- Email: [email protected]
CT in patients with gynecological malignancies
Gynecologic Oncology 94 (2004) 680 – 684 www.elsevier.com/locate/ygyno
The diagnostic accuracy of 18F-Fluorodeoxyglucose PET/CT in patients with gynecological malignancies Dan Grisaru a,*,1, Benny Almog a,1, Charles Levine b, Ur Metser c, Ami Fishman d, Hedva Lerman c, Joseph B. Lessing a, Einat Even-Sapir c a
Department of Obstetrics and Gynecology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel b Department Radiology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel c Department Nuclear Medicine, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel d Department of Obstetrics and Gynecology, Meir Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel Received 29 November 2003 Available online 8 July 2004
Abstract Objective. To evaluate the diagnostic accuracy of integrated positron emission tomography/computerized tomography (PET/CT) in patients with gynecological cancer. Methods. Fifty-three consecutive patients with gynecologic malignancies were included. The patients were referred to our tertiary center to undergo a PET/CT scan. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of PET/CT were compared with the conventional imaging assessments [CT, magnetic resonance imaging (MRI) and ultrasonography (US)]. Results. All tested values were higher for PET/CT than those for the conventional modalities: sensitivity 0.97 vs. 0.40, specificity 0.94 vs. 0.65, PPV 0.97 vs. 0.70, and NPV 0.94 vs. 0.34, respectively. Conclusion. PET/CT is a reliable modality for assessing the extent of disease in patients with gynecologic malignancy. D 2004 Elsevier Inc. All rights reserved. Keywords: Positron emission tomography/computerized tomography; Staging; Follow-up
Introduction Positron emission tomography (PET) imaging with 18FFluorodeoxyglucose (FDG) is gaining popularity in the routine diagnosis of cancer patients. Scintigraphy is successful in providing the functional data of suspected active tumor sites, but it may be limited in its inability to define the precise anatomic localization of suspected lesions, thus often necessitating correlation with other anatomic modalities, including computerized tomography (CT) and magnetic resonance imaging (MRI). Precise alignment of the data obtained by two different modalities can be difficult to achieve and errors are not uncommon. Novel systems designed as hybrids of a PET or single photon emission
computer tomography (SPECT) device integrated with CT are now available. Emission (PET or gamma camera coincidence imaging) and transmission (low- or high-resolution CT) studies are performed in the same setting using the same device and without changing the patient’s position, thereby allowing for highly accurate fusion of the images acquired by both modalities. The objective of the present study was to assess the diagnostic accuracy of PET/CT compared to the conventional methodologies of CT, MRI and ultrasonography (US) in patients with gynecological cancer.
Patients and methods Patients
* Corresponding author. Department of Obstetrics and Gynecology, Lis Maternity Hospital, Tel-Aviv Sourasky Medical Center, 6 Weizmann Street, Tel-Aviv 64239, Israel. Fax: +972-3-9625670. E-mail address: [email protected] (D. Grisaru). 1 These authors equally contributed to the study. 0090-8258/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2004.05.053
Fifty-three consecutive patients with proven gynecologic malignancy were included in the present study. Each patient had undergone a comprehensive evaluation of her clinical status and was scheduled for routine staging or
D. Grisaru et al. / Gynecologic Oncology 94 (2004) 680–684 Table 1 PET/CT in the patient’s work-up at the staging phase (n = 18) #
Organ
5
ovary
8 13 14 16 21 24
cervix uterus uterus ovary uterus uterus
27 30 32 34 36 38 39
cervix uterus uterus cervix cervix cervix cervix
42 49 50 55
cervix cervix cervix vagina
Metastatic disease
Remarks
Standard imaging
PET/CT
Histological evidence of disease
+/
+
+
PET/CT accurately localized a mass for core biopsy that was not evident on standard CT
+
+
+
+
false negative CT false positive CT false negative CT
+
+
+
PET/CT accurately localized the tumor to the uterus in accordance with histology; CT falsely localized it to the cervix
reconstructed using an OSEM algorithm. CT data were used for attenuation correction. The studies were read on an eNTEGRA workstation (eNTEGRA, ELGEMS, Haifa, Israel) equipped with fusion software, which allows the display of PET images (with and without attenuation correction), of CT images and of the fused data of both modalities.
