- Citado por SciELO
versão impressa ISSN 1698-4447
Med. oral patol. oral cir. bucal (Ed.impr.) vol.10 no.4 Ago./Out. 2005
The diagnostic possibilities of Positron Emission Tomography (PET)
Posibilidades diagnósticas de la Tomografía por Emisión de Positrones (PET):
Aplicaciones en la patología oncológica bucal y maxilofacial
Daniela Carranza Pelegrina (1), Francisco Lomeña Caballero (2), Marina Soler Peter (3), Leonardo Berini Aytés (4),
Cosme Gay Escoda (5)
(1) Licenciada en Odontología. Residente del Máster de Cirugía e Implantología Bucal. Facultad de Odontología de la Universidad de Barcelona
(2) Consultor del Servicio de Medicina Nuclear, Hospital Clínico y Provincial de Barcelona. Director de la Unidad PET de CETIR, Barcelona
(3) Especialista en Medicina Nuclear. Unidad PET de CETIR, Barcelona.
(4) Profesor Titular de Patología Quirúrgica Bucal y Maxilofacial. Profesor del Máster de Cirugía e Implantología Bucal.
Facultad de Odontología de la Universidad de Barcelona
(5) Catedrático de Patología Quirúrgica Bucal y Maxilofacial. Director del Máster de Cirugía e Implantología Bucal. Facultad de Odontología de la Universidad de Barcelona. Servicio de Cirugía Bucal, Implantología Bucofacial y Cirugía Maxilofacial. Centro Médico Teknon. Barcelona
Prof. Dr. Cosme Gay Escoda
Centro Médico Teknon
Received: 24-12-2003 Accepted: 12-03-2005
Carranza-Pelegrina D, Lomeña-Caballero F, Soler-Peter M, Berini-Aytés L, Gay-Escoda C. The diagnostic possibilities of positron emission tomography (PET). Med Oral Patol Oral Cir Bucal 2005;10:331-42.
The principles of positron emission tomography (PET), recently introduced as a diagnostic procedure into the health sciences, are described. The principle clinical applications apply to a particular group of specialties: cardiology, neurology, psychiatry, and above all oncology.
Key words: Positron emission tomography, head and neck neoplasia, imaging diagnosis.
Se describen los principios de la tomografía por emisión de positrones (PET) como procedimiento diagnóstico de reciente introducción en el campo de las Ciencias de la Salud. Las aplicaciones clínicas principales se dan en un grupo concreto de especialidades: la cardiología, neurología, psiquiatría y sobre todo la oncología.
Palabras clave: Tomografía por emisión de positrones, neoplasias de cabeza y cuello, diagnóstico por la imagen.
In different areas of the health sciences, new strategies for the diagnosis and clinical follow-up of patients are being developed, especially high-resolution computerized tomography (HRCT), magnetic resonance imaging (MRI) and positron emission tomography (PET). The latter has generated a radical change of direction in image diagnosis, introducing us to the concept of the molecular image (1).
This technique was first introduced into Spain in 1995 by the Universidad Cumplutense de Madrid, and then in 1996 by the Navarra University Clinic. At the time of writing, there are more than 15 operational PET units in Spain.
Our aim is to review the literature published on the diagnostic possibilities of PET in oral oncology. This study has been made through the bibliographic search of articles published on the subject in books and journals of oncology and nuclear medicine. The citations were selected through the Medline database. All sources are from the period 1995-2003, although in certain cases older articles were searched if they contained necessary information.
THE PRINCIPLES OF POSITRON EMISSION TOMOGRAPHY
PET is a non-invasive diagnostic imaging technique based on the exploration of organs and systems through their metabolism (functional, enzymatic, hormonal or pharmacological mechanisms) and providing high-resolution images.
This diagnostic method requires the administration of a radioactive tracer to the patient. This tracer is a substance marked by a positron-emitting isotope, which, thanks to its physicochemical characteristics, concentrates in a specific tissue. A large range a radiopharmaceuticals are currently available, as can be seen in Table 1 (1, 2).
