy and anatomy with CT has synergistically improved the efficacy of nuclear medicine imaging across a broad spectrum of clinical applications, that include some of the oldest imaging studies of endocrine dysfunction.

. The Main Isotopes and Corresponding Collimators Used for Planar and SPECT Scintigraphy

…

. Commonly Used Radiopharmaceuticals for Endocrine Scintigraphy

…

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Endocrine Scintigraphy with Hybrid SPECT/CT

Ka Kit Wong, Lorraine M. Fig, Ehab Youssef, Alice Ferretti, Domenico Rubello,

and Milton D. Gross

Nuclear Medicine/Radiology Department (K.K.W., E.Y., M.D.G.), University of Michigan Hospital, Ann Arbor, Michigan

48109; Nuclear Medicine Service (K.K.W., L.M.F., M.D.G.), Department of Veterans Affairs Health System, Ann Arbor,

Michigan 48105; and Department of Nuclear Medicine (A.F., D.R.), Radiology, Medical Physics, Santa Maria della

Misericordia Hospital, 45100 Rovigo, Italy

Nuclear medicine imaging of endocrine disorders takes advantage of unique cellular properties of endocrine

organs and tissues that can be depicted by targeted radiopharmaceuticals. Detailed functional maps of bio-

distributions of radiopharmaceutical uptake can be displayed in three-dimensional tomographic formats, using

single photon emission computed tomography (CT) that can now be directly combined with simultaneously

acquired cross-sectional anatomic maps derived from CT. The integration of function depicted by scintigraphy

and anatomy with CT has synergistically improved the efficacy of nuclear medicine imaging across a broad

spectrum of clinical applications, which include some of the oldest imaging studies of endocrine dysfunction.

(Endocrine Reviews 35: 717–746, 2014)

Introduction

II. Hybrid SPECT/CT Technology

A. History of SPECT and SPECT/CT systems

B. Technological characteristics of latest generation

SPECT/CT hybrid scanners

C. Quantitative SPECT/CT for radiometabolic

dosimetry

D. Patient radiation dose exposure

E. Radioisotopes commonly used for investigation of

endocrine dysfunction

III. Radioiodine SPECT/CT Imaging of Thyroid Cancer

123

131

I thyroid cancer scans

B. Staging, management, prognosis, and tumor

dosimetry

IV. Somatostatin Receptor Scintigraphy With SPECT/CT

for Staging of Neuroendocrine Tumors

111

In-DTPA-octreotide imaging of neuroendo-

crine tumors

111

In- and

99m

Tc- labeled radionuclide imaging of

medullary thyroid cancer

V. Adrenal Cortical Imaging With

131

I-NP59 SPECT/CT

VI. Sympathetic Adrenomedullary Imaging With

SPECT/CT

123

131

I-MIBG imaging of pheochromocytoma

and paraganglioma

123

131

I-MIBG imaging of neuroblastoma

VII. Parathyroid and Thyroid Scintigraphy With

SPECT/CT

99m

Tc-sestamibi parathyroid scintigraphy

99m

Tc-pertechnetate thyroid scans

C. Miscellaneous endocrine applications of

SPECT/CT

VIII. Current Clinical Role of SPECT/CT in the Diagnostic

Workup of Endocrine Disorders

A. Protocols for SPECT/CT use

B. Economic evaluation and cost-effectiveness

C. Guidelines for indications and role

D. Strategies for reducing radiation exposure

IX. Summary and Future Directions

I. Introduction

The histories of nuclear medicine and endocrinology

have long been linked by radionuclide assessment of

thyroid gland function using iodine-131 (

131

I), a radio-

isotope of stable iodine and one of the earliest examples of

a molecular probe, initially believed to reflect thyroid io-

dine trapping and organification and subsequently found

to be mediated by Na

⫹

⫺

symporter (NIS) expression (1–

3). Radioiodine was first used to treat hyperthyroidism in

the early 1940s (4), with commercial production and dis-

tribution of

131

I for medical uses by the US Atomic Energy

ISSN Print 0163-769X ISSN Online 1945-7189

Printed in U.S.A.

Received March 18, 2013. Accepted June 16, 2014.

First Published Online June 30, 2014

Abbreviations: CT, computed tomography; 3D, three-dimensional; 4D, four-dimensional;

DMSA, dimercaptosuccinic acid; DTPA, diethylene triamine penta-acetic acid; EDDA, eth-

ylenediamine diacetic acid; FDG,

F-fluorodeoxyglucose;

F-DOPA,

F-dihydroxyphe-

nylalanine; HYNIC, 6-hydrazinopyridine-3-carboxylic acid;

123

I, radioiodine-123;

131

I, ra-

dioiodine-131;

131

I-NP59,

131

I-6-

␤

-iodomethyl-19-norcholesterol;

111

In, indium-111;

MEN, multiple endocrine neoplasia; MIBG, metaiodobenzylguanidine; MRI, magnetic res-

onance imaging; MTC, medullary thyroid cancer; NET, neuroendocrine tumor; NIS, sodi-

um-iodide symporter; PET, positron emission tomography; PGL, paraganglioma; PHEO,

pheochromocytoma; SPECT, single photon emission CT; SRS, somatostatin receptor scin-

tigraphy; SSTR, somatostatin receptor;

99m

Tc, technetium-99m; TOC, Tyr3-octreotide;

WDTC, well-differentiated thyroid cancer.

REVIEW

doi: 10.1210/er.2013-1030 Endocrine Reviews, October 2014, 35(5):717–746 edrv.endojournals.org 717

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 27 August 2015. at 02:50 For personal use only. No other uses without permission. . All rights reserved.

Laboratory at Oak Ridge, Tennessee, beginning in 1946

(5). From those early beginnings to the present,

131

I con-

tinues as an integral part of the management of well-dif-

ferentiated thyroid cancer (WDTC), used for radioiodine

scintigraphy to detect thyroid cancer metastases and as a

radiotherapeutic agent with

␤

-particle emission for thy-

roid remnant radioablation and treatment of WDTC me-

tastases (6).

In much the same manner as the clinical deployment of

131

I, development of radiopharmaceuticals that target

unique cellular properties of normal and neoplastic endo-

crine tissues has greatly expanded the clinical applications

of radionuclide scintigraphy for the study of endocrine

disorders. Somatostatin receptor scintigraphy (SRS) and

metaiodobenzylguanidine (MIBG) imaging are two prime

examples of successful radiotracers in current clinical use

for staging of neuroendocrine tumors (NETs) and deter-

mining the likely efficacy of long-acting somatostatin an-

alog and radionuclide-based therapy options. Although

providing unique information regarding endocrine phys-

iology and dysfunction, scintigraphy inherently suffers

from low spatial resolution and a paucity of anatomic

information, rendering diagnostic interpretation depen-

dent on pattern-recognition of radiopharmaceutical bio-

distributions. Hybrid single photon emission computed

tomography (SPECT)/computed tomography (CT) imag-

ing devices, capable of combining simultaneously ac-

quired functional maps with cross-sectional anatomic CT

data, have created a powerful new approach to diagnostic

imaging, improving the efficacy of nuclear medicine stud-

ies of endocrine disorders (7–10).

II. Hybrid SPECT/CT Technology

A. History of SPECT and SPECT/CT systems

1. Photon detection and imaging

The radioisotopes used in conventional nuclear medi-

cine emit monoenergetic photons, ie, quanta with a spe-

cific and known spectrum of energy. Many types of de-

tectors are available to identify ionizing radiation, but for

imaging

␥

-photons, scintillation crystals coupled with an

appropriate focusing collimator are used for their high

count radiation detection efficiency. Commercial scintil-

lation cameras (hence the name “scintigraphy”) intro-

duced for

␥

-imaging are based on the original design pro-

posed by Anger in 1958 where incident radiation emitted

by a radiopharmaceutical is converted into light energy,

collected through light guides, and converted into an elec-

tric signal by a matrix of photo-multiplier tubes (11, 12).

In the energy range typical of nuclear medicine radiophar-

maceuticals (71–365 keV; Table 1), the primary detector

material used is a monocrystal of sodium iodide activated

with thallium, NaI(Tl). This fundamental approach al-

lows accurate measurement and reconstruction of the spa-

tial distribution of

␥

-photons. An important aspect affect-

ing image quality is selection of the unique direction of

incident

␥

-photons, achieved through the use of a colli-

mator placed directly in front of the crystal, which serves

to decrease scattered photons. Collimator hole diameter

and thickness of the intervening septae affect count effi-

ciency and spatial resolution. These collimator character-

istics are used to advantage to select between high-reso-

lution vs high-sensitivity or more general all-purpose

collimation, depending upon the characteristic energy

spectrum of the isotope employed and the imaging pro-

cedure to be performed.

2. Single photon emission CT

In 1963, Kuhl and Edwards (13) introduced the first

tomographic device based on a series of scans obtained at

different angles relative to the organ/tissue of interest with

collimated scintillation detectors that allowed acquisition

of transaxial brain “scintiscans” (14). However, it wasn’t

until the 1980s that a concentrated effort was made to

develop rotating SPECT systems for clinical applications.

During SPECT acquisition, the

␥

-camera rotates around

the patient, with multiple two-dimensional projections

(views) acquired at equally distributed angles, covering

arcs of 180° or 360°. These projections are used for three-

dimensional (3D) reconstruction of the image volume and,

like other tomographic modalities, are presented as cross-

sectional “slices” reconstructed by computer-based ana-

lytical or iterative algorithms (15). Filtered back-projec-

Table 1. The Main Isotopes and Corresponding Collimators Used for Planar and SPECT Scintigraphy

Radionuclide T

1/2

␥

, keV (% Emissions) Collimator Type

99m

Tc 6.0 h 140.5 (89) Low energy

123

I13.2 h 159.0 (83) Low energy

201

Tl 3.0 d 70.8 (46) Low energy

111

In 2.8 d 171.3 (90), 245.4 (94) Medium energy

Ga 3.26 d 93.3 (39), 184.6 (21), 300.2 (17) Medium energy

131

I8.0 d 364.5 (82) High energy

Abbreviation: T

1/2

, half-life.

718 Wong et al Endocrine SPECT/CT Endocrine Reviews, October 2014, 35(5):717–746

tion, an analytical method initially applied for SPECT, is

a mathematical process that uses Fourier transforms to

superimpose and normalize imaging projections, generat-

ing an estimate of the radioactivity contained within each

volume element (voxel) (15). Conversely, the statistical

image reconstruction algorithms, so-called iterative meth-

ods, create reconstructed images by successive estimates

and comparisons with the measured data. The result of

each comparison is used to modify the current estimate in

repeating iterations until the difference between estimated

and measured data is small. Despite their early devel-

opment in the 1970s, iterative reconstructive methods

had to wait for computer technology to “catch up” de-

cades later (13, 16). Iterative methods produce images

of higher quality than filtered back-projection, with the

ability to perform attenuation, scatter, and partial vol-

ume corrections (15).

3. First hybrid SPECT/CT systems

One of the main sources of image degradation with

SPECT is attenuation of photons by overlying body tis-

sues. The amount of attenuation depends on path length

(distance to the detector), the types of tissue, and emitted

photon energy. An “attenuation map” is necessary to cor-

rect for proportionally decreased detected radiation from

targets located deeper within the body. One of the first

methods developed for attenuation correction was the

Chang method, a geometric model applied primarily to

brain scans (17). Subsequently, transmission source-based

attenuation correction was introduced in the mid-1980s,

where emission-transmission scanning was performed us-

ing an external radiation source for acquiring transmis-

sion images (18). More recently, high-resolution struc-

tural imaging with CT in conjunction with functional

emission tomographic data was proposed by Lang et al

(19), who developed the first prototype of a dual-modality

SPECT/CT system. The first commercial system with hy-

brid SPECT/CT capability combined a dual-detector

␥

-camera with an independent low-dose x-ray tube, co-

positioned in the same scanner gantry in an “in-line” con-

figuration. Although this device was not a diagnostic-

quality CT scanner, its usefulness in improving SPECT

interpretation was reported in several studies (20, 21).

Early steps in the development of commercial SPECT/CT

scanners required accurate conversion of x-ray attenua-

tion maps to the

␥

-photon energy of the SPECT study (22,

23) and to correct coregistration of SPECT and CT images.

Hybrid scanners acquire SPECT and CT data sequentially

with the patient in an optimally stationary, fixed position.

Once the appropriate calibrations for SPECT and CT

alignment are executed, the two studies are acquired

coregistered and can be easily superimposed (fused).

B. Technological characteristics of latest generation

SPECT/CT hybrid scanners

1. Technological innovations

Recent dual-modality SPECT/CT systems include inte-

grated dual-head SPECT and multislice CT. Multislice CT

scanners adopt third-generation slip-ring geometry (tube

and detector bank linked and rotating together) along

with the multislice technology, consisting of multiple, par-

allel arcs of detectors that collect data from more slices at

the same time (up to 64 slices or rows in the latest gener-

ation SPECT/CT systems) (24).

2. Reconstruction algorithm innovations

The current iterative reconstruction algorithms use CT

information and system-response models to perform

state-of-the-art quantification methods (25) (Figure 1). In-

novations include: 1) CT-based photon attenuation cor-

rection—CT data in Hounsfield units from the transmis-

sion scan is converted to a map of attenuation coefficients

matching the effective energy and the resolution of the

emission SPECT (22); 2) scatter correction—scattered

photons, which have lost their original direction and also

a part of their energy, are detected using dual, triple, or

multiple energy windows (26, 27) to estimate the amount

of scattered photons in the image and subtract this value

from the reconstructed images (28, 29); 3) partial volume

effect correction—compensates for an apparent loss of

counts in small structures using either recovery coefficient

methods (25, 30) or methods incorporating anatomic cor-

rection information (30–32); and 4) motion correction—

patient motion occurring between emission (SPECT) and

transmission (CT) scans leads to incorrect superimposi-

tion of the attenuation map and SPECT datasets. For in-

voluntary motion (breathing or heartbeat), physiological

gating of image acquisition can reduce these artifacts (33).