Table 2 PET/CT for suspected recurrence (n = 35) #
Organ
1
ovary
+
ovary ovary cervix
+/
+
+
+
+
+ +
+ +
6 7
ovary cervix
+
+
+
9 10 11
ovary ovary vulva
12 15 17
ovary cervix cervix
18 19 22 23 26 28 29 31 35
tube ovary cervix ovary ovary cervix cervix cervix cervix
37 40 41 43 44 45 46 47
ovary ovary cervix uterus ovary ovary uterus GTN
48 51 52 53 54 56
cervix cervix ovary ovary ovary ovary
+
+/
+
+
false negative CT
follow-up imaging studies for suspected recurrence. Standard imaging procedures (CT, MRI or both) were performed in various outpatient services, and the patients were then referred to our tertiary center for a PET/CT study. The PET/CT study was interpreted by one expert physician (E.E-S.) who had no knowledge of the results obtained by the other modalities. PET/CT procedure The patients fasted at least 4 h before an intravenous injection of 370 – 666 MBq (10 – 18 mCi) 18F-FDG. Scanning from the base of the skull through the midthigh was carried out by the Discovery LS PET/CT system (GE Medical systems, Milwaukee, WI). CT acquisition obtained with 140 kV, 80 mA, and 0.8 s per CT rotation, a pitch of 6 and a table speed of 22.5 mm/s. The patient received no specific breath-holding instructions for this scan. A PET emission scan was performed immediately after CT and without changing the patient’s position. Scanning was carried out in five to eight bed positions with an acquisition time of 5 min for each one. PET images were
Evidence of pelvic or distant recurrence Standard imaging
2 3 4
PET/CT diagnosed spinal cord compression, missed by MRI false positive MRI
681
PET/CT
Histology/ clinical evidence of disease +
false negative PET/CT
+ +
+ +
Nonconclusive CT Lung metastasis by PET/CT
+
+
+ +
+ +
+
+
+
+
+ + + +
+ + + +
Lung recurrence by PET/CT false positive CT false negative CT Positive lymph nodes were missed by CT false negative CT false positive CT Distant recurrence in inguinal nodes missed by CT false positive CT false negative CT
+ + +
+ + +
false negative CT
+ + +
+ + +
false negative CT false negative CT false negative CT
+ + +
+ +
+ + + + + +
+ + + + + +
+
+
+ +/ +
+ not possiblea
+ + +
+ +
false negative CT
false positive CT
GTN, gestational trophoblastic neoplasia. Due to anaphylactic reaction to contrast medium.
a
Remarks
false positive PET/CT false negative CT false negative CT false negative CT
682
D. Grisaru et al. / Gynecologic Oncology 94 (2004) 680–684
Statistics The accuracy of the imaging studies was confirmed either by histology (obtained during surgical exploration or guided biopsies) and by clinical and radiological outcomes (all negative tissue diagnosis were followed to confirm the negative histology). The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for the PET/CT and the standard imaging procedures.
Results Eighteen of the fifty-three study patients underwent PET/CT for staging as part of their diagnostic workup and 35 for suspected recurrence. The mean F SD age of the study cohort was 56 F 15 years (range 20– 85). The primary tumor sites were cervical cancer (n = 21), uterine cancer (n = 8), ovarian cancer (n = 19), vulvar cancer (n = 1), vaginal cancer (n = 1), primary peritoneal tumor (n = 1), tubal cancer (n = 1) and gestational trophoblastic neoplasia (n = 1). Table 1 summarizes the data of the 18 patients who underwent PET/CT at diagnosis for staging. The standard imaging procedures disclosed metastatic spread in five patients and was inconclusive in another two (39%). Five patients who had a negative preoperative conventional
imaging evaluation had histologically proven metastatic disease (28% false negative). PET/CT accurately detected all sites of metastases and there were no false positive sites. Table 2 summarizes the data of the 35 patients who underwent PET/CT for suspected recurrence. The standard imaging modalities disclosed recurrence of the tumor in eight patients and was inconclusive in two patients (29% true positive). The recurrence was missed in 16 patients (46% false negative). PET/CT disclosed recurrent or metastatic disease in all the tumor sites that were overlooked by standard imaging. PET/CT was false negative in one patient (it missed the peritoneal miliary spread in a patient with ovarian cancer) and false positive in one patient (it suggested pelvic disease outside the uterus in a patient with gestational trophoblastic disease, and no pelvic disease was detected at explorative laparotomy). The sensitivity, specificity, positive predictive value and negative predictive value of the PET/CT results for the entire study group were higher than those of the standard imaging modalities (0.97 vs. 0.40, 0.94 vs. 0.65, 0.97 vs. 0.70, and 0.94 vs. 0.34, respectively).
Discussion CT is the most commonly used imaging modality in the routine management of cancer patients. CT detection of a
Fig. 1. Staging of cervical cancer. (A) Whole body PET image. (B) Transaxial images (top left image, CT; top right image, PET; bottom left image, fused PET/ CT image). Three liver metastases were identified (arrows). (C) Transaxial images. A small lung metastasis was identified (arrow). (D) Coronal images (left image, CT; middle image, PET; right image, fused PET/CT). An abdominal metastatic lymph node was detected (arrow).
