ORIGINAL PAPERS

 

Patterns of extension of gastrointestinal stromal tumors (GIST) treated with imatinib (Gleevec^®) by ¹⁸F-FDG PET/CT

Patrones de extensión de los tumores del estroma gastrointestinal (GIST) tratados con imatinib (Gleevec^®) mediante PET/TC con 18F-FDG

 

 

Eulalia Valls-Ferrusola, Juan Ramón García-Garzón, Ana Ponce-López, Marina Soler-Peter, Silvia Fuertes-Cabero, Merce Moragas-Solanes, Eduard Riera-Gil, Ignasi Carrió-Gasset and Francisco Lomeña-Caballero

Unit of PET/CT. CETIR Grupo Médico-ERESA. Esplugues de Llobregat, Barcelona. Spain

Correspondence

 

 

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ABSTRACT

Background and aim: currently it is recognized the usefulness of 18F-FDG PET in assessing response to therapy with imatinib (Gleevec^®) in the gastrointestinal tract sarcomas (GIST). To facilitate the follow-up of these studies is important to know the patterns of metastatic spread. The aim of this paper is to describe patterns observed in the ¹⁸F-FDG PET/CT.
Method: retrospective study included 29 patients who underwent ¹⁸F-FDG PET/CT after being diagnosed with unresectable or metastatic GIST. In total, 87 PET/CT studies were performed (1-6 controls per patient) with a mean time of follow-up 6-36 months. We analyzed the location of the lesions evidenced in PET, CT and fusion. Images were evaluated visually and semiquantitatively (SUV). In cases in which has been considered necessary, additional images have been undertaken: PET delayed imaging, intravenous contrast CT and inspiratory chest CT.
Results: the most common primary site was the stomach (41%), small bowel (35%), and rectum (24%). Significant changes in the location of metastatic disease between pre-treatment and the monitoring were observed, with the appearance of more extra-abdominal disease.
Conclusions: individualization of protocol studies and interpretation of PET, CT and fused images were required for evaluation of treatment response to imatinib. Hybrid ¹⁸F-FDG PET/CT provides an accurate determination of the extent of GIST. While the most common metastatic site is the liver and peritoneum, in the following cases are common extra-abdominal disease.

Key words: GIST. ¹⁸F-FDG PET/CT. Metastases.

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RESUMEN

Introducción y objetivo: actualmente está reconocida la utilidad de la ¹⁸F-FDG-PET en la evaluación de la respuesta a la terapia con imatinib (Gleevec^®) en los sarcomas del tracto gastrointestinal (GIST). Para facilitar la valoración comparativa de estos estudios es importante conocer sus patrones de diseminación metastásica. El objetivo de este trabajo es describir estos patrones evidenciados en la ¹⁸F-FDG-PET/TC.
Método: estudio retrospectivo de 29 pacientes a los que se les realizó una ¹⁸F-FDG-PET/TC, tras haber sido diagnosticados de un GIST irresecable o metastásico.
En total se realizaron 87 estudios PET/TC (1-6 controles por paciente) con tiempo medio posterior de seguimiento entre 6-36 meses. Se analizó la localización de las lesiones evidenciadas en las imágenes PET, TC y de fusión, y se valoraron las imágenes de forma visual y semicuantitativa (SUV). En aquellos casos en los que para la valoración de las imágenes se ha considerado necesario se han realizado exploraciones adicionales: imágenes tardías PET, TC con contraste endovenoso y TC inspiratorio torácico.
Resultados: la localización primaria más frecuente fue la gástrica (41%), el intestino delgado (35%) y el recto (24%). Son muy significativos los cambios en la localización de la enfermedad metastásica entre el estudio pre-tratamiento y los controles de seguimiento, observándose evolutivamente la aparición de mayor enfermedad extra-abdominal.
Conclusiones: para la evaluación de la respuesta a la terapia es necesaria la valoración de las imágenes integradas y la individualización del protocolo de la exploración. La exploración híbrida PET/TC proporciona una precisa determinación de la extensión del GIST. Si bien la localización metastásica más habitual es el hígado y el peritoneo, en el seguimiento son frecuentes los casos con enfermedad extra-abdominal.

Palabras clave: GIST. ¹⁸F-FDG PET/TC. Metástasis.

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Introduction

GIST are gastrointestinal stromal tumors, account for 6% of all sarcomas and 3% of gastrointestinal tract tumors, described incidence of 1-2 cases/100,000 population (1). Over 90% of cases occur in patients older than 40 years, with a slight predominance in men (2).

