Medicare Australia-approved indications for FDG-PET are summarised in Table 1. It is important to emphasise that FDG-PET is not a 'cancer scan'. It shows areas of abnormal glucose metabolism. Non-malignant causes of FDG uptake are relatively common and should always be considered in the differential diagnosis (Fig. 1). Clinically implausible or unexpected abnormalities may require further confirmatory investigation. There are innumerable causes of FDG uptake that are not due to malignancy. Many of these can be recognised on correlation with patient history/physical examination or typical imaging patterns. Common causes are infection (including tuberculosis – see Fig. 2), inflammation (sarcoidosis and granulomatous diseases), trauma, enthesopathies and fractures.
Fig. 2
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Diagnostic FDG-PET scan
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FDG-PET CT scan of a patient with cutaneous squamous cell carcinoma (primary site of malignancy not shown) metastatic to right cervical and axillary nodes. The unexpected additional PET scan findings of marked FDG uptake in both lung apices led to a diagnosis of inter current active tuberculosis.
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FDG-PET F-18 fluorodeoxyglucose positron emission tomography
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FDG-PET (and PET CT) has been shown to be more accurate than conventional imaging in a variety of malignancies in many clinical settings (for example staging, restaging, detection of occult primary site, rising tumour markers, assessment of residual mass, detecting radionecrosis from viable tumour). It is also cost-effective as PET often leads to upstaging of disease, thus reducing futile attempts at curative therapies, and helping allocation of finite resources to patients most likely to actually benefit from aggressive intervention.
Malignancies that typically have very high levels of FDG uptake include squamous cell carcinomas of the head and neck, oesophagus, most lung cancers, melanoma, most types of lymphoma, high-grade sarcoma and metastatic colon carcinoma. Gastric, uterine, cervical, breast, testicular and thyroid malignancies may also be usefully evaluated, but not all are reimbursed by Medicare (see Table 1).
Primary liver tumours generally have low FDG uptake (due to intracellular dephosphorylation of FDG) and may not be distinguishable from normal background liver, but liver metastases are sensitive to imaging. Other malignancies where FDG-PET is not useful (high false negative rate) include bronchoalveolar cell carcinoma of the lung, carcinoid tumours, mucinous adenocarcinomas and some low-grade sarcomas.
Malignancies of the urinary tract (such as renal cell, transitional cell and prostate carcinomas) are not well imaged due to variable FDG uptake in the tumours and high background levels of FDG in urine.
FDG-PET is not sensitive in detecting cerebral metastases because there is a high background uptake and the brain is not routinely included in the imaging field. However, FDG-PET may be indicated in the evaluation of primary brain tumours.
Bony metastases that cause densely sclerotic reaction (typically prostate cancer) are best imaged with bone scans as these lesions may be poorly FDG-avid. FDG-PET is much more sensitive for lytic, soft tissue or marrow lesions.
Table 1
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Medicare-approved indications for FDG-PET*
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Oncology
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Diagnosis
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Solitary pulmonary nodule that cannot be pathologically characterised or biopsied, and metastatic squamous cell carcinoma in cervical nodes with unknown primary
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Staging
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Non-small cell lung cancer, cervical, oesophageal, gastric, head and neck carcinomas and lymphoma
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Restaging for suspected recurrence
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Epithelial ovarian carcinoma, lymphoma and head and neck carcinoma
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Biopsy guidance
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Primary brain tumours and bone/soft tissue sarcomas
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Evaluation of residual structural lesions
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Primary brain tumours, colorectal carcinoma, sarcoma and lymphoma
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Assessment before definitive oncology surgery
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Apparently isolated liver or lung metastasis in colorectal carcinoma, apparently limited metastatic disease in melanoma
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Other conditions
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Epilepsy
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Evaluation of refractory epilepsy being evaluated for surgery where location of epileptogenic focus is not clear
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Myocardial viability
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Prior to revascularisation in the presence of impaired left ventricular function when standard viability testing is negative or inconclusive
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* only some facilities are eligible under Medicare FDG-PET F-18 fluorodeoxyglucose positron emission tomography
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Staging of non-small cell lung cancer
Historically, the five-year survival rate after surgery of even clinical stage I lung cancer is only 50%, with much of the mortality being accounted for by undetected metastatic disease.
FDG-PET has an important role in staging and treatment planning in non-small cell lung cancer. Studies have shown that a staging PET scan predicts patient prognosis and mortality much more accurately than conventional imaging techniques.
FDG-PET detects unsuspected metastatic disease in 10–20% of patients, with a higher yield in patients with more clinically advanced disease. Confirmation of metastatic disease leads to decreased iatrogenic morbidity from fewer futile thoracotomies.
FDG-PET is the most accurate non-invasive means of mediastinal nodal staging, with a pooled sensitivity and specificity of 74% and 85%.1Its particular strengths are identifying benign (hyperplastic) but enlarged lymph nodes and to a lesser extent detection of metastatic disease in small sub-centimetre nodes. However, biopsy is still considered the gold standard. FDG-PET positive nodes should be confirmed by biopsy as they may be due to inflammation. Micrometastatic disease cannot be detected by any current non-invasive imaging technique.
External beam radiation therapy is also commonly used in the management of lung cancer. There is increasing interest in incorporating metabolic data from PET scans into radiotherapy planning systems, leading to PET-guided changes in radiotherapy fields. Clinical trial results of patient outcomes with this approach are currently sparse.