D. Grisaru et al. / Gynecologic Oncology 94 (2004) 680–684
tumor is based primarily on the presence of an abnormal mass or an enlargement of organs. Involvement of lymph nodes depends mostly on size criteria [10]. PET using 18FFDG as the injected radiopharmaceutical is a functional imaging modality of tumor tissue representing the increased metabolic rate and glucose consumption characterizing malignant cells [1]. Detection of tumor tissue by PETFDG does not require the presence of a mass and thus may provide definitive information earlier than the anatomic imaging modalities. Metastatic lymph nodes which are less than 1 cm in diameter may be reliably identified by PET imaging. The major limitation of PET alone is its inability to give precise anatomical information. Various registration methods of PET and CT, either visual or mathematical, have been reported and describe a number of problems in comparing the recordings of findings performed by different systems at separate settings. A CT performed within 6 weeks of a PET study, for instance, can be considered ‘‘contemporary’’ for diagnostic purposes, but it is of limited value for accurate anatomic correlation. The time gap between the PET and diagnostic CT acquisitions can be responsible for differences in the reporting of tumor size. Mobile lesions, mainly in the abdomen, such as small peritoneal metastases, pose another registration challenge. Assessments of the role of CT for detection of peritoneal metastases in patients with ovarian cancer have found that even when surgical findings were available as the standard of reference, a site-by-site comparison could not be performed [4]. When monitoring the response to therapy in patients with known malignancies, a residual mass is not necessarily a residual tumor since it may be composed solely of fibrotic tissue. Moreover, while a mass that can be seen to be shrinking in size on repeated CT studies is considered a criterion of response to treatment, it is not possible to conclude that a complete response had been achieved based on these CT findings. 18F-FDG is a tumor viability agent and its uptake within a mass reflects the presence of a viable tumor tissue, thus the absence of 18F-FDG uptake may confirm with confidence that the patient has achieved a complete response. The fused PET/CT images obtained by the system used in the current study allow not only determination of the presence or absence of tumor, but also differentiation between necrotic and fibrotic regions and remnants of tumor within the residual mass detected on CT. In the current study, PET/CT detected metastatic spread resulting in a change of disease staging at the time of diagnosis (Fig. 1). These findings agree with the results presented by Belhocine et al. [3] who showed the benefit of PET in diagnosing extrapelvic metastases at staging as well as recurrences of cervical cancer. Those authors used PET scanning followed by MRI as the technique for functionalanatomic registration and found MRI to be superior for the evaluation of the local extension of tumor. Recent reports have suggested improved diagnostic accuracy of PET/CT for early diagnosis of metastases and the
683
detection of relapse in various human malignancies [5,7,19]. The current report presents preliminary results of the diagnostic accuracy of hybrid imaging in detecting and correctly defining the functional and anatomic imaging characteristics in gynecologic malignancies. These study results clearly show an advantage of integrating PET with CT to achieve better anatomic definition of the FDG uptake lesions suspected as tumor sites, for the identification of small abdominal and pelvic tumor sites, and for discriminating between physiologic and malignant sites of uptake. The overall improved diagnostic accuracy achieved by PET/CT is demonstrated by reduction of the false positive and false negative rates of each of the modalities when interpreted separately. The use of PET in cervical cancer is well documented [3,8,9,12,15,18,20], while its use in uterine cancer is limited [2,11,14]. We believe this to be the first series of combined PET/CT in the staging phase of uterine cancer. The contribution of PET/CT for the localization of extra-
Fig. 2. Ovarian cancer recurrence (unexplained rising markers). (A) A whole body image of CT, PET and PET/CT. (B) Transaxial images (top left image, CT; top right image, PET; bottom left image, fused PET/CT image). An 8-mm retroperitoneal metastatic 8-mm lymph node was detected.
684
D. Grisaru et al. / Gynecologic Oncology 94 (2004) 680–684
pelvic disease at staging or at the evaluation of recurrence in this type of tumor may be beneficial to the management of the patient—although these patients have surgical staging procedures—but larger series of patients with uterine cancer evaluated by PET/CT would be required to delineate its effect on outcome. Previous publications reported disappointing results on the role of PET in ovarian cancer, primarily due to its low specificity compared to other modalities, such as the CT, MRI or US [16]. These conclusions may, however, be the result of a lack of anatomical correlation of the 18F-FDG uptake with anatomic data. Makhija et al. [13] reported that the use of PET/CT may improve the specificity of FDG assessment in ovarian and tubal tumors. In our current series, we used PET/ CT primarily for follow-up. It is noteworthy that conventional imaging modalities such as CT, MRI and US lack the sensitivity to consistently detect recurrence of ovarian cancer [6]. PET has been used to detect recurrence of ovarian cancer but with low sensitivity and specificity [17]. One reason for this may be the difficulty in imaging the abdomen and the pelvis with 18F-FDG PET interpretation alone due to physiologic uptake of 18F-FDG in the bowel and bladder. Anatomic – metabolic fusion imaging may improve the anatomic specificity. The addition of PET/CT in the evaluation of the patients with increasing CA125 levels improved our ability to detect recurrent disease and, based on these complementary findings, several patients were selected for a salvage treatment (Fig. 2). In conclusion, this preliminary report describes PET/CT imaging in a large variety of gynecological malignancies. Integrated PET/CT imaging appears to be of high diagnostic accuracy both at diagnosis and in the evaluation of suspected recurrence. We included patients with a variety of gynecologic cancers, both at diagnosis, and at evaluation for recurrence. It is quite likely that the accuracy of PET/CT will vary with the extent, location, and histology of the disease, so that the values calculated for sensitivity, specificity, and so on, in this patient population may differ in other patient population. Therefore, we are expanding the study to evaluate the accuracy of PET/CT by specific malignancy.
