The use of combined positron emission tomography/computed tomography (PET/CT) has reduced the incidence of false-positive examinations, allowing easier differentiation of physiologic ﬂuorodeoxyglucose (FDG) uptake from pathologic uptake, more accurate localization of lesions, and detection of lesions without an anatomical correlative abnormality. In addition, PET/CT offers incremental beneﬁts over PET and CT separately in the evaluation of patients with head and neck carcinoma.
is an Oncologic Imaging Fellow, Department of Radiology,
University of Pittsburgh Medical Center, Pittsburgh PA.
The use of combined positron emission tomography/computed
tomography (PET/CT) has reduced the incidence of false-positive
examinations, allowing easier differentiation of physiologic
fluorodeoxyglucose (FDG) uptake from pathologic uptake, more
accurate localization of lesions, and detection of lesions without
an anatomical correlative abnormality. In addition, PET/CT offers
incremental benefits over PET and CT separately in the evaluation
of patients with head and neck carcinoma.
Head and neck
Squamous cell carcinoma of the head and neck
A recent study from the University of Pittsburgh showed that
PET/CT had an overall sensitivity of 98%, a specificity of 92%, and
an accuracy of 94% for evaluating patients with known or suspected
squamous cell carcinoma (SCC) of the head and neck.
A similar study by Schoder et al
compared PET and PET/CT in patients with any malignant lesion of
the head and neck and showed that PET/CT had a higher accuracy for
depicting cancer than PET alone (96% versus 90%).
Patients with SCC who have not had a mucosal primary tumor
identified represent 1% to 5% of all patients diagnosed with SCC.
The use of PET has been studied in this patient population with a
reported sensitivity ranging from 5% to 60%, but larger studies
have suggested a sensitivity in the range of 25% to 35%.
Preliminary studies suggest that combined PET/CT may offer a slight
increase in overall sensitivity (33% to 57%) for detecting unknown
primary tumors, but may offer significantly more information
regarding biopsy localization.
Several studies have shown the benefit of PET in evaluating
regional nodal spread.
The use of PET/CT can add additional localization information, such
as the precise nodal levels involved and even which of the nodes
within a level are abnormal. It can also show contralateral disease
that may not be seen on CT alone; this has a drastic impact on
patient management, usually indicating the need for bilateral
radical neck dissections rather than a unilateral approach.
Studies have shown that PET (and, more recently, PET/CT) is more
sensitive (88% to 100%) and specific (75% to 100%) compared with
combined data for CT and magnetic resonance (MR) (sensitivity 38%
to 90% and specificity 38% to 85%) for the detection of recurrent
or residual disease both at the primary site and for nodal
The added ability of PET/CT to accurately localize disease makes it
more appealing than PET alone (Figure 1), since PET can help
determine the presence or absence of disease but often cannot
indicate precise localization.
Initial diagnosis and staging-
Although more aggressive forms of thyroid carcinoma have been
reported to show FDG uptake at the time of diagnosis, most
well-differentiated thyroid malignancies are not FDG-avid early in
the disease process. There is a well-described "flip-flop"
phenomenon, as first reported by Feine et al,
in which there is an apparent temporal reversal of FDG and iodine
uptake by tumors. Many well-differentiated thyroid malignancies
that are initially iodine-avid do not demonstrate much FDG uptake.
Over time, lesions may show partial or complete reversal of iodine
and FDG avidity, making them potentially good candidates for PET or
PET/CT imaging. In addition, a large percentage of metastatic
lesions from well-differentiated thyroid malignancies are initially
iodine-avid, and several early studies showed that when using FDG,
PET had low sensitivities for detecting metastatic lesions. The
largest study evaluating patients with differentiated thyroid
cancer reported that FDG-PET had a sensitivity of 75% and a
specificity of 90%.
Despite the variability observed with FDG in staging patients with
thyroid malignancies, the use of FDG-PET is well-documented in
patients with negative iodine-131 (I-131) scans and increasing
thyroglobulin levels. The sensitivity of FDG-PET in these select
patients can be up to 94%.
Other types of thyroid malignancies have been less well evaluated
with FDG-PET. In our experience, PET/CT has been very helpful in
localizing lesions that were not apparent on CT in patients with
rising thyroglobulin levels and a negative I-131 scan (Figure 2).
Initial diagnosis (solitary pulmonary nodule
Through its extensive use, several studies have emerged that have
shown the utility of PET imaging in the evaluation of pulmonary
nodules; many of these have shown the sensitivity and specificity
of FDG-PET imaging to be approximately 90%.
In most evaluations, the sensitivity tends to be higher than the
specificity, which is because of the lack of specificity of FDG. In
areas where fungal infections or other infectious/inflammatory
processes are prevalent, the specificity tends to be even
A meta-analysis summarized the data for 1474 nodules from 40
studies and showed that the overall combined sensitivity and
specificity of FDG-PET was 91.2%, although a sensitivity and
specificity of 96.8% and 77.8%, respectively, was more reflective
of the findings in clinical practice.
