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Positron emission tomography with 18F-fluorodeoxyglucose in patients with uterine sarcoma
original articles
Positron emission tomography with 18F-fluorodeoxyglucose in patients with uterine sarcoma A.C. REBOLLO AGUIRRE, C. RAMOS FONT, M.E. BELLÓN GUARDIA, D. CABELLO GARCÍA, M. GALLEGO PEINADO, A. RODRÍGUEZ FERNÁNDEZ AND J.M. LLAMAS ELVIRA Department of Nuclear Medicine. Hospital Universitario Virgen de las Nieves. Granada.
Abstract. — Objective. To describe our experience with 18F-fluorodeoxyglucose positron emission tomography (FDGPET), in patients with uterine sarcomas, both under suspicion of recurrence and in tumour staging as an incidental pathology finding after hysterectomy. Material and methods. A retrospective review of FDG-PET performed in 10 patients with clinical diagnosis of uterine sarcoma (7 patients with suspicion of recurrence and three for initial staging) was carried out between April 2002 and January 2006. Mean age was 52.2 years. The time of evolution after initial diagnosis varied from one month to 15 years (median time: 14 months). Lesions were classified as 8 leiomyosarcomas and 2 carcinosarcomas. FIGO staging classified 5 patients as stage I, 1 patient as stage III, and 4 patients as stage IV. Results. In 4 of 7 patients with suspicion of recurrence, there were discrepancies between the information provided by positron emission tomography (PET) and conventional imaging techniques (CIT). FDG-PET was negative in three cases of inconclusive CAT. PET was negative in one case with pulmonary metastases. There was concordance between the FDG-PET and CIT findings in the 3 staging studies. Pathological confirmation was obtained in 5 cases, with a mean follow-up time of 14 months. Conclusions. FDG-PET may be useful in the follow up of uterine sarcoma patients and when the tumour is an incidental finding in hysterectomy for other causes.
cia como en estadificación tumoral tras hallazgo casual en la pieza de histerectomía. Material y métodos. Se revisaron retrospectivamente (abril 2002-enero 2006) los estudios de FDG-PET realizados a 10 pacientes diagnosticadas de sarcoma uterino, 7 por sospecha de recurrencia y 3 por estudio de extensión. La edad media fue de 52,2 años. El tiempo de evolución desde el diagnóstico inicial oscilaba entre 1 mes y 15 años (mediana: 14 meses). Histológicamente, las lesiones correspondieron a 8 leiomiosarcomas y 2 carcinosarcomas. La estadificación según la clasificación FIGO de las pacientes fue: 5 casos en estadio I, 1 en estadio III y 4 en estadio IV. Resultados. En 4 de las 7 pacientes con sospecha de recurrencia existió discrepancia entre la información proporcionada por la tomografía por emisión de positrones (PET) y las técnicas de imagen convencionales. En tres casos de tomografía axial computarizada no concluyente la FDG-PET fue negativa y las pacientes no presentaron evidencia de enfermedad. La PET resultó negativa en una paciente con metástasis pulmonares. En los 3 estudios de estadificación hubo concordancia entre los hallazgos de la FDG-PET y las técnicas de imagen convencionales. Existió confirmación histológica de las lesiones en 5 pacientes, con un seguimiento medio de 14 meses. Conclusión. La FDG-PET puede ser útil en el seguimiento de las pacientes con sarcoma uterino y cuando el tumor es un hallazgo casual en una histerectomía por otras causas.
KEY WORDS: FDG-PET, uterine sarcoma, uterine cancer, staging, recurrence, follow up.
PALABRAS CLAVE: FDG-PET, sarcoma uterino, cáncer de cuerpo de útero, estadificación, recurrencia, seguimiento.
TOMOGRAFÍA POR EMISIÓN DE POSITRONES CON F-FLUORDESOXIGLUCOSA EN PACIENTES CON SARCOMA UTERINO
18
Resumen.— Objetivo. Describir nuestra experiencia con la tomografía por emisión de positrones con FDG-PET en pacientes con sarcoma uterino, tanto con sospecha de recurren-
Received: 31-07-2006. Accepted: 06-02-2007. Correspondence: A. CUSTODIO REBOLLO AGUIRRE Servicio de Medicina Nuclear Hospital Universitario Virgen de las Nieves Avda. Fuerzas Armadas, 2. 18014 Granada E-mail: [email protected]
INTRODUCTION
Uterine sarcoma is an uncommon, very aggressive malignant tumour which constitutes less than 5% of all malignant neoplasia of the uterine corpus, and as a whole represents 1-2% of malignant gynaecological tumours. The most common histological types are leiomyosarcomas, mixed mesodermal tumours and endometrial stroma sarcomas. The mean age of patients at diagnosis is 60 years and the clinical presentation is usually quite non-specific. The
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diagnostic techniques do not usually provide definitive data, and in up to 50% of cases, the diagnosis is made on the anatomicopathological study of the surgical specimen. The treatment of choice is surgery, while the role of adjuvant radiotherapy and/or chemotherapy is more controversial.1, 2 In recent years there has been increasing interest in the role of positron emission tomography (PET) with 2-[18F]fluoro-2-deoxy-D-glucose (18FDG) (FDGPET) in the management of patients with gynaecological neoplasia, but its clinical application is still very limited.3-13 The use of FDG-PET in the clinical management of patients with uterine sarcomas has been examined in few studies. In the literature, Umesaki et al,14 in a series of cases, described the effectiveness of FDG-PET in the diagnosis of uterine sarcomas with magnetic resonance (MR) and Doppler ultrasound, and recently, Murakami et al,15 in a prospective study, evaluated the utility of FDG-PET for the detection of recurrence in the follow-up of patients with uterine sarcomas. The usefulness of PET in the clinical management of patients with uterine sarcomas has also been described in isolated clinical cases. Thus, Jadvar and Fischman16 presented the first case of abdominal recurrence of a uterine leiomyosarcoma detected on an FDG-PET. Umesaki et al17 related the preoperative diagnosis of a uterine leiomyosarcoma with the combined use of MR and FDG-PET. Finally, Chander and Ergun18 described a case of uterine sarcoma diagnosed with PET and computerised axial tomography (CAT) and its usefulness in differentiating between benign and malignant lesions. Below, we describe our experience with FDG-PET in patients with uterine sarcomas, both with suspicion of recurrence and in tumour staging after incidental finding in the hysterectomy specimen.