These radiotracers decay in a very short time (anything from a few minutes to some hours), emitting positrons, which, after interacting with the electrons of the atoms that make up the molecular tissue, then undergo a process of annihilation. As a result, two photons of 511 Kev of energy are formed in an almost coincident and opposite direction (1, 3, 4). These photons interact with two opposite tomographic detectors. The tomographic reconstruction of the PET images is obtained thanks to the capture of said emission by coincidence techniques, known as electronic collimation (1, 5).
Through filtered retro projection or 3D techniques, representative images can be obtained of the spacial distribution of the radiotracer in the interior of the organism. The resolution achieved depends on the tomograph, but is usually between 4-6 mm, obtaining high-quality images (1). PET therefore allows the detection and quantification of the distribution of a radionuclide positron emitter in the interior of the human organism (1, 2).
APPLICATIONS OF POSITRON EMISSION TOMOGRAPHY
1. Application in investigation
One of the principle applications of positron emission tomography is in the biomedical investigation of humans, since, thanks to the use of specific radioactive tracers, we can very precisely quantify different physiological cellular phenomena in vivo. In this way, this diagnostic imaging technique can measure many of the biological characteristics of malignant tumors. Examples are: the consumption of glucose, the consumption of various amino acids, DNA synthesis, protein metabolism, pH, hormonal membrane receptors, hypoxia, the effects of chemotherapy, genetic expression and transfer, the kinetics of the cytostatic drugs and the permeability of the hematoencephalic barrier in braintumors, among others (5-7).
PET also provides the opportunity for the imaging of the pharmacokinetics and pharmacodynamics of different drugs. The same drugs marked with C11 or F18 can be used as radiotracers, or their effect on blood flow, glucose metabolism or the occupation of specific receptors can be measured.
This technique could be useful in the design and development of new drugs, being applied in clinical trials in phases 1 and 2 of basic experimentation, even in phases 3 and 4, on large series of human beings (5). The complete experimental and clinical investigation, both in animals and in humans, requires the availability of a cyclotron, a multi-crystal, multi-ring PET tomographic system and a PET camera for small animals.
2. Clinical applications
Neurology, psychiatry, cardiology and finally oncology are the principal medical specialties where the clinical applications of PET are found in the literature (1, 5). In the field of neurology, PET allows the diagnostic study of diverse pathologies, since it provides the most precise way of viewing cerebral metabolism. Currently its basic application is found in the study of refractory epilepsy to drug treatment and in the diagnosis of some dementias such as Alzheimers disease (1). In cardiac pathology, PET studies are useful in the evaluation of myocardial viability (1).
The application of positron emission tomography in oncology is based on the fact that neoplastic cells present an abnormal growth with respect to normal cells. Therefore, the metabolism of tumoral tissues requires a higher than normal supply of nutrients (1, 2). Radiotracers are available that are analogous to the substances that participate in physiopathological processes.
The uses of PET-FDG accepted by the North American agency, HCFA (Health Care Financing Agency) in April 2001 are summarized as follows:
· Differential diagnosis of solitary, pulmonary nodules
· Diagnosis of the extension of non-microcytic lung cancer
· Localization of relapses with re-staging of lymphomas
· Localization of relapses with re-staging in head and neck cancer
· Localization of relapses with re-staging in colorectal cancer
· Localization of relapses with re-staging in cancer of the esophagus
· Localization of relapses and revaluation of melanomas
3. Radiotracers in oncology
A wide variety of radiotracers are available, C11, N13, O15 and F18, their utility is based on the study of the biological properties of the tumors. These radiotracers, like their natural analogues, are very common elements in organic molecules and so can either substitute them (C11, N13, O15), or be easily interchanged (hydrogen atoms for F18) (2). The majority of radioactive positron emitting elements are generated in particle accelerators known as cyclotrons. One of their properties is that of having a very short half-life (O15, 2 minutes; N13, 10 minutes; C11, 20.4 minutes: F18, 110 minutes). Therefore, the use of tracers marked with O15, N13 and C11 are limited exclusively to those PET units possessing their own cyclotron (1, 2).
