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Nuclear medicine in oncology 1: Lymphoma, and cancer of the lung, colon, and oesophagus
Nuclear medicine techniques allow imaging of pathophysiology.
Division of Nuclear
Medicine, Department of Medical Imaging and Clinical Oncology,
Stellenbosch University and Tygerberg Hospital, Cape
Town, South Africa
Corresponding author:
A Ellmann (ae1@sun.ac.za)
Nuclear medicine provides an opportunity to image pathophysiology, while radiology mainly shows morphology. Over the last few decades hybrid imaging modalities have been developed in which nuclear medicine instrumentation has been combined with computed tomography (CT) and, more recently, with magnetic resonance imaging (MRI). This allows the clinician to combine the imaging of pathophysiology with the anatomical localisation of such lesions.
Conventional nuclear medicine imaging can be performed using various radiopharmaceuticals, mainly labelled with technetium-99m (Tc-99m), e.g. Tc-99m methylene diphosphonate (MDP) for skeletal scanning. In past decades, positron emission tomography combined with CT (PET/CT) has been used routinely for the assessment of solid tumours, including lymphomas, and lung and colorectal cancers.1 , 2 The most frequently used PET radiopharmaceutical is fluorine-18 (F-18) fluorodeoxyglucose (FDG), which reflects cellular glucose metabolism.
Lymphoma
Traditionally, a CT scan was the standard imaging technique to evaluate patients with lymphoma. CT is now complemented by FDG-PET/CT as a metabolic imaging technique.
Before the availability of PET/CT in South Africa, the two nuclear medicine modalities most frequently used in lymphoma patients were skeletal scintigraphy to detect skeletal metastases and gallium-67 scanning to evaluate disease extent and tumour response following treatment. These two modalities have largely been replaced by PET/CT.3
The use of FDG-PET/CT in lymphoma patients is well established for several indications, e.g. staging, evaluating therapy response, and restaging after therapy. It is also of value in suspected disease recurrence and for radiotherapy planning. This is useful in both Hodgkin and high-grade non-Hodgkin lymphomas, including diffuse, large B-cell lymphoma, plasmablastic lymphoma, mantle-cell lymphoma, high-grade follicular lymphoma, anaplastic large-cell lymphoma and Burkitt’s lymphoma. These subtypes typically demonstrate intense uptake of FDG. PET/CT scans should not be routinely requested in the management of patients with low-grade lymphomas, except to evaluate treatment response. In such cases a baseline (pre-treatment) study is necessary to determine whether the tumour is FDG avid or not, as a significant proportion of low-grade lymphomas take up only minimal FDG, resulting in poor sensitivity. In such cases, PET/CT should not be used for follow-up after treatment.
Staging. FDG-PET/CT can be used to evaluate the extent of disease. It offers improved accuracy over conventional CT staging and the opportunity for comparison with, and correct interpretation of, subsequent interim and restaging PET/CT. Several published papers have confirmed that lymphoma patients can be upstaged in as many as 20% of cases, while downstaging was reported in less than 10% of cases.
Treatment monitoring . Mid-treatment PET/CT is a powerful prognostic tool as an indicator of progression-free and overall survival. PET/CT is preferred to CT alone, as both metabolic and anatomical response can be measured. Metabolic response is evident at an earlier point than anatomical response. Findings are described as complete or partial metabolic response, no response or disease progression. These findings may be used to make decisions with regard to therapy, especially in cases of drug or radiotherapy toxicity or disease progression. Although an early response indicates a good prognosis, evidence is still lacking that a change in treatment following a PET/CT scan, showing poor/no response, improves outcome.
Restaging. Morphological changes on
CT scanning were traditionally used to evaluate treatment
response, a reduction in tumour size being a criterion. Residual
masses may represent fibrotic scar tissue or viable lymphoma
cells. The absence of FDG uptake after treatment with or without
residual masses on CT scanning is highly predictive of
progression-free survival and overall survival in both Hodgkin
and aggressive non-Hodgkin lymphomas (Fig. 1). These studies
should be performed at least 3 weeks after the last dose of
chemotherapy and 3 months after radiotherapy. This allows the
inflammation secondary to treatment to subside, as inflammatory
processes can also concentrate FDG, thereby raising the
potential of false positives.