Nonphysiological patient motion can be corrected by a

postacquisition manual shifting of images technique, with

cross-correlation methods (34), or with correction meth-

ods implemented within the iterative reconstruction algo-

rithm (35–37).

C. Quantitative SPECT/CT for radiometabolic dosimetry

The ability to estimate internal dosimetry is often useful

in planning and managing radionuclide therapy. Conju-

gated views with planar imaging or stand-alone SPECT

acquisition allow rough dosimetric approximation, with

variability ranging from 30 to 100% (7, 38). Hybrid

SPECT/CT systems provide a more accurate approach to

dosimetry because CT data can be used to create patient-

specific, anatomically corrected, 3D target organ/tissue

attenuation and density maps. SPECT/CT-based 3D do-

simetry can thus be used to calculate radiation dose to both

doi: 10.1210/er.2013-1030 edrv.endojournals.org 719

target and nontarget tissues with the therapeutic goals of

maximizing radiation dose to an endocrine malignancy

and, at the same time, limiting radiation exposure to other

sensitive tissues (eg, lung, kidney, bone marrow) (38).

D. Patient radiation dose exposure

The effective dose attributable to SPECT acquisition

from the radiopharmaceutical biodistribution ranges be-

tween 3 and 12 mSv, depending on the radiopharmaceu-

tical type and activity used (39, 40). The effective dose

from typical multislice CT scans performed during dual-

modality SPECT/CT examinations calculated for low-

dose protocols (20 –40 mA, 120 –130 kV) is an additional

2- to 4-mSv exposure from the CT scan with 40-cm length

(ie, single SPECT/CT bed position) (7). In cases of

SPECT/CT multiple bed positions, the effective dose val-

ues for each bed should be added together. The CT

component of SPECT/CT is typically “nondiagnostic,”

performed for anatomic correlation and attenuation cor-

rection, with lower tube energies and without iv contrast

enhancement, and as such, it does not replace conven-

tional diagnostic contrast-enhanced CT protocols.

E. Radioisotopes commonly

used for investigation of

endocrine dysfunction

As discussed earlier,

131

I has a

364-keV

␥

-emission and half-life (8

d) suitable for thyroid cancer imag-

ing, and its

␤

-particle emission al-

lows radionuclide therapy of thyroid

cancer metastases. Another radioio-

dine isotope, iodine-123 (

123

I), can

be used for diagnostic imaging.

123

has the advantage of a lower 159-

keV

␥

-emission better suited for

modern

␥

-cameras, providing higher

quality imaging. Also, because

123

lacks particulate emissions, it has not

been implicated in the so-called

“stunning” of thyroid tissues re-

ported after diagnostic doses of

131

(41). Drawbacks to the use of

123

I are

the higher cost for the isotope and

the shorter half-life (13 h), preclud-

ing multiday imaging and leading to

greater complexity of dosimetry

calculations.

SRS is a whole-body imaging

technique that depicts biodistribu-

tions of radiolabeled somatostatin

analogs (43). Somatostatin is a reg-

ulatory peptide with affinity for G

protein-coupled membrane-bound somatostatin receptor

(SSTR) subtypes 1–5, including 2A and 2B, which are

overexpressed in NETs (42–44). Peptide-based imaging

with somatostatin analogs has advantages of high speci-

ficity, good tissue penetration, rapid clearance, and low

antigenicity (42). The most common radiopharmaceutical

used for SRS is indium-111 (

111

In)-diethylene triamine

penta-acetic acid (DTPA)-octreotide (

111

In-pentetreotide)

with affinity for SSTR2 and SSTR5. Normal physiological

distribution occurs in liver, spleen, kidneys and bladder,

gallbladder, and bowel. Mild uptake is seen in the pitu-

itary, thyroid, adrenal glands, and head of the pancreas.

SRS provides evidence for targeting of tumor tissue be-

cause octreotide uptake in NETs can be used to predict

therapeutic success with

Y- or

177

Lu-labeled somatosta-

tin analogs (45).

123

I- and

131

I-labeled MIBG is a “false neurotransmit-

ter” analog of norepinephrine, used to image NETs.

MIBG accumulation shares norepinephrine transporter

uptake with affinity for vesicular monoamine transporter

and incorporation into neurosecretory vesicles (44, 46,

47). Physiological MIBG uptake is seen in the salivary

Figure 1.

Figure 1. Illustration of the image formation chain. During SPECT reconstruction, corrections are

made for the four main confounding effects, producing a 3D measured count distribution. With

a calibration step, this count distribution can also be translated into an activity distribution (25).

720 Wong et al Endocrine SPECT/CT Endocrine Reviews, October 2014, 35(5):717–746

glands, thyroid (unless blocked with potassium iodide),

heart, liver, spleen, kidneys, and bladder, with variable

uptake in the adrenal medulla and in brown fat. Thera-

peutic doses of

131

I-MIBG may be employed for the treat-

ment of metastatic NETs (48).

Technetium-99m (

99m

Tc)-sestamibi, a lipophilic cation

of the isonitrile family, is accumulated and retained in the

mitochondria of oxyphil-rich parathyroid adenomas.

99m

Tc-sestamibi has been used to perform parathyroid

scintigraphy in conjunction with

99m

Tc-pertechnetate or

123

I for thyroid tissue subtraction (49). In 1992, Taillefer

introduced a dual-phase protocol with

99m

Tc-sestamibi

alone to exploit its differential kinetic properties in thyroid

and parathyroid tissues (50). Parathyroid adenomas dis-

play focal radiotracer retention and delayed washout com-

pared to normal thyroid tissues. This dual-phase single

isotope technique (early 10- to 20-min and delayed 2-h

time-points) has similar diagnostic accuracy to dual-iso-

tope subtraction methods but is simpler to perform. Table

2 lists the commonly used radiopharmaceuticals in endo-

crine scintigraphy.

III. Radioiodine SPECT/CT Imaging of

Thyroid Cancer

Thyroid cancer is the most common endocrine malignancy

in adults, with 60 220 (14 910 males, 45 310 females)

newly diagnosed cases reported in the United States in

2013 (51). The incidence of WDTC has continued to in-

crease over the last three decades, in part due to earlier

detection of so-called papillary thyroid “microcarcino-

mas” (size ⬍1.0 cm), although other factors (eg, dietary,

environmental) may also be involved (52, 53). The prog-

nosis for most patients with WDTC is excellent, with a

10-year survival of approximately 93% for papillary thy-

roid cancer and approximately 85% for follicular thyroid

cancer. However, mortality increases to 25–45% at 10

years in higher-risk patients (TNM stages III/IV), and re-

currences may occur in one-third of patients (54–56). Tu-

mor staging using systems such as the American Joint

Committee on Cancer (AJCC) TNM seventh edition or

MACIS (Metastasis, Age at presentation, Completeness of

surgical resection, Invasion [extrathyroidal], Size) pro-

vides important prognostic information. Contemporary

guidelines for diagnosis and management of WDTC em-

phasize schema for risk stratification based on risk of re-

currence, rather than older staging systems designed to

predict survival (6, 57).

After diagnosis, total or near-total thyroidectomy, and

in some cases cervical lymph node resection, is performed

to remove the primary tumor and establish histopathol-

ogy. Furthermore, removal of the normal thyroid tissues,

which accumulate radioiodine more avidly than tumor,

facilitates subsequent radioiodine imaging and therapy.

For patients with locoregional disease or distant metasta-

ses, treatment with

131

I has been shown to improve out-

comes (54, 55). Previously, radioiodine ablation of rem-

nant thyroid tissue was performed in most cases to

facilitate clinical surveillance; however, because statistical

evidence indicates that

131

I neither decreases recurrence

nor increases survival in low-risk patients (stage I disease),

radioiodine ablation is no longer routinely performed in

Table 2. Commonly Used Radiopharmaceuticals for Endocrine Scintigraphy

Radiopharmaceutical Molecular Target/Mechanism of Uptake

131

I (radioiodine isotope) Affinity for the NIS expressed by differentiated thyroid cancer,

␤

-particle emission allows

radionuclide therapy

123

I (radioiodine isotope) Affinity for the NIS expressed by differentiated thyroid cancer

111

In-DTPA-octreotide

(

111

In-pentetreotide)

Somatostatin analog with affinity for somatostatin receptors expressed by endocrine

neoplasms

111

In-DOTA-lanreotide Somatostatin analog with affinity for somatostatin receptors expressed by endocrine

neoplasms

99m

Tc-EDDA/HYNIC-TOC Somatostatin analog with affinity for somatostatin receptors expressed by endocrine

neoplasms

123

I-MIBG Catecholamine analog with uptake by the norepinephrine transporter expressed by neural

crest tumors

131

I-MIBG Catecholamine analog with uptake by the norepinephrine transporter expressed by neural

crest tumors,

␤

-particle emission allows radionuclide therapy

131

I-NP59 Cholesterol analog that enters the cortisol synthesis pathway of adrenocortical tumors

99m

Tc-sestamibi (methoxyisobutylisonitrile) Uptake in benign and malignant tumor cells dependent on cell membrane and

mitochondrial potentials

99m

Tc-tetrofosmin (lipophilic diphosphine) Uptake in benign and malignant tumor cells dependent on cell membrane and

mitochondrial potentials

99m

Tc-pertechnetate (

99m

Tc-0

)Trapping in the thyroid gland via the NIS and Na

⫹

/Cl

⫺

channels

99m

Tc(V)-DMSA Uptake in benign and malignant tumors dependent on metal complex equilibrium and pH

Abbreviation: DOTA, 1,4,7,10–tetra-azacyclododecane–1,4,7,10–tetra-acetic acid.

doi: 10.1210/er.2013-1030 edrv.endojournals.org 721

this group (54 –56, 58– 60). Risk stratification and careful

patient selection are key to this approach.

123

131

I thyroid cancer scans

131

I imaging has poor spatial resolution, and collimator

septal penetration of the high-energy 364 keV

␥

-emissions

produces artifacts that degrade image quality. The paucity

of anatomical information provided by planar or SPECT

imaging often leads to difficulties in distinguishing benign

from malignant etiologies (61–63). Diagnostic CT has

played a limited role in initial WDTC workup due to the

need to avoid iodinated contrast when contemplating ra-

dioiodine treatment and the high frequency of nodal me-

tastases in otherwise anatomically normal neck lymph

nodes. Coregistration of tomographic functional and an-

atomic information with hybrid SPECT/CT has been the

subject of several reviews (64–69) which conclude that

radioiodine

131

123

I SPECT/CT is a powerful diagnostic

tool that overcomes many of the limitations of planar im-

aging (70–99) (Table 3).

1. Strategies for SPECT/CT

131

I SPECT/CT scans have used diagnostic doses be-

tween 37 and 430 MBq (1–11 mCi) (89, 90, 94–96, 100)

and postradioiodine therapy doses of 1.1 to 9.7⫹GBq (30

to 260⫹mCi) (70, 74, 75, 77– 80, 84– 88, 90–92, 97, 99)

with patients prepared under endogenous hypothyroid-

ism or exogenous recombinant human TSH stimulation.

Investigators have found radioiodine SPECT/CT useful in

the immediate postsurgical setting, either with preablation

diagnostic (94, 95, 100) or post-therapy scanning (70, 74,

75, 77–81, 83, 85, 86, 91, 92, 98, 99), and also for long-

term surveillance (72, 73, 77, 89, 90).

131

I SPECT/CT was

first reported in 2001 by Even-Sapir et al (20) in a sub-

group of four patients with thyroid cancer studied with

SPECT/CT. In a larger group of 71 patients, the addition

of anatomical information from SPECT/CT allowed bet-

ter characterization of neck uptake and more accurate dif-

ferentiation of foci outside the neck as benign vs metastatic

disease. Incremental diagnostic value of SPECT/CT over

Table 3. Utility of

131

123

I SPECT/CT for Diagnostic and Post-Therapy Thyroid Cancer Scans

Advantages of SPECT/CT (Refs) Comments and Findings

Localization and characterization of radioactivity

foci (74, 77, 78, 80, 84, 92, 95, 97)

SPECT/CT depicts benign vs malignant uptake in the neck (ie, thyroid

remnant vs cervical nodal disease) with incremental diagnostic value

compared to planar imaging in 21–64% of patients.

Clarification of equivocal findings (70, 72, 77,

78, 99)

SPECT/CT clarified findings otherwise equivocal (ie, inconclusive,

indeterminate, unclear) on planar imaging, as benign uptake or

metastatic disease in 15–30% of patients.

Confirmation of cryptic findings (73, 120, 121) SPECT/CT is able to confirm cryptic findings, physiological variants, and

benign mimics of disease in the neck, thorax, abdomen, and pelvis.

Evaluation of distant metastatic disease (70, 72,

75, 77–79, 84, 89, 91, 92, 95, 97, 99)

SPECT/CT is useful for evaluating distant sites of disease and it may obviate

the need for additional diagnostic CT when pulmonary and bone

metastases are confirmed. Incremental diagnostic value of SPECT/CT over

planar imaging for distant metastases is reported in 40–100% of

patients.

Identification of non-iodine-avid disease

(72, 79, 99)

SPECT/CT provides anatomical information from the CT component and

detects non-iodine-avid disease in between 3 and 21% of patients.

Improved diagnostic performance due to

increased specificity (72, 79)

Diagnostic

123

I SPECT/CT has sensitivity of 50% and specificity of 100%,

compared to planar scans with sensitivity of 41% and specificity of 68%.

Diagnostic 131I SPECT/CT has sensitivity of 62% and specificity of 98%,

compared to planar scans with sensitivity of 62% and specificity of 78%.

Improved interobserver agreement and reader

confidence (91, 95)

Interobserver disagreement for neck foci occurred in 24 of 42 (57%)

patients on planar imaging, decreasing to 9 of 42 (21%) on SPECT/CT.

SPECT/CT increases reader confidence.

Staging (TNM) and risk stratification (10, 77, 78,

86, 99, 100)

Preablation diagnostic

131

I SPECT/CT detected regional metastases (35%)

and distant metastases (8%); changing TNM stage in 4% of younger and

25% of older patients. Post-therapy

131

I SPECT/CT changed stage in 6.1–

26.4% patients

Change in management (74, 77, 78, 84, 89, 90,

92, 94)

SPECT/CT led to change in management in between 2 and 58% of patients;

SPECT/CT can affect decisions regarding surgical referral, to treat or not

treat with

131

I, selection of

131

I dose, external-beam radiation therapy

referral, ordering FDG PET.