Although several studies have reported the utility of FDG-PET and
PET/CT in the evaluation of solitary pulmonary nodules (it is not
generally indicated for multiple pulmonary nodules), there are
several potential limitations in clinical practice that must be
considered. For instance, several nonmalignant inflammatory and
infectious processes such as tuberculosis and fungal infections can
take up FDG and mimic the appearance of a malignant nodule on PET
or PET/CT scans.
Sarcoidosis, silicosis, and other granulomatous processes can also
appear similar to malignant nodules; therefore, it is necessary to
know patient details regarding exposure, as well as pertinent
In addition, the CT portion of a combined PET/CT can often provide
additional information for further characterization of pulmonary
Although newer high-resolution PET scanners have an intrinsic
spatial resolution close to 4 mm, in general most scanners in use
today can detect 6- to 12-mm lesions, as long as they are
relatively metabolically active. However, false-negative studies
can be seen in primary or metastatic nodules that are less
metabolically active, such as bronchoalveolar cell carcinoma (BAC).
Even a 3-cm BAC may not be detected on PET or PET/CT using FDG
because of the lack of FDG uptake; BAC may be undetectable on
FDG-PET up to 57% of the time.
Another primary tumor with reportedly low relative FDG uptake is
carcinoid, which (like BAC) can be a cause of false-negative PET.
However, FDG- PET has a very high negative predictive value for a
solitary pulmonary nodule, so a patient who may not tolerate an
invasive procedure can be followed with serial CT to assess the
stability or resolution of disease.
Non-small-cell lung cancer-
Alone, PET has not been shown to be particularly useful in
determining the T status of the primary lesion and is generally not
helpful in determining chest wall involvement. However, because CT
is better at predicting chest wall involvement, PET/CT would
intuitively be the preferred modality. A recent study by Cerfolio
showed that PET/CT more accurately predicted T status (70%) than
did PET alone (47%).
In the more important role of assessing the mediastinum, several
studies have shown that FDG-PET is more accurate than CT (Figure
3). One of the largest studies comparing PET with CT for the
evaluation of the mediastinum showed PET to have a sensitivity and
specificity of 91% and 86%, respectively, compared with 75% and 66%
Although size criteria are often helpful for the radiologist in
determining whether a node is malignant or not, there is poor
correlation between nodal size and the presence of metastatic
disease in the mediastinum; metastatic disease has been reported in
21% of normal-sized nodes and up to 40% of enlarged nodes have been
free of malignancy.
In addition, compared with conventional work-up, evaluation with
PET imaging has been shown to reduce the number of futile
thoracotomies by up to 41%, usually by showing the presence of
unsuspected contralateral mediastinal involvement or distant
Several other studies have shown that PET imaging is more sensitive
and specific than CT and can change patient management up to 67% of
reported that integrated PET/CT provided additional information in
20 of 49 patients (41%) beyond that provided by conventional visual
correlation of PET and CT.
In addition, PET/CT has been shown to detect more distant
metastatic lesions than other imaging modalities at the time of
The presence and precise localization of extrathoracic metastases
are better evaluated by PET/CT because of its ability to detect
small lesions that may not have mass effect, enhancement, or
In the restaging evaluation of patients with lung cancer, one of
the most challenging aspects is differentiating recurrent or
residual tumor from posttherapy changes. Both processes can appear
identical on CT, challenging the modality for the posttreatment
patient with lung cancer. Conversely, by definition, scar and
fibrosis are dead tissue and should not result in any FDG uptake,
making PET or PET/CT ideal for this indication. Positron emission
tomography has been shown to have a sensitivity of 98% to 100% for
the differentiation of tumor from posttreatment changes in the
Radiation pneumonitis is a cause of false-positive FDG-PET. In
addition, the evaluation of the primary tumor is generally not
possible in the setting of radiation pneumonitis. Because of the
radiosensitivity of the lung, patients who have had radiation to
the lungs are not typically reevaluated for 2 to 4 months after
their last treatment. However, the inflammatory effects of
radiation can last >1 year.
Although FDG-PET may be falsely negative in identifying the
primary tumor in up to 20% of cases (particularly in patients with
FDG-PET will often show the primary tumor to some degree (Figure
Most studies that evaluated the ability of PET and PET/CT to stage
patients with newly diagnosed esophageal carcinoma have shown the
major benefit to be that of determining the M status of the
patient. Many studies confirmed the inability of PET to accurately
predict T or N status because of its relatively low sensitivity. A
prospective study of 74 patients by Flamen et al
reported that PET had a sensitivity of only 33% compared with
endoscopic ultrasound (EUS) (81%), confirming earlier studies from
the University of Pittsburgh, which showed the sensitivity for
locoregional nodal involvement to be 41% to 45%.
