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Oct 19, 2007 - carcinosarcoma. Methods Patients with histologically confirmed uterine carcinosarcoma were enrolled. Abdominal and pelvic mag-.
Eur J Nucl Med Mol Imaging (2008) 35:484–492 DOI 10.1007/s00259-007-0533-z

ORIGINAL ARTICLE

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F-fluorodeoxyglucose positron emission tomography in uterine carcinosarcoma

Kung-Chu Ho & Chyong-Huey Lai & Tzu-I Wu & Koon-Kwan Ng & Tzu-Chen Yen & Gigin Lin & Ting-Chang Chang & Chun-Chieh Wang & Swei Hsueh & Huei-Jean Huang

Received: 18 April 2007 / Accepted: 6 July 2007 / Published online: 19 October 2007 # Springer-Verlag 2007

Abstract Purpose Uterine carcinosarcomas clinically confined to the uterus usually harbor occult metastases. We conducted a pilot study to evaluate the value of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in uterine carcinosarcoma. Methods Patients with histologically confirmed uterine carcinosarcoma were enrolled. Abdominal and pelvic magnetic resonance imaging (MRI)/whole-body computed toK.-C. Ho : T.-C. Yen Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan C.-H. Lai : T.-I. Wu : T.-C. Chang : H.-J. Huang (*) Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 5 Fu-Shin Street, Kueishan, Taoyuan 333, Taiwan e-mail: [email protected] K.-K. Ng : G. Lin Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan C.-C. Wang Department of Radiation Oncology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan

mography (CT) scan, and whole-body 18F-FDG PET or PET/CT were undertaken for primary staging, evaluating response, and restaging/post-therapy surveillance. The clinical impact of 18F-FDG PET was determined on a scan basis. Results A total of 19 patients were recruited and 31 18FFDG PET scans (including 8 scans performed on a PET/CT scanner) were performed. Positive impacts of scans were found in 36.8% (7/19) for primary staging, 66.7% (2/3) for monitoring response, and 11.1% (1/9) for restaging/posttherapy surveillance. PET excluded falsely inoperable disease defined by MRI in two patients. Aggressive treatment applying to three patients with PET-defined resectable stage IVB disease seemed futile. Two patients died of disease shortly after salvage therapy restaged by PET. With PET monitoring, one stage IVB patient treated by targeted therapy only was alive with good performance. Using PET did not lead to improvement of overall survival of this series compared with the historical control (n=35) (P=0.779). Conclusions The preliminary results suggest that 18F-FDG PET is beneficial in excluding falsely inoperable disease for curative therapy and in making a decision on palliation for better quality of life instead of aggressive treatment under the guidance of PET. PET seems to have limited value in post-therapy surveillance or restaging after failure. Keywords 18F-FDG . PET . Uterine carcinosarcoma . Malignant mixed müllerian tumor . Clinical impact

Introduction S. Hsueh Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan

Uterine carcinosarcoma (or malignant mixed müllerian tumor), one of the uterine sarcomas, is a rare tumor with extremely aggressive behavior and poor prognosis. Con-

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Eur J Nucl Med Mol Imaging (2008) 35:484–492

ventionally, the behavior and patterns of spread of uterine carcinosarcoma are thought to be similar to those of poorly differentiated endometrial adenocarcinoma. The current studies about uterine carcinosarcoma have disclosed a more aggressive tumor biology and behavior of carcinosarcoma than that of high-risk endometrial adenocarcinoma. Patients with disease clinically confined to the uterus (stage I or II) are frequently found to have unexpected metastases at the time of surgery [1–6]. Comprehensive surgical staging should be performed in the potentially curable patients because locoregional extension, regional lymph node metastases, and intraperitoneal dissemination are common. There is 20–55% upstaging in patients with uterine carcinosarcoma by the finding of extrauterine disease [1– 6]. Even with surgical exploration, there is a substantial percentage of occult disease undetected by clinical-surgical staging methods that would manifest within a short time from primary treatment [3, 4]. The diagnostic methods of conventional imaging modalities such as computed tomography (CT) or magnetic resonance imaging (MRI) are usually size and morphology dependent. MRI or CT may be a useful tool for staging uterine carcinosarcoma [7, 8]. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has an important role for a variety of cancers including gynecologic cancers, particularly for cancers with advanced, recurrent, or metastatic lesions [9–13]. A metabolic image like 18F-FDG PET has the potential to get a more comprehensive evaluation for metastases. However, there is only limited information about primary spread patterns of uterine carcinosarcoma using 18F-FDG PET [14–18]. The aim of this prospective pilot study was to determine the value of 18F-FDG PET in the management of uterine carcinosarcoma.