Fluorodeoxyglucose (18FDG) is the only PET tracer with an established clinical application. This is due to be the fact that its availability, stability in vitro and the F18 half-life (110 minutes), allows its transport in monodoses, from those centres with a cyclotron where it is made, to other centres where a PET tomograph is available. These conditions do not yet apply to any other radiotracer. Therefore, 18FDG is the only tracer that can be used in centres that do not have their own cyclotron (1, 2, 5). 18FDG permits the imaging and quantification of one of the most interesting physiological parameters in tumor cells, the glucolytic metabolism. The advances in radiopharmaceutics favor the incorporation of new tracers into clinical practice with different biological characteristics and which are more sensitive and specific in the detection of different tumors (2).
The uptake or capture of this radiotracer depends, among other factors, on the histology of the tumor. A hyperuptake is usually associated with a high expression of GLUT-1, to an increased activity of the hexokinases and to the existence of a large number of viable cells, typical characteristics of a high grade of histological differentiation (2).
There are other radiotracers, such as marked amino acids, that may be useful in the study of tumors. Among these notably are the recently introduced C11-L-methyl-methionine and N-methyl-C11-alpha- Methylaminoisobutyric acid (C11-MeAIB) (2, 8).
4. Application in oncology of the head and neck
Malignant tumors of the head and neck, including those situated in the oral cavity, constitute 5% of all cancers, squamous cell carcinoma being the most frequent neoplasia in this area (95%). In 99% of cases, patients present visible or palpable primary tumors so a direct or endoscopic biopsy could serve to obtain a certain diagnosis (9).
These neoplasias principally propagate and disseminate via the lymphatic system. The dissemination towards the cervical lymph nodes will determine the type of treatment and the prognosis for the patient, tumoral staging is therefore fundamental. 60% of patients present palpable adenopathies at the time of diagnosis, although only 40% are metastatic adenopathies. Furthermore, the 5-year survival is greater than 50% in the absence of metastatic adenopathies, but is reduced to 30% when lymph nodes are affected (9).
PET can be used in the diagnosis of benignity or malignancy of a primitive tumor detected by other techniques, to establish the diagnosis of extension prior to treatment of a known neoplasia, to differentiate between a residual tumor and the changes produced following surgery, radio or chemotherapy, to guide a biopsy, to locate a relapse suspected either clinically or by the increase in tumoral markers, to carry out a new study of extension or re-staging following the diagnosis of a relapse, for the early evaluation of the response to treatment and to look for the primitive tumor in a patient with metastasis of unknown origin (9-12).
In the initial diagnostic phase (figure 1), as previously mentioned, lymphatic involvement will determine the prognosis and most opportune treatment; this is generally based on the excision of the primary tumor, with or without cervical lymph node removal. On many occasions this involvement is subclinical, confirmation not being possible after the application of other diagnostic imaging techniques. The majority of published studies demonstrate the superiority of PET against MRI, CT, echography and palpation. In this application, positron emission tomography can have a sensitivity of 80-100% and a specificity of 85-94%, whilst the other techniques offer a sensitivity of 65-88% and a specificity of 40-85%. PET-FDG will detect adenopathies of up to 5 mm. It has been established that PET has a negative predictive value of almost 100%, in cases where there has been no lymph node uptake of FDG, thus avoiding many negative cervical lymph node removals.
The reason for false positives is due mainly to the existence of reactive non-tumor lymph nodes, and false negatives originate from a partial or microscopic lymph node involvement, or when the size is less than 3 mm. Even so, due to the limited percentage of cases with negative palpation in which PET determines the lymphatic involvement, the application of this technique is arguable in this situation. On the other hand, false negatives can occur in patients with minimal lymph node involvement, which makes it risky to omit lymph node removal on negative PET results. For this reason, this application remains reserved for those cases with high risk of local or distant lymph node metastasis (12).