Prognosis (75, 85) SPECT/CT: sensitivity of 78%, specificity of 100% for predicting disease-free

status at 29 mo median. Lymph nodes with size ⬍0.9 mL on SPECT/CT

respond to

131

I treatment.

Tumor dosimetry (139) Feasible when considering radioiodine treatment of macroscopic iodine-avid

disease.

722 Wong et al Endocrine SPECT/CT Endocrine Reviews, October 2014, 35(5):717–746

planar imaging was reported in 41 of 71 (57%)

patients (90).

2. Diagnostic interpretation

Common to all published studies to date is the ability of

SPECT/CT to provide more precise anatomic localization

of radioactivity, aiding the characterization of radioiodine

uptake as benign (in remnant thyroid tissues or due to

physiological biodistribution) or malignant (in cervical

lymph nodes or distant metastases) (Figure 2). A major

strength of

131

I SPECT/CT is to substantially reduce equiv-

ocal scan findings frequently encountered on planar im-

aging. In 147 patients, post-therapy

131

I SPECT/CT clar-

ified all 25 equivocal interpretations in the neck as either

regional lymph nodes or remnant thyroid tissues. For dis-

tant foci, SPECT/CT removed uncertainty on planar im-

aging in 21 of 52 (40%) foci of

131

I uptake by distinguish-

ing metastases from benign physiological “mimics” of

disease (78). Similar findings have been reported with

preablation diagnostic

131

I SPECT/CT (95, 96).

Diagnostic radioiodine planar imaging for surveillance

of thyroid cancer has a sensitivity that varies between 40

and 75% (in part, dependent upon the

131

I dose admin-

istered) and high specificity of 90–100% (61, 89, 90).

SPECT/CT using

123

I was found to have superior accu-

racy, with sensitivity and specificity of 50% and 100%,

respectively, compared to SPECT (45% and 89%) and

planar imaging (41% and 61%) (72). Another study of

diagnostic

131

I SPECT/CT in 123 pa-

tients found that sensitivity of both

planar imaging and SPECT/CT for

the detection of iodine-avid disease

was 62%, although SPECT/CT had

significantly higher specificity than

the planar imaging (94 vs 74%),

which is the major strength of its

use (79).

Non-iodine-avid disease due to

the lack or subsequent loss of NIS

expression occurs in 20–30% of

WDTC at the time of diagnosis and is

seen more frequently with Hürthle

cell cancer, with papillary subtypes

with unfavorable features (eg, tall

cell, columnar, cribiform), and

with poorly differentiated (insular)

cancer (101). Radioiodine

131

SPECT/CT can localize additional

non-iodine-avid disease on the CT

component in as many as 32 of 148

(21.6%) patients (99). Detection of

non-iodine-avid disease signifi-

cantly impacts clinical manage-

ment by directing treatment to additional surgical in-

tervention or external beam radiation therapy and also

identifies the need for alternative imaging strategies

such as

F-fluorodeoxyglucose (FDG) positron emis-

sion tomography (PET).

3. SPECT/CT identification of metastatic disease

Interpretation of

131

I uptake in the central neck can

be challenging, depending on patients’ body habitus.

SPECT/CT accurately identifies cervical nodal metastases,

often in lymph nodes of normal size. SPECT/CT has de-

picted rare parapharyngeal metastases (occurring in 2.5%

of 561 patients) that, owing to their location, may not be

apparent with preoperative neck ultrasound and thus are

not resected during neck compartment dissection (82).

WDTC has a predilection to metastasize distantly to

lung and bone and more rarely to soft tissues: liver, brain,

skin, and other sites. Pulmonary metastases on planar

scintigraphy are characterized as either micronodular or

macronodular disease, and miliary lung metastases may

escape detection on chest x-ray or even diagnostic chest

CT.

131

I SPECT/CT is useful for evaluation of distant met-

astatic disease (72, 74, 77–79, 89, 92, 94, 95), and after

confirmation of pulmonary or bone metastases with

SPECT/CT, further diagnostic CT may be omitted (99). In

the thorax, SPECT/CT can precisely localize malignancy

to lung, bone (ribs, sternum, or spine), or mediastinal

Figure 2.

Figure 2. Diagnostic preablation 37 MBq (1 mCi)

131

I scan in a 23-year-old female status after

total thyroidectomy for multifocal papillary thyroid carcinoma. A and B, Planar anterior and

posterior images at 24 hours demonstrate that several foci increased radiotracer activity in the

neck, including right superior neck (arrow) and multiple foci in the thorax (arrowheads). C–F,

Axial CT and SPECT/CT fusion images confirm that the activity in the neck represents a cervical

lymph node metastasis (arrows), and the activity in the thorax represents bilateral micronodular

lung metastases (arrowheads).

doi: 10.1210/er.2013-1030 edrv.endojournals.org 723

lymph nodes (Figure 3). A spectrum of rare metastatic sites

depicted on

131

I SPECT/CT has been described (87, 88),

with reports of metastatic disease in unanticipated tumor

locations; eg, liver, kidney, muscle, and trachea (93,

102–110).

4. SPECT/CT evaluation of benign uptake

Radioiodine scintigraphy has numerous physiological

variants and potential disease “mimics” that must be rec-

ognized for accurate image interpretation (111–113). The

NIS is an intrinsic thyrocyte-based plasma membrane gly-

coprotein that allows an increase of cytoplasmic iodine

concentration 20 to 40 times above plasma levels (1, 114,

115). NIS is expressed in thyroid, salivary glands, gastric

mucosa, lactating mammary glands (114), and nonlactat-

ing breasts in young women (116, 117) and has also been

detected in the lacrimal glands, choroid plexus, ciliary

body of the eye, skin, placenta, and thymus (1, 114–116,

118, 119). Knowledge of these biodistributions will pre-

vent false-positive interpretation.

131

I SPECT/CT was used for evaluation of a wide range

of cryptic findings occurring in 40 of 184 (22%) scans,

including a spectrum of physiological benign etiologies

(73). Although these variants are usually recognized on

planar imaging, SPECT/CT resolves diagnostic uncer-

tainty with greater confidence and improved accuracy

(120, 121). Numerous case reports have demonstrated the

utility of SPECT/CT for confirmation of benign “mimics”

of disease; eg, blocked nasolacrimal

duct, lingual thyroid, thymus, struma

ovarii, ovarian teratoma, menstruat-

ing uterus, and radioiodine accumula-

tion in simple renal cysts (93, 102–

110, 122–126).

5. Comparison of

131

I SPECT/CT to

other imaging modalities

The established role of FDG PET

in WDTC is to search for occult me-

tastases in patients with elevated thy-

roglobulin levels suggesting persis-

tent or recurrent disease, despite

nonlocalizing

131

I scintigraphy.

FDG PET has particular value when

thyroglobulin levels are high and/or

when distant metastases are sus-

pected (63, 127–131).

131

I SPECT/

CT, FDG PET, and

99m

Tc-methylene

diphosphonate bone scans were

compared in patients with suspected

thyroid cancer bone metastases.

131

SPECT/CT had sensitivity of 92%

and specificity of 98%, which was

similar to FDG PET sensitivity of 85% and specificity of

88%, with both modalities superior to

99m

Tc-methylene

diphosphonate bone scintigraphy (83). In another study,

131

I SPECT/CT and FDG PET had similar diagnostic per-

formance, although

131

I SPECT/CT was observed to out-

perform FDG PET when there was a history of a single

131

therapy, whereas FDG PET had better sensitivity in pa-

tients after multiple radioiodine treatments (81).

B. Staging, management, prognosis, and

tumor dosimetry

1. SPECT/CT for staging of WDTC

Accurate staging and risk stratification are important

for the management of thyroid cancer to guide therapeutic

decisions and intensity of surveillance. Post-therapy

131

SPECT/CT imaging shows improved characterization of

nodal (N) and distant metastatic (M) status for TNM stag-

ing, compared to planar imaging (70, 75, 80, 86, 90, 92,

99). At the time of the first radioablation, SPECT/CT led

to reclassification of the cervical nodal (N) status in 20 of

57 (35%) patients (86). In another study, SPECT/CT

changed the N score in 12 of 33 (36.4%) patients and the

M score in four of 19 (21.4%) directly, leading to man-

agement changes in 10 (24.4%) patients (77).

Preablation diagnostic SPECT/CT changed TNM stag-

ing in 10 of 48 (21%) patients by identification of regional

and distant metastases before the first radioiodine abla-

Figure 3.

Figure 3. False-positive uptake depicted on preablation diagnostic 37 MBq (1 mCi)

131

I scan in a

57-year-old female status after total thyroidectomy for resection of invasive, multifocal follicular

thyroid carcinoma. A and B, Planar anterior and posterior images demonstrate focal uptake in

the central neck (arrowhead) suspicious for residual disease, and in the right thorax (arrows)

suspicious for metastasis. C–F, Axial CT and SPECT/CT fusion images localize the activity to the

patient’s tracheostomy (arrows), due to retained secretions (arrows) and the thoracic uptake to

osseous metastasis of the right sixth rib (arrows).

724 Wong et al Endocrine SPECT/CT Endocrine Reviews, October 2014, 35(5):717–746

tion, thereby allowing patient-specific selection of

131

Iac

tivities; eg, lower activities, 1.1 GBq (30 mCi) for remnant

ablation in low-risk patients; and higher activities, 3.7 to

7.7⫹GBq (100 to 200⫹mCi) for treatment of thyroid

cancer (94). In 320 patients, the impact of preablation

diagnostic

131

I SPECT/CT on TNM stage was significant,

resulting in a change in staging in 4% of younger patients

(⬍45 y) and 25% of older patients (ⱖ45 y) (100). In

younger patients, distant metastases were detected in five

of 138 (4%) cases and nodal metastases in 61 of 138

(44%) cases. In the older group, distant metastases were

detected in 18 of 182 (10%) patients and nodal metastases

in 51 of 182 (28%).

Information obtained from SPECT/CT at the first ra-

dioablation has extended our knowledge regarding the

incidence of nodal metastases in T1 tumors. Using a com-

bination of pN1 (surgical neck dissection) and sN1

(SPECT/CT) in a bicentric study of 151 patients, lymph

node metastases occurred in 26% of T1 (ⱕ2.0 cm) tumors

and 22% of microcarcinomas (ⱕ1.0 cm) (80). In another

study in which SPECT/CT contributed to N staging, T1a

tumors occurred in 49 of 320 (15%) patients and were

associated with nodal metastases in 28 of 49 (57%) pa-

tients, and unsuspected distant metastases were detected

in two of 49 (4%) (100).

2. Changes in management and prognostic indicators

Radioiodine SPECT/CT has been reported to change

clinical management in 11–58% of patients (74, 79, 94,

99). Changes include decisions to use or withhold radio-

iodine treatment, guidance on surgical planning, selection

of patients for external beam radiation therapy, and the

use of alternative imaging strategies such as FDG PET.

Actual changes to management strategies depend upon the

specific clinical context and treatment protocols at a given

institution. Avoidance of unnecessary

131

I therapy is im-

portant when residual and/or metastatic disease has been

excluded and the use of empiric

131

I treatment would re-

sult in unnecessary radiation exposure (133, 134). For

example, in 13 children with WDTC, SPECT/CT (

123

Ior

131

I) precisely localized all neck foci of radioiodine, in-

cluding benign etiologies, and supported a decision not to

use therapeutic

131

I in two children (76).

131

I SPECT/CT imaging for follow-up and surveillance

also provides prognostic information regarding the suc-

cess of radioiodine treatment. A neck nodal volume of

⬍0.9 mL as assessed on SPECT/CT was highly likely to

respond to

131

I therapy alone without surgical resection

(85). In a study of 170 patients to identify prognostic fac-

tors predicting treatment failure at 2 years, TNM staging,

macroscopic cervical lymph node disease, and positivity of

planar and SPECT/CT imaging were identified as significant

predictive factors, with only SPECT/CT as an independent

prognostic indicator after multivariate analysis (75).

3. Tumor dosimetry

Diagnostic radioiodine SPECT/CT imaging provides

the opportunity to identify patients with unsuspected me-

tastases, defines the target(s) of

131

I therapy, and permits

adjustment of prescribed therapeutic radioactivity and do-

simetry calculations when high-dose

131

I therapy is con-

sidered (94, 135). The aim of the initial

131

I treatment is to

destroy as much malignant mass as possible, with the tu-

mor radiation-absorbed dose as the best predictor of suc-

cess. Absorbed doses of ⬎7800 cGy have been estimated

as necessary to destroy residual carcinomas (137, 138). An

example of the utility of SPECT/CT to measure volumes of

regional metastases, perform tumor dosimetry, and

thereby determine the optimal radioiodine therapy dose

has been reported (139).

IV. Somatostatin Receptor Scintigraphy

With SPECT/CT for Staging of

Neuroendocrine Tumors

NETs comprise a rare, heterogeneous group of neoplasms

derived from endocrine stem cells of the amine precursor

uptake and decarboxylation system. They have a widely

variable natural history and prognosis (140, 141), with the

potential to cause clinical syndromes due to hypersecre-

tion of biogenic amines and polypeptides (142–144). The

annual incidence of these neoplasms is increasing due to

greater awareness and earlier detection; however, despite

earlier diagnosis and sensitive biochemical markers, met-

astatic disease is often present at diagnosis (44, 141, 142).

Enterochromaffin NETs derived from enteroendocrine

cells within the epithelial lining of the digestive and respi-

ratory tracts and from pancreatic islet cells were previ-

ously classified based on secretory activity as carcinoid

tumors (50% of NETs) with the classical triad of flushing,

hypotension, and diarrhea, or noncarcinoid tumors (eg,

gastrinomas, glucagonomas, insulinomas, and others).

