PET-CT in oncologyNC Purandare, V Rangarajan
Bio-Imaging Unit, Tata Memorial Hospital, Dr. E Borges Road, Parel, Mumbai-400 012, Maharashtra, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.65277
Source of Support: None, Conflict of Interest: None
Diagnostic imaging plays a pivotal role in cancer management. Imaging has made rapid strides in the past few years with new modalities and new indications getting added all the time. Molecular and metabolic imaging with 18F Flurodeoxyglucose Positron Emission Tomography (FDG PET) and other non-FDG isotopes have revolutionized oncologic imaging and changed our approach towards cancer diagnosis, staging and imaging surveillance. The evidence for the use of FDG PET is mounting every day with newer indications getting added to the literature. The main focus of our discussion will be to understand the basic principles of FDG PET imaging and to study a few of its clinical applications in oncology.
Keywords: Diagnostic imaging, humans, neoplasms, positron emission tomography
In the past few decades, as oncologists and oncosurgeons attempted to cure many types of cancers or at least provide patients with a longer disease-free life, there has been a spectacular parallel and supportive evolution in imaging technology. Currently, imaging plays a pivotal role in the management of all cancers. It is used for screening, for preliminary diagnosis, to establish the extent and distribution of disease, for biopsy guidance, staging, prognostication, therapeutic planning, judging response to therapy and restaging. In oncology, the role of imaging has shifted from merely providing anatomical information to providing insight into tumor biology using techniques such as Computerised Tomography (CT) and Magnetic Resonance Imaging (MRI) perfusion imaging, MR spectroscopy and Positron Emission Tomography (PET) imaging. These techniques can demonstrate metabolic response to therapy which precedes anatomical changes. If there is less than optimal response to treatment on early assessment then the treatment regime can be changed accordingly, thus avoiding the potential morbidities associated with a toxic treatment regime which has no therapeutic benefit.
18 F-Flurodeoxyglucose (FDG) PET has in the last few years become an established modality in the management of several cancers. It is an imaging technique that provides information about the functional and metabolic changes associated with cancer. PET scanning requires the use of molecules that are labeled with radio nuclides. Numerous such positron-emitting radio-isotopes exist and are used in clinical experiments and research. However, in clinical practice the principal radio-isotope used is the positron-emitting 18 F-FDG which is a glucose analogue labeled with 18 F. The positron emitters including 18 F FDG have short half lives and are produced in cyclotrons. FDG is injected intravenously and is transported from the plasma to the cells by glucose transporters (GLUT 1 and GLUT 4). It then undergoes phosphorylation within the cell by the enzyme hexokinase and is converted to FDG-6-phosphate. FDG-6-phosphate is not further metabolized and gets trapped in the cell. Cancer cells demonstrate increased anaerobic glycolysis (Warburg effect)  which is believed to be due to upregulation of glucose transporters and hexokinase and reduced levels of glucose-6-phosphatase thus limiting further metabolism of the tracer in cancer cells.  The basic aspects of FDG PET and PET-CT such as radiopharmaceuticals, instrumentation, scanning protocol, physiological uptake patterns and benign variants are beyond the scope of this article. The current clinical indications and future applications of FDG PET in certain common cancers will be subsequently discussed.
FDG PET and PET-CT play an important role in the initial diagnosis, staging, response assessment and restaging of various cancers. The common cancers which can be evaluated by PET that are approved by the Centers for Medicare and Medicaid services (CMS) United States, include melanoma, lymphoma, lung cancer, esophageal cancer, head and neck cancer, breast cancer and thyroid cancer. PET, however, has been found to be useful in several other cancers such as gastric cancer, testicular cancer, endometrial and ovarian cancers, hepatocellular carcinoma, biliary and pancreatic cancers and soft tissue sarcomas. A national PET registry has been established in the United States to increase coverage of FDG PET studies for cancers which are not covered by medicare. No such registry or guidelines exist in India, the indications for PET scanning being largely based on Western data and literature.