However, in a smaller study by Flanagan et al,
the sensitivity of PET for detecting locoregional nodal involvement
was considerably higher (76%) than other studies and was also
higher than CT (45%). More recently, Kato et al
evaluated 149 patients for the potential incremental value of PET
over CT and found that with regard to staging, PET had a 14%
overall incremental value over CT. However, they also reported a
similarly low sensitivity for regional lymph-node detection (32%).
The utility of PET and PET/CT in determining locoregional nodal
involvement is a consequence of the high specificity, where
observed nodal disease is highly suggestive of metastatic
Positron emission tomography/CT will likely offer some diagnostic
improvement over PET or CT that is performed separately. A recent
study by Bar-Shalom and colleagues
reported that PET/CT had an incremental value over PET for
interpretation of 25 of 115 (22%) sites, offering increased
confidence and improved lesion localization in 15%.
For M staging, PET has been shown to be more sensitive and
accurate than CT or EUS in detecting distant metastatic disease.
Although PET has been shown to be extremely helpful in the
posttreatment patient, several cases of false-positive scans have
been reported following therapy, reducing the specificity of PET,
particularly in the early period following therapy.
However, FDG-PET has been shown to have a sensitivity and
specificity of 100% and 57%, respectively, for local recurrence,
92% and 83% for detection of regional disease recurrence, and 95%
and 80% for distant disease, compared with traditional anatomical
imaging methods, shown to be 83% and 92% for regional recurrence
and 80% and 70% for distant recurrence.
Early studies by Wahl et al
and other groups suggested that PET may have a high sensitivity for
detecting primary breast lesions >1 cm, but in the largest study
to date, Avril and colleagues
found that almost 40% of primary breast carcinomas <2 cm were
not seen with PET imaging using FDG.
There are few studies evaluating the role of FDG-PET in patients
with lesions <1.5 cm. Based on the data presented by Avril et
it is unlikely that FDG-PET or PET/CT will play a significant role
in the screening process for breast cancer in the near future.
However, most studies have suggested that FDG-PET has a high
positive predictive value, so that an incidental lesion or a lesion
seen in a symptomatic patient should be considered malignant until
proven otherwise (Fig-ure 5). The absence of FDG uptake in the
breast does not exclude the presence of disease.
Several studies that evaluated the use of PET in examining the
axilla showed variable sensitivity (33% to 100%) and specificity
(66% to 100), depending on the type of interpretation (sensitive
versus specific) and the size criteria used.
Most reports suggest that, with the current level of scanner
technology, FDG-PET is inadequate for evaluating micrometastatic
disease in the axilla. The largest prospective mulitcenter study
examining the use of FDG-PET for axillary nodal metastases reported
a sensitivity and specificity of 61% and 80%, respectively, in
patients who had at least 1 probably or definitely involved
axillary node on PET.
In contrast to the limited role that FDG-PET plays in evaluating
the axilla, it has been shown to be very useful for identifying
unsuspected internal mammary lymph nodes and distant metastases. In
the study by Eubank et al,
30% of pa-tients had unsuspected disease in the mediastinum or
internal mammary lymph node chain that was identified only by
It is clear from a number of studies that FDG-PET has a very high
sensitivity (92% to 100%) for detecting breast cancer recurrence.
However, depending on when PET or PET/CT is performed in the
posttherapeutic period, the specificity tends to be less (72% to
82%). In addition, detecting osseous lesions can be problematic.
Cook et al
compared FDG-PET to traditional bone scanning and found that FDGPET
was superior to traditional bone scanning for detecting osteolytic
metastases, although the overlap between the ability of the 2
modalities to detect different lesions is unlikely to allow FDG-PET
to replace bone scanning. In preliminary reports of the use of
PET/CT for detecting recurrence in patients with suspected
recurrence based on clinical examination or tumor markers, PET/CT
detected lesions in 77% of patients, leading to a change in
clinical management in 36%.
In our experience, in patients with breast carcinoma, PET/CT is
often helpful in accurately localizing lesions (particularly
osseous or soft tissue metastases) that are subtle on anatomical
imaging or do not have a correlative CT abnormality. In addition,
PET/CT helps to differentiate physiologic FDG uptake from
Response to therapy-
Several studies have shown the ability of FDG-PET to predict
responders from nonresponders by evaluating changes in standard
With anatomical imaging studies, bulky areas of disease are often
difficult to evaluate in the early posttherapy period. Combined
PET/CT offers the strength of FDG-PET in determining early changes
in metabolic activity, with the ability of CT to accurately
localize areas of persistent disease. It can also assist in
localizing areas with persistent uptake for potential biopsy
FDG-PET and PET/CT have become the primary diagnostic imaging
tests for evaluating various malignancies, including those in the
head, neck, and chest, as detailed above. The future of PET and
PET/CT imaging will certainly address the specificity limitations
of the current clinical tracer, FDG, and will target more specific