Fig. 1. Whole body PET MIP views in a
63-year-old woman with follicular
lymphoma,
scanned before and
after completion of
chemotherapy.
A baseline F-18 FDG-PET/CT scan shows extensive disease,
with widespread lymph node involvement above and below the
diaphragm. The follow-up scan after completion of
chemotherapy shows a complete response.
Suspected recurrence. PET/CT is only indicated in patients with clinical, biochemical, or radiological evidence of recurrence. Routine scanning should not be performed for monitoring of otherwise well patients.
Radiotherapy planning . FDG-PET/CT may be used for radiotherapy planning, but patients should then be positioned on a flat bed in the therapy position. The metabolic findings are combined with the anatomical findings to determine the radiotherapy fields. Close liaison with radiation oncology is essential to ensure that patients are scanned in the correct therapy position, using the necessary immobilisation devices.
Cancer of the lung
Lung cancer incidence has increased rapidly over the last few decades, with the 5-year survival still being relatively poor. Imaging plays an integral role in the evaluation of patients with lung cancer. FDG-PET/CT is now an accepted part of the imaging assessment.4-6 It is useful in characterising solitary pulmonary nodules (SPNs), staging disease, monitoring treatment response and for radiotherapy planning. Its primary role is in potentially operable non-small-cell lung carcinoma (NSCLC) and in cases of early-stage small-cell lung carcinoma (SCLC). There is poor uptake of FDG in bronchoalveolar carcinoma, some adenocarcinomas and well-differentiated neuro-endocrine tumours. Neuro-endocrine tumours are better evaluated with somatostatin analogue imaging.
Solitary pulmonary nodules. FDG-PET/CT is the most accurate,
non-invasive imaging modality for the evaluation of SPNs
(Fig. 2). The combination of the anatomical and
metabolic images combines the sensitivity of the CT and the
specificity of the PET, resulting in improved overall accuracy.7 PET/CT
may produce false-positive results, specifically in inflammatory
conditions, including tuberculosis. It may be false negative in
lesions smaller than 1 cm and in tumour types with a low-glucose
metabolism, e.g. bronchoalveolar carcinoma.
Fig. 2. Transaxial views of 3 cases referred for PET/CT to evaluate SPN. Case A: true positive, with FDG uptake in histologically proven adenocarcinoma. Case B: true negative, with absent FDG uptake in proven tuberculosis. Case C: false positive, with avid FDG uptake in tuberculosis. (A1 - C1 CT slices; A2 - C2 FDG-PET slices; A3 - C3 fused images.)
Tumour staging . The initial staging of a patient with NSCLC is important, as it has therapeutic and prognostic implications. CT remains the initial study for staging, but it frequently produces false-negative results when lymph nodes are smaller than 1 cm. PET/CT has a higher diagnostic accuracy than CT alone, although it cannot replace histological confirmation of nodal involvement. It serves as a roadmap to identify nodal areas for tissue diagnosis.
Distant metastases of NSCLC frequently involve the adrenal
glands, brain, liver and skeleton. It is important to identify
metastases, as this has a significant influence on the choice of
therapy (Fig. 3). Although skeletal scintigraphy using Tc-99m
MDP is sensitive for detecting skeletal metastases, FDG-PET/CT
has a higher sensitivity and specificity. It is difficult to
detect brain metastases with FDG-PET/CT because of the high
glucose consumption in the normal brain. Brain metastases are
therefore better detected using contrast-enhanced CT or MRI. As
PET/CT has superior accuracy in the detection of lymph node
involvement and distant metastases, it has resulted in fewer
futile thoracotomies in a significant number of patients.
Fig. 3. Whole body FDG-PET/CT MIP view (A) and transaxial fused images (B) in a 62-year-old man who presented with a 4-month history of weight loss and right-sided chest pain. CT detected a mass in the right upper lobe of the lung confirmed to be a non-small-cell carcinoma. He was referred for PET/CT for staging, for possible surgical resection of the primary tumour. View B1 demonstrates uptake of FDG in the primary tumour with a necrotic centre (dotted arrow in A and B1). A mid-abdominal transaxial cut (B2) demonstrates a metastasis in the left adrenal gland (thin solid arrow). In addition, an abnormal FDG concentration is noted in a soft tissue mass in the left iliac fossa, also showing central photopenia consistent with necrosis (bold solid arrow in A and B3).
