The role of positron emission tomography (PET) in evaluating head and neck cancer is evolving rapidly. Its sensitivity and accuracy in diagnosing nodal disease, evaluation of unknown primary disease, and the follow-up of posttherapy recurrence are key factors in its growth. PET imaging provides biological insights that permit selection and targeting of more effective treatments.
Dr. Rajendran
is an Assistant Professor of Nuclear Medicine in the Department
of Radiology at the University of Washington, Seattle, WA.
Head and neck cancer is a major public health problem, affecting
nearly 50,000 new patients a year in the United States (4% of all
new cancers). Ironically, even though it is largely preventable
because of close association with common carcinogens, such as
tobacco and alcohol, its incidence remains unchanged, is
disproportionately higher in lower socioeconomic groups, and is
prevalent among military veterans (8% of all new cancers). The
majority of these cancers are squamous cell carcinomas, although
other tumor types, particularly those arising from the salivary
glands, cause greater challenges in management. In spite of several
advances in diagnosis, a vast majority of head and neck cancers are
still diagnosed in advanced stages and show poor response to
treatment, with recurrences in half of patients. The clinical
course of these neoplasms is difficult to predict based on current
clinicopathological prognostic criteria.
Radiotherapy is an important primary treatment modality for the
majority of patients with head and neck cancer. Use of concurrent
chemotherapy has further improved treatment results but is
associated with higher normal tissue toxicity. While neck
irradiation effectively controls microscopic disease, it results in
a higher morbidity when the radiation dose is intensified to a
larger treatment volume using conventional techniques. Currently,
treatment decisions are based on data extrapolated from
retrospective institutional series and cannot be applied reliably
to treatment planning for individual patients, limiting the ability
to tailor the intensity and apply targeted therapy for an
individual patient without increasing toxicity. Close proximity of
important normal tissues/organs, such as salivary glands, requires
more stringent radiation dosimetry. Biological insights on these
cancers obtained by positron emission tomography (PET) imaging will
permit selection and targeting of more efficacious and less morbid
treatments.
PET principles
F-18 fluorodeoxyglucose (FDG) is identical to glucose and is
taken up and phosphorylated in cells, but cannot proceed past
hexose-6-phosphate chemically and becomes trapped inside the cell.
Uptake and utilization of FDG reflects the rate of glycolysis and,
thus, the rate of glucose metabolism in tumors. While there is no
single explanation for the increased glycolysis seen in neoplastic
tissues, cancer cells in general have increased aerobic glycolysis
(Warburg effect). This, combined with a higher concentration of
neoplastic cells in a tumor form the basis for the successful use
of FDG in tumor imaging. Diagnosis of malignancy by PET depends on
higher FDG uptake in tumor tissue than that of the background. For
that reason, it is important to make sure that the blood glucose
levels are not high (¾ 150 mg) in patients with diabetes mellitus.
The use of insulin to lower the blood sugar prior to FDG scan is
generally not advisable, as it would pump the FDG into the muscles,
resulting in interpretive difficulties.
Uptake of FDG has been expressed in several ways--the most
common one being the standardized uptake value (SUV). It is the
ratio of FDG concentration in a region of interest to its
concentration in the whole body. Several factors affect the
calculated SUV, including body surface area, partial volume effect,
and time after tracer injection. Commercial availability of FDG
radiopharmaceutical and dedicated PET scanners have resulted in the
popularity, and widespread clinical use of PET imaging. Recent
Medicare approval of the use of PET in head and neck cancer has
boosted its clinical application.
The popularity of PET has increased significantly in recent
times with predicted future annual revenues approaching nearly a
billion dollars by 2007. Bold commercial ventures in marketing PET
tracers, such as FDG, from a nationwide network of radiopharmacies
seem to have been successful, obviating the need for on-site
cyclotrons in PET facilities.
Greater resolution of modern PET scanners allows detection of
tumors as small as 4.5 to 8 mm.
1
However, because of the influence of partial volume effects,
caution should be used in interpreting smaller lesions,
particularly when semiquantitative methods, such as SUV, are used
to establish malignancy. Several authors have attempted making
adjustments to SUV to improve its accuracy.
2-4
Staging
Tumors located in certain anatomical sites (eg, piriform sinus,
epiglottis, or Waldeyer's ring) are often inaccessible to clinical
examination, and anatomic imaging, such as magnetic resonance
imaging (MRI) and computed tomography (CT), may not be helpful in
their evaluation. However, FDG-PET has proven very successful in
these locations.
Although up to 11% of patients with oral carcinoma are reported
to have distant metastases at presentation, nearly 30% will
ultimately fail in distant sites.
5
In view of this, some authors have recommended whole-body scan for
all patients imaged.
6
In such cases, FDG-PET compares favorably with CT, MRI, and
ultrasound (US); PET: sensitivity 70%, specificity 82%, accuracy
75%; US: 84%, 68%, 76%; CT: 66%, 74%, 70%; MRI: 64%, 69%, 66%.
7,8
Including the chest and at least the upper abdomen in the imaging
fields will help identify distant metastases and improve staging.
This approach might also increase the chances for detecting
synchronous primary sites in the aerodigestive tract that are
exposed to the same carcinogens associated with the cancer
originally diagnosed. In spite of high sensitivity, FDG-PET has a
limited role in establishing the diagnosis of primary tumors.