Recent revisions to the classification system propose that

NETs be grouped according to their differentiation, how

closely they resemble their non-neoplastic counterparts,

and grade, a measure of their biological aggressiveness and

malignant potential based upon mitotic rates and Ki-67

index (140, 142). These features, combined with staging

systems such as the AJCC TNM seventh edition, more

appropriately reflect the prognosis of NETs and guide sub-

sequent management and therapy.

111

In-DTPA-octreotide scintigraphy is considered a

first-line imaging modality for staging of NETs, with an

doi: 10.1210/er.2013-1030 edrv.endojournals.org 725

overall sensitivity of 80–90% for carcinoid and 50–70%

for pancreatic NET (with especially low sensitivity for in-

sulinoma due to the lack of SSTR2 expression). Specificity

is high at 88–97% (46, 47, 140), although false-positives

occur due to uptake in physiological

structures or due to inflammation or

infection.

111

In-DTPA-octreotide imaging of

neuroendocrine tumors

SPECT/CT for neuroendocrine

imaging was first evaluated in mixed

patient groups undergoing

123

I-

MIBG,

111

In-DTPA-octreotide, and

123/131

I scintigraphy (20, 21, 145,

146). Improved diagnostic accuracy

of SPECT/CT over planar and

SPECT imaging has been consis-

tently reported for SRS, frequently

resulting in changes to management

plans (147–157) (Figure 4 and Table

4). The precise anatomic localization

of radioactivity using SPECT/CT

provides insight into the etiology of

uptake as benign or malignant, re-

ducing the number of equivocal find-

ings encountered on planar imaging

(148, 156, 157). Furthermore, the

CT component of SPECT/CT can

provide valuable additional ana-

tomic information that aids in image

interpretation. In one study, SPECT/CT

more accurately characterized 163

of 169 (96%) tumor foci compared

to only 138 of 169 (81%) foci on

planar and SPECT (152). In another study, SPECT/CT

had incremental diagnostic value compared to planar im-

aging, with superior localization and/or detection of ad-

ditional lesions in 23 of 44 (52%) cases, although no ad-

Figure 4.

Figure 4. Bronchial carcinoid in a 32-year-old man demonstrated with

111

In-pentetreotide SPECT/

CT. A and B, Whole-body anterior and posterior images at 24 hours show focal activity in the left

thorax (arrows). There is otherwise physiological distribution of radioactivity in the remainder of

the body. C–E, Coronal SPECT, CT, and fused SPECT/CT localize thoracic activity to a calcified

mass adjacent to the descending aorta (arrows). Axial CT (not shown) demonstrated an

endobronchial location compatible with endobronchial carcinoid.

Table 4. Utility of SPECT/CT for Somatostatin Receptor and Sympathoadrenomedullary Scintigraphy

Advantages of SPECT/CT (Refs) Comments and Findings

Localization and characterization of radioactivity foci

(95, 149–151, 202, 203)

SPECT/CT has superior localization, characterization and detection rate of

lesions compared to planar imaging in 37–73% of patients.

Clarification of equivocal findings (156) SPECT/CT clarifies findings otherwise equivocal on planar imaging, as

benign uptake or metastatic disease in 27/98 (28%) foci.

Improved diagnostic performance (147, 152, 155–157,

192, 202–206, 208)

99m

Tc/

111

In-labelled octreotide SPECT/CT for staging NETs has sensitivity

92–97% and specificity 88–100% compared to SPECT with sensitivity

of 79–83% and specificity of 64 –100%;

131

123

I-MIBG SPECT/CT for

PHEO/PGL has sensitivity of 87–100% and specificity of 94–100%

compared to SPECT with sensitivity of 90% and specificity of 68%;

111

In-DTPA-octreotide SPECT/CT has higher sensitivity than side-by-side

visual analysis or software fusion of separate SPECT and CT data.

Improved interobserver agreement (148, 155) Agreement

␬

: Planar

␬

⫽0.59, SPECT

␬

⫽0.74, SPECT/CT

␬

⫽0.86.

Change in management (150, 151) SPECT/CT changes management in 13.9–40% of patients.

Attenuation-correction (153) Attenuation-corrected SPECT/CT leads to increased uptake in 30% of

lesions with no change to diagnostic performance.

Additional benefits of SPECT/CT (95, 155, 159, 160) Improved reader confidence, allows single time-point imaging at 24 h, and

can perform patient-specific and tumor-specific dosimetry.

726 Wong et al Endocrine SPECT/CT Endocrine Reviews, October 2014, 35(5):717–746

ditional benefit occurred when planar images were

negative (151).

99m

Tc-ethylenediamine diacetic acid

(EDDA)/6-hydrazinopyridine-3-carboxylic acid (HYNIC)-

Tyr3-octreotide (TOC) SPECT/CT has sensitivity of 92% and

specificity of 88% for NET staging (158).

99m

Tc-EDDA/

HYNIC-octreotide and

111

In-DTPA-octreotide SPECT/CT

have been reported to have higher sensitivity and specificity than

SPECT or diagnostic CT imaging (156, 157). Hybrid

SPECT/CT somatostatin receptor imaging is easier to perform

and more accurate than previous techniques for performing ret-

rospective software fusion or side-by-side analysis of SPECT

and CT (147). Attenuation-corrected images using CT-based

maps increase lesion contrast and/or intensity in the abdomen

(153).

SPECT/CT SRS increases interobserver agreement, as

reported in two studies: SPECT/CT

␬

was reported as 0.86

in both, compared to planar imaging

␬

of 0.56 and 0.59,

respectively (148, 155). Furthermore, SPECT/CT allows

imaging to be compressed into a single time-point at 24

hours, improving the efficiency of scheduling (155).

SPECT/CT has been used to perform individualized do-

simetry in patients receiving

177

Lu-DOTA-octreotate

treatment of metastatic NETs (159). Using whole-body

imaging and blood and urine measurements at 24-, 96-,

and 168-hour time-points, the absorbed dose to the kidney

was calculated with SPECT/CT and this represented the

organ receiving the highest radiation dose for most pa-

tients. This method was also adapted for purposes of cal-

culating doses, with the goal of limiting bone marrow

radiation dose. In a study of 12 patients undergoing

99m

Tc-

EDDA/HYNIC-TOC imaging of NETs, SPECT/CT afforded

the calculation of radiation dosimetry identifying the

highest absorbed radiation doses to liver, spleen, kidneys,

and bladder (160).

111

In- and

99m

Tc- labeled radionuclide imaging of

medullary thyroid cancer

Medullary thyroid cancers (MTCs) are derived from

parafollicular (C cells) of neural crest origin, comprising

3–12% of all thyroid cancers. MTC is often an indolent

disease where, after surgery, up to 40% of patients will

have residual or recurrent neoplasm identified by elevated

serum calcitonin or carcinoembryonic antigen tumor bio-

markers (161). All molecular imaging techniques for MTC

have limited sensitivities:

99m

Tc(V) dimercaptosuccinic

acid (DMSA) (50–80%),

201

Tl-thallium (19%),

99m

Tc-

sestamibi (47%),

123/131

I-MIBG (25–30%),

111

In-oc-

treotide (50–75%) (162), and recently,

99m

Tc-EDDA/

HYNIC-TOC (80%) (163).

111

In-octreotide SPECT/CT

was able to depict a paratracheal MTC recurrence (164),

whereas another report described a multiple endocrine

neoplasia (MEN) 2B patient with

99m

Tc-(V)DMSA

SPECT/CT imaging of bone metastases (165). To our

knowledge, due to the rarity of MTC, no dedicated co-

horts have been studied with SPECT/CT, although initial

utility has been reported in small case series (166, 167).

V. Adrenal Cortical Imaging With

131

I-NP59

SPECT/CT

131

I-6-

␤

-iodomethyl-19-norcholesterol (

131

I-NP59) is a

cholesterol precursor analog developed in the early 1970s

that is incorporated into the cholesterol synthesis pathway

via packaging into lipoproteins in the adrenal cortex

(168). Adrenal cortical imaging with

131

I-NP59 has been

used in the workup of hormonally active adrenal nodules

(169). Unilateral

131

I-NP59 uptake has been shown to

correlate with hormone hypersecretion by adrenocortical

adenomas (169) and selects patients suitable for surgical

intervention with high efficacy by lateralizing radiotracer

uptake to the side of hypersecretion (170–173).

Traditionally,

131

I-NP59 scans have been interpreted

on posterior planar images of the upper abdomen acquired

4–8 days after iv injection of 37 MBq (1 mCi)

131

I-NP59.

Patients with suspected hyperaldosteronism receive phar-

macological adrenosuppressive preparation with dexa-

methasone (174). A large study found that planar

131

I-

NP59 accuracy was 71% in primary aldosteronism and

100% in Cushing’s syndrome (175). The addition of 3D

SPECT images improves contrast resolution and the abil-

ity to detect smaller lesions (176) and allows the use of

semiquantitative parameters such as adrenal-to-liver up-

take ratios to aid diagnosis of pre- and subclinical Cush-

ing’s disease (177, 178).

131

I-NP59 SPECT/CT has proven

useful for primary hyperaldosteronism related to smaller

adenomas (in one report able to detect the culprit 0.8 mm

adrenocortical microadenoma not apparent on CT) (179)

and to assist in the diagnosis of subclinical or atypical

hyperaldosteronism in chronic renal failure (180, 181). In

29 patients with inconclusive adrenal venous sampling,

131

I-NP59 SPECT/CT had sensitivity of 81.8% compared

to SPECT of 68.2% and planar imaging of 40.9% (182).

The increased sensitivity of SPECT/CT was attributed to

the ability to detect functioning adenomas 1.5 cm or

smaller, and as small as 6 mm in one patient (182). One of

the strengths of

131

I-NP59 is for lateralization of hyper-

functioning cortical adenomas predicting biochemical

cure after surgical resection of the adenoma (170–173).

131

I-NP59 imaging is superior to CT for this indication.

SPECT/CT may further refine the utility of the

131

I-NP59

scan for lateralization by allowing direct assessment of

function within adrenal nodules (both for Cushing’s and

Conn’s syndromes) and minimizing false-positive inter-

doi: 10.1210/er.2013-1030 edrv.endojournals.org 727

pretations (318). Identification of bilateral adrenal uptake

is important to exclude a process of macrohyperplasia, for

which surgical approaches will be ineffective.

VI. Sympathetic Adrenomedullary Imaging

With SPECT/CT

Chromaffin NETs are derived from sympathomedullary

cells of postganglionic sympathetic neurons (183), the ma-

jority being located in the adrenal medulla or in an extra-

adrenal location near the celiac axis or aortic bifurcation

(organ of Zuckerkandl) (143, 144). Those arising in the

adrenal gland are called pheochromocytomas (PHEOs),

whereas those arising from extra-adrenal tissues are para-

gangliomas (PGLs). Patients may present with symptoms

of biogenic amine excess (141, 183), with PHEO occur-

ring in 0.5% of hypertensive patients and 4% of inciden-

tally discovered adrenal masses (143). PGLs are generally

intra-abdominal in 85%, thoracic in 15%, and cervical in

1–3% of patients (143). Cervical PGLs are usually of para-

sympathetic origin, do not contain chromaffin cells, and

are frequently nonsecretory.

Conventional imaging techniques, CT and magnetic

resonance imaging (MRI), have excellent sensitivities of

93–100% for adrenal PHEO and 90% for extra-adrenal

PGL (141, 183). The specificity is lower, at around 80%,

and another limitation is that cross-sectional, site-targeted

imaging may not readily detect a multifocal process. Func-

tional

123

I-MIBG is a widely used modality that is highly

specific to characterize suspicious adrenal lesions and pro-

vides whole-body screening for metastatic disease (143,

184).

123

I-MIBG has sensitivity of 83–100% and speci-

ficity of 95–100%, preferable to earlier

131

I-MIBG imag-

ing with a lower sensitivity of 77–90% (44, 46, 47). A

recent meta-analysis confirmed high

123

I-MIBG sensitiv-

ity of 94% and specificity of 95% for PHEO imaging

(185). SRS imaging is generally considered a second-line

test to MIBG for PHEO or PGLs; however, SRS is pre-

ferred to MIBG for head and neck PGLs (186–189). Rou-

tine performance of

123

I-MIBG imaging in sporadic, uni-

lateral adrenal masses fully characterized on CT or MRI

has been questioned, particularly because MIBG sensitiv-

ity is lower for detection of extra-adrenal or metastatic

disease (190, 191). However, some authors have sug-

gested a role for MIBG in the presence of genetic mutations

with increased malignant potential (192).

123

131

I-MIBG imaging of pheochromocytoma

and paraganglioma

123/131

I-MIBG SPECT/CT is valuable for evaluation of

PHEO and PGL (193–201). One study found that

SPECT/CT had incremental diagnostic value over planar

scintigraphy in up to 53% of cases (202) (Figure 5). In

another study,

123

I-MIBG SPECT/CT had sensitivity and

specificity of 100% in 22 patients, changing the diagnosis

in three of 14 scan-positive cases and three of eight scan-

negative cases (192).

123/131

I-MIBG SPECT/CT improved

localization and interpretation in 12 of 16 (75%) diag-

nostic cases and nine of 12 (75%) therapeutic cases, es-

pecially when radioactive foci were near or overlapping

regions of physiological MIBG uptake, such as adjacent to

liver, spleen, or bladder (203).

123

I-MIBG SPECT/CT was

compared with MRI in 22 patients with suspected PHEO.

Sensitivity was 87.5% for both modalities, and specificity

of SPECT/CT was 93% as compared to MRI of 97%.

After SPECT/MRI software fusion, there was 100% sen-

sitivity and specificity on a per patient and per lesion anal-

ysis (204). When CT or MRI appearances are indetermi-

nate, the high specificity of

123

I-MIBG imaging has

traditionally been used to confirm that an adrenal mass

represents a PHEO, lateralizing the disease process before

operation to ensure surgical cure (190, 191). In the setting

of known or suspected genetic predisposition, in which

PGL and metastatic disease occur more commonly,

123

I-

MIBG SPECT/CT improves evaluation for staging before

surgery and is of use for depicting bilateral adrenal in-

volvement, which when discovered, would modify the sur-

gical approach.

