FDG-PET/CT provides added valuein routine multiple imaging scans

May 1, 2009

PET identifies the presence of a metabolically active tumor within the body after injection of a radioactive tracer.

PET identifies the presence of a metabolically active tumor within the body after injection of a radioactive tracer. CT uses x-rays to image the anatomy of patients. PET/CT systems combine the modalities to produce an image that shows the functional information from PET and the anatomical information from CT simultaneously. The resultant data are displayed as a fused PET/CT image.

The most common radioactive PET tracer is the glucose analog fluorine-18 FDG. F-18 FDG is injected intravenously and is taken up by normal and tumor cells in much the same way as glucose. Information on tracer uptake can be used to gather functional information.

Cardiac muscle, for example, preferentially uses free fatty acids as an energy source, but it can also use glucose, lipids, or amino acids if required. Glucose uptake within the heart varies among people and can change considerably within an individual over a short period in relation to his or her blood glucose level. Brain cells are fueled solely by glucose, and glucose activity within the brain is always high. The metabolic rate of many tumors is much higher than that of normal cells, and tumors consequently use considerably more glucose.

F-18 FDG has a half-life of approximately 109 minutes. Patients scheduled for a PET/CT examination involving injection of F-18 FDG should fast for at least four hours beforehand. This ensures that most tissues are using free fatty acids as their energy source. Diabetic patients are advised to take their normal insulin or medication.

Patients are advised to lie down and relax for approximately 45 minutes after injection to allow time for the radiotracer to accumulate in metabolically active cells. Any unnecessary patient movement during this period may result in uptake by muscle. Patients who are tense or shiver during this time often have FDG uptake in their neck muscles. Brown fat activation can cause confusion. Brown fat is seen more commonly in thin individuals during the winter months, and generally in young women with anxiety and stress.

The PET/CT examination is normally carried out from the base of the skull to the midthigh, the so-called partial body scan. Some patients, those with melanoma, for example, may have a whole-body scan, from skull vertex to feet, depending on the location of the primary tumor. This is because of the widespread and unpredictable lymphatic dissemination that characterizes this disease. Patients with head and neck disease may have scans that include the entire skull, and patients with softtissue sarcomas may also require additional views.

A semiquantitative method called the standardized uptake value (SUV) is often used as a parameter for measuring the uptake of FDG by tissue or lesions.

ONCOLOGY APPLICATIONS

The hybrid modality has many applications in oncology:

• Lung cancer. FDG-PET/CT is used to assess solitary pulmonary nodules and to stage non-small cell lung cancer (Figure 1).1 It is additionally used to assess mediastinal lymphadenopathy, identify distant metastatic disease, and detect recurrent disease. FDG-PET/CT can assist with radiotherapy planning and therapy monitoring, while also acting as a prognostic indicator of time to progression.

Approximately 85% of metabolically active pulmonary nodules are malignant.2 FDG-positive pulmonary nodules should be assumed to be malignant until proven otherwise. Exceptions to this rule include postinflammatory lesions such as sarcoidosis, granulomatous conditions, inflammation, infection, and adenomas. Solitary pulmonary nodules that are FDG-negative include bronchoalveolar cancer, scar adenocarcinoma, carcinoid tumors, and neuroendocrine tumors (partly avid).

• Breast cancer. FDG-PET/CT can be used for staging and restaging, though local staging is performed mainly with MRI and mammography. It can also be used to monitor response to therapy and to plan radiotherapy.

One study found that FDG-PET was 88% sensitive and 80% specific for breast cancer. False-negative results were returned for 12% of all breast cancer cases.3

• Lymphoma. Applications include initial diagnosis and staging, assessing response to therapy and monitoring residual disease, identifying recurrent disease, seeking out suitable sites for biopsy, disease surveillance, radiotherapy planning, and prognostic stratification.