MATERIAL AND METHODS
A retrospective observational study was carried out, reviewing the FDG-PET studies practiced between April 2002 and January 2006 on 10 patients diagnosed with uterine sarcoma after surgery. In addition, 7 cases had received chemotherapy and 6 external radiotherapy. In 7 of the patients, the reason 190
for requesting the examination was suspicion of tumour recurrence and in 3 was tumour staging, since the tumour was an incidental finding in the anatomopathological study of the hysterectomy specimen. The patients had a mean age of 52.2 years (range: 33-70 years). In patients with suspicion of recurrence, the time of evolution from initial diagnosis varied between 1 month and 15 years (median: 14 months), and in the cases for staging between 1 and 3 months. Histologically, the primary lesions corresponded to 8 leiomyosarcomas and 2 mixed mesodermal tumours (carcinosarcomas). At the time of initial diagnosis of patients with suspicion of recurrence, 4 cases were at stage 1 and 3 at stage IV, according to the classification of the International Federation of Gynecology and Obstetrics (FIGO).19 The 3 patients in tumour staging were classified as stages I, III and IV, respectively. A dedicated tomograph, Siemens model ECATEXACT 47 (Siemens-CTI, Knoxville, Tennessee, U.S.), was used to carry out the PET studies. Preparation prior to the examination required a 6 hour fast and blood glucose less than 120 mg/dl. In addition, a muscle relaxant (diazepam 5-10 mg orally) was administered to all the patients 30 minutes before injection of the radiopharmaceutical agent, and bladder catheterization was performed. Image acquisition was between 45 and 60 minutes after the administration of tracer. The dose administered was 210-370 MBq of 18FDG, intravenously. The acquisition protocol consisted of a body study from the base of the cranium to the upper third of the lower limbs, with emission images (5 minutes) and transmission images (3 minutes) in 2D mode. The data obtained were acquired on a 128 x 128 matrix. Processing and reconstruction of the images was carried out using an iterative method, OSEM (ordered subset expectation maximization), 2 iterations and 8 subsets, on a SUN work station (SUN Microsystems, Mountain View, California, U.S.). Attenuation correction of the emission images was made with transmission data from an external 68Ge source. Qualitative analysis of the images obtained in the three space planes (coronal, sagittal and transversal) was performed. Those studies which showed 18FDG uptakes which were not explained by physiological processes were
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Rebollo Aguirre AC et al. Positron emission tomography with 18F-fluorodeoxyglucose in patients with uterine sarcom
Fig. 1.— Positron emission 18 Ftomography with fluorodeoxyglucose, axial and coronal sections, in which a supravesical focus of increased uptake, lateralised to the right, is observed; this was interpreted as a right iliac metastatic adenopathy which was confirmed by surgery. As an incidental finding, a photopenic defect is observed in the upper pole of the left kidney, compatible with a simple renal cyst, confirmed by ultrasound (patient no. 5).
interpreted as pathological. All studies were evaluated by two nuclear medicine specialists (ACRA, CRF). In this study, the semi-quantitative analysis of the pathological uptakes using the SUV (standardized uptake value) calculation was not taken into account when it came to assessing the lesions in the patients. Since the patients were referred from different health centres, the technical characteristics of the conventional imaging diagnostic equipment (CAT and MR) used were different in each case.
RESULTS
In 7 patients, the FDG-PET was performed because of suspicion of tumour recurrence. Of these, there were discrepancies between the PET findings and the conventional imaging techniques in 4 cases. In 3 patients with inconclusive CAT studies, the PET was negative, and the patients were found without evidence of disease 4, 6 and 10 months after the examination had been performed, respectively (no. 1, 3 and 7). In one case with pulmonary metastases on CAT and local pelvic relapse on MR, the PET was negative (no. 6). In 3 patients, both the FDGPET and the conventional imaging techniques detected tumour recurrences. In 2 cases, the PET and CAT showed the same lesions: pulmonary metastases (no. 10) and one 3 cm iliac adenopathy (no. 2), respectively. Finally, in one patient, the PET
showed pulmonary and bone metastases, and the CAT only the pulmonary lesions (no. 8). In 3 patients, the PET was performed for tumour staging. In two cases, the FDG-PET and conventional imaging techniques provided the same information. In one case, both abdominopelvic CAT and PET detected a 2 cm adenopathy in the right internal iliac chain (fig. 1), which was surgically removed and treated with radiotherapy; fourteen months later, the patient did not present clinical evidence of disease with negative pelvic MR and PET (no. 5). In the other patient, the abdominopelvic PET and CAT were negative, and there was no evidence of disease 11 months later (no. 4). In the remaining patient, the FDG-PET was superior to conventional imaging techniques. The CAT of the thorax, abdomen and pelvis showed only pulmonary metastases, while the PET showed pulmonary, bone and suprarenal metastases, with subsequent confirmation of the bone metastases on MR and disease progression (no. 9). All patients were followed-up clinically and with imaging techniques (5 CAT, 3 MR and 8 PET). The mean follow-up time of patients with suspicion of recurrence was 17 months (range: 4-40 months), and in the cases of initial staging was 12.3 months (range: 11-14 months). In 5 cases, histological confirmation of the lesions was obtained (4 surgeries, 1 cytology). Two patients died during the follow-up period. The results obtained are shown in table 1.