123

I-MIBG SPECT/CT was compared with

F-dihy-

droxyphenylalanine PET/CT in 12 patients with meta-

static PGL.

123

I-MIBG SPECT/CT had a sensitivity of

75% (38% per lesion), compared with

F-dihydroxy-

phenylalanine sensitivity of 100% (98% per lesion)

(205). In a comparison study between

123

I-MIBG

SPECT/CT and

C-hydroxyephedrine PET/CT,

123

I-

MIBG SPECT/CT had sensitivity of 93% compared to

C-hydroxyephedrine PET/CT sensitivity of 99%;

both had specificity of 100% (206). Despite lower sen-

sitivity in these studies,

123

I-MIBG scans retain a unique

role to inform on potential efficacy of

131

I-MIBG

therapy.

123

131

I-MIBG imaging of neuroblastoma

Neuroblastoma is the most common tumor of infants,

accounting for 8–10% of all childhood malignancies

(207). This neoplasm is derived from sympathetic neuro-

blast cells located in the adrenal medulla (40–60%), ret-

roperitoneum (20%), and mediastinum (10%) (207).

Functional

123

I-MIBG imaging in neuroblastoma has an

overall sensitivity of 97% and specificity of 100% (185).

The feasibility of software fusion of

123

I-MIBG

SPECT/CT images was first reported in pediatric patients

in 2001 (208). In three children evaluated for neuroblas-

728 Wong et al Endocrine SPECT/CT Endocrine Reviews, October 2014, 35(5):717–746

toma,

123

I-MIBG SPECT/CT confirmed true positive pla-

nar scan findings and clarified the clinical significance of

nonspecific foci of radiotracer uptake. The CT added an

estimated 1.5 mSv radiation dose but provided the advan-

tage of a single imaging session, important for children

who may require sedation for imaging (209). A review of

the utility of pediatric SPECT/CT recommended the com-

bination of contrast-enhanced CT with SPECT to reduce

the number of imaging visits (210).

VII. Parathyroid and Thyroid

Scintigraphy With SPECT/CT

Primary hyperparathyroidism is the

most common cause of hypercalce-

mia in the outpatient setting, affect-

ing two to three of 500 women and

one of 2000 men (211, 212), with a

peak incidence in the fourth and fifth

decades of life (213). Diagnosis is

based on elevated serum and ionized

calcium levels with elevated or nor-

mal intact PTH levels in the presence

of normal renal function (211). Cur-

rently, most patients diagnosed with

hyperparathyroidism are asymp-

tomatic as a result of widespread

screening biochemical laboratory

tests (211). The etiology is due to a

single parathyroid adenoma in 85–

96% of cases, chief cell hyperplasia

in 10%, and a parathyroid cancer in

⬍1–4% (211, 213–215).

Parathyroid adenomas range in size

between 100 mg and 100 g, with a cor-

relation between size and serum calcium

levels (211, 213). The majority are spo-

radic, although associated genetic disor-

ders such as MEN1 and MEN2A and

familial hyperparathyroidism are de-

scribed (211). Secondary hyperpara-

thyroidism arises in the setting of

chronic renal failure, gastrointesti-

nal malabsorption, or osteomala-

cia, with compensation for hy-

pocalcemia (49). So-called “tertiary

hyperparathyroidism” occurs when

compensatory mechanisms result

in autonomous function. Surgical

extirpation of hyperfunctioning

gland(s) is the treatment for primary hy-

perparathyroidism, and for tertiary hy-

perparathyroidism when medical treat-

ment fails (216).

The traditional surgical procedure of bilateral four-

gland exploration without preoperative imaging is cura-

tive in ⬎90% of cases in the hands of an experienced

surgeon. Because similar success rates are achieved with

unilateral exploration via a minimally invasive approach

(217), there has been a shift to preoperative localization of

the “culprit” gland, with or without intraoperative

␥

-probe assistance (49), and intraoperative PTH monitor-

Figure 5.

Figure 5. Pheochromocytoma on

123

I-MIBG scanning in a 54-year-old male with hypertension

and recurrent symptoms of catecholamine hypersecretion. A and B,

123

I-MIBG 24-hour static

planar anterior and posterior images show focal activity in the region of the right adrenal gland

(arrowhead). C–H, Axial and coronal SPECT, CT, and fused SPECT/CT clearly depict a right

adrenal mass with intense focal MIBG accumulation (arrows) compatible with

pheochromocytoma. No additional foci of uptake were seen elsewhere in the body. Note that

the z-axis field-of-view of the SPECT/CT has been limited to reduce radiation exposure because

surgical planning relies mainly on the axial views.

doi: 10.1210/er.2013-1030 edrv.endojournals.org 729

ing (success based on a ⬎50% fall in PTH at 10 min after

gland excision) (211). Advantages of the minimally inva-

sive approach include smaller incisions (2- to 4-cm lower

neck incision) with improved cosmetic results, shorter op-

erating times, and faster patient recovery (211, 218). Sur-

gical failure is more common in multiglandular disease

(double adenoma or multiglandular hyperplasia) reported

in 2–5% of patients (211, 216) with the rate of ectopic and

multiglandular disease estimated at 44–70% in reopera-

tive cohorts (216). Furthermore, reoperation for hyper-

parathyroidism has higher failure rates.

The parathyroid glands are usually located in the per-

ithyroid sheath, with the superior glands lying posterior to

the upper third of the thyroid, whereas the inferior glands

are located posterior to the lower third of the thyroid.

Normal glands weigh 20–45 mg and measure 6 ⫻3mm

and are typically not seen on any imaging modalities. Para-

thyroid tissue is composed of parenchymal chief and mi-

tochondria-rich oxyphilic cells, both of which secrete

PTH. Anatomic variants include accessory parathyroid

glands (13%), three parathyroid glands (3%), and con-

genital absence such as in the Di-George syndrome (211,

213). Ectopic adenomas occur in 10–20% of cohorts; su-

perior parathyroid glands have a 1% ectopic rate, com-

pared with the inferior parathyroid glands exhibiting ec-

topia in 20–35% (211, 219). Ectopic locations include

paraesophageal (28%), mediastinal (26%), intrathymic

(24%), intrathyroidal (11%), carotid sheath (9%), and

high cervical sites (2%) (213).

Imaging modalities for preoperative localization of

parathyroid adenoma include ultrasound, parathyroid

scintigraphy, CT, and MRI (211, 214, 215). Dual-phase

99m

Tc-sestamibi is the most widely used protocol for para-

thyroid scintigraphy (49, 216). Planar images are acquired

with static views of the neck as well as the thorax to include

the mediastinum. Pinhole collimation results in superior

spatial resolution (49, 220), and oblique angle views in-

crease the separation of the posteriorly positioned para-

thyroid adenoma from overlying thyroid tissue. SPECT

has superior sensitivity to planar imaging (221, 222), im-

proving object contrast, removing overlying tissues, and

increasing depth information from 3D images (221, 223,

224). The reported sensitivity of planar parathyroid scin-

tigraphy ranges from 54 to 96% (216). In a meta-analysis

of 20 225 patients with primary hyperparathyroidism,

parathyroid scintigraphy had a sensitivity of 88% for de-

tection of single adenomas; however, sensitivity fell to

30% for multiple adenomas and to 45% for multigland

hyperplasia (225, 226). Detection of rare intrathyroidal

adenomas is challenging (227). In a small study of patients

with tertiary hyperparathyroidism, parathyroid imaging

had a sensitivity of 76% (228).

False-negative studies occur with small adenomas (217,

229); larger adenomas measuring 1.9–3.5 cm are more

likely to be true positive than smaller 0.3- to 1.8-cm lesions

(74 vs 40%; P⬍.001) (224). A prior history of parathy-

roid surgery affects detection rates, with the sensitivity of

parathyroid SPECT reported to decrease from 61% in pa-

tients with no prior surgery to 33% for reoperative ex-

ploration (226).

99m

Tc-sestamibi parathyroid scintigraphy

1. SPECT/CT for parathyroid scintigraphy

Minimally invasive surgical procedures rely upon ac-

curate preoperative localization of hyperfunctioning

parathyroid adenomas. As early as 2002, Rubello et al

(230) reported a patient in whom SPECT/CT precisely

identified an ectopic parathyroid adenoma. The following

year, SPECT/CT depicted ectopic parathyroid glands in

four patients, aiding surgical planning (231). The utility of

SPECT/CT for detection of cervical parathyroid adeno-

mas has been confirmed in multiple subsequent

SPECT/CT studies in primary, secondary, and tertiary hy-

perparathyroidism and subgroups of patients with con-

current nodular thyroid disease, multigland disease, and

in those with previously failed surgery (232–249). Regard-

less of the protocols used, parathyroid scintigraphy

SPECT/CT has been found to improve sensitivity and

specificity for detection of single adenomas, providing key

preoperative localization information. SPECT/CT aids

identification and surgical planning for ectopic parathy-

roid adenomas (211, 213, 216, 250) (Table 5).

2. Strategies and protocols for SPECT/CT

parathyroid scintigraphy

Most studies reporting parathyroid SPECT/CT have

used dual-phase

99m

Tc-sestamibi protocols with doses

ranging between 340 and 1110 MBq (231–237, 239–

249).

99m

Tc-sestamibi/

123

I subtraction SPECT/CT with si-

multaneous dual-isotope acquisition is feasible, although

technically demanding (238). Most investigators use hy-

brid

␥

-cameras with integrated SPECT/CT capability

(232–245), although some use software-fused CT-MIBI

from separately acquired SPECT and CT images (246–

248). Typically CT parameters have been low-dose, “so-

called” nondiagnostic studies without iv contrast (eg, mAs

2.5 and kVP 140).

Some investigators advocate early time-point SPECT/CT

imaging (15–20 min postinjection) (233, 236–239, 244,

246 –248), whereas others recommend delayed time-point

acquisitions (60–120 min postinjection) (232, 234, 235,

237, 240–243), with no apparent difference in detection

rates between early and delayed SPECT/CT (237).

730 Wong et al Endocrine SPECT/CT Endocrine Reviews, October 2014, 35(5):717–746

3. Image interpretation

SPECT/CT has sensitivities ranging from 70 to 100%

and specificities from 83 to 100%; these vary depending

on cohort studied, protocols used, surgical follow-up,

study design, and whether patient- or lesion-based anal-

ysis was used (232–246). SPECT/CT is clearly more sen-

sitive than planar imaging. In 110

patients with primary hyperparathy-

roidism, SPECT/CT had sensitivity

(72%) compared to SPECT (62%)

and planar (57%) imaging; all had

similar high specificity (⬎98%) (237).

Comparing SPECT to SPECT/CT, a

few authors report similar sensitivity

(233, 238, 239), although most have

found that SPECT/CT increases both

sensitivity (235, 237, 241, 244, 246,

247, 249) and specificity (240, 244).

Overall, there appears to be a sequen-

tial step-up in sensitivity between pla-

nar (59–76%), SPECT (67–97%),

and SPECT/CT (77–100%) imaging

techniques (235, 239, 244).

One of the major advantages of

SPECT/CT has been for preoperative

identification and localization of ad-

enomas in unusual retrotracheal

sites and of ectopic parathyroid ad-

enomas (230, 232, 251–259). The

rates of ectopic locations vary be-

tween 10 and 20% in SPECT/CT co-

horts (231, 232, 234–246) (Figure

6). SPECT/CT is beneficial for surgi-

cal planning, with one study demon-

strating that at surgery, the loca-

Table 5. Utility of

99m

Tc-Sestamibi SPECT/CT for Preoperative Localization of Parathyroid Adenoma

Advantages of SPECT/CT (Refs) Comments and Findings

Lateralization (212, 230–249, 255–259) SPECT/CT is better able to indicate the side of the adenoma, compared to planar and

SPECT.

Neck quadrant localization (232, 235, 239,

242, 244)

SPECT/CT is better able to indicate the neck quadrant of the adenoma, compared to

planar and SPECT.

Ectopic localization (231–234, 236–244,

246–248, 256)

SPECT/CT provides incremental diagnostic value and improves localization of ectopic

glands (rate 10–20%).

Improved diagnostic performance (232, 234–

236, 238–246, 248, 249)

99m

Tc-sestamibi SPECT/CT parathyroid scan

Planar: sensitivity, 57–76%; specificity, 77–100%

SPECT: sensitivity, 59–97%; specificity, 79–100%

SPECT/CT: sensitivity, 70–97%; specificity, 83–100%

99m

Tc-sestamibi/

123

I subtraction SPECT/CT parathyroid scan

SPECT: sensitivity, 71%; specificity, 48%

SPECT/CT: sensitivity, 70%; specificity, 96%

Improved interobserver agreement and reader

confidence (233, 237, 243)

Agreement

␬

SPECT/CT

␬

⫽0.76–0.79

SPECT/CT

␬

⫽0.91, SPECT

␬

⫽0.39

Cost-effectiveness and surgical planning (232,

235, 239–241, 244, 246–249)

SPECT/CT use was cost-effective for planning minimally invasive parathyroid adenoma

resection, SPECT/CT assists surgical planning of eu to pic and ec to pic adenomas.

Mean operating time decreased from 56 to 38 min compared to SPECT in one

study and from 62 to 36 min in another study.

Figure 6.

Figure 6. Ectopic parathyroid adenoma in a 73-year-old woman with prior hemithyroidectomy,

presenting with hypercalcemia. A and B, Anterior early 20-minute and delayed 2-hour planar

images show focal radiotracer uptake and retention at the thoracic inlet (arrows). C–E, Axial

SPECT, CT, and SPECT/CT localizes this activity to a soft tissue abnormality in the anterior

mediastinum (arrows), consistent with ectopic parathyroid adenoma. This was surgically removed

via a lower neck incision approach.

doi: 10.1210/er.2013-1030 edrv.endojournals.org 731

tion(s) of resected adenomas was ⬍19 mm from the

predicted location derived from the SPECT/CT scan (234).

SPECT/CT improves interobserver agreement and

reader confidence (243). One study found SPECT alone

had a poor

␬

value of 0.39 compared to SPECT/CT

␬

value

of 0.91 (233). Interobserver agreement in another study

was highest (

␬

⫽0.76 – 0.79) for dual-phase imaging when

SPECT/CT was included and lowest for single-phase im-

aging, regardless of protocol (

␬

⫽0.50–0.61) (237).