Another indication for PET is in the detection of relapses (Figure 2). When faced with a warning sign, whether clinical or analytical, exploration is not easy due to the structural atrophy or the cicatricial fibrosis produced following surgery and radiotherapy. The majority of conventional techniques are ineffective when it comes to distinguishing between recurrent or residual lesions and changes, to a certain extent physiological, observable following treatment. Furthermore, the biopsy, above all when done blind, may not be adequate if it does not coincide with tumor tissue, or for complications produced (such as tissular necrosis for example), in the already very deteriorated tissue. PET-FDG detects very early foci of residual cancerous disease on demonstrating an increase in the glucolytic metabolism of tumor tissue and in differentiating it from cicatricial tissue, whose glucose consumption is reduced (9). In these cases PET offers a sensitivity of 85-100% and a specificity of 82-100%, data that demonstrate its superiority against conventional techniques. It also allows the guiding of the biopsy, eliminating false negatives (12).
Finally, the ability of this diagnostic imaging technique to detect primary tumors in metastatic lesions of unknown origin is to be highlighted (Figure 3). On many occasions the first indication arises from the appearance of a cervical lymphadenopathy. The different image studies (CT, MRI), or endoscopy do not discover even 20% of primitive tumors that are generally located on the base of the tongue, the cavum or the lung.
The final report, of an investigation supported by the Agencia de Evaluación de Tecnología Sanitaria del Instituto de Salud Carlos III (Expediente 00/10028) provides a systematic revision and a meta analysis of the situation, concluding that when all other techniques have failed, PET is still able to detect 43% of primary tumors, allowing the immediate initiation of treatment (20). In Table 2 the values for the sensitivity and specificity of PET-FDG applied to carcinomas of the head and neck found in the literature are presented.
ADVANTAGES OF POSITRON EMISSION TOMOGRAPHY
PET is a diagnostic imaging technique which provides functional information on tissular biochemistry and perfusion, in contrast to other techniques such as computerized tomography (CT) or magnetic resonance imaging (MRI), which are diagnostic modalities based on the study of the morphology or the anatomy of the organs (1, 5, 13-15).
Thus, both CT and MRI present criteria for determining the malignancy of a tissue that depends exclusively on the morphometric analysis, and therefore have important limitations in diagnostic oncology.
Neoplastic cells have an increase in glucose consumption. Thus, the tumor mass presents a comparatively higher glucose metabolism with respect to healthy tissue (5, 13, 16, 17). The increase in the glucolytic activity of the tumor cells is also related to cellular proliferation and grade of malignancy. This data means that neoplasias are ideal candidates for specific metabolic imaging (1, 5, 18).
Two characteristics make PET an excellent diagnostic tool in oncology. Firstly, it is highly sensitivity in the detection of hyperuptake of FDG in tumoral lesions, with a high negative predictive value. Secondly, it is possible to explore the entire human body in one single exploration (2, 12). This last characteristic allows the diagnosis of distant metastases that usually go unnoticed, as demonstrated by Teknos et al. (14) in their study, where they confirm the utility of FDG-PET when studying stage 3 and 4 carcinomas of head and neck, detecting hidden metastases principally in the mediastinal lymph nodes.
It is also possible to rapidly evaluate the capacity of a patient to respond to treatment or on the contrary if it is necessary to substitute or complement the therapy applied.
The diagnostic imaging techniques based on the morphometric analysis of tissues, as may be the case with HRCT, present a reduced specificity and sensitivity on differentiating between the appearance of the usual post-treatment tissular alterations and possible relapses, giving rise to false positive or false negative results (4,18). Schechter et al. (19) highlight the value of PET when contributing to the differentiation between residual lesions or relapses and the tissular changes resulting from the anti-neoplastic treatment.