GIST were originally classified as leiomyomas, leiomyosarcomas and leiomyosarcomas, characterized by expression of a mutated membrane receptor tyrosine kinase activity (CD117 or C-KIT) in 90% of cases. Additionally, 60-70% of cases also express CD34 (transmembrane glycoprotein). These characteristic allows specifical treatment with drugs that inhibit signal transduction mediated by KIT, inhibiting proliferation and promoting apoptosis of tumor. Imatinib (Gleevec^®) is the drug used in clinical practice to treat cases in which the primary lesion is unresectable or when there metastatic lesions (1,3). Ten percent of cases do not express the membrane receptor CD117 (1).

About 30% of patients were asymptomatic and diagnosed was made for an incidental radiological finding or at the time of autopsy. Clinical manifestations are related to the location and tumor size, the most frequent abdominal pain, intestinal bleeding, anemia, weight loss, nausea and vomiting (2,4). The most frequent primary tumor location is the stomach, 50-60% of patients, followed by the small bowel, with 25-35%(2). The colon, rectum and esophagus are less frequent locations (5).

At the time of primary tumor diagnosis, 15-27% of the cases have already metastasized. Over 50% of high risk GIST present with recurrence or metastases within a period of 10 years. It has come to describe disease progression at 30 years of primary tumor diagnosis (3,6,7). GIST malignant forms represent 20-30% of total, (4) many of them incurable with a median survival after diagnosis of about 12-19 months (3).

The most common metastatic site is the liver (65%), followed by the peritoneum (50%), with 20% of patients with metastases in both locations. While extra-abdominal locations are considered very rare (< 10%) (6,8). Many studies have shown a significant increase in survival in patients with metastatic or recurrent GIST treated with imatinib. In addition, you can change the dose of treatment and even have appeared others treatments derived from tyrosine kinase as sorafenib, so it is very important, proper monitoring of these patients.

The degree of uptake of ¹⁸F-fluorodeoxyglucose (¹⁸FFDG) in GIST is usually intense. This described a correlation between histological grade of malignancy and ¹⁸F-FDG avidity by GIST, which seems to reflect the metabolic mitotic activity, so that PET may be a direct measure of tumor aggressiveness and thus of prognosis (3,9,10).

The main utility of ¹⁸F-FDG PET/CT in GIST patients is to monitor response to treatment with imatinib. Metabolic changes in response to Imatinib may be manifested at 24 hours after administration of a single dose, so PET scan predicts therapeutic response to imatinib earlier as morphological CT changes (3,11).

However, to establish treatment response is essential to know the metastatic spread in GIST patients. Therefore, the aim our observational study is to describe these patterns of metastatic spread. Figures 1, 2, 3

 

Materials and methods

Retrospective study including 29 patients, 10 women and 19 men, mean age 60 ± 12 years, who were attended in the last 4 years, for a ¹⁸F-FDG PET/CT study after have been diagnosed with unresectable GIST or metastatic disease. None had started treatment with Imatinib. All were scanned again with PET/CT to assess the efficacy of treatment. In total, 87 studies were evaluated ¹⁸F-FDG PET/CT (between 1-6 controls per patient) with a mean follow-up of 6 to 36 months.

PET/CT studies were performed at 60 ± 10 minutes after injection of 370 ± 185 MBq of ¹⁸F-FDG in a PET/CT scanner Gemini (Philips) equipped with GSO crystals and 16 helical CT. Reconstructed images were done using full 3D reconstruction.

PET/CT included whole body, from the base of the skull to the upper third of the lower limbs. Additionally, delayed PET images were acquired, intravenous contrast CT and inspiratory chest CT. The assessment of all PET/CT studies was performed visually and semiquantitatively (SUVmax) independently by two nuclear medicine and a specialist in radiology.

For each patient, we analyzed, in each of the controls, all new abnormal deposits of ¹⁸F-FDG. In addition, we recorded changes of activity in each of these images, but without establishing criteria for treatment response, since it is not the aim of our study.

Lesions that involved a change of staging have been characterized by cytology and/or histology.

 

Results

- Primary tumor: the most common primary site was the stomach (12-41% of cases) followed closely by the small bowel (10-35%), and a lower percentage of patients, rectal location (7-24%).