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Table 1 PATIENT CHARACTERISTICS AND RESULTS OF THE IMAGING TECHNIQUE Age
Reason TNM for request
Histology
Conventional imaging techniques
PET
Evolution
1
45
R
IA
Leiomyosarcoma G2
CAT thorax: inconclusive
Negative
No evidence of disease Follow-up 6 months
2
62
R
IA
Leiomyosarcoma G1
CAT abdomen-pelvis: iliac adenopathy
Iliac adenopathy
3
59
R
IB
Carcinosarcoma
CAT abdomen-pelvis: inconclusive
Negative
No evidence of disease Follow-up 22 months
4
33
S
IB
Leiomyosarcoma G3
CAT abdomen-pelvis: negative
Negative
No evidence of disease Follow-up 12 months
5
49
S
IB
Leiomyosarcoma G3
CAT abdomen-pelvis: iliac adenopathy
Iliac adenopathy
6
40
R
IV
Leiomyosarcoma G2
CAT thorax: pulmonary metastases MR pelvis: local relapse
Surgery and chemotherapy No evidence of disease Follow-up 40 months
Surgery and radiotherapy No evidence of disease Follow-up 14 months
Negative
Chemotherapy Disease progression Follow-up 10 months. Exitus No evidence of disease Follow-up 4 months
7
47
R
IV
Leiomyosarcoma G3
CAT abdomen-pelvis: inconclusive
Negative
8
51
R
IV
Leiomyosarcoma
CAT thorax: pulmonary metastases
Pulmonary and bone metastases
9
66
S
IV
Leiomyosarcoma
CAT thorax: Pulmonary, bone and pulmonary metastases suprarenal metastases CAT abdomen-pelvis: negative
Chemotherapy Disease progression Follow-up 11 months
10
70
R
IV
Carcinosarcoma G1
CAT thorax: Pulmonary metastases pulmonary metastases CAT abdomen-pelvis: negative
Chemotherapy Disease progression Follow-up 14 months
Chemotherapy and radiotherapy Disease progression Follow-up 23 months. Exitus
CAT: computerised axial tomography; MR: magnetic resonance; PET: positron emission tomography; R: suspicion of recurrence; S: initial staging; TNM: tumour staging.
DISCUSSION
In our series, 7 patients were referred due to suspicion of tumour recurrence. The FDG-PET data modified the information provided by conventional imaging techniques in only 3 cases. In the 3 patients with inconclusive CAT, the PET was negative and the patients do not currently show evidence of disease. This fact may suggest the negative predictive value of FDG-PET for ruling out the presence of disease in patients with uterine sarcoma. On the other hand, both FDG-PET and conventional imaging techniques detected the lesions in 3 cases. Finally, in a patient with pulmonary metastases on CAT and disease progression, the PET was negative. Recently, Murakami et al15 assessed the clinical usefulness of FDG-PET for the early detection of recurrence in the post-treatment follow-up of 8 192
patients with uterine sarcomas at FIGO stage I (4 leiomyosarcomas, 3 carcinosarcomas and 1 endometrial stroma sarcoma), and compared the results with CAT and ultrasound. In 5 of the 8 patients (3 carcinosarcomas and 2 leiomyosarcomas) recurrence was confirmed. The sensitivity of PET for the detection of recurrence was 100%, in comparison with 60% for CAT and ultrasound. The two false negatives on the CAT and ultrasound occurred in intraperitoneal lesions of less than 2 cm. However, the PET findings did not modify the prognosis in 3 of the 5 patients with recurrence, and the other two cases had a survival greater than one year after being treated with surgery and chemotherapy. For these authors, the main application of FDG-PET in the follow-up of uterine sarcomas would be the confirmation of recurrence, providing information on the localised or disseminated character of the disease
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and allowing the establishment of early treatment, with a significant repercussion in patient survival. The usefulness of FDG-PET in the follow-up of patients with uterine corpus cancer has been made clear in several studies. Belhocine et al20 assessed the contribution of FDG-PET in the follow-up of 34 women with endometrial carcinoma. FDG-PET detected recurrence in 26 cases and modified the therapeutic management in 35% of patients. 85% of recurrences were detected in patients with advanced stages of the disease and high risk of recurrence. Saga et al21 evaluated 30 FDG-PET studies of 21 patients after surgery for endometrial cancer and compared the results with conventional imaging techniques and serum tumour marker levels. FDG-PET showed greater diagnostic power (100% sensitivity, 88% specificity, 93% precision) than CAT and/or MR (84% sensitivity, 86% specificity, 85% precision) and tumour markers (100% sensitivity, 70% specificity, 83% precision), detecting unknown lesions in 19% of cases, with modification of the therapeutic strategy in a third of the patients. Finally, Chao et al22 analysed the usefulness of adding FDG-PET to the clinical management of 41 patients with advanced endometrial cancer, with suspicion of recurrence or post-rescue therapy follow-up. The results in this group showed that 48% of the PET studies had a positive clinical impact in the therapeutic management of the patients: 22% for initial staging, 73% in follow-up for recurrence and 57% for rescue therapy. In the 3 patients who were referred for tumour staging, in those in whom the uterine sarcoma was an incidental finding in the hysterectomy specimen, both FDG-PET and conventional imaging techniques gave similar results for the selection of the treatment strategy. Thus, the patient with a single iliac adenopathy was referred for surgery and subsequent radiotherapy, the case with disseminated disease was treated with chemotherapy and in the patient with negative studies, the disease was considered to be limited to the uterine corpus. There are few studies on the usefulness of PET in the diagnosis and staging of patients with uterine corpus cancer. Umesaki et al,14 in a group of five patients, described the effectiveness of FDG-PET in the diagnosis of uterine sarcomas, in comparison with MR and Doppler ultrasound. The series included four primary tumours (2 leiomyosarcomas, 1 carcinosarcoma and 1 endometrial stroma