Materials and methods Patients The eligibility criteria were: (1) histologically proven uterine carcinosarcoma and any of (2) through (7): (2) for primary staging, (3) immediate postoperative state with unrecognized carcinosarcoma before surgery, (4) monitoring of initially unresected/incompletely resected sites of tumor (histologically proven or lesion score ≥3 by MRI/ CT), (5) post-therapy surveillance of suspected recurrence (symptomatic, clinically palpable mass or detected by ultrasound, MRI/CT score ≥3 on two successive tests 1 month apart), (6) restaging at documented recurrence/ persistence, or (7) annual surveillance within 2 years after initial treatment for stage III and IV disease, and (8) willing to receive an image-guided biopsy or surgical exploration if

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indicated, (9) willing to receive active treatment if staging/ restaging confirmed the feasibility, and (10) signed informed consent. Exclusion criteria included (1) clinically disseminated disease with ≥ 3 sites of documented metastasis, (2) unwilling to undergo contrast-enhanced MRI/CT and 18FFDG PET scans, (3) medically or psychologically unfit to receive active treatment, or (4) a history of another malignancy except basal cell carcinoma of the skin. Clinical evaluation included tumor markers of CEA and CA125, imaging studies of chest X-ray, pelvic sonography, abdominal and pelvic MRI and/or whole-body CT, and whole-body 18F-FDG PET scan. The 18F-FDG PET scan was undertaken within 1 week after performance of MRI and/or CT. After comprehensive clinical workup, all patients underwent surgical staging. For inoperable patients or unresectable lesions, tissue biopsy or aspiration cytology was done to clarify the pathologic result.

MRI/CT imaging CT images were obtained with a multislice CT scanner (Somatom Plus 4, Version A40, Siemens AG Medical, Forchheim, Germany). For all patients, oral meglumine diatrizoate (Gastrografin, Schering Health Care, West Sussex, UK) was administered for bowel preparation. Craniocaudal scanning from the upper neck to the symphysis pubis was performed. An intravenous iodinated medium, iothalamate (Conray, Mallinckrodt Medical, St. Louis, MO, USA) or iohexol (Omnipaque, GE Healthcare, Waukesha, WI, USA), was used as bolus for contrast-enhanced CT. With the Somatom Plus 4 CT scanner, contiguous 5-mm slices were obtained from the neck, chest, and abdomen to pelvis [10, 11]. MR images were obtained with a 1.5-T Magnetom Vision or a Magnetom Expert Scanner (Siemens Medical Systems, Erlangen, Germany), using a phased-array body coil with a maximum 50-cm transverse field of view. For the pelvis and abdomen, transaxial, sagittal, and coronal sections, T2-spin echo [time repetition/time echo (TR/TE), 4,000/99], and T1-spin echo (TR/TE, 500/15) sequences were used. Matrix size was 256×256 pixels. Slice thickness in the transaxial and sagittal planes was 5 mm and 8 mm in coronal planes for the pelvis and abdomen [10, 11].

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F-FDG PET imaging

After fasting for ≥6 h, the patient was placed in a quiet environment, 5 mg of diazepam was given orally, continuous intravenous hydration was instituted, and a Foley catheter was inserted; then 333–407 MBq FDG was given intravenously. In order to prevent radioactivity stasis in the

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urinary bladder, we administered 20 mg furosemide intravenously to each patient immediately prior to scanning. Seven sequential 18F-FDG PET images, from the vertex to the upper thigh, with axial collimation (two-dimensional mode), were obtained beginning 40 min after FDG administration with the use of an ECAT EXACT HR+ PET camera (CTI, Knoxville, TN, USA), with a full-width at half-maximum of 4.5 mm and a 15-cm transaxial field of view. In addition, three sets of PET images in threedimensional mode, from T-11 to the upper thigh, beginning 3 hours after 18F-FDG injection, were obtained in some patients if questionable lesions were detected by PET images acquired in the first two-dimensional mode sequence [10, 11]. A transmission scan was obtained with Ge68 rod sources in each bed position to correct for photon attenuation. Accelerated maximum likelihood reconstruction and ordered subsets expectation maximization (OSEM) were applied for the reconstruction of both the transmission and the emission scans. After May 2006, 18F-FDG PET studies in our institute were performed on the Discovery ST16 PET/CT scanner (GE Healthcare, Waukesha, WI, USA). No intravenous contrast enhancement was used. PET/CT images were obtained 50 min after intravenous injection of 18F-FDG (333–407 MBq). Sixteen-detector multislice CT images were acquired using speed of rotation and couch movement of 0.5 s/rotation and 35 mm/s, respectively. The images were reconstructed in 3.3-mm slice width during normal respiration. CT images were rebinned from a 512×512 matrix to a 128×128 matrix and matched to the pixel size of the PET data in order to match the in-slice resolution of the PET emission images. The CT images were subsequently converted to maps of PET attenuation coefficients. Without changing the patient’s position, a whole-body PET emission scan was performed over the same area as was covered by CT with six bed positions. All acquisitions were carried out in 2-D mode, the protocol comprising an emission scan with 3 min/bed position. PET images were reconstructed using CT attenuation maps. Transaxial emission images of 3.3×3.3×3.27 mm3 (in plane matrix size 128×128, 47 slices per bed position) were reconstructed using OSEM with four iterations and ten subsets. The axial field of view was 157 mm, with acquisition of 47 slices/bed position.