For head and neck squamous cell cancers (HNSCC), PET can be used for initial staging, monitoring response to therapy, restaging and long-term surveillance. PET and PET-CT have a limited role in defining the T stage of the primary. MRI and contrast-enhanced CT scan due to their better resolution and ability to depict anatomy in detail are preferred over PET scan. However, PET-CT performed with intravenous contrast is a good alternative for assessing the primary tumor extent at initial presentation.  It plays an important role in identifying disease in nodes in unexpected locations and also in detecting unexpected distant metastatic sites. In patients with advanced loco-regional disease PET can detect occult distant metastatic disease in up to 10% of patients.  The inherent whole body coverage of PET as compared to the more loco-regional approach of CT and MRI scanning makes it more suitable to unmask sites of unexpected distant metastases. In the setting of clinically N0 (nodes not palpable at initial presentation) PET has not been found to be very useful as per recent literature.  This is because of the limited resolution of PET for lesions less than 5 mm and its inability to detect microscopic disease. Selective neck dissection and sentinel node biopsy is more useful in this regard. In patients presenting with cervical nodal metastases detection of primary tumor site is important as it may define the site and extent of surgery and also delineate the field of radiotherapy. Multiple studies have evaluated the role of PET in detecting occult primary with variable results. The sensitivity of PET to detect the primary site of tumor varies from 10-60% according to recent review of 11 studies.  PET-CT has been found to be very useful in the setting of assessment after chemoradiation. It has a higher specificity for detecting residual disease than contrast CT when it is performed eight weeks after treatment.  Numerous studies have shown that PET has a very good accuracy in detecting local and regional nodal recurrences during surveillance. It is of particular value in detecting sites of distant failure before a definitive salvage therapy is planned for loco-regional recurrence. For well-differentiated thyroid cancers PET-CT is used to detect sites of metastatic disease which are scintigraphically negative on radioiodine studies with persistently high thyroglobulin levels.  Similarly, for patients of medullary cancers with high calcitonin levels, PET-CT has been found to be useful to detect sites of disease recurrence. 
FDG PET is an integral part of staging of non-small cell lung cancer (NSCLC) as it very often improves the detection of nodal and distant metastases thus altering patient management. Though PET has a very good sensitivity in detecting the primary tumor it is not very often used for initial T staging owing to the better resolution of contrast-enhanced CT scan which can provide the anatomic detail that is required for surgical planning. Since surgical resection and future use of adjuvant therapy depends on the nodal stage, increasing emphasis is being laid on the ability of PET to accurately stage mediastinal nodal disease. FDG PET complements CT findings in providing information about loco-regional nodal disease that can impact patient management. In a recent meta-analysis comparing PET and CT in mediastinal nodal staging of NSCLC patients, PET showed an overall sensitivity of 83% and specificity of 92% compared with overall sensitivity of 52% and specificity of 78% for CT scan.  Owing to the high negative predictive value of a normal PET for excluding mediastinal nodal disease there have been reports suggesting the need to obviate mediastinoscopy if a PET scan is negative for mediastinal nodes. However, there is still no definite consensus on this issue and invasive staging of the mediastinum is still recommended by many authors despite a negative PET scan.
For metastatic disease whole body PET imaging is being increasingly used due to its better accuracy. It has a higher sensitivity, specificity than CT for detecting disease in bones, adrenals and extrathoracic lymph nodes. PET imaging stages intra and extrathoracic disease in a single study, detects occult metastasis in up to 24% cases selected for curative surgical resection and is also found to be cost-effective. , FDG PET is also being evaluated for assessing the prognosis and therapeutic response. Studies have shown that when PET is performed after completion of chemoradiation there is a strong association between decrease in FDG uptake of the primary tumor and nodes and the patient outcome  and also that PET is superior to CT in response assessment [Figure 1]. There is also evidence that PET performed as early as after one cycle of chemotherapy can predict responders early who have better long-term survival as compared to the PET non-responders.  PET has been very useful in detecting tumor recurrence after definitive surgery, chemo or radiation therapy earlier than conventional imaging modalities. For the evaluation of a solitary pulmonary nodule (SPN) PET is used to differentiate between benign and malignant nodules. Generally speaking an SPN with intense FDG uptake is considered to be malignant and a standardized uptake value (SUV) of 2.5 is considered to be a cutoff above which lesions are more likely to be malignant. However, this is not always true and infective/granulomatous lesions like tuberculosis, sarcoidosis etc can show intense FDG uptake whereas cancers like bronchioloalveolar carcinomas (BAC) may show poor or no FDG uptake.