4. Special patient subgroups

SPECT/CT is useful in patients who have previously

undergone surgery (257). In 28 patients with a prior his-

tory of thyroid or parathyroid surgery, SPECT/CT pre-

dicted the site of the “missing” gland in 86% of patients,

compared to only 43% with SPECT alone (248), provid-

ing useful anatomic information in the presence of dis-

torted postsurgical neck anatomy owing to prior surgery

(236). In a cohort of patients selected for the presence of

multiglandular disease, the overall imaging sensitivity was

low, with SPECT positive in only four of 30 (13.3%) pa-

tients, CT in 11 of 30 (36.7%), but with slightly increased

detection rates using SPECT/CT (46.7%) (246). The ac-

curacy of SPECT/CT in patients with coexisting nodular

thyroid disease has been studied in 48 hyperparathyroid

patients with concurrent nodular thyroid glands; early

time-point SPECT/CT had a sensitivity of 77% and spec-

ificity of 97%, superior to SPECT sensitivity of 67% and

specificity of 87% (244). Others have also reported similar

findings (240, 242). In addition to multinodular thyroid

goiters, false-positive findings may also occur due to in-

flammatory disease, thyroid cancer, brown fat, osteitis

fibrosa cystica (brown tumors), and autotransplanted

glands (216, 260–263). Similar to FDG PET/CT, where

FDG uptake can occur in metabolically active brown ad-

ipose tissue,

99m

Tc-sestamibi uptake in mitochondria-rich

brown fat is identified on SPECT/CT in 6.3% cases with

implications for false-positive interpretative errors

(264–266).

5. Diagnostic workup of hyperparathyroidism and role of

parathyroid SPECT/CT

At the present time, most patients with hyperparathy-

roidism are asymptomatic at diagnosis (267). Selection for

surgery is based on calcium levels, renal function, bone

mineral densitometry, age ⬍50 years, and symptomatol-

ogy. Nonparathyroid causes of hypercalcemia such as ma-

lignancy, familial hypocalciuric hypercalcemia, and med-

ication effects should be excluded (267). Neck ultrasound

and parathyroid scintigraphy have equivalent diagnostic

performance and are accepted as first-line imaging tests

(268–271). When there is unequivocal identification of a

parathyroid adenoma on either test, the surgeon may pro-

ceed confidently to a minimally invasive procedure (218).

Parathyroid scintigraphy has the advantage of being able

to detect extracervical ectopically located adenomas,

whereas neck ultrasound is best utilized when there is co-

existing nodular thyroid disease (121, 218). By contrast,

CT and MRI have not been recommended as primary im-

aging alternatives due mainly to low sensitivity for detec-

tion of parathyroid disease.

If both parathyroid scintigraphy and neck ultrasound

are negative, then four-dimensional (4D)-CT has been

proposed as an alternative test with good sensitivity and

specificity (218, 272). Its major disadvantage to date has

been the higher radiation dose to the thyroid gland, lim-

iting its use in the younger patient population. In the sit-

uation when all imaging tests are negative, some authors

have advocated proceeding to four-gland exploration, ac-

cepting a lower cure rate of around 89% (273, 274). Ob-

servation with serial imaging is another valid option. Pa-

tients with recurrent hyperparathyroidism in the setting of

a prior history of neck surgery are challenging to manage

due to more difficult reoperation and higher failure rates.

They warrant a comprehensive imaging evaluation, and

additional strategies proposed include selective venous

sampling (275), 4D-CT (218), and

C-methionine PET

(276). Table 6 summarizes diagnostic performance of var-

ious procedures and imaging tests for parathyroid ade-

noma localization.

Several studies have shown that the use of SPECT/CT

improves lateralization rates of parathyroid adenoma and

is more successful for quadrant localization compared to

planar and SPECT imaging. However, there is still some

difficulty in ascribing whether the location of a detected

adenoma is superior or inferior when correlated with the

surgical findings (232, 235, 240–242, 244, 277). The ad-

vantages of SPECT/CT for assisting the planning of the

minimally invasive surgical approach recommend its rou-

tine use, when available. Preoperative detection of an ec-

topic adenoma on SPECT/CT is unquestionably of value

before surgery (278). SPECT/CT provides accurate assess-

ment in patients with coexisting thyroid nodular disease

(240, 242, 279), particularly when combined with neck

ultrasound (242). However, for patients with multiglan-

dular disease or double adenomas, and for those under-

going reoperative surgical procedures, the sensitivity of

SPECT/CT appears lower (246, 248, 281) when com-

pared to selective venous sampling (281), and therefore it

is not expected to have a major impact for these more

challenging patient subgroups.

732 Wong et al Endocrine SPECT/CT Endocrine Reviews, October 2014, 35(5):717–746

99m

Tc-pertechnetate thyroid scans

SPECT/CT has been used with

99m

Tc-pertechnetate

thyroid scintigraphy to localize uptake within a thyroglos-

sal duct cyst (283) and to evaluate Marine-Lenhart syn-

drome, the rare entity of Graves’ disease combined with

hyperfunctioning thyroid nodules (284). Traditionally,

thyroid scintigraphy is correlated with thyroid ultra-

sound; however, SPECT/CT offers a more direct method

to assess the functional status of thyroid nodules (285,

286). Two studies have reported the use of

123

I SPECT/CT

to depict uptake in an obstructive lingual thyroid (124,

287). A lingual thyroid was successfully treated with ra-

dioiodine ablation in a patient at high surgical risk (287)

(Figure 7).

Table 6. Diagnostic Performance of Imaging Studies, Catheter-Based, and Surgical Procedures for Localization of

Parathyroid Adenoma

Test or Procedure

Overall

Sensitivity

Range, %

Pooled Sensitivity

(95% CI) Comments

Neck ultrasound Accepted role as first-line test

Primary HPT 70–100 76% (70–81) Ultrasound performed by surgeons or radiologists is equivalent.

Single adenoma N/A 79% (77–80) Readily available. No ionizing radiation.

Multiglandular disease N/A 35% (30–40) Concurrent evaluation for thyroid nodular disease.

Double adenoma N/A 16% (4–28) Operator dependent. Difficult in obese patients.

Thyroid abnormalities 47– 84 N/A Unable to detect ectopic glands.

Prior neck surgery 36–63 N/A

Sestamibi scintigraphy Accepted role as first-line test.

Planar and SPECT Able to detect ectopic glands.

Primary HPT 54–100 79% (64 –91) SPECT is more sensitive than planar.

Secondary HPT 35–90 58% (52–65) False-positive results due to thyroid nodules.

Single adenoma 54–96 88% (87– 89)

Multiglandular disease 25–58 45% (41–48)

Double adenoma N/A 30% (⫺2to62)

Thyroid abnormalities Decreased N/A

SPECT/CT N/A Novel technology being validated.

Primary HPT 70–100 N/A SPECT/CT is more specific than SPECT.

Multiglandular disease 47 N/A Good localization of ectopic glands.

Thyroid abnormalities 77–90 N/A Improved lateralization and neck quadrant localization

compared to SPECT.Prior neck surgery 26–85

CT 40–86 45% Not considered first line.

Generally low sensitivity and high radiation exposure.

MRI 43–88 54% Not considered first line.

Generally low sensitivity and low specificity due to lymph nodes

and thyroid nodules.

Selective venous sampling “Gold standard” invasive test.

Primary HPT 71 N/A Possible role in reoperative cohorts.

Prior neck surgery 71–90 N/A

Four-gland exploration 90 –95% cure rate N/A Historical “gold standard.”

Intraoperative PTH monitoring ⬎97 N/A Used for guiding minimally invasive surgery.

Useful for multiglandular or double adenomas.

High rates of cure (up to 97%) have been reported without use

of intraoperative PTH monitoring.

4D-CT 94 89% Novel technique being validated.

Possible role in reoperative cohorts.

High radiation dose to the thyroid.

Difficult interpretive criteria.

C-MET PET

Primary HPT

Prior neck surgery 83 81% (74–86) Novel technique being validated.

67 N/A Potential role in reoperative cohorts.

Poor availability.

FDG PET 86 N/A Novel technique being validated.

Surgical exploration with negative

imaging tests

89% cure rate N/A Lower cure rate when imaging tests are negative.

Balance lower cure rate against symptoms.

Resort to four-gland exploration vs observation with repeat

imaging.

Abbreviations: CI, confidence interval; HPT, hyperparathyroidism; MET, methionine; N/A, not available. Composite table from the following primary and secondary

sources: Refs. 121, 218, 225, 268–276.

doi: 10.1210/er.2013-1030 edrv.endojournals.org 733

C. Miscellaneous endocrine applications of SPECT/CT

SPECT/CT has been used in the research setting to de-

velop novel applications for the study of endocrine disor-

ders (288). For Graves’ eye disease,

99m

Tc-EDDA/

HYNIC-TOC SPECT/CT was used to localize radiotracer

uptake to the orbits. Orbital

99m

Tc-TOC uptake was re-

lated to the activity of Graves’ orbitopathy and may be a

feasible technique to assess treatment response to corti-

costeroids (289). Novel preoperative

99m

Tc-folate

SPECT/CT was used to investigate nonfunctioning pitu-

itary adenomas (290).

VIII. Current Clinical Role of SPECT/CT in the

Diagnostic Workup of Endocrine Disorders

A. Protocols for SPECT/CT use

Currently, SPECT/CT cameras, in a manner similar to

PET/CT, are becoming more widely disseminated in the

United States, predominately at tertiary medical institu-

tions. SPECT/CT is a technological tool applied to the

radionuclide study, rather than a type of imaging modality

in itself. Protocols for SPECT/CT include routine use vs

selective indications to localize and evaluate radioactivity

foci that are otherwise problematic to interpret on planar

or SPECT, based on the growing list of indications and

evidence for utility with endocrine scintigraphy (9). The

SPECT/CT component for parathy-

roid scintigraphy was recently ap-

proved for Centers for Medicare and

Medicaid Services reimbursement, al-

though other indications for SPECT/

CT do not as yet have separate bill

codings. In most institutions, the CT

portion of the study is acquired with

nondiagnostic (low-dose kVP and

mAs) parameters without iv con-

trast, with the intent to perform an-

atomical localization and attenua-

tion correction (291). Therefore,

SPECT/CT does not replace dedi-

cated diagnostic contrast-enhanced

CT, although SPECT/CT use in a

problem-solving capacity may obvi-

ate the need for further workup of

equivocal findings with diagnostic

CT imaging.

B. Economic evaluation and

cost-effectiveness

The current economic climate

mandates scrutiny directed at the ris-

ing costs of healthcare, and the cli-

nician should be mindful of the increasing costs related to

medical imaging while ordering appropriate investiga-

tions for their patients. Economic evaluation studies gen-

erally require descriptions of a given intervention in com-

parison to alternative tests or treatments, the perspective

of the study, the measured outcomes, the method of cost-

ing including adjustments, an outline of the time horizon,

and a discussion of uncertainties related to the analysis

(292, 293), helping to give insight into how best to allocate

scarce healthcare resources.

Cost-effectiveness analysis is the most appropriate type

of study for comparing an imaging modality to an alter-

native test, with the costs and beneficial effects on out-

comes examined and weighed against each other (294).

Economic evaluation studies in nuclear medicine in the

pre-SPECT/CT era have predominately been focused on

proving the effectiveness of PET for cancer staging and

myocardial perfusion studies for the diagnosis of coronary

artery disease. For endocrine disorders, cost-effectiveness

has been reported for radioiodine as first-line treatment of

Graves’ hyperthyroidism compared to surgery (294), ra-

dioiodine uptake measurements in the diagnostic workup

of thyrotoxicosis (295), evaluation of thyroid nodule ma-

lignant potential with sestamibi scans (296, 297), staging

of NETs using somatostatin scintigraphy (298, 299),

workup of adrenal incidentaloma with

131

I-NP59 imaging

Figure 7.

Figure 7. A 53-year-old woman with hypothyroidism had progressive globus sensation and

symptoms of airway obstruction when lying supine. Radioiodine 0.5 mCi

123

I planar scan at 4

and 24 hours showed absent thyroid gland in the neck with a focal uptake in the region of the

oral cavity (not shown). A–F, CT and

123

I SPECT/CT fusion images precisely localized radioiodine

uptake to a soft tissue mass at the base of the tongue (arrows), with higher attenuation than

surrounding soft tissue. The 24-hour

123

I uptake within this lingual thyroid was measured at

13.5%.

734 Wong et al Endocrine SPECT/CT Endocrine Reviews, October 2014, 35(5):717–746

(300, 301), and use of

131

I-MIBG therapy for treatment of

carcinoid syndrome (302). Parathyroid scintigraphy for

preoperative localization of adenomas is cost-effective be-

cause the costs of protracted or failed surgery due to an

unidentified ectopic adenoma outweigh those related to

imaging (292, 303, 304). Another study showed that min-

imally invasive parathyroid surgery using preoperative

parathyroid scintigraphy led to a $3000 reduction in

charges compared to nondirected bilateral neck explora-

tion, attributed to reduced operative times, early hospital

discharge, and avoidance of re-exploration (305).

To date, the number of studies examining the cost-ef-

fectiveness of SPECT/CT applied to endocrine scintigra-

phy is limited to parathyroid scintigraphy (306). Table 7

summarizes the current published evidence on endocrine

SPECT/CT for diagnostic performance and economic

evaluation. Parathyroid SPECT/CT results in a reduction

in mean operating times from 56 to 38 minutes, compared

to SPECT alone. The same authors also reported in 55

patients (27 with SPECT and 28 with SPECT/CT) a re-

duction in mean operating times from 62 to 36 minutes,

resulting in estimated cost savings of €98 (US $136) per

patient (240). However, these results are not directly ap-

plicable to costs in the United States.