Image interpretation All images including MRI, CT, and 18F-FDG PET scan were interpreted visually by use of a 5-point scoring system: 0=no visible lesion; 1=visible lesion(s) without significance; 2=equivocal lesion(s); 3=probable malignant lesion(s); and 4=obvious malignant lesion(s). A score≥3

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was considered as positive for malignancy. Scores for each anatomic site were finally determined and recorded at a weekly multidisciplinary Gynecologic Oncology Combined Conference [10, 11].

Surgical and postoperative treatment It is our policy that all patients with histologically confirmed carcinosarcoma should undergo surgery unless an unresectable situation is clinically obvious. Limited distant nodal or upper abdominal metastasis does not preclude an initial surgical intervention. For extrapelvic peritoneal metastasis, surgical resection is performed for focal lesion and abandoned for diffuse peritoneal metastasis. Surgical staging consisted of washing cytology, abdominal total hysterectomy, bilateral salpingo-oophorectomy, bilateral pelvic lymph node dissection, para-aortic lymph node dissection, omentectomy, and appendectomy. Those with deep myometrial invasion, cervical extension, or retroperitoneal nodal metastasis will receive postoperative radiation, and chemotherapy will be given concurrently or sequentially with radiotherapy. Adjuvant chemotherapy alone is recommended for stage IA-B. Chemotherapeutic regimens usually involve combinations of ifosfamide with cisplatin, doxorubicin, or paclitaxel. Hormone or molecular targeted therapy is used for inoperable cases according to molecular diagnosis of target protein and gene expression studies, such as estrogen, progesterone, epidermal growth factor receptors, luteinizing hormone-releasing hormone receptor mRNA, etc. [19–22].

Confirmation of disease status To evaluate the nature of a lesion discovered on 18F-FDG PET performed on a PET-only scanner, we applied an image fusion technique to further define the site of interest [12]. Histologic or cytologic confirmation was obtained through CT- or sonography-guided biopsy when appropriate. If biopsy of the lesion of interest was not feasible or the lesion was equivocal by clinical judgment, a follow-up scan with a CT/MRI or a PET scan was performed 3–6 months later to assess the interval status of the lesion. If both CT/ MRI and PET showed negative results, no further intervention would be performed. The largest diameter of falsenegative lesion ignored and the smallest diameter of true-positive lesion detected by 18F-FDG PET scan are determined by histologic measurement of the lesion size, respectively. Following a comprehensive workup, consensus on disease status of the site(s) of interest and further management was reached at the joint tumor conference for

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each patient. Outcome was determined via surgical findings, follow-up imaging studies, and the clinical course.

Clinical impact after

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F-FDG PET

The clinical impact of the 18F-FDG PET was considered positive if (1) detection of additional lesion(s) not found by conventional imaging (MRI and/or CT) and the management was modified due to the additional findings in 18FFDG PET study, (2) ruling out false-positive MRI/CT lesions and avoidance of unnecessary aggressive therapy or endorsement of a curative intent, (3) PET resulted in a change of management to palliation, avoiding a futile curative or salvage attempt and maintaining quality of life, or endorsed a palliative treatment, avoiding invasive biopsy for apparently multiple distant metastases, or (4) PET provided supportive data for the monitoring efficacy of medical treatment. The clinical impact was considered negative if 18F-FDG PET led to unnecessary, additional invasive procedures. The 18F-FDG PET results was determined to be no clinical impact if (1) 18F-FDG PET and MRI/CT results were concordantly correct, (2) a discordant finding between 18F-FDG PET and MRI/CT had tissue proof or image follow-up but did not affect treatment, or (3) concordant false-positive or false-negative findings did not affect surgical staging or treatment [13]. The clinical impact was designated indeterminate if a discordant finding between 18F-FDG PET and MRI/CT had no tissue proof or image follow-up.

Statistical analysis Overall survival was defined as the length of time from the date of initial diagnosis of uterine carcinosarcoma to either the date of death or of last follow-up. Survival curves were calculated with the Kaplan-Meier method and the curves were compared using the log-rank test. A two-tailed value of P