Diagnosis of solitary pulmonary nodule
Pulmonary nodules are becoming an increasingly common diagnostic problem with more widespread use of CT scanning. No evaluation is complete without clinical risk factor assessment. Many pulmonary nodules cannot be characterised on CT, and may be difficult to biopsy. For lesions greater than 8–10 mm in size, FDG-PET has been shown to differentiate between benign and malignant nodules (sensitivity 87%, specificity 83%)2 and decreases the biopsy rate of benign lesions.
Lesions that are hypermetabolic should be considered malignant until proven otherwise. Granulomatous disease and infections are also hypermetabolic conditions and may be considered 'false positive' for malignancy, although they require specific diagnosis and treatment in their own right.
While complete absence of FDG uptake indicates a benign lesion, low levels of FDG uptake can be seen in carcinoid, bronchoalveolar and well differentiated adenocarcinomas. Stability on serial anatomical imaging over a two-year period is also considered an indicator that a lesion is benign.
Lymphoma
Staging
Accurate staging is integral to the development of a management plan for most types of lymphoma. FDG-PET has superseded gallium scans in functional evaluation of both Hodgkin's and non-Hodgkin's lymphoma, and is considered the most accurate imaging test for this condition.
Overall, FDG-PET is more sensitive than CT scan in detecting extranodal (particularly marrow, liver and spleen – see Fig. 3) and small volume nodal involvement, and changes management during initial staging in a median of 10.5% of cases.3There is often variation between studies and pooled statistical data due to the many different histological subtypes, therapies and grades of biological behaviour of Hodgkin's and in particular non-Hodgkin's lymphoma.
Some lymphoma subtypes have variable or low FDG uptake including mucosa-associated lymphoid tissue (MALT)-type, small lymphocytic and marginal-zone lymphoma.
Fig. 3
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Staging of Hodgkin's lymphoma using FDG-PET
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Maximum intensity projection image of a staging FDG-PET scan of a 68-year-old man with newly diagnosed Hodgkin's lymphoma. There are markedly FDG-avid lymph nodes in a symmetrical pattern above and below the diaphragm. Note the pathological diffusely increased uptake in the spleen (more than liver uptake). FDG-PET is a more sensitive indicator of diffuse splenic involvement, which is not possible to diagnose in the absence of splenomegaly on CT.
FDG-PET F-18 fluorodeoxyglucose positron emission tomography
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Restaging and assessing response to therapy
There is great interest in early prediction of response to chemotherapy. Identification of poor responders would lead to early change to second-line therapies, and there is potential to truncate therapy in good responders. The latter is particularly relevant in young patients with Hodgkin's disease where there are significant delayed toxicities from curative therapy. Prospective trials, particularly those in which truncation of therapy is guided by PET scan response, are still lacking.4
Studies also suggest that persistently positive PET scans several cycles into therapy implies the presence of chemotherapy resistant clones and therefore a worse prognosis.
Post-therapy FDG-PET scans can show a variety of features including diffuse skeletal uptake from bone marrow hyperplasia (particularly in the setting of colony stimulating factor use), thymic hyperplasia in younger patients, and inflammatory FDG uptake in recently irradiated tissues. The scan should therefore ideally be scheduled just prior to commencing the next cycle of therapy, or at least eight weeks after the completion of radiotherapy.
Residual masses
Assessment of remission status with CT is often uncertain due to the presence of residual masses after therapy, which may represent inactive scar tissue or residual active malignancy. PET (and PET CT) is considered the most accurate method of assessing this, with radiotherapy or further chemotherapy being considered for patients with active disease. Persistent FDG uptake in a residual mass is also an adverse prognostic marker.
Colorectal cancer
Metastatic disease confined to liver or lung is now treated with surgical resection as a potentially curative procedure. FDG-PET aids greatly in patient selection by identifying sites of occult disease that would preclude surgery.
Analogous to lymphoma, FDG-PET is accurate in determining the aetiology of residual pelvic masses after therapy, and also has a role in the setting of rising carcinoembryonic antigen (CEA) with normal CT or MRI.
FDG-PET is not useful in the detection or primary staging of colon cancer due to the extremely variable physiological colonic uptake patterns. The exception to this is rectal cancer, where detection of nodal disease may influence neoadjuvant radiation or chemotherapy before definitive surgery.
Other indications
The site of an otherwise occult primary malignancy can be identified on PET in 25% of cases of metastatic head and neck squamous carcinoma (Fig. 4). FDG-PET is also used in post-therapy evaluation of head and neck cancer, where residual disease and sequelae of treatment may be difficult to distinguish on CT scan. A negative PET scan in this setting has a high negative predictive value but should only be performed at least 8–12 weeks after completion of therapy to avoid false positive results from residual inflammation.5
FDG-PET is useful for biopsy guidance in a variety of conditions, particularly soft tissue sarcomas which may have histological heterogeneity, and in larger necrotic masses to identify sites of viable tumour. Other indications for which PET is used include distinguishing radionecrosis from residual tumour in brain malignancies, and planning radiation therapy fields.
Fig. 4
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Diagnosing occult primary malignancy using FDG-PET
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FDG-PET CT scan of a 55-year-old man with metastatic squamous cell carcinoma to right cervical lymph nodes from an unknown primary site. Abnormal FDG uptake in the right tonsil was subsequently proven to be the primary site. A repeat FDG-PET scan (not shown here) six months after therapy was normal.
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FDG-PET F-18 fluorodeoxyglucose positron emission tomography
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Incidental findings
Significant incidental findings are noted in up to 3% of scans, and often are an indicator of occult synchronous malignancies. Many malignancies also share common risk factors, particularly in head and neck, lung and upper gastrointestinal tract tumours in smokers. Other 'incidental' findings of particular significance that should not be ignored are FDG-avid thyroid nodules and focal uptake in the large bowel, which are associated with around a 25% risk of malignancy.