Acknowledgment Esther Eshkol is thanked for editorial assistance.
References [1] Bar-Shalom R, Valdivia AY, Blaufox MD. PET imaging in oncology. Semin Nucl Med 2000;30:150 – 85.
[2] Belhocine T, De Barsy C, Hustinx R, Willems-Foidart J. Usefulness of (18)F-FDG PET in the post-therapy surveillance of endometrial carcinoma. Eur J Nucl Med Mol Imaging 2002;29:1132 – 9. [3] Belhocine T, Thille A, Fridman V, Albert A, Seidel L, Nickers P, et al. Contribution of whole-body 18FDG PET imaging in the management of cervical cancer. Gynecol Oncol 2002;87:90 – 7. [4] Coakley FV, Choi PH, Gougoutas CA, Pothuri B, Venkatraman E, Chi D, et al. Peritoneal metastases: detection with spiral CT in patients with ovarian cancer. Radiology 2002;223:495 – 9. [5] Costa DC, Visvikis D, Crosdale I, Pigden I, Townsend C, Bomanji J, et al. Positron emission and computed X-ray tomography: a coming together. Nucl Med Commun 2003;24:351 – 8. [6] De Rosa V, Mangoni di Stefano ML, Brunetti A, Caraco C, Graziano R, Gallo MS, et al. Computed tomography and second-look surgery in ovarian cancer patients. Correlation, actual role and limitations of CT scan. Eur J Gynaecol Oncol 1995;16:123 – 9. [7] Ell PJ, von Schulthess GK. PET/CT: a new road map. Eur J Nucl Med Mol Imaging 2002;29:719 – 20. [8] Grigsby PW, Siegel BA, Dehdashti F. Lymph node staging by positron emission tomography in patients with carcinoma of the cervix. J Clin Oncol 2001;19:3745 – 9. [9] Grigsby PW, Siegel BA, Dehdashti F, Mutch DG. Posttherapy surveillance monitoring of cervical cancer by FDG-PET. Int J Radiat Oncol Biol Phys 2003;55:907 – 13. [10] Hopper KD, Singapuri K, Finkel A. Body CT and oncologic imaging. Radiology 2000;215:27 – 40. [11] Lentz SS. Endometrial carcinoma diagnosed by positron emission tomography: a case report. Gynecol Oncol 2002;86:223 – 4. [12] Lin WC, Hung YC, Yeh LS, Kao CH, Yen RF, Shen YY. Usefulness of (18)F-fluorodeoxyglucose positron emission tomography to detect para-aortic lymph nodal metastasis in advanced cervical cancer with negative computed tomography findings. Gynecol Oncol 2003;89: 73 – 6. [13] Makhija S, Howden N, Edwards R, Kelley J, Townsend DW, Meltzer CC. Positron emission tomography/computed tomography imaging for the detection of recurrent ovarian and fallopian tube carcinoma: a retrospective review. Gynecol Oncol 2002;85:53 – 8. [14] Nakahara T, Fujii H, Ide M, Mochizuki Y, Takahashi W, Yasuda S, et al. F-18 FDG uptake in endometrial cancer. Clin Nucl Med 2001;26: 82 – 3. [15] Park DH, Kim KH, Park SY, Lee BH, Choi CW, Chin SY. Diagnosis of recurrent uterine cervical cancer: computed tomography versus positron emission tomography. Korean J Radiol 2000;1:51 – 5. [16] Rieber A, Nussle K, Stohr I, Grab D, Fenchel S, Kreienberg R, et al. Preoperative diagnosis of ovarian tumors with MR imaging: comparison with transvaginal sonography, positron emission tomography, and histologic findings. Am J Roentgenol 2001;177:123 – 9. [17] Rose PG, Faulhaber P, Miraldi F, Abdul-Karim FW. Positive emission tomography for evaluating a complete clinical response in patients with ovarian or peritoneal carcinoma: correlation with second-look laparotomy. Gynecol Oncol 2001;82:17 – 21. [18] Ryu SY, Kim MH, Choi SC, Choi CW, Lee KH. Detection of early recurrence with 18F-FDG PET in patients with cervical cancer. J. Nucl Med 2003;44:347 – 52. [19] Townsend DW, Beyer T. A combined PET/CT scanner: the path to true image fusion. Br J Radiol. [Spec No] 2002;75:S24 – 30. [20] Yeh LS, Hung YC, Shen YY, Kao CH, Lin CC, Lee CC. Detecting para-aortic lymph nodal metastasis by positron emission tomography of 18F-fluorodeoxyglucose in advanced cervical cancer with negative magnetic resonance imaging findings. Oncol Rep 2002;9:1289 – 92.