Lymphoma is probably the most frequent indication in oncology for performing PET scans. Whole body FDG PET plays a vital role in almost all the aspects of the workup of lymphoma like initial diagnosis, staging, restaging, assessing response to therapy and long-term surveillance. Not all lymphomas are equally FDG avid. It is important to be aware of the histology before interpreting the results of the PET study. Hodgkin's disease (HD), diffuse large B cell lymphoma (DLBCL), follicular lymphoma and mantle cell lymphoma show good degree of FDG avidity. Peripheral T cell lymphoma and marginal zone lymphoma show poor to moderate FDG uptake. PET is considered to be as good or superior to CT scanning in the staging of lymphomas. It is definitely better in detection of extra-nodal disease and in particular splenic involvement.  It plays a complementary role to bone biopsy to assess bone marrow involvement.  FDG PET-CT has found to more accurate and better than CT alone and PET alone for staging and is also cost-effective. The degree of FDG uptake correlates well with the histological grade of lymphoma and provides important information about the prognosis. 
A negative FDG PET scan at the end of therapy indicates excellent treatment response, good prognosis and a possible progression-free survival [Figure 2], whereas persistent increased FDG uptake during or at the end of therapy is indicative of residual disease and a high chance of relapse. , PET has also been used to assess response early during the course of treatment. Early response assessment by PET is a good independent predictor of progression-free and disease-free survival in lymphoma patients. The ability of FDG PET to detect relapse earlier in nodes as well as additional sites not seen on CT lead to earlier administration of salvage therapy with a potential for better outcome.
Malignant melanomas can metastasize to any part of the body and hence the best imaging option would be the one which would image the entire body. Whole body FDG PET is the most suitable imaging modality for assessing melanoma. In Stage I disease where the survival rates are higher than 85-90%, PET may not influence management or survival.  Likewise in advanced Stage IV disease with a poor survival PET may not be able to change management or influence survival. For Stage II disease, sentinel node biopsy because of its ability to detect micrometastasis has been proven to be superior to PET.  It is in Stage III disease with regional nodal metastases that PET has maximum impact as it can unmask distant metastatic sites and thus influence management regarding surgery with or without adjuvant treatment. It has a similar impact on potentially limited or surgically resectable Stage IV disease, where it can detect occult metastatic sites and prevent futile surgical procedures.
The main role of FDG PET is breast cancer is detection of metastatic disease. PET scan can be useful in patients with non-palpable breast lesions, dense breasts, equivocal mammography results and after mammoplasty. The sensitivity and specificity of PET to detect the primary lesion range from 80-100%.  The most important advantage of PET at initial staging is the detection of unsuspected distant metastases in one single study. It can also detect internal mammary nodal involvement which is not routinely sampled at surgery. Though PET has shown reasonable sensitivity and specificity for detection of axillary nodal metastasis, it is limited in its ability to detect micrometastasis. Also, it cannot demonstrate the number of involved nodes which is a very important prognostic factor.
The ability of PET to accurately stage loco-regional recurrence in breast cancer is very important because though most recurrences are treated with systemic treatment, isolated loco-regional recurrences or solitary metastatic sites can also be treated with surgery and radiation therapy. 
Patients who undergo induction chemotherapy before surgery for locally advanced breast cancer benefit from PET scan as it allows differentiation of responders from non-responders early in the course of treatment. FDG PET has also been proven to be superior to bone scintigraphy (radionuclide bone scan) in detecting osteolytic skeletal metastases in breast cancer patients. 