Economic evaluation of an emerging imaging technol-

ogy early in its clinical deployment may lack generaliz-

ability. Furthermore, outcome measurements and cost-ef-

fectiveness analyses of imaging tests are often difficult to

perform because technological advancement regularly

outpaces peer-reviewed medical literature. For example,

recent studies have reported cost-effectiveness of 4D-CT

or neck ultrasound when compared to parathyroid scin-

tigraphy (planar and SPECT); however, these imaging mo-

dalities have not yet been compared to parathyroid

SPECT/CT (307, 308). Future economic evaluation stud-

ies of SPECT/CT to determine its role in the diagnosis of

endocrine disorders are anticipated to be forthcoming.

C. Guidelines for indications and role

A number of medical organizations and societies have

advocated the use of SPECT/CT in their guidelines on the

management and treatment of endocrine disorders. For

example, the Society of Nuclear Medicine and Molecular

Imaging (SNMMI) 2006 procedure guideline for

SPECT/CT lists imaging of tumors, thyroid, and parathy-

roid disorders as appropriate indications for SPECT/CT

(291), with the strongest evidence of utility of SPECT/CT

found for parathyroid scintigraphy and thyroid cancer im-

aging, followed by octreotide and MIBG imaging (9). Both

the SNMMI and the European Association of Nuclear

Medicine and Molecular Imaging (EANMMI) guidelines

on parathyroid scintigraphy recommend a major role for

SPECT/CT for localization of ectopic parathyroid adeno-

mas (213, 214). Its routine use in the preoperative setting

remains investigational at present. The SNMMI 2012

guidelines on radioiodine therapy of thyroid disease dis-

cuss a potential role for preablation diagnostic

123

Ior

131

whole-body thyroid cancer scans with SPECT/CT in the

immediate postsurgical setting to detect unsuspected re-

gional and distant metastatic disease, potentially changing

staging and management (309). The American Thyroid

Association 2009 and EANMMI 2008 guidelines on thy-

roid cancer management discuss the use of SPECT/CT as

an emerging imaging technique, including a potential fu-

ture role for performing dosimetry (6, 310). The American

Association of Clinical Endocrinologists/American Col-

lege of Endocrinology thyroid cancer guidelines include

the use of diagnostic SPECT, although not SPECT/CT at

Table 7. Test Performance and Economic Evaluation Studies of SPECT/CT for Endocrine Scintigraphy

Parameters

131

123

I Thyroid

Cancer Scan

111

In-DTPA

Octreotide

Scan

131

123

I-MIBG

Scan

131

I-NP59

Adrenal

Cortical Scan

99m

Tc-Sestamibi

Parathyroid

Scan

Localization ⫹⫹⫹⫹ ⫹⫹⫹⫹ ⫹⫹⫹⫹ ⫹⫹ ⫹⫹⫹⫹

Characterization ⫹⫹⫹⫹ ⫹⫹⫹⫹ ⫹⫹⫹⫹ ⫹⫹ ⫹⫹⫹⫹

Clarification of equivocal uptake ⫹⫹⫹⫹ ⫹⫹⫹⫹ ⫹⫹⫹ ⫹⫹ ⫹⫹

Sensitivity ⫹ ⫹⫹ ⫹⫹ ⫺ ⫹⫹⫹

Specificity ⫹⫹⫹⫹ ⫹⫹⫹⫹ ⫹⫹⫹ ⫺ ⫹⫹⫹⫹

Interobserver agreement ⫹⫹⫹ ⫹⫹⫹ ⫺ ⫺ ⫹⫹⫹

Staging ⫹⫹⫹⫹ ⫹⫹⫹ ⫺ N/A N/A

Preoperative localization N/A ⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹⫹

Surgical times reduced N/A N/A N/A N/A ⫹⫹⫹

Dosimetry ⫹⫹⫹ ⫹⫹⫹ ⫹⫹ N/A N/A

Cost-effectiveness ⫺⫺⫺⫺⫹⫹

Ordering of additional imaging reduced ⫹⫹ ⫹⫹ ⫹⫹ ⫺ ⫹

Change in management ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫺ ⫹⫹⫹

Improved quality of life ⫺⫺⫺⫺⫺

Increased life expectancy ⫺⫺⫺⫺⫺

Abbreviation: N/A, not available.

doi: 10.1210/er.2013-1030 edrv.endojournals.org 735

present (311). The SNMMI and EANMMI guidelines on

octreotide imaging consider SPECT as the standard of

care, and when available, SPECT/CT is recommended for

attenuation correction and localization of octreotide-avid

lesions (312, 313). The SNMMI guidelines for MIBG im-

aging of paraganglioma and pheochromocytoma state

that the use of SPECT/CT is “highly recommended” due

to improved diagnostic accuracy (314), a sentiment shared

by the EANMMI guidelines (315). Dosimetry calculations

based on SPECT and SPECT/CT have been advocated for

131

I-MIBG therapy (314) and for somatostatin peptide

receptor therapy (316). The use of SPECT/CT for other

endocrine disorders remains investigational, with no cur-

rent role recommended in the workup of thyroid or ad-

renal nodules (6, 132, 136, 280, 282, 317).

D. Strategies for reducing radiation exposure

Radiation exposure due to medical sources continues to

increase, with much of the increase attributed to repetitive

radiological procedures both for diagnostic intent and fol-

low-up. The largest contribution to overall medical radi-

ation exposure is from contrast-enhanced CT, which may

require multiple image acquisitions during various phases

of contrast washout. Image quality for CT is strongly de-

pendent on x-ray intensity (ie, exposure); for this reason,

the compromise made is summarized with the As Low As

Reasonably Achievable (ALARA) principle to achieve the

highest diagnostic quality imaging while using the lowest

radiation exposure for patients. The issue of dose reduc-

tion from medical imaging is of great importance, and in

recent years software has been developed; in particular,

the latest-generation iterative reconstruction algorithms

designed for diagnostic CT are able to reduce image noise

while improving the overall image quality as compared to

older filtered back-projection image reconstruction meth-

ods. Increasing use of SPECT/CT, normally performed

with low-dose noncontrast enhanced CT protocols, is an-

ticipated to only modestly contribute to collective radia-

tion doses. Nonetheless, many strategies can be used to

achieve a reduction in patient dose from SPECT/CT, in-

cluding: 1) optimization of the CT acquisition protocols

(tube current, peak voltage, rotation time, helical pitch) in

order to obtain data for localization and SPECT attenu-

ation correction; 2) the systematic use of software able to

reduce the patient CT dose, in particular the automatic

exposure control, the anatomically adapted tube current

modulation, and adopting the latest-generation iterative

image reconstruction algorithms; 3) the use of the mini-

mum CT scan field-of-view coverage tailored for each im-

aging procedure; 4) correct selection of patients and

procedure; 5) consideration of alternative imaging proce-

dures, such as ultrasound or MRI, that do not have ion-

izing radiation effects, when appropriate; 6) a careful se-

lection in the pediatric population, using examination

protocols modified according to the child’s size; and 7)

avoidance of repetitive diagnostic CT for evaluations of

equivocal findings.

IX. Summary and Future Directions

Hybrid SPECT/CT is a powerful diagnostic tool that al-

lows precise localization of the distribution of radioactiv-

ity uptake from radiopharmaceuticals, reducing the num-

ber of equivocal findings encountered on traditional

planar scintigraphy, with the functional-anatomic coreg-

istration increasing accuracy of imaging interpretation.

Further advantages of the SPECT/CT approach include

incremental gains in interobserver agreement, reader con-

fidence, and improved staging of endocrine malignancies,

with SPECT/CT providing unique prognostic information

that alters subsequent patient management. Future re-

search directions include defining the role of SPECT/CT in

the investigation of endocrine disorders, improving quan-

titative methods for tumor-specific dosimetry, and explo-

ration of possible utility of novel hybrid SPECT/MRI, and

other unique combinations of imaging modalities.

Acknowledgments

Address all correspondence and requests for reprints to: Ka Kit Wong,

MBBS, University of Michigan Health System, Department of Radiol-

ogy, Division of Nuclear Medicine, B1G505 University Hospital SPC

5028, 1500 East Medical Center Drive, Ann Arbor, MI 48109–5028.

E-mail: kakit@med.umich.edu.

Disclosure Summary: The authors have nothing to declare.

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Sep 2021

Abstract Background The digital cadmium–zinc–telluride (CZT)-based SPECT system has many advantages, including better spatial and energy resolution. However, the impacts of different acquisition and reconstruction parameters on CZT SPECT quantification might still need to be validated. This study aimed to evaluate the impacts of acquisition parameters (the main energy window and acquisition time per frame) and reconstruction parameters (the number of iterations, subsets in iterative reconstruction, post-filter, and image correction methods) on the technetium quantification of CZT SPECT/CT. Methods A phantom (PET NEMA/IEC image quality, USA) was filled with four target-to-background (T/B) ratios (32:1, 16:1, 8:1, and 4:1) of technetium. Mean uptake values (the calculated mean concentrations for spheres) were measured to evaluate the recovery coefficient (RC) changes under different acquisition and reconstruction parameters. The corresponding standard deviations of mean uptake values were also measured to evaluate the quantification error. Image quality was evaluated using the National Electrical Manufacturers Association (NEMA) NU 2–2012 standard. Results For all T/B ratios, significant correlations were found between iterations and RCs (r = 0.62–0.96 for 1–35 iterations, r = 0.94–0.99 for 35–90 iterations) as well as between the full width at half maximum (FWHM) of the Gaussian filter and RCs (r = − 0.86 to − 1.00, all P values

A Clinical Challenge: Endocrine and Imaging Investigations of Adrenal Masses

Article

Jul 2021

Incidentalomas are reported in 3%-4% of patients who undergo abdominal anatomic imaging, making adrenal mass evaluation a common occurrence. An adrenal mass can be caused by a variety of pathologies, such as benign cortical and medullary tumors, malignant tumors (primary or secondary), cysts, hyperplasia, hemorrhage, or more rarely infection/inflammation processes. Functioning tumors usually have increased hormonal production but they are less common. Regardless of their functional status, some tumors have the potential to behave aggressively. Anatomic and functional imaging together with biologic evaluation play a vital role in adrenal pathology subtyping. Most patients are initially evaluated by CT or MRI, which allows for tumor characterization (to a certain extent) and can rule out malignant behavior based on the absence of tumor growth during longitudinal follow-up. In the remaining patients for whom CT or MRI fail to characterize the pathogenesis of adrenal tumors, the use of specialized molecular imaging techniques should be performed after hormonal screening. This review emphasizes well-established and emerging nuclear medicine imaging modalities and describes their use across various clinical scenarios.

Impacts of Acquisition and Reconstruction Parameters on the Absolute Technetium Quantification of the Cadmium-zinc-telluride Based SPECT/CT System: A Phantom Study

Preprint

Full-text available

Jan 2021

Background Various acquisition and reconstruction parameters may affect the accuracy of the absolute SPECT quantification. However, many of the impacts of these parameters have not well been studied. This study aimed to evaluate the impacts of acquisition parameters (main energy window and acquisition time per frame) and reconstruction parameters (the number of iterations and subsets in iterative reconstruction, post-filter, and image correction methods) on the technetium quantification of the cadmium-zinc-telluride based SPECT/CT system. Methods A phantom (PET NEMA/IEC image quality, USA) was filled with a 16:1 sphere-to-background activity concentration ratio of technetium and all spheres had 132400.81Bq/ml of radioactivity. Mean uptake values (calculated mean concentrations for spheres) were measured to evaluate the recovery coefficient (RC) changes under different acquisition and reconstruction parameters. Corresponding standard deviations of mean uptake values were also measured to evaluate the quantification error. Image quality was evaluated using the National Electrical Manufacturers Association (NEMA) NU 2-2012 standard. Results For six spheres of the phantom, significant correlations were found between iterations and RCs (r=0.60~0.98 for 1~35 iterations, r=0.96~0.99 for 35~90 iterations, all P-values <0.05) as well as between the full width at half maximum (FWHM) of the Gauss filter and RCs (r=-0.90～-1.00, all P-values <0.05). 1~35 iterations had higher regression coefficients compared with those of 35~90 iterations (0.67~1.16 vs. 0.02~0.17). The AC (attenuation correction)+SC (scatter correction) +RR (resolution recovery correction) combination had more close to 100% RCs (42.42%~98.04%) with better image quality (31.52%~83.57%) than those of other correction combinations (all P-values <0.05). No significant statistical difference was found between the 15% energy window and the 20% energy window (P-value=0.061), nor between the 5 seconds/frame and 120 seconds/frame of acquisition time (P-value=0.943) in terms of RCs. Conclusions The CZT-SPECT/CT showed a good quantification accuracy of technetium. The favorable acquisition parameters may be 15% energy window and 40 seconds/frame of acquisition time. The favorable reconstruction parameters could be 35 iterations, 20 subsets, the AC+SC+RR correction combination, and FWHM 0.7mm of Gauss filter.

Induction of oxidative/nitrosative stress following Tc-99m pertechnetate thyroid scintigraphy in human

Article

Sep 2019

Objective: Oxidative/nitrosative stress may be triggered by various sources, and ionizing radiation may also initiate oxidative/nitrosative stress. This is the first study; we aimed to investigate the induction of oxidative and nitrosative stress due to ionizing radiation in patients undergoing Tc99m pertechnetate thyroid scintigraphy. Method: Totally 26 patients (16 female,10 male) undergoing Tc-99m pertechnetate thyroid scintigraphy were included in this study. The patients were aged between 20 and 50 years (58.0±16.3 years). The blood samples were taken from patients 20 minutes after intravenous injection of Tc99m pertechnetate in the dose used clinically (5 miliCurie) before the patients were taken to the thyroid imaging. Control group was selected from 30 healthy subjects (15 female,15 male). The control group was aged between 17 and 72 years (57.0±14.0 years). The blood samples were taken both patients and control group for measuring antioxidant enzymes (catalase and superoxide dismutase), malondialdehyde, nitric oxide, and nitrotyrosine as oxidative/nitrosative stress biomarkers. Results: In this study, we found that activities of antioxidant enzymes increased in patients compared to control (p<0.05). Further, malondialdehyde levels as an indicator of oxidative stress were higher in patients than control group (p<0.05).The levels of nitric oxide and nitrotyrosine as nitrosative stress biomarkers also increased in patients compared to control groups (p<0.05). Conclusions: We thought that Tc-99m pertechnetate might cause an increase in reactive oxygen and nitrogen species and may cause oxidative/nitrosative damage at the cellular level. Our results indicated that the dose of Tc-99m pertechnetate given in these patients undergoing thyroid scintigraphy could be tolerable.