The diagnostic accuracy of 18F-Fluorodeoxyglucose PET/CT in patients with gynecological malignancies Dan Grisaru a,*,1, Benny Almog a,1, Charles Levine b, Ur Metser c, Ami Fishman d, Hedva Lerman c, Joseph B. Lessing a, Einat Even-Sapir c a
Department of Obstetrics and Gynecology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel b Department Radiology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel c Department Nuclear Medicine, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel d Department of Obstetrics and Gynecology, Meir Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel Received 29 November 2003 Available online 8 July 2004
Abstract Objective. To evaluate the diagnostic accuracy of integrated positron emission tomography/computerized tomography (PET/CT) in patients with gynecological cancer. Methods. Fifty-three consecutive patients with gynecologic malignancies were included. The patients were referred to our tertiary center to undergo a PET/CT scan. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of PET/CT were compared with the conventional imaging assessments [CT, magnetic resonance imaging (MRI) and ultrasonography (US)]. Results. All tested values were higher for PET/CT than those for the conventional modalities: sensitivity 0.97 vs. 0.40, specificity 0.94 vs. 0.65, PPV 0.97 vs. 0.70, and NPV 0.94 vs. 0.34, respectively. Conclusion. PET/CT is a reliable modality for assessing the extent of disease in patients with gynecologic malignancy. D 2004 Elsevier Inc. All rights reserved. Keywords: Positron emission tomography/computerized tomography; Staging; Follow-up
Introduction Positron emission tomography (PET) imaging with 18FFluorodeoxyglucose (FDG) is gaining popularity in the routine diagnosis of cancer patients. Scintigraphy is successful in providing the functional data of suspected active tumor sites, but it may be limited in its inability to define the precise anatomic localization of suspected lesions, thus often necessitating correlation with other anatomic modalities, including computerized tomography (CT) and magnetic resonance imaging (MRI). Precise alignment of the data obtained by two different modalities can be difficult to achieve and errors are not uncommon. Novel systems designed as hybrids of a PET or single photon emission
computer tomography (SPECT) device integrated with CT are now available. Emission (PET or gamma camera coincidence imaging) and transmission (low- or high-resolution CT) studies are performed in the same setting using the same device and without changing the patient’s position, thereby allowing for highly accurate fusion of the images acquired by both modalities. The objective of the present study was to assess the diagnostic accuracy of PET/CT compared to the conventional methodologies of CT, MRI and ultrasonography (US) in patients with gynecological cancer.
Patients and methods Patients
* Corresponding author. Department of Obstetrics and Gynecology, Lis Maternity Hospital, Tel-Aviv Sourasky Medical Center, 6 Weizmann Street, Tel-Aviv 64239, Israel. Fax: +972-3-9625670. E-mail address: [email protected] (D. Grisaru). 1 These authors equally contributed to the study. 0090-8258/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2004.05.053
Fifty-three consecutive patients with proven gynecologic malignancy were included in the present study. Each patient had undergone a comprehensive evaluation of her clinical status and was scheduled for routine staging or
D. Grisaru et al. / Gynecologic Oncology 94 (2004) 680–684 Table 1 PET/CT in the patient’s work-up at the staging phase (n = 18) #
Organ
5
ovary
8 13 14 16 21 24
cervix uterus uterus ovary uterus uterus
27 30 32 34 36 38 39
cervix uterus uterus cervix cervix cervix cervix
42 49 50 55
cervix cervix cervix vagina
Metastatic disease
Remarks
Standard imaging
PET/CT
Histological evidence of disease
+/
+
+
PET/CT accurately localized a mass for core biopsy that was not evident on standard CT
+
+
+
+
false negative CT false positive CT false negative CT
+
+
+
PET/CT accurately localized the tumor to the uterus in accordance with histology; CT falsely localized it to the cervix
reconstructed using an OSEM algorithm. CT data were used for attenuation correction. The studies were read on an eNTEGRA workstation (eNTEGRA, ELGEMS, Haifa, Israel) equipped with fusion software, which allows the display of PET images (with and without attenuation correction), of CT images and of the fused data of both modalities.