A comparison of PET/CT and contrast- enhanced CT when assessing organ involvement in lymphoma found the sensitivity of the two modalities to be 88% and 50%, respectively. The specificity of PET/CT was 100%, while contrastenhanced CT was 90% specific.4

False-positive results can be due to infection, inflammation, FDG uptake in cardiac muscle or the bowel, and thymic hyperplasia. Mucosa-associated lymphatic tissue lymphoma, lymphocytic non-Hodgkin’s lymphoma, chronic myelogenous leukemia, and other nonaggressive lymphomas can lead to falsenegative diagnoses.

• Esophageal cancer. Many etiological factors have been shown to be associated with esophageal cancer. Smoking and excessive alcohol intake are believed to contribute directly in many cases.

The two main histological subtypes are squamous cell cancer, which primarily affects the upper two-thirds of the esophagus, and adenocarcinoma, which normally is found in the lower third of esophagus. Predisposing factors include Barrett’s esophagus, gastroesophageal reflux, and possibly previous mediastinal radiotherapy.

ROLE OF FDG-PET/CT

FDG-PET/CT is useful in the following:

• Preoperative staging to identify nodal and disseminated metastases;
• Demonstration of recurrent disease and assessment of response to therapy, including neoadjuvant chemotherapy; and
• Prediction of therapy response and overall prognosis.

False-negative results may be due to small T1 lesions, local nodes applied close to the primary tumor, or linitis plastica. Peritoneal metastases may be missed on PET if they are very small, but they are then often detected on CT. Gastritis, Barrett’s esophagus, esophagitis, a normal contracted stomach, and physiological uptake in the gastric outlet can lead to false-positive diagnoses.

• Colorectal cancer. The five-year survival rate for colorectal cancer is 50%. Risk factors include age, diet, colonic polyps, chronic ulcerative colitis, and familial polyposis.

FDG-PET/CT can be used as a primary staging tool and in assessing recurrent disease. It is also performed prior to metastectomy, when assessing tumor response to chemo- or radiotherapy, and on masses that are difficult to biopsy. Patients with an unexplained rise in serum carcinoembryonic antigen and a history of colorectal cancer may also be imaged with FDG-PET/CT.

One study found that the sensitivity and specificity of PET/CT to colon cancer recurrence in patients after resection were 96.5% and 82.1%, respectively. Using serum CEA levels led to a sensitivity of 62% and a specificity of 87.5%.5

False-positive diagnoses may be caused by physiological uptake of FDG, inflammation (e.g., diverticulitis or colitis), polyps, and uptake caused by postoperative changes at the stoma site.

Small-volume disease, some mucinsecreting tumors, and carcinoid tumors can lead to false-negative calls. Peritoneal metastases can go undiagnosed on PET, though they may be picked up on CT.

• Head/neck cancer. Most head and neck cancers occur in the tongue base or tonsillar fossa. Occurrence is linked strongly to alcohol and tobacco use. Treatment may involve surgery, radiotherapy, and/or chemotherapy.

FDG-PET/CT can be used for staging, identifying sites of recurrence (Figure 2), distinguishing postoperative changes from residual disease, finding the site of an unknown primary tumor, and assessing response to therapy. It may also be used as a prognostic tool. PET/CT has been shown to be more accurate than PET alone for the depiction of head and neck cancers (96% versus 90%; p = 0.03).6

• Skin cancer. Approximately 75% of all skin cancers are basal cell carcinoma, while the remainder are squamous cell carcinoma and malignant melanoma. Almost all melanoma metastases greater than 1 cm in diameter are detected by FDG-PET/CT. Combined imaging is twice as accurate as CT alone for the detection of distant disease. PET/CT avoids unnecessary surgery and results in significant management change.

Patients with malignant melanoma who have suspected nodal or distant metastatic involvement or a high risk of such spread may undergo an FDGPET/ CT scan for staging purposes. The combined imaging modality may also be used to restage melanoma patients prior to surgical metastectomy and to confirm suspected recurrence.