sarcoma) and one recurrence of a leiomyosarcoma. PET was positive in the five cases (100%), whilst the MR and ultrasound were only positive in four (80%) and two (40%), respectively. The mean SUV of the sarcomas was 4.5 ±1.3 (mean ± SD), with a range between 3.0 and 6.3, concluding that FDG-PET may be more useful than conventional imaging techniques in the preoperative diagnosis of uterine sarcomas. Recently, Torizuka et al,23 in a retrospective study, studied the value of FDG-PET in the prediction of the degree of invasion of the myometrium in 22 patients with uterine corpus cancer at stage I (5 IA, 11 IIB and 6 IC) in comparison with MR. Histologically, the lesions corresponded to 17 endometrial adenocarcinomas, 4 carcinosarcomas and 1 clear cell carcinoma. All the primary tumours were visualised on the PET and a statistically significant difference was observed between the maximum SUV (p < 0.05) of patients with deep invasion of the myometrium (stage IC, SUV 15.69 ± 4.73, range 8.83-21.84) and that of patients with superficial invasion (stages IA and IB, SUV 9.09 ± 3.29, range 2.68-15.41). There was also a statistically significant correlation between the SUV and tumour size (p < 0.05). Using an SUV cut-off value of 12.0 for differentiation between these two groups, the PET results were correct in 19 patients and incorrect in 3 cases. The MR results were correct in 17 of the 22 patients. MR overestimated the degree of invasion in 4 cases with stage IB and was inconclusive in one patient with stage IC; 4 of these 5 patients were post-menopausal. Finally, Horowitz et al24 assessed the usefulness of FDG-PET pre-operatively for the detection of pelvic and para-aortic metastatic adenopathies in 19 women diagnosed with uterine corpus cancer. For the detection of the adenopathies, the sensitivity of FDGPET was 67% and the specificity 94%; furthermore, 84% of the primary tumours showed uptake of 18 FDG. With these results, they considered that FDGPET could not substitute lymphadenectomy, although it may be useful in very obese patients with contraindications for surgery or referred for evaluation after a primary hysterectomy for other causes. The main limitation of this study is the limited number of patients included in the series, since uterine sarcomas are an uncommon pathology and do not form part of the authorised clinical indications included in the recommended protocol for use of
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PET.25 Histological confirmation of the lesions was only obtained in 5 patients, while clinical follow-up was carried out in the remainder (mean time of 17 months in patients with suspicion of recurrence and 12.3 months in cases of tumour staging). Furthermore, there was great variability in the followup protocols of the patients since they were from different health centres. These facts limit the performance of a more exhaustive statistical analysis of the results, with the determination of the diagnostic validity parameters. In patients with uterine sarcomas, one of the main problems in the interpretation of FDG-PET images is precisely determining the localisation of the lesions and differentiating between the pathological uptake foci and physiological uptakes of the abdomen and pelvis.5, 26, 27 Moreover, there may be changes in the physiological uptake of 18FDG in the endometrium and ovaries, related with the phase of the patient’s menstrual cycle.28 During menstruation, accumulation can be observed in the uterus, due to intrauterine bleeding.29-31 Therefore, it is essential to know the gynaecological and surgical history of the patient for correct interpretation of the PET images. Uptakes of 18FDG have been described in several benign gynaecological pathologies (leiomyomas, endometriosis, serous and mucinous cystadenoma, corpus luteum cyst).26, 27, 32 Thus, Ak et al33 relate the uptake of FDG in four patients with uterine leiomyomas, referred for study for suspicion of malignant gynaecological neoplasia. Although the cause of uptake of 18FDG in uterine leiomyomas is unknown, it could be explained by the existence of high levels of receptors and growth factors, proliferation of smooth muscle cells and high levels of glycogen in the endometrium of the myomatous uterus. However, intense uptake of FDG in a uterine leiomyoma may be related with the existence of malignancy.34 Although there is evidence which suggests the usefulness of FDG-PET in the management of gynaecological cancers, the limited anatomical resolution of the technique and the physiological distribution of the radiopharmaceutical agent cause a decrease in the sensitivity and specificity figures in the evaluation of the disease in comparison with the results obtained in other oncological pathologies.4, 26, 27 The use of image fusion programs or of hybrid PET-CAT/MR equipment will allow more precise characterisation and localisation of 18FDG uptakes, by combining an 194
anatomical and functional imaging technique. All this will probably have a bearing in improvement of the initial staging, therapeutic planning and subsequent follow-up of the disease.11, 35-37
CONCLUSION
FDG-PET may be useful in the follow-up of patients with uterine sarcoma, to reject or confirm the existence of recurrence and to establish the localised or disseminated character of the disease. It may also be useful in the evaluation of patients who undergo hysterectomy for other causes in which the sarcoma is an incidental finding in the histopathological study of the surgical specimen. Given the limited number of articles in the literature at present, new studies to determine the role of FDG-PET in patients with uterine sarcoma are necessary.