- Pre-treatment study: twenty-six of the 29 patients in pre-treatment PET/CT showed lesions suspicious for metastasis. Of these, in 21 patients, the disease was intra-abdominal, while only in 5 patients disease was detected intra- and extra-abdominal sites. In none, extra-abdominal disease location alone was observed.

The most metastatic common intra-abdominal site was: liver (19 patients), followed by peritoneal implants (12 patients), infra-diaphragmatic lymphnodes (1 patient). The extra-abdominal locations were infrequent (2 micro lung nodules, 2 pleural implants, 2 supra-diaphragmatic lymphnodes, 1 soft tissue implant).

- PET/CT follow-up: in the various post-treatment controls, 10 of the 26 patients showed new lesions suspicious of metastasis. Of these, in four patients, the disease was intra-abdominal, in three intra- and extra-abdominal and in three patients extra-abdominal, exclusively.

In spite of pre-treatment studies, in follow-up PET/CT, extra-abdominal metastatic site was more frequent (2 lung lesions, 2 pleural implants, 2 bone lesions, 2 subcutaneous lesions, 1 supra-diaphragmatic lymph-node) that intra-abdominal, while the peritoneal is the single most frequent (5 patients), liver (2 patients), infradiaphragmatic lymphonode (1 patient).

In both, pre-treatment and follow-up studies, SUV showed the highest values in liver metastases and peritoneal implants, with a large variability in all metastatic sites.

Table I and II collected location data of primary GIST, metastatic lesions, pre-treatment and follow-up false positives, indicating the SUV of all deposits of 18FFDG assessed.

- Limitations: in six patients, the abnormal deposits of ¹⁸F-FDG being false positives: three in oropharyngeal cavity, one esophagitis, one soft tissue process and one inflammation in the lung. In four of these, the study also detected other lesions, finally diagnosed as metastases.

Infracentimetric lung lesions by CT in three patients were the only metastatic lesions showing no uptake of ¹⁸F-FDG.

 

Discussion

In patients with GIST, not suitable for surgical approach, treated with imatinib, literature describes intra-abdominal location as the most common, highlighting liver involvement (2,4). Our results in pre-treatment studies confirm that the most common site is the liver, on many occasions associated with peritoneal involvement. Also shows that are uncommon extra-abdominal metastatic sites.

Imatinib treatment response in patients with GIST is widely studied by PET (3,7) reason that was not included in our study. However, in our series, we diagnosed new hypermetabolic lesions in 10 patients (38.5%) related with the aggressiveness of the disease.

This observational study shows significant changes in the location of metastatic disease between pre-treatment and follow-up studies. In follow-up studies more extraabdominal disease appears. Thus, in seven patients new disease were located intra-abdominal (3 associated with additional involvement), 6 extra-abdominal metastases (and more importantly, in 3 of these, without intra-abdominal M1). This is the crucial teaching point of our series.

For correct re-staging in monitoring these patients, ¹⁸FFDG PET/CT has several technological advantages over other diagnostic tests. First, high affinity of ¹⁸F-FDG in GIST patients permit to detect small lesions. Secondly, as a whole body technique allows the diagnoses of disease in remote locations, rare described. Furthermore, the use of integrated PET/CT scanners results in a correct anatomical localization of the hypermetabolic foci, substantially reducing false positives. If required, the procedure of PET/CT can be completed with a CT with intravenous contrast or thoracic inspiration.

Thus, PET/CT, in these patients, allows for maximum diagnostic capabilities, especially considering the followup when metastatic lesions appear most often in unusual locations, especially at extra-abdominal site.

However, as reflected in our study, there have been false positives, so that all hypermetabolic foci, especially at infrequent location, must be corroborated by cytology or histology (FNA/BAG).

Treatment response to imatinib is the established indication of ¹⁸F-FDG PET/CT in GIST patients. Our study, observational and retrospective, suggests that the location of metastatic progression in patients during treatment with Imatinib is different for each developmental stage.

It is probably necessary to conduct a prospective longitudinal study, where in addition to assessing metabolic response to therapy, can replicate the process of metastatic spread as observed in our series.

 

References

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Correspondence:
Eulàlia Valls Ferrusola
Unidad PET/TC
CETIR Grupo Médico-ERESA
C/ Josep Anselm Clavé, 100
08950 Esplugues de Llobregat. Barcelona, Spain
e-mail: evalls@cetir.es

Received: 17-01-2012
Accepted: 10-04-2012