FDG-PET/CT has a possible, but as yet unproven, role in monitoring response to therapy and disease surveillance. Most melanoma metastases are highly FDG-avid. Ocular melanoma is the main exception. Radiology researchers have shown the sensitivity, specificity, and accuracy of PET/CT for the depiction of melanoma metastases to be 98%, 94%, and 96%, respectively.7

• Gynecological malignancies. Ovarian cancer is associated with late presentation and poor prognosis. The role of FDG-PET has largely been limited to the assessment of recurrent disease. Moving to PET/CT is likely to make this investigation even more successful and reduce the number of false-positive reports.

Uterine carcinomas, such as cancers of the endometrium and cervix, tend to present earlier, and patients have much better survival rates. Although studies have shown that FDG accumulates in endometrial cancers, PET/CT is not used for the routine management of these tumors. There is, however, growing evidence that FDG-PET and PET/CT can contribute to the management of patients with cervical cancer.8

Both CT and (more often) MRI are used to stage carcinoma of the cervix. Lymph node staging is fundamental to the management of cervical cancer in terms of both survival and treatment. Nodal staging with structural imaging methods is limited, however, by the arbitrary 1-cm cutoff for the differentiation of malignancy from benign disease. It is now accepted that small nodes can harbor disease and that large nodes may only be reactive. A more accurate assessment of nodal involvement, perhaps using PET to add functional information, is required.

• Unknown primary tumors. Unknown primary tumors can be localized, staged, and restaged with FDG-PET/CT.9 The modality may also be used to monitor response to therapy and for radiotherapy planning.

INFECTION, INFLAMMATION

Infectious and noninfectious inflammatory conditions may demonstrate high FDG uptake. This is because glucose metabolism is elevated by stimulated inflammatory cells, macrophage proliferation, and healing.

FDG accumulation in inflammatory or infectious tissue may reduce specificity in patients with cancer. In patients with suspected infection and no known history of cancer, FDG-PET/CT can be a useful tool for localizing the infectious disease.

Differentiation of the cause of FDG uptake in complex clinical cases-following tumor resection, for example-is possible with sophisticated methods such as kinetic analysis and dual or more time-point PET examinations. Dual and time-point PET scans are performed after two to three hours to see the difference in SUV values after FDG injection. The CT component of PET/CT can also help when differentiating between residual and recurrent cancer and infectious or inflammatory lesions.

FDG-PET/CT avoids many of the disadvantages associated with radiolabeled leukocyte scans, which include the complex cell-labeling procedure, handling and possible cross-contamination of blood samples, high radiation dose, low counts (leukocyte), and time from imaging to diagnosis.

FDG-PET has also been used in the imaging evaluation of patients with fever of unknown origin. One study involving PET reported a positive predictive value of 87% and a negative predictive value of 95% in detecting sites of infection or inflammation.10 PET offers many advantages over gallium scintigraphy in this setting, including higher spatial resolution, better image quality, and decreased time from imaging to diagnosis.

Interest is growing in the use of PET/CT for the evaluation of patients with suspected osteomyelitis and infected limb prosthesis implants. A report of 39 patients with suspected soft-tissue and bone infections found pooled sensitivity and specificities for FDG-PET of 98% and 75%, respectively.11 FDG-PET has a high negative predictive value for osteomyelitis, such that a negative scan effectively excludes that condition. High sensitivity (100%) and specificity (88%) have also been reported for PET in the diagnosis of chronic musculoskeletal infections in both the axial and appendicular skeleton.12

FDG-PET/CT could potentially play a role in localizing infection in patients with disseminated tuberculosis.13 Biopsies guided by FDG-PET/CT could also help distinguish between lymphoma and opportunistic infections in immunodeficient patients. Subsequent follow-up should be carried out to assess the response to the therapy. Little has been published on this application at the moment, though investigations are ongoing.