The important role of PET in staging colorectal cancer is in assessing regional nodal involvement and distant metastases. At the time of the initial surgery of Colorectal Cancer (CRC) hepatic metastases are present in up to 10-25% cases. PET has been found to be superior to CT scan in the identification of hepatic metastases with sensitivity of 88% and specificity of 100% for PET versus 38% and 97% respectively for CT. 
About 25% of operated CRC fail loco-regionally and about 20% show isolated recurrence that is amenable for surgical excision. PET is accurate in detecting pelvic recurrences and differentiating them from post-treatment fibrosis which shows similar features on CT. Intrahepatic metastasis can be treated with curative surgical resection whereas presence of extrahepatic disease precludes surgery. PET has a greater sensitivity and specificity for detection of both intra and extrahepatic disease than conventional imaging and can lead to management change in about 18-43% cases when recurrent or metastatic CRC is suspected. , After treatment of hepatic metastasis with procedures such as radio frequency ablation and transarterial chemoembolisation, PET is often used to differentiate between post-treatment changes and residual/recurrent disease. Recurrent disease in the ablated region or elsewhere is picked up early by PET as compared to CT.
Neuroendocrine tumors (NET) are a heterogeneous group of neoplasms that arise from the neural crest. These tumors have an ability to overexpress somatostatin (SST) receptors. Scintigraphy with radiolabeled SST analogues with 123 I, 111 In and 99m Tc have been used so far to diagnose these tumors. Somatostatin receptor scintigraphy (SRS) though is useful for whole body imaging, has certain limitations in organs with high physiological uptake like the liver and for detection of small lesions due to the detection limitations for Single photon emission computed tomography (SPECT ). Though FDG PET has a much higher spatial resolution and is widely used for oncology it is not primarily recommended for NET due to its poor sensitivity to detect tumors with low metabolic activity and slow growth.  Morphologic imaging modalities like contrast-enhanced CT scan provide excellent spatial resolution of images and can detect very small tumors of neuroendocrine origin, but they lack the specificity to diagnose malignant involvement as they rely on size and contrast enhancement criteria.
PET technology using 68Ga-labeled 1, 4, 7, 10 - tetraazacyclododecane-N, N9, N99, N999-tetraacetic acid-D-Phe1-Tyr3- octreotide (68Ga-DOTA-TOC) has shown promising results in various studies.
It has been shown to have a much higher diagnostic accuracy for detection and staging of NET as compared to SRS and CT scanning [Figure 3]. With easier and more widespread availability of the radioisotope, PET with 68 Ga-DOTA-TOC studies will certainly be the cornerstone of neuroendocrine tumor imaging in the near future.
Conventional bone scanning is still the most common procedure for assessing bone metastasis in cancers with high risk of skeletal involvement like breast, lung and prostate cancers etc. However, it lacks specificity in accurately differentiating benign processes from malignant involvement.
F-18 fluoride is a PET tracer which can be used for bone imaging and has the same mechanism of uptake as other bone scintigraphic agents used in nuclear imaging. There are now a few studies in the literature stating the higher sensitivity of F-18 fluoride PET-CT over bone scanning with Tc-99m-methylene diphosphonate (MDP) [Figure 4]. Also, the specificity increases due to the CT component of the PET-CT which gives precise anatomic correlation and identifies nonspecific benign processes. 
Imaging modalities are evolving at a staggering pace to provide improved evaluation of cancer. Our understanding of imaging criteria and experience in image interpretation are also improving. In addition to the traditional roles of imaging in cancer (i.e., localization and staging), extensive research is being done on functional and metabolic imaging with PET imaging to predict cancer aggressiveness and monitoring therapeutic response. Future developments in onco-imaging include more precise patient stratification for different management options and novel methods for guidance and assessment of newer cancer therapies. Judgments about which particular therapy or combination of therapies is optimal for a given patient often hinges on the results of imaging examinations. As the incidence of cancer rises due to rising life expectancy, the role of FDG PET will continue to expand with more indications getting approved and newer tumor-specific radio-isotopes being developed.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]