Table 2 PET/CT for suspected recurrence (n = 35) #
Organ
1
ovary
+
ovary ovary cervix
+/
+
+
+
+
+ +
+ +
6 7
ovary cervix
+
+
+
9 10 11
ovary ovary vulva
12 15 17
ovary cervix cervix
18 19 22 23 26 28 29 31 35
tube ovary cervix ovary ovary cervix cervix cervix cervix
37 40 41 43 44 45 46 47
ovary ovary cervix uterus ovary ovary uterus GTN
48 51 52 53 54 56
cervix cervix ovary ovary ovary ovary
+
+/
+
+
false negative CT
follow-up imaging studies for suspected recurrence. Standard imaging procedures (CT, MRI or both) were performed in various outpatient services, and the patients were then referred to our tertiary center for a PET/CT study. The PET/CT study was interpreted by one expert physician (E.E-S.) who had no knowledge of the results obtained by the other modalities. PET/CT procedure The patients fasted at least 4 h before an intravenous injection of 370 – 666 MBq (10 – 18 mCi) 18F-FDG. Scanning from the base of the skull through the midthigh was carried out by the Discovery LS PET/CT system (GE Medical systems, Milwaukee, WI). CT acquisition obtained with 140 kV, 80 mA, and 0.8 s per CT rotation, a pitch of 6 and a table speed of 22.5 mm/s. The patient received no specific breath-holding instructions for this scan. A PET emission scan was performed immediately after CT and without changing the patient’s position. Scanning was carried out in five to eight bed positions with an acquisition time of 5 min for each one. PET images were
Evidence of pelvic or distant recurrence Standard imaging
2 3 4
PET/CT diagnosed spinal cord compression, missed by MRI false positive MRI
681
PET/CT
Histology/ clinical evidence of disease +
false negative PET/CT
+ +
+ +
Nonconclusive CT Lung metastasis by PET/CT
+
+
+ +
+ +
+
+
+
+
+ + + +
+ + + +
Lung recurrence by PET/CT false positive CT false negative CT Positive lymph nodes were missed by CT false negative CT false positive CT Distant recurrence in inguinal nodes missed by CT false positive CT false negative CT
+ + +
+ + +
false negative CT
+ + +
+ + +
false negative CT false negative CT false negative CT
+ + +
+ +
+ + + + + +
+ + + + + +
+
+
+ +/ +
+ not possiblea
+ + +
+ +
false negative CT
false positive CT
GTN, gestational trophoblastic neoplasia. Due to anaphylactic reaction to contrast medium.
a
Remarks
false positive PET/CT false negative CT false negative CT false negative CT
682
D. Grisaru et al. / Gynecologic Oncology 94 (2004) 680–684
Statistics The accuracy of the imaging studies was confirmed either by histology (obtained during surgical exploration or guided biopsies) and by clinical and radiological outcomes (all negative tissue diagnosis were followed to confirm the negative histology). The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for the PET/CT and the standard imaging procedures.
Results Eighteen of the fifty-three study patients underwent PET/CT for staging as part of their diagnostic workup and 35 for suspected recurrence. The mean F SD age of the study cohort was 56 F 15 years (range 20– 85). The primary tumor sites were cervical cancer (n = 21), uterine cancer (n = 8), ovarian cancer (n = 19), vulvar cancer (n = 1), vaginal cancer (n = 1), primary peritoneal tumor (n = 1), tubal cancer (n = 1) and gestational trophoblastic neoplasia (n = 1). Table 1 summarizes the data of the 18 patients who underwent PET/CT at diagnosis for staging. The standard imaging procedures disclosed metastatic spread in five patients and was inconclusive in another two (39%). Five patients who had a negative preoperative conventional
imaging evaluation had histologically proven metastatic disease (28% false negative). PET/CT accurately detected all sites of metastases and there were no false positive sites. Table 2 summarizes the data of the 35 patients who underwent PET/CT for suspected recurrence. The standard imaging modalities disclosed recurrence of the tumor in eight patients and was inconclusive in two patients (29% true positive). The recurrence was missed in 16 patients (46% false negative). PET/CT disclosed recurrent or metastatic disease in all the tumor sites that were overlooked by standard imaging. PET/CT was false negative in one patient (it missed the peritoneal miliary spread in a patient with ovarian cancer) and false positive in one patient (it suggested pelvic disease outside the uterus in a patient with gestational trophoblastic disease, and no pelvic disease was detected at explorative laparotomy). The sensitivity, specificity, positive predictive value and negative predictive value of the PET/CT results for the entire study group were higher than those of the standard imaging modalities (0.97 vs. 0.40, 0.94 vs. 0.65, 0.97 vs. 0.70, and 0.94 vs. 0.34, respectively).
Discussion CT is the most commonly used imaging modality in the routine management of cancer patients. CT detection of a
Fig. 1. Staging of cervical cancer. (A) Whole body PET image. (B) Transaxial images (top left image, CT; top right image, PET; bottom left image, fused PET/ CT image). Three liver metastases were identified (arrows). (C) Transaxial images. A small lung metastasis was identified (arrow). (D) Coronal images (left image, CT; middle image, PET; right image, fused PET/CT). An abdominal metastatic lymph node was detected (arrow).