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Positron emission tomography with 18F-fluorodeoxyglucose in patients with uterine sarcoma A.C. REBOLLO AGUIRRE, C. RAMOS FONT, M.E. BELLÓN GUARDIA, D. CABELLO GARCÍA, M. GALLEGO PEINADO, A. RODRÍGUEZ FERNÁNDEZ AND J.M. LLAMAS ELVIRA Department of Nuclear Medicine. Hospital Universitario Virgen de las Nieves. Granada.
Abstract. — Objective. To describe our experience with 18F-fluorodeoxyglucose positron emission tomography (FDGPET), in patients with uterine sarcomas, both under suspicion of recurrence and in tumour staging as an incidental pathology finding after hysterectomy. Material and methods. A retrospective review of FDG-PET performed in 10 patients with clinical diagnosis of uterine sarcoma (7 patients with suspicion of recurrence and three for initial staging) was carried out between April 2002 and January 2006. Mean age was 52.2 years. The time of evolution after initial diagnosis varied from one month to 15 years (median time: 14 months). Lesions were classified as 8 leiomyosarcomas and 2 carcinosarcomas. FIGO staging classified 5 patients as stage I, 1 patient as stage III, and 4 patients as stage IV. Results. In 4 of 7 patients with suspicion of recurrence, there were discrepancies between the information provided by positron emission tomography (PET) and conventional imaging techniques (CIT). FDG-PET was negative in three cases of inconclusive CAT. PET was negative in one case with pulmonary metastases. There was concordance between the FDG-PET and CIT findings in the 3 staging studies. Pathological confirmation was obtained in 5 cases, with a mean follow-up time of 14 months. Conclusions. FDG-PET may be useful in the follow up of uterine sarcoma patients and when the tumour is an incidental finding in hysterectomy for other causes.
cia como en estadificación tumoral tras hallazgo casual en la pieza de histerectomía. Material y métodos. Se revisaron retrospectivamente (abril 2002-enero 2006) los estudios de FDG-PET realizados a 10 pacientes diagnosticadas de sarcoma uterino, 7 por sospecha de recurrencia y 3 por estudio de extensión. La edad media fue de 52,2 años. El tiempo de evolución desde el diagnóstico inicial oscilaba entre 1 mes y 15 años (mediana: 14 meses). Histológicamente, las lesiones correspondieron a 8 leiomiosarcomas y 2 carcinosarcomas. La estadificación según la clasificación FIGO de las pacientes fue: 5 casos en estadio I, 1 en estadio III y 4 en estadio IV. Resultados. En 4 de las 7 pacientes con sospecha de recurrencia existió discrepancia entre la información proporcionada por la tomografía por emisión de positrones (PET) y las técnicas de imagen convencionales. En tres casos de tomografía axial computarizada no concluyente la FDG-PET fue negativa y las pacientes no presentaron evidencia de enfermedad. La PET resultó negativa en una paciente con metástasis pulmonares. En los 3 estudios de estadificación hubo concordancia entre los hallazgos de la FDG-PET y las técnicas de imagen convencionales. Existió confirmación histológica de las lesiones en 5 pacientes, con un seguimiento medio de 14 meses. Conclusión. La FDG-PET puede ser útil en el seguimiento de las pacientes con sarcoma uterino y cuando el tumor es un hallazgo casual en una histerectomía por otras causas.
KEY WORDS: FDG-PET, uterine sarcoma, uterine cancer, staging, recurrence, follow up.
PALABRAS CLAVE: FDG-PET, sarcoma uterino, cáncer de cuerpo de útero, estadificación, recurrencia, seguimiento.
TOMOGRAFÍA POR EMISIÓN DE POSITRONES CON F-FLUORDESOXIGLUCOSA EN PACIENTES CON SARCOMA UTERINO
18
Resumen.— Objetivo. Describir nuestra experiencia con la tomografía por emisión de positrones con FDG-PET en pacientes con sarcoma uterino, tanto con sospecha de recurren-
Received: 31-07-2006. Accepted: 06-02-2007. Correspondence: A. CUSTODIO REBOLLO AGUIRRE Servicio de Medicina Nuclear Hospital Universitario Virgen de las Nieves Avda. Fuerzas Armadas, 2. 18014 Granada E-mail: [email protected]
INTRODUCTION
Uterine sarcoma is an uncommon, very aggressive malignant tumour which constitutes less than 5% of all malignant neoplasia of the uterine corpus, and as a whole represents 1-2% of malignant gynaecological tumours. The most common histological types are leiomyosarcomas, mixed mesodermal tumours and endometrial stroma sarcomas. The mean age of patients at diagnosis is 60 years and the clinical presentation is usually quite non-specific. The
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diagnostic techniques do not usually provide definitive data, and in up to 50% of cases, the diagnosis is made on the anatomicopathological study of the surgical specimen. The treatment of choice is surgery, while the role of adjuvant radiotherapy and/or chemotherapy is more controversial.1, 2 In recent years there has been increasing interest in the role of positron emission tomography (PET) with 2-[18F]fluoro-2-deoxy-D-glucose (18FDG) (FDGPET) in the management of patients with gynaecological neoplasia, but its clinical application is still very limited.3-13 The use of FDG-PET in the clinical management of patients with uterine sarcomas has been examined in few studies. In the literature, Umesaki et al,14 in a series of cases, described the effectiveness of FDG-PET in the diagnosis of uterine sarcomas with magnetic resonance (MR) and Doppler ultrasound, and recently, Murakami et al,15 in a prospective study, evaluated the utility of FDG-PET for the detection of recurrence in the follow-up of patients with uterine sarcomas. The usefulness of PET in the clinical management of patients with uterine sarcomas has also been described in isolated clinical cases. Thus, Jadvar and Fischman16 presented the first case of abdominal recurrence of a uterine leiomyosarcoma detected on an FDG-PET. Umesaki et al17 related the preoperative diagnosis of a uterine leiomyosarcoma with the combined use of MR and FDG-PET. Finally, Chander and Ergun18 described a case of uterine sarcoma diagnosed with PET and computerised axial tomography (CAT) and its usefulness in differentiating between benign and malignant lesions. Below, we describe our experience with FDG-PET in patients with uterine sarcomas, both with suspicion of recurrence and in tumour staging after incidental finding in the hysterectomy specimen.