Monitoring treatment response . As metabolic changes reflect treatment response more sensitively than morphological changes, the use of PET/CT in the evaluation of treatment response is well established. Residual masses on CT may be due to tumour fibrosis or residual tumour tissue. These can be differentiated using PET/CT.
Radiotherapy planning . Radiotherapy is a key treatment modality in patients with both NSCLC and SCLC. The metabolic information obtained from a PET scan can be incorporated into the radiation treatment plan, enabling more accurate treatment plans to be drawn up than when using CT alone.8
Colorectal carcinoma
This malignancy is one of the common neoplastic diseases, with early diagnosis being key to long-term survival. If the disease is localised, surgery is the treatment of choice. In patients with locally advanced disease, prognosis can be improved by using neoadjuvant chemo-radiotherapy. It is therefore important to accurately stage the disease and to detect local or distant recurrence timeously. Many imaging modalities are available for this purpose, including FDG-PET/CT as a metabolic tracer.9 , 10
Using FDG-PET/CT in the pre-operative staging of disease
may be potentially advantageous, but a substantial impact on
clinical management has not yet been demonstrated. FDG-PET/CT
has been recognised as appropriate in the restaging of
patients with suspected recurrence when elevated serum tumour
markers (e.g. carcino-embryonic antigen (CEA)) are found, when
conventional imaging is non-diagnostic and in apparently
isolated local recurrence or metastases prior to surgery (Fig.
4). FDG-PET was shown to result in a change in clinical
management in about 30% of patients with recurrent colorectal
cancer.11
This was due to the detection of early recurrence with
metabolic changes in normal-sized structures before
morphological changes occurred, or in lesions missed on
contrast-enhanced CT because of altered morphology due to
previous surgery.
Fig. 4. Whole body FDG-PET/CT in a 62-year-old patient after left hemicolectomy and chemotherapy for colon carcinoma. The patient presented with a single liver metastasis, which was treated with radiofrequency ablation. MIP view (A1) of follow-up FDG-PET/CT study; transaxial (A2) and fused (A3) views demonstrated a small area of doubtful significance in the right lobe of the liver (A1 - A3). A follow-up study 3 months later confirmed recurrence of the lesion in the liver (B1 - B3). The lesion is indicated with a red + sign.
PET has been shown to be more sensitive than conventional imaging for detecting extrahepatic metastatic disease in patients considered for liver metastasectomy, and has the potential to alter treatment in up to 27% of patients.12
The use of FDG-PET/CT is also advantageous in the restaging of recurrent colorectal cancer because of the identification of additional unexpected metastatic sites, leading to upstaging of the disease. PET/CT has a higher sensitivity than CT in the abdominal cavity, and for detecting metastatic lymph nodes and peritoneal involvement.13 PET/CT is also of value for the detection of unexpected extra-abdominal metastases, mainly in the lungs.
Oesophageal carcinoma
Oesophageal cancer is very prevalent in South Africa. FDG-PET/CT is not generally used in the diagnosis of oesophageal carcinoma, as endoscopy (with ultrasound) is the standard technique. PET/CT has a low sensitivity for locoregional lymph node metastases, but is valuable for the detection of distant metastases (M staging), as this is crucial for the differentiation between locoregional and systemic disease (Fig. 5). The use of PET/CT led to the upstaging of patients in as many as 20% of cases, with downstaging in 5%.14
Fig. 5. Whole body FDG-PET/CT MIP view (A), transaxial (B1) and sagittal (B2) fused images in a 64-year-old man with oesophageal carcinoma (thin arrows) and vertebral involvement (thick arrows), which rendered him inoperable.
PET/CT has been validated as a surrogate marker for therapy response assessment.15 Its appropriate use for evaluating response to therapy has not been well defined, but it does correlate with clinical response and survival.
If tumour recurrence is suspected, PET/CT provides the most accurate whole body restaging tool, significantly better than conventional imaging using CT and endoscopic ultrasound.
When PET was used in radiotherapy planning it resulted in changes in target volumes, as areas with high metabolic activity were also included.
Table 1 provides a summary of the various internationally
accepted indications for the use of FDG-PET/CT in the tumours
described in this paper.
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