For their part, necrotic and cicatricial tissues do not take up FDG, and the uptake of FDG in inflamed tissues (pneumonia, bronchitis, vasculitis, etc.) is less than in malignant neoplastic lesions. However, false positives have been described in inflammations, infections and granulomas (sarcoidosis, tuberculosis, histoplasmosis, aspergillosis, etc.) (2). In such cases, the use of C11-methionine as a radiotracer may be of interest (2).
In general, it is believed that PET presents a superior grade of specificity and sensitivity with respect to other diagnostic imaging techniques such as MRI or CT (20). However, other authors such as McGuirt et al. (21) consider PET, MRI and CT, to have an equivalent diagnostic capacity, although they do highlight the superiority of PET over clinical examination.
In this way, PET, when used appropriately during the post-operative period, would additionally permit the evaluation of the evolution and possible recovery following radiotherapy of carcinomas of head and neck (22).
Numerous authors (4, 16, 22) agree on the diagnostic difficulty that exists in the detection of metastatic cervical lymph nodes in squamous cell carcinomas of the upper aerodigestive tract. PET is a diagnostic modality that could be of great utility in the localization of tumor activity in areas where this is apparently clinically negative. These metastases frequently remain hidden or inaccessible to clinical detection. The risk of errors in detection using different diagnostic techniques has been evaluated by some authors (16); specifically, for palpation this is between 20 and 28%, for HRCT between 7.5 and 28% and for MRI 16%.
Two very important disadvantages should be highlighted. The first is the scant availability of PET units in Spain, and the second is their high cost, although the cost benefit relationship does justify the economic outlay.
Resolution is approximately 6 mm in the visualization of the image, which impedes the detection of micrometastases, which is also a certain disadvantage.
Another disadvantage of FDG-PET is that while FDG accumulates in areas of intense metabolic tumor activity, it can also do so in other areas of the organism that present the same characteristic, but in a physiological manner. Amongst those we can name: the digestive tract, the thyroid gland, striated muscle, the myocardium, bone marrow, the brain, and the genitourinary tract. The PET/HRCT scanner has been demonstrated to be useful in the differentiation of physiological accumulations of the radiotracers against hyperuptakes that are produced as a consequence of the presence of malignant lesions. In the head and neck the increased accumulations of FDG may be due to the normal hyperuptake of a striated muscle, as for example in the sternocleidomastoid muscle. Furthermore, the patient should be instructed not to speak during the administration of the radiotracer as this favors its uptake by the laryngeal muscles and could cause confusion in the interpretation of the PET (23).
Goerres et al. (24) evaluated the artifacts that may appear in patients with dental implants suspected of having an inflammatory or neoplastic pathology, after being examined using the PET or the hybrid PET/HRCT systems. The objective of the study was to evaluate the influence of the dental implants on the quality of the PET images comparing the uncorrected images, the images corrected by Germanio 68 attenuation (PET (Ge68)) and the PET/HRCT. They detected a significant difference in the quality of the image of the lips and tip of the nose, which appeared darker on the uncorrected images with respect to the corrected ones. Artefacts in the HRCT were seen in 33 patients, and in 28 of those these artefacts were also detectable in the PET images. The direct comparison between PET (Ge68) and PET/HRCT demonstrated a difference in the appearance of artefacts in 3 of 17 patients. The malignant lesions were equally visible in images using either method of correction. They conclude that dental implants, fixed protheses etc., may cause artefacts in the images corrected with attenuation both in PET (Ge68) and in the PET/HRCT, they therefore recommend that these patients are evaluated by means of PET images (24).
The perspectives for the future lead us to hybrid systems that combine PET and HRCT. The PET+HRCT, or PET+MRI fusion has been undertaken, until now, in a retrospective manner through a system of coregistration via software. The fusion of PET+HRCT images is highly useful in oncology, since it can be used to check that the pathological deposition of a tracer, such as FDG, coincides with the enlarged mass or adenopathy detected by HRCT. This facilitates the taking of samples and the guiding of biopsies or, even, the planning of radiotherapy. The hybrid systems allow the patient to be subjected to both tests during one single exploratory session (2, 23).
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