D. Grisaru et al. / Gynecologic Oncology 94 (2004) 680–684
tumor is based primarily on the presence of an abnormal mass or an enlargement of organs. Involvement of lymph nodes depends mostly on size criteria [10]. PET using 18FFDG as the injected radiopharmaceutical is a functional imaging modality of tumor tissue representing the increased metabolic rate and glucose consumption characterizing malignant cells [1]. Detection of tumor tissue by PETFDG does not require the presence of a mass and thus may provide definitive information earlier than the anatomic imaging modalities. Metastatic lymph nodes which are less than 1 cm in diameter may be reliably identified by PET imaging. The major limitation of PET alone is its inability to give precise anatomical information. Various registration methods of PET and CT, either visual or mathematical, have been reported and describe a number of problems in comparing the recordings of findings performed by different systems at separate settings. A CT performed within 6 weeks of a PET study, for instance, can be considered ‘‘contemporary’’ for diagnostic purposes, but it is of limited value for accurate anatomic correlation. The time gap between the PET and diagnostic CT acquisitions can be responsible for differences in the reporting of tumor size. Mobile lesions, mainly in the abdomen, such as small peritoneal metastases, pose another registration challenge. Assessments of the role of CT for detection of peritoneal metastases in patients with ovarian cancer have found that even when surgical findings were available as the standard of reference, a site-by-site comparison could not be performed [4]. When monitoring the response to therapy in patients with known malignancies, a residual mass is not necessarily a residual tumor since it may be composed solely of fibrotic tissue. Moreover, while a mass that can be seen to be shrinking in size on repeated CT studies is considered a criterion of response to treatment, it is not possible to conclude that a complete response had been achieved based on these CT findings. 18F-FDG is a tumor viability agent and its uptake within a mass reflects the presence of a viable tumor tissue, thus the absence of 18F-FDG uptake may confirm with confidence that the patient has achieved a complete response. The fused PET/CT images obtained by the system used in the current study allow not only determination of the presence or absence of tumor, but also differentiation between necrotic and fibrotic regions and remnants of tumor within the residual mass detected on CT. In the current study, PET/CT detected metastatic spread resulting in a change of disease staging at the time of diagnosis (Fig. 1). These findings agree with the results presented by Belhocine et al. [3] who showed the benefit of PET in diagnosing extrapelvic metastases at staging as well as recurrences of cervical cancer. Those authors used PET scanning followed by MRI as the technique for functionalanatomic registration and found MRI to be superior for the evaluation of the local extension of tumor. Recent reports have suggested improved diagnostic accuracy of PET/CT for early diagnosis of metastases and the
683
detection of relapse in various human malignancies [5,7,19]. The current report presents preliminary results of the diagnostic accuracy of hybrid imaging in detecting and correctly defining the functional and anatomic imaging characteristics in gynecologic malignancies. These study results clearly show an advantage of integrating PET with CT to achieve better anatomic definition of the FDG uptake lesions suspected as tumor sites, for the identification of small abdominal and pelvic tumor sites, and for discriminating between physiologic and malignant sites of uptake. The overall improved diagnostic accuracy achieved by PET/CT is demonstrated by reduction of the false positive and false negative rates of each of the modalities when interpreted separately. The use of PET in cervical cancer is well documented [3,8,9,12,15,18,20], while its use in uterine cancer is limited [2,11,14]. We believe this to be the first series of combined PET/CT in the staging phase of uterine cancer. The contribution of PET/CT for the localization of extra-
Fig. 2. Ovarian cancer recurrence (unexplained rising markers). (A) A whole body image of CT, PET and PET/CT. (B) Transaxial images (top left image, CT; top right image, PET; bottom left image, fused PET/CT image). An 8-mm retroperitoneal metastatic 8-mm lymph node was detected.
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pelvic disease at staging or at the evaluation of recurrence in this type of tumor may be beneficial to the management of the patient—although these patients have surgical staging procedures—but larger series of patients with uterine cancer evaluated by PET/CT would be required to delineate its effect on outcome. Previous publications reported disappointing results on the role of PET in ovarian cancer, primarily due to its low specificity compared to other modalities, such as the CT, MRI or US [16]. These conclusions may, however, be the result of a lack of anatomical correlation of the 18F-FDG uptake with anatomic data. Makhija et al. [13] reported that the use of PET/CT may improve the specificity of FDG assessment in ovarian and tubal tumors. In our current series, we used PET/ CT primarily for follow-up. It is noteworthy that conventional imaging modalities such as CT, MRI and US lack the sensitivity to consistently detect recurrence of ovarian cancer [6]. PET has been used to detect recurrence of ovarian cancer but with low sensitivity and specificity [17]. One reason for this may be the difficulty in imaging the abdomen and the pelvis with 18F-FDG PET interpretation alone due to physiologic uptake of 18F-FDG in the bowel and bladder. Anatomic – metabolic fusion imaging may improve the anatomic specificity. The addition of PET/CT in the evaluation of the patients with increasing CA125 levels improved our ability to detect recurrent disease and, based on these complementary findings, several patients were selected for a salvage treatment (Fig. 2). In conclusion, this preliminary report describes PET/CT imaging in a large variety of gynecological malignancies. Integrated PET/CT imaging appears to be of high diagnostic accuracy both at diagnosis and in the evaluation of suspected recurrence. We included patients with a variety of gynecologic cancers, both at diagnosis, and at evaluation for recurrence. It is quite likely that the accuracy of PET/CT will vary with the extent, location, and histology of the disease, so that the values calculated for sensitivity, specificity, and so on, in this patient population may differ in other patient population. Therefore, we are expanding the study to evaluate the accuracy of PET/CT by specific malignancy.