MATERIAL AND METHODS
A retrospective observational study was carried out, reviewing the FDG-PET studies practiced between April 2002 and January 2006 on 10 patients diagnosed with uterine sarcoma after surgery. In addition, 7 cases had received chemotherapy and 6 external radiotherapy. In 7 of the patients, the reason 190
for requesting the examination was suspicion of tumour recurrence and in 3 was tumour staging, since the tumour was an incidental finding in the anatomopathological study of the hysterectomy specimen. The patients had a mean age of 52.2 years (range: 33-70 years). In patients with suspicion of recurrence, the time of evolution from initial diagnosis varied between 1 month and 15 years (median: 14 months), and in the cases for staging between 1 and 3 months. Histologically, the primary lesions corresponded to 8 leiomyosarcomas and 2 mixed mesodermal tumours (carcinosarcomas). At the time of initial diagnosis of patients with suspicion of recurrence, 4 cases were at stage 1 and 3 at stage IV, according to the classification of the International Federation of Gynecology and Obstetrics (FIGO).19 The 3 patients in tumour staging were classified as stages I, III and IV, respectively. A dedicated tomograph, Siemens model ECATEXACT 47 (Siemens-CTI, Knoxville, Tennessee, U.S.), was used to carry out the PET studies. Preparation prior to the examination required a 6 hour fast and blood glucose less than 120 mg/dl. In addition, a muscle relaxant (diazepam 5-10 mg orally) was administered to all the patients 30 minutes before injection of the radiopharmaceutical agent, and bladder catheterization was performed. Image acquisition was between 45 and 60 minutes after the administration of tracer. The dose administered was 210-370 MBq of 18FDG, intravenously. The acquisition protocol consisted of a body study from the base of the cranium to the upper third of the lower limbs, with emission images (5 minutes) and transmission images (3 minutes) in 2D mode. The data obtained were acquired on a 128 x 128 matrix. Processing and reconstruction of the images was carried out using an iterative method, OSEM (ordered subset expectation maximization), 2 iterations and 8 subsets, on a SUN work station (SUN Microsystems, Mountain View, California, U.S.). Attenuation correction of the emission images was made with transmission data from an external 68Ge source. Qualitative analysis of the images obtained in the three space planes (coronal, sagittal and transversal) was performed. Those studies which showed 18FDG uptakes which were not explained by physiological processes were
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Fig. 1.— Positron emission 18 Ftomography with fluorodeoxyglucose, axial and coronal sections, in which a supravesical focus of increased uptake, lateralised to the right, is observed; this was interpreted as a right iliac metastatic adenopathy which was confirmed by surgery. As an incidental finding, a photopenic defect is observed in the upper pole of the left kidney, compatible with a simple renal cyst, confirmed by ultrasound (patient no. 5).
interpreted as pathological. All studies were evaluated by two nuclear medicine specialists (ACRA, CRF). In this study, the semi-quantitative analysis of the pathological uptakes using the SUV (standardized uptake value) calculation was not taken into account when it came to assessing the lesions in the patients. Since the patients were referred from different health centres, the technical characteristics of the conventional imaging diagnostic equipment (CAT and MR) used were different in each case.
RESULTS
In 7 patients, the FDG-PET was performed because of suspicion of tumour recurrence. Of these, there were discrepancies between the PET findings and the conventional imaging techniques in 4 cases. In 3 patients with inconclusive CAT studies, the PET was negative, and the patients were found without evidence of disease 4, 6 and 10 months after the examination had been performed, respectively (no. 1, 3 and 7). In one case with pulmonary metastases on CAT and local pelvic relapse on MR, the PET was negative (no. 6). In 3 patients, both the FDGPET and the conventional imaging techniques detected tumour recurrences. In 2 cases, the PET and CAT showed the same lesions: pulmonary metastases (no. 10) and one 3 cm iliac adenopathy (no. 2), respectively. Finally, in one patient, the PET
showed pulmonary and bone metastases, and the CAT only the pulmonary lesions (no. 8). In 3 patients, the PET was performed for tumour staging. In two cases, the FDG-PET and conventional imaging techniques provided the same information. In one case, both abdominopelvic CAT and PET detected a 2 cm adenopathy in the right internal iliac chain (fig. 1), which was surgically removed and treated with radiotherapy; fourteen months later, the patient did not present clinical evidence of disease with negative pelvic MR and PET (no. 5). In the other patient, the abdominopelvic PET and CAT were negative, and there was no evidence of disease 11 months later (no. 4). In the remaining patient, the FDG-PET was superior to conventional imaging techniques. The CAT of the thorax, abdomen and pelvis showed only pulmonary metastases, while the PET showed pulmonary, bone and suprarenal metastases, with subsequent confirmation of the bone metastases on MR and disease progression (no. 9). All patients were followed-up clinically and with imaging techniques (5 CAT, 3 MR and 8 PET). The mean follow-up time of patients with suspicion of recurrence was 17 months (range: 4-40 months), and in the cases of initial staging was 12.3 months (range: 11-14 months). In 5 cases, histological confirmation of the lesions was obtained (4 surgeries, 1 cytology). Two patients died during the follow-up period. The results obtained are shown in table 1.