Grundprinzipien der Szintigraphie und SPECT (Einzelphotonen-Emissionscomputertomographie)

Chapter

Apr 2024

Basic Principles of Scintigraphy and SPECT (Single-Photon Emission Computed Tomography)

Chapter

Nov 2022

Scintigraphy is a medical examination performed in gamma cameras after the detection of gamma ray emissions from radioactive isotopes. It can acquire static or dynamic planar images, including whole-body sweep scans or tridimensional images after the reconstruction of multiple-angle planar acquisitions (single-photon emission computed tomography—SPECT). After radiation emission, a few steps are necessary before imaging reconstruction including collimation to improve spatial resolution, signal amplification, and a computational positioning system. Hybrid equipment is available to simultaneously acquire SPECT images and anatomic images through a conventional computed tomography (SPECT-CT).KeywordsScintigraphyPlanarSPECTSPECT-CT

Integration of molecular imaging in the personalized approach of patients with adrenal masses

Article

Mar 2022
Q J Nucl Med Mol Imag

Adrenal masses are a frequent finding in clinical practice. Many of them are incidentally discovered with a prevalence of 4% in patients undergoing abdominal anatomic imaging and require a differential diagnosis. Biochemical tests, evaluating hormonal production of both adrenal cortex and medulla (in particular, mineralocorticoids, glucocorticoids and catecholamines), have a primary importance in distinguishing functional or non-functional lesions. Conventional imaging techniques, in particular computerized tomography (CT) and magnetic resonance imaging (MRI), are required to differentiate between benign and malignant lesions according to their appearance (size stability, contrast enhanced CT and/or chemical shift on MRI). In selected patients, functional imaging is a non-invasive tool able to explore the metabolic pathways involved thus providing additional diagnostic information. Several single photon emission tomography (SPET) and positron emission tomography (PET) radiopharmaceuticals have been developed and are available, each of them suitable for studying specific pathological conditions. In functional masses causing hypersecreting diseases (mainly adrenal hypercortisolism, primary hyperaldosteronism and pheochromocytoma), functional imaging can lateralize the involvement and guide the therapeutic strategy in both unilateral and bilateral lesions. In non-functioning adrenal masses with inconclusive imaging findings at CT/MR, [18F]-FDG evaluation of tumor metabolism can be helpful to characterize them by distinguishing between benign nodules and primary malignant adrenal disease (mainly adrenocortical carcinoma), thus modulating the surgical approach. In oncologic patients, [18F]-FDG uptake can differentiate between benign nodule and adrenal metastasis from extra-adrenal primary malignancies.

Leveraging network using controlled weight learning approach for thyroid cancer lymph node detection

Article

Oct 2021

Identification of cervical metastatic lymph nodes (LN) on I-131 post-ablation whole-body planar scans (WBS) for cancer staging is crucial for patients with papillary thyroid cancer (PTC). The existing deep network is plagued by instability in finding the under-represented LN classes on highly complex WBS, where end-to-end tuned models that can account for this uncertainty region for multi-class locations are needed. Hence, as a key contribution of this study, we designed a novel leveraging segmentation network with input guidance (LSIG) end-to-end training model without pre and post-processing features that can learn ideal parameter settings depending on the quantity of multiple-object instances. To improve the co-occurrence of classes and control the false positive regions, we proposed a re-weighting negative control (RNC) mechanism that combines two key components, namely the re-weighting (Rw) term and the negative control function (NcF). This unified approximation of weighted training would leverage the network to control and learn the desired weights of true positives towards the LN region. As an end-to-end network training, we utilize a Unet-like convolution neural network (CNN) model. The performance of the LSIG is compared with the CNN-based networks, based on the ground truth (GT) mask developed using post-ablation single-photon emission computed tomography (SPECT/CT). Furthermore, the effectiveness of the two components used in the LSIG framework is evaluated on WBS datasets. Our proposed LSIG with a fully guided (Fg) LS-FgCNN model yielded a superior performance with high AUC value of 94.9%, which is 14.6% higher than the previous network for PTC.

Deep learning enables automated localization of the metastatic lymph node for thyroid cancer on 131I post-ablation whole-body planar scans

Article

Full-text available

May 2020

The accurate detection of radioactive iodine-avid lymph node (LN) metastasis on 131I post-ablation whole-body planar scans (RxWBSs) is important in tracking the progression of the metastatic lymph nodes (mLNs) of patients with papillary thyroid cancer (PTC). However, severe noise artifacts and the indiscernible location of the mLN from adjacent tissues with similar gray-scale values make clinical decisions extremely challenging. This study aims (i) to develop a multilayer fully connected deep network (MFDN) for the automatic recognition of mLNs from thyroid remnant tissue by utilizing the dataset of RxWBSs and (ii) to evaluate its diagnostic performance using post-ablation single-photon emission computed tomography. Image patches focused on the mLN and remnant tissues along with their variations of probability of pixel positions were fed as inputs to the network. With this efficient automatic approach, we achieved a high F1-score and outperformed the physician score (P < 0.001) in detecting mLNs. Competitive segmentation networks on RxWBS displayed moderate performance for the mLN but remained robust for the remnant tissue. Our results demonstrated that the generalization performance with the multiple layers by replicating signal transmission overcome the constraint of local minimum optimization, it can be suitable to localize the unstable location of mLN region on RxWBS and therefore MFDN can be useful in clinical decision-making to track mLN progression for PTC.

131I/123I-metaiodobenzylguanidine (mIBG) scintigraphy: procedure guidelines for tumour imaging.

Article

Full-text available

Dec 2010
Eur J Nucl Med

The aim of this document is to provide general information about mIBG scintigraphy in cancer patients. The guidelines describe the mIBG scintigraphy protocol currently used in clinical routine, but do not include all existing procedures for neuroendocrine tumours. The guidelines should therefore not be taken as exclusive of other nuclear medicine modalities that can be used to obtain comparable results. It is important to remember that the resources and facilities available for patient care may vary from one country to another and from one medical institution to another. The present guidelines have been prepared for nuclear medicine physicians and intend to offer assistance in optimizing the diagnostic information that can currently be obtained from mIBG scintigraphy. The corresponding guidelines of the Society of Nuclear Medicine (SNM) and the Dosimetry, Therapy and Paediatric Committee of the EANM have been taken into consideration, and partially integrated into this text. The same has been done with the most relevant literature on this topic, and the final result has been discussed within a group of distinguished experts. Bombardieri E, Giammarile F, Aktolun C, Baum RP, Bischof Delaloye A, Maffioli L, Moncayo R, Mortelmans L, Pepe G, Reske SN, Castellani MR, Chiti A; European Association for Nuclear Medicine. Eur J Nucl Med Mol Imaging. 2010 Dec;37(12):2436-46. doi: 10.1007/s00259-010-1545-7. PMID: 20644928

The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours

Article

Full-text available

Jan 2014

111In-pentetreotide scintigraphy: procedure guidelines for tumour imaging.

Article

Jul 2010
Eur J Nucl Med

This document provides general information about somatostatin receptor scintigraphy with (111)In-pentetreotide. This guideline should not be regarded as the only approach to visualise tumours expressing somatostatin receptors or as exclusive of other nuclear medicine procedures useful to obtain comparable results. The aim of this guideline is to assist nuclear medicine physicians in recommending, performing, reporting and interpreting the results of (111)In-pentetreotide scintigraphy. Bombardieri E, Ambrosini V, Aktolun C, Baum RP, Bishof-Delaloye A, Del Vecchio S, Maffioli L, Mortelmans L, Oyen W, Pepe G, Chiti A; Oncology Committee of the EANM. Eur J Nucl Med Mol Imaging. 2010 Jul;37(7):1441-8. doi: 10.1007/s00259-010-1473-6. PMID: 20461371

The interpretation of 131i scans in the evaluation of thyroid cancer, with an emphasis on false positive findings

Article

Jun 2003
NUCL MED COMMUN

Combined transmission and 99mTc-sestamibi emission tomography for localization of mediastinal parathyroid glands

Article

Jan 2003

Aim: Although parathyroid scintigraphy using 99mTc-sestamibi is considered the best preoperative localization method for hyperfunctioning parathyroid tissue it lacks the anatomical details required for successful, minimal invasive surgery of ectopic parathyroid lesions. This study presents the role of combined SPECT/X-ray-CT imaging in a single device for localization of mediastinal parathyroid glands. Methods: 99mTc-sestamibi SPECT/ X-ray-CT was performed by gamma camera-mounted anatomical X-ray tomography (GMAXT; GE Medical systems, Millenium VG with Hawkeye) in four patients with ectopic parathyroid glands (two patients with primary, two with persistent secondary hyperparathyroidism). The device contains an X-ray tube and a set of detectors that rotate around the patient combined with a gamma camera. For comparison with GMAXT additionally high resolution computed tomography images of the neck and mediastinum were performed. Results: Correct preoperative localization was achieved. The parathyroid glands were located in the anterior mediastinum. High resolution computed tomography could not provide further details. Three patients were operated by a minimal invasive open and one patient by a transsternal approach because of concomitant aortic valve replacement. Conclusion: 99mTc-sestamibi/X-ray-CT fusion imaging in a single device can accurately localise ectopic or supernumerary mediastinal parathyroid tumours in primary and secondary hyperparathyroidism. Morbidity, radiation exposure, time, and costs are reduced by avoiding multiple diagnostic examinations and minimal invasive parathyroid surgery becomes possible.

American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer: Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer

Article

Jan 2009

Empiric radioactive iodine dosing regimens frequently exceed maximum tolerated activity levels in elderly patients with thyroid cancer (vol 47, pg 1587, 2006)

Article

Jan 2007

Tuttle

Position of nuclear medicine techniques in the diagnostic work-up of neuroendocrine tumors

Conference Paper

Jun 2004

In recent years nuclear medicine has contributed to the impressive development of the knowledge of neuroendocrine tumors in terms of biology (receptor scintigraphy), pharmacology (development of new tracers), and therapy (radiometabolic therapy). At present, it is impossible to plan the management of a patient affected by a neuroendocrine tumor without performing nuclear medicine examinations. The contribution of nuclear medicine had affected and improved the management of these patients by offering various important options that are part of the modern diagnosis and treatment protocols. The clinical experience and the literature confirm that, among the wide variety of tracers and nuclear medicine modalities available today, metaiodobenzylguanidine (MIBG) and DTPA-D-Phe-octreotide (pentetreotide) are the radiopharmaceuticals of current clinical use. Several new somatostatin analogues are under investigation. Positron emission tomography (PET) supplies a range of labelled compounds to be used for the visualization of tumor biochemistry. In addition to the first routinely used PET tracer in oncology, F-18-labelled deoxyglucose (FDG), a number of radiopharmaceuticals based on different precursors such as fluorodopamine and 5-hydroxytryptophan (5-HTP) are going to gain a clinical role. Of course, the diagnosis of neuroendocrine tumors has to be based on integrated information derived from different examinations including nuclear medicine studies. The clinical presentation of neuroendocrine tumors is highly variable: sometimes they manifest typical or atypical symptoms but they may also be detected by chance during an X-ray or ultrasound examination carried out for other reasons. At disease presentation nuclear medicine modalities are sometimes able to direct physicians towards the clinical diagnosis thanks to the specificity of their imaging mechanisms. They also play a role in disease staging and restaging, patient follow-up and treatment monitoring. In addition, the biological characterisation of neuroendocrine tissues (receptor status, glucose metabolism, differentiation, etc.) allows the interpretation of radiopharmaceutical uptake as a prognostic parameter and sometimes as a predictor of the response to treatment.

Role of Single Photon Emission Computed Tomography/Computed Tomography in Localization of Ectopic Parathyroid Adenoma A Pictorial Case Series and Review of the Current Literature

Article

Aug 2009

The parathyroid glands are located posterior to the upper and lower poles of the thyroid and are derived from the third and fourth pharyngeal pouches. Usually there are only 2 superior glands, whereas only 40% of patients have their inferior glands located near the inferior thyroid poles. Ectopic locations include the carotid sheath, anterior mediastinum, retropharynx, or intrathyroidal locations. Single photon emission computed tomography/computed tomography (SPECT/CT) offers the advantage of combining function and anatomy for exact localization of ectopic parathyroid adenomas. In this pictorial review, we present 4 cases of hyperparathyroidism caused by ectopic parathyroid adenomas and review the literature on the additional value of their localization with SPECT/CT. Combined SPECT/CT scanners permit more reliable localization of ectopic adenomas. The additional information can aid in exact preoperative localization. In one study of 16 patients, SPECT/CT identified 39% more lesions compared with SPECT imaging alone. In other comparisons of planar, SPECT and SPECT/CT imaging modalities, SPECT/CT permitted the highest reader confidence in localization, especially for mediastinal adenomas. Larger studies are needed to establish the role and cost-effectiveness of SPECT/CT.

False positive I-131 whole body scans in thyroid cancer

Article

Jun 2000

Well differentiated thyroid cancer is a rare disease in the UK. It is the only cancer which, having metastasized, remains curable by radioisotope: therapy with I-131. The main indication for administering repeat doses of I-131 is the appearance of abnormal uptake in a whole body scan following diagnostic or therapeutic I-131 administration. False positive scans, showing the presence of I-131 uptake in the absence of residual thyroid tissue or metastases can occur, although they are uncommon. Unless recognized as a false positive,I-131 uptake may result in diagnostic error and lead to administration of an unnecessary therapy dose. We describe a series of nine patients in whom the scans showed false positive uptake of I-131, including cases where the cause of the uptake is still uncertain. We demonstrate the common sites of false positive uptake, discuss the underlying mechanisms and suggest a systematic approach to the interpretation of whole body scans in order to prevent unnecessary treatment with I-131.

Endocrine scintigraphy with hybrid SPECT/CT

Abstract and Figures

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