Patients with occult nodal disease have the worst prognosis.
Positron emission tomography will help assess nodes that are
equivocal on CT or MRI. Evaluation of patients with unknown primary
tumors can be clinically challenging, and both clinical and
standard radiological imaging show poor sensitivity in this
situation. FDG-PET has been found to be useful in diagnosing nearly
one-third of these cases.
9-11
FDG-PET gives better results in detecting cervical lymph nodes
than do conventional imaging techniques that essentially have a
size criteria of >1 cm. FDG-PET has a sensitivity of 93% and
nodes as small as 4 mm have been detected; it has a high negative
predictive value (98%) for node-negative (N0) disease.
12
Thus, negative FDG uptake in the neck has a high reliability for
excluding lymph-node metastases and helps limit the extent of
treatment--surgery and or radiotherapy.
Lack of anatomic details might cause problems in localizing
metabolically active tissues. This can be circumvented by fusion of
PET images with CT or MRI. Popularity and usage of combined PET/CT
systems is likely to increase during the next decade.
5,13,14
Pitfalls
Nonspecific muscle uptake in the neck could mask uptake in
smaller nodes, as can intense uptake in the primary tumor. Muscle
uptake can be minimized by using low doses of a muscle relaxant
such as lorazepam. FDG-PET also shows nonspecific uptake in sites
of inflammation or infection and in certain normal organs or sites
that might pose difficulties in interpretation. Palatine tonsils,
tongue, and laryngeal muscles show uptake normally, which is
considered physiologic unless correlative abnormality is identified
on CT or MRI.
15,16
Inflammatory reactions induced by radiation therapy dictate that
follow-up scans are sufficiently delayed in order for the uptake to
normalize, in some cases up to 4 months. While it is not a
significant problem for patients receiving only chemotherapy,
superimposed infections associated with chemotherapy might still
pose challenges for interpretation. Uptake can be seen in the
normal thyroid gland and is frequently seen in thyroiditis,
hyperthyroidism, and, on occasions, in malignant nodules. The SUV
is also frequently used to establish malignancy (see below).
Recurrent or persistent neck disease after
chemotherapy/radiation therapy
Recurrent cancer can be difficult to diagnose using conventional
imaging studies, mainly because of treatment-induced changes in
normal tissue. Postradiotherapy reactive fibrosis produces problems
in interpreting CT images, especially in differentiating it from
active residual disease.
17
FDG-PET has been found to be superior in identifying recurrence
with a high degree of accuracy (88%) when compared with standard
imaging--CT, MRI, or both (66%).
18-21
Serial FDG-PET scans used to follow patients undergoing
radiotherapy have indicated a mixed use for SUV. Four-month, rather
than 1-month post-radiation scans are found to be a more accurate
predictor of the presence of cancer. The SUV has been used by many
authors as a means to differentiate these two conditions. A value
above the threshold value range of 2 to 3.5 is usually used to
diagnose malignant disease. However, there is a wide variation in
the cut-off values used by various studies. In general, tumors with
higher pathologic grade have a higher SUV.
3,22-24
Dual-time point imaging has been recommended as a means to
differentiate neoplastic conditions from inflammation.
25
Evaluation of treatment response
Both absolute pretreatment SUV and its change on serial FDG
scans have been investigated as a prognostic indicator and as a
measure of response in patients undergoing radiation therapy or
chemotherapy. The SUV can characterize tumors with aggressive
biological and clinical behavior prior to treatment and the
information used to institute more aggressive treatment strategies.
Tumors with a high initial SUV tend to show greater local failure
after treatment.
26
It can also be used to decide the intensity of treatment.
27
Metabolic activity declines in tumors that respond to
treatment.
PET-directed treatment
High sensitivity and negative predictive value of FDG-PET can be
used to select the appropriate treatment or define radiation
treatment fields as well as dose intensity of both radiotherapy and
chemotherapy. A negative PET finding in the neck has a high
negative predictive value for nodal disease and can be used in
reducing the amount of normal tissue included in radiation
treatment volume or in modifying the extent of surgical neck
dissection. Image fusion and use of intensity-modulated
radiotherapy (IMRT) promise the ability for dose modulation with
lower toxicity.
Other PET tracers for use in head and neck
cancer
Fluorodeoxyglucose is the most commonly used tracer in the
evaluation of head and neck cancer. However, a number of other PET
radiopharmaceuticals are being investigated and appear promising
for answering specific questions and in directing treatment. These
include cell proliferation tracers [C-11]-thymidine and
[F-18]-fluorothymidine; amino acids, such as [C-11]-methionine;
membrane synthesis tracers [C-11]-acetate; and hypoxia tracers,
such as [F-18]-fluoromisonidazole (FMISO). While these agents are
not yet in routine clinical use, they hold the promise for
successful applications in specific clinical situations.
Conclusion
The role of PET in evaluating head and neck cancer is evolving
rapidly. Its sensitivity and accuracy in diagnosing nodal disease,
evaluation of unknown primary disease, and in the follow-up of
posttherapy recurrence are primarily responsible for evolution. It
is a valuable tool in following response to treatment (radiotherapy
and chemotherapy) and has the ability to direct more intensified
and less morbid radiotherapy to metabolically active foci. Lack of
anatomic details in PET can be circumvented by either image fusion
with CT or MRI or by using combined PET/CT systems, which are
gaining greater popularity among radiologists.
AR