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Table 1 PATIENT CHARACTERISTICS AND RESULTS OF THE IMAGING TECHNIQUE Age
Reason TNM for request
Histology
Conventional imaging techniques
PET
Evolution
1
45
R
IA
Leiomyosarcoma G2
CAT thorax: inconclusive
Negative
No evidence of disease Follow-up 6 months
2
62
R
IA
Leiomyosarcoma G1
CAT abdomen-pelvis: iliac adenopathy
Iliac adenopathy
3
59
R
IB
Carcinosarcoma
CAT abdomen-pelvis: inconclusive
Negative
No evidence of disease Follow-up 22 months
4
33
S
IB
Leiomyosarcoma G3
CAT abdomen-pelvis: negative
Negative
No evidence of disease Follow-up 12 months
5
49
S
IB
Leiomyosarcoma G3
CAT abdomen-pelvis: iliac adenopathy
Iliac adenopathy
6
40
R
IV
Leiomyosarcoma G2
CAT thorax: pulmonary metastases MR pelvis: local relapse
Surgery and chemotherapy No evidence of disease Follow-up 40 months
Surgery and radiotherapy No evidence of disease Follow-up 14 months
Negative
Chemotherapy Disease progression Follow-up 10 months. Exitus No evidence of disease Follow-up 4 months
7
47
R
IV
Leiomyosarcoma G3
CAT abdomen-pelvis: inconclusive
Negative
8
51
R
IV
Leiomyosarcoma
CAT thorax: pulmonary metastases
Pulmonary and bone metastases
9
66
S
IV
Leiomyosarcoma
CAT thorax: Pulmonary, bone and pulmonary metastases suprarenal metastases CAT abdomen-pelvis: negative
Chemotherapy Disease progression Follow-up 11 months
10
70
R
IV
Carcinosarcoma G1
CAT thorax: Pulmonary metastases pulmonary metastases CAT abdomen-pelvis: negative
Chemotherapy Disease progression Follow-up 14 months
Chemotherapy and radiotherapy Disease progression Follow-up 23 months. Exitus
CAT: computerised axial tomography; MR: magnetic resonance; PET: positron emission tomography; R: suspicion of recurrence; S: initial staging; TNM: tumour staging.
DISCUSSION
In our series, 7 patients were referred due to suspicion of tumour recurrence. The FDG-PET data modified the information provided by conventional imaging techniques in only 3 cases. In the 3 patients with inconclusive CAT, the PET was negative and the patients do not currently show evidence of disease. This fact may suggest the negative predictive value of FDG-PET for ruling out the presence of disease in patients with uterine sarcoma. On the other hand, both FDG-PET and conventional imaging techniques detected the lesions in 3 cases. Finally, in a patient with pulmonary metastases on CAT and disease progression, the PET was negative. Recently, Murakami et al15 assessed the clinical usefulness of FDG-PET for the early detection of recurrence in the post-treatment follow-up of 8 192
patients with uterine sarcomas at FIGO stage I (4 leiomyosarcomas, 3 carcinosarcomas and 1 endometrial stroma sarcoma), and compared the results with CAT and ultrasound. In 5 of the 8 patients (3 carcinosarcomas and 2 leiomyosarcomas) recurrence was confirmed. The sensitivity of PET for the detection of recurrence was 100%, in comparison with 60% for CAT and ultrasound. The two false negatives on the CAT and ultrasound occurred in intraperitoneal lesions of less than 2 cm. However, the PET findings did not modify the prognosis in 3 of the 5 patients with recurrence, and the other two cases had a survival greater than one year after being treated with surgery and chemotherapy. For these authors, the main application of FDG-PET in the follow-up of uterine sarcomas would be the confirmation of recurrence, providing information on the localised or disseminated character of the disease
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and allowing the establishment of early treatment, with a significant repercussion in patient survival. The usefulness of FDG-PET in the follow-up of patients with uterine corpus cancer has been made clear in several studies. Belhocine et al20 assessed the contribution of FDG-PET in the follow-up of 34 women with endometrial carcinoma. FDG-PET detected recurrence in 26 cases and modified the therapeutic management in 35% of patients. 85% of recurrences were detected in patients with advanced stages of the disease and high risk of recurrence. Saga et al21 evaluated 30 FDG-PET studies of 21 patients after surgery for endometrial cancer and compared the results with conventional imaging techniques and serum tumour marker levels. FDG-PET showed greater diagnostic power (100% sensitivity, 88% specificity, 93% precision) than CAT and/or MR (84% sensitivity, 86% specificity, 85% precision) and tumour markers (100% sensitivity, 70% specificity, 83% precision), detecting unknown lesions in 19% of cases, with modification of the therapeutic strategy in a third of the patients. Finally, Chao et al22 analysed the usefulness of adding FDG-PET to the clinical management of 41 patients with advanced endometrial cancer, with suspicion of recurrence or post-rescue therapy follow-up. The results in this group showed that 48% of the PET studies had a positive clinical impact in the therapeutic management of the patients: 22% for initial staging, 73% in follow-up for recurrence and 57% for rescue therapy. In the 3 patients who were referred for tumour staging, in those in whom the uterine sarcoma was an incidental finding in the hysterectomy specimen, both FDG-PET and conventional imaging techniques gave similar results for the selection of the treatment strategy. Thus, the patient with a single iliac adenopathy was referred for surgery and subsequent radiotherapy, the case with disseminated disease was treated with chemotherapy and in the patient with negative studies, the disease was considered to be limited to the uterine corpus. There are few studies on the usefulness of PET in the diagnosis and staging of patients with uterine corpus cancer. Umesaki et al,14 in a group of five patients, described the effectiveness of FDG-PET in the diagnosis of uterine sarcomas, in comparison with MR and Doppler ultrasound. The series included four primary tumours (2 leiomyosarcomas, 1 carcinosarcoma and 1 endometrial stroma