Acknowledgment Esther Eshkol is thanked for editorial assistance.
References [1] Bar-Shalom R, Valdivia AY, Blaufox MD. PET imaging in oncology. Semin Nucl Med 2000;30:150 – 85.
[2] Belhocine T, De Barsy C, Hustinx R, Willems-Foidart J. Usefulness of (18)F-FDG PET in the post-therapy surveillance of endometrial carcinoma. Eur J Nucl Med Mol Imaging 2002;29:1132 – 9. [3] Belhocine T, Thille A, Fridman V, Albert A, Seidel L, Nickers P, et al. Contribution of whole-body 18FDG PET imaging in the management of cervical cancer. Gynecol Oncol 2002;87:90 – 7. [4] Coakley FV, Choi PH, Gougoutas CA, Pothuri B, Venkatraman E, Chi D, et al. Peritoneal metastases: detection with spiral CT in patients with ovarian cancer. Radiology 2002;223:495 – 9. [5] Costa DC, Visvikis D, Crosdale I, Pigden I, Townsend C, Bomanji J, et al. Positron emission and computed X-ray tomography: a coming together. Nucl Med Commun 2003;24:351 – 8. [6] De Rosa V, Mangoni di Stefano ML, Brunetti A, Caraco C, Graziano R, Gallo MS, et al. Computed tomography and second-look surgery in ovarian cancer patients. Correlation, actual role and limitations of CT scan. Eur J Gynaecol Oncol 1995;16:123 – 9. [7] Ell PJ, von Schulthess GK. PET/CT: a new road map. Eur J Nucl Med Mol Imaging 2002;29:719 – 20. [8] Grigsby PW, Siegel BA, Dehdashti F. Lymph node staging by positron emission tomography in patients with carcinoma of the cervix. J Clin Oncol 2001;19:3745 – 9. [9] Grigsby PW, Siegel BA, Dehdashti F, Mutch DG. Posttherapy surveillance monitoring of cervical cancer by FDG-PET. Int J Radiat Oncol Biol Phys 2003;55:907 – 13. [10] Hopper KD, Singapuri K, Finkel A. Body CT and oncologic imaging. Radiology 2000;215:27 – 40. [11] Lentz SS. Endometrial carcinoma diagnosed by positron emission tomography: a case report. Gynecol Oncol 2002;86:223 – 4. [12] Lin WC, Hung YC, Yeh LS, Kao CH, Yen RF, Shen YY. Usefulness of (18)F-fluorodeoxyglucose positron emission tomography to detect para-aortic lymph nodal metastasis in advanced cervical cancer with negative computed tomography findings. Gynecol Oncol 2003;89: 73 – 6. [13] Makhija S, Howden N, Edwards R, Kelley J, Townsend DW, Meltzer CC. Positron emission tomography/computed tomography imaging for the detection of recurrent ovarian and fallopian tube carcinoma: a retrospective review. Gynecol Oncol 2002;85:53 – 8. [14] Nakahara T, Fujii H, Ide M, Mochizuki Y, Takahashi W, Yasuda S, et al. F-18 FDG uptake in endometrial cancer. Clin Nucl Med 2001;26: 82 – 3. [15] Park DH, Kim KH, Park SY, Lee BH, Choi CW, Chin SY. Diagnosis of recurrent uterine cervical cancer: computed tomography versus positron emission tomography. Korean J Radiol 2000;1:51 – 5. [16] Rieber A, Nussle K, Stohr I, Grab D, Fenchel S, Kreienberg R, et al. Preoperative diagnosis of ovarian tumors with MR imaging: comparison with transvaginal sonography, positron emission tomography, and histologic findings. Am J Roentgenol 2001;177:123 – 9. [17] Rose PG, Faulhaber P, Miraldi F, Abdul-Karim FW. Positive emission tomography for evaluating a complete clinical response in patients with ovarian or peritoneal carcinoma: correlation with second-look laparotomy. Gynecol Oncol 2001;82:17 – 21. [18] Ryu SY, Kim MH, Choi SC, Choi CW, Lee KH. Detection of early recurrence with 18F-FDG PET in patients with cervical cancer. J. Nucl Med 2003;44:347 – 52. [19] Townsend DW, Beyer T. A combined PET/CT scanner: the path to true image fusion. Br J Radiol. [Spec No] 2002;75:S24 – 30. [20] Yeh LS, Hung YC, Shen YY, Kao CH, Lin CC, Lee CC. Detecting para-aortic lymph nodal metastasis by positron emission tomography of 18F-fluorodeoxyglucose in advanced cervical cancer with negative magnetic resonance imaging findings. Oncol Rep 2002;9:1289 – 92.