sarcoma) and one recurrence of a leiomyosarcoma. PET was positive in the five cases (100%), whilst the MR and ultrasound were only positive in four (80%) and two (40%), respectively. The mean SUV of the sarcomas was 4.5 ±1.3 (mean ± SD), with a range between 3.0 and 6.3, concluding that FDG-PET may be more useful than conventional imaging techniques in the preoperative diagnosis of uterine sarcomas. Recently, Torizuka et al,23 in a retrospective study, studied the value of FDG-PET in the prediction of the degree of invasion of the myometrium in 22 patients with uterine corpus cancer at stage I (5 IA, 11 IIB and 6 IC) in comparison with MR. Histologically, the lesions corresponded to 17 endometrial adenocarcinomas, 4 carcinosarcomas and 1 clear cell carcinoma. All the primary tumours were visualised on the PET and a statistically significant difference was observed between the maximum SUV (p < 0.05) of patients with deep invasion of the myometrium (stage IC, SUV 15.69 ± 4.73, range 8.83-21.84) and that of patients with superficial invasion (stages IA and IB, SUV 9.09 ± 3.29, range 2.68-15.41). There was also a statistically significant correlation between the SUV and tumour size (p < 0.05). Using an SUV cut-off value of 12.0 for differentiation between these two groups, the PET results were correct in 19 patients and incorrect in 3 cases. The MR results were correct in 17 of the 22 patients. MR overestimated the degree of invasion in 4 cases with stage IB and was inconclusive in one patient with stage IC; 4 of these 5 patients were post-menopausal. Finally, Horowitz et al24 assessed the usefulness of FDG-PET pre-operatively for the detection of pelvic and para-aortic metastatic adenopathies in 19 women diagnosed with uterine corpus cancer. For the detection of the adenopathies, the sensitivity of FDGPET was 67% and the specificity 94%; furthermore, 84% of the primary tumours showed uptake of 18 FDG. With these results, they considered that FDGPET could not substitute lymphadenectomy, although it may be useful in very obese patients with contraindications for surgery or referred for evaluation after a primary hysterectomy for other causes. The main limitation of this study is the limited number of patients included in the series, since uterine sarcomas are an uncommon pathology and do not form part of the authorised clinical indications included in the recommended protocol for use of
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PET.25 Histological confirmation of the lesions was only obtained in 5 patients, while clinical follow-up was carried out in the remainder (mean time of 17 months in patients with suspicion of recurrence and 12.3 months in cases of tumour staging). Furthermore, there was great variability in the followup protocols of the patients since they were from different health centres. These facts limit the performance of a more exhaustive statistical analysis of the results, with the determination of the diagnostic validity parameters. In patients with uterine sarcomas, one of the main problems in the interpretation of FDG-PET images is precisely determining the localisation of the lesions and differentiating between the pathological uptake foci and physiological uptakes of the abdomen and pelvis.5, 26, 27 Moreover, there may be changes in the physiological uptake of 18FDG in the endometrium and ovaries, related with the phase of the patient’s menstrual cycle.28 During menstruation, accumulation can be observed in the uterus, due to intrauterine bleeding.29-31 Therefore, it is essential to know the gynaecological and surgical history of the patient for correct interpretation of the PET images. Uptakes of 18FDG have been described in several benign gynaecological pathologies (leiomyomas, endometriosis, serous and mucinous cystadenoma, corpus luteum cyst).26, 27, 32 Thus, Ak et al33 relate the uptake of FDG in four patients with uterine leiomyomas, referred for study for suspicion of malignant gynaecological neoplasia. Although the cause of uptake of 18FDG in uterine leiomyomas is unknown, it could be explained by the existence of high levels of receptors and growth factors, proliferation of smooth muscle cells and high levels of glycogen in the endometrium of the myomatous uterus. However, intense uptake of FDG in a uterine leiomyoma may be related with the existence of malignancy.34 Although there is evidence which suggests the usefulness of FDG-PET in the management of gynaecological cancers, the limited anatomical resolution of the technique and the physiological distribution of the radiopharmaceutical agent cause a decrease in the sensitivity and specificity figures in the evaluation of the disease in comparison with the results obtained in other oncological pathologies.4, 26, 27 The use of image fusion programs or of hybrid PET-CAT/MR equipment will allow more precise characterisation and localisation of 18FDG uptakes, by combining an 194
anatomical and functional imaging technique. All this will probably have a bearing in improvement of the initial staging, therapeutic planning and subsequent follow-up of the disease.11, 35-37
CONCLUSION
FDG-PET may be useful in the follow-up of patients with uterine sarcoma, to reject or confirm the existence of recurrence and to establish the localised or disseminated character of the disease. It may also be useful in the evaluation of patients who undergo hysterectomy for other causes in which the sarcoma is an incidental finding in the histopathological study of the surgical specimen. Given the limited number of articles in the literature at present, new studies to determine the role of FDG-PET in patients with uterine sarcoma are necessary.
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