Gynecologic Oncologic Imaging With PET/CT Paul Grant, MD,*,† Christopher Sakellis, MD,*,† and Heather A. Jacene, MD*,† FDG-PET/CT has been evaluated in a variety of gynecologic malignancies in a variety of settings and is approved by the Centers for Medicare & Medicaid Services for the initial and subsequent treatment strategies of these malignancies. Cervical cancer is typically very FDG avid, and FDG-PET/CT appears to be most valuable for initial staging, radiation therapy planning, and detection of recurrent disease. For ovarian cancer, the most value of FDG-PET/ CT appears to be for detecting recurrent disease in the setting of rising CA-125 level and negative or equivocal anatomical imaging studies. Initial studies evaluating response to therapy are promising and further work in this area is needed. FDG uptake in both nonmalignant and physiological processes in the pelvis can make interpretation of FDGPET/CT in this region challenging and knowledge of these entities and patterns can avoid misinterpretation. Some of the most common findings relate to the cyclic changes that occur as part of the menstrual cycle in premenopausal women. Mucinous tumors and low-volume or peritoneal carcinomatosis are causes of false-negative results on FDG-PET/CT studies. As new tracers are developed, comparisons with patient outcomes and standards of care (eg, FDG-PET/CT) will be needed. Semin Nucl Med 44:461-478 C 2014 Elsevier Inc. All rights reserved.

Introduction

P

ET integrated with CT (PET/CT) is now a well-established noninvasive imaging tool in oncology. The combined technique is advantageous over other imaging modalities because it realizes the power of detecting functional changes, which often occur earlier than anatomical ones, with precise localization and structural information in a single study. PET/ CT also provides quantitative information that can be useful for monitoring changes in disease status over time or as a function of treatment. PET/CT is most commonly used with the radiotracer FDG. FDG is a glucose analogue that preferentially accumulates in malignant tissues owing to their higher rates of glycolysis. Numerous other pathways are disrupted or upregulated in cancer cells providing additional targets for imaging. Some have been evaluated in gynecologic malignancies, including 11C-methione, 18F-fluoro17-beta-estradiol (FES), 60Cu-diacetyl-bis(N4 methylthiosemicarbazone) (ATSM), and 64Cu-ATSM. A previous major disadvantage for FDG-PET/CT imaging was poor reimbursement. Data from the prospective *Department of Imaging, Dana-Farber Cancer Institute, Boston, MA. †Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. Address reprint requests to Heather A. Jacene, MD, 450 Brookline Ave, DL203, Boston, MA 02215. E-mail: [email protected]

http://dx.doi.org/10.1053/j.semnuclmed.2014.06.005 0001-2998/& 2014 Elsevier Inc. All rights reserved.

National Oncologic PET Registry were published in 2008 and demonstrated that after FDG-PET/CT, the intended management was changed in 41.4% for patients with ovarian cancer and in 32.7% with cervical cancer.1 Similar rates of changes were reported when the indications for FDG-PET/CT were categorized as initial staging, restaging, or suspected recurrence. The Centers for Medicare & Medicaid Services (CMS) announced coverage for initial and subsequent treatment strategies for ovarian and cervical cancer shortly thereafter in 2009. This review discusses the role of PET/CT in gynecologic malignancies. Most of the published experience evaluates ovarian and cervical cancer with FDG-PET/CT. Therefore, the major focus is on FDG-PET/CT, but other potentially useful radiotracers have also been discussed. Additionally, the review is structured to provide some background information on epidemiology and pattern of spread, which we also find helpful for image interpretation.

Cervical Cancer Epidemiology, Clinical Presentation, and Prognosis Cervical cancer is the third most common neoplasm in women worldwide.2 The many risk factors include human papilloma virus (HPV) infection, increased number of sexual partners, 461

462 early age of first coitus, smoking, and diethylstilbestrol exposure. Recent studies indicate that HPV infection is the main cause of cervical cancer, responsible for up to 75% of cases.3 The most common histologic type is squamous cell carcinoma (75%) with adenocarcinoma subtypes (eg, clear cell, small cell, and adenosquamous) accounting for the rest.4-6 Clinically, patients typically present with postcoital bleeding followed by metrorrhagia or menorrhagia. Later stages are associated with chronic anemia and then rectal or bladder symptoms or both. The most important prognostic parameters at the time of diagnosis include tumor size, parametrial invasion, and lymph node spread (especially para-aortic).7 The overall 5-year survival rate is 67.9%. This number drastically improves if the disease is confined to the primary site (90.9%) and becomes much worse if there are regional lymph node (57.1%) or distant metastases (16.1%).8

Clinical Staging and Pattern of Spread Cervical cancer is staged clinically, most widely with the International Federation of Gynecologists and Obstetricians (FIGO) staging system. Many staging procedures have been used over the years, including physical examination, chest radiography, intravenous pyelogram, and cystoscopy. Surgical staging with lymphadenectomy has also been used and has aided the ability to approximate the true size and extent of the tumor. Studies have shown a large discrepancy between clinical and surgical staging, ranging from  25% in early-stage disease (stage IIA) to 65%-90% in more advanced tumors (Zstage IIB).9 This is a critical distinction because the early stages are treated surgically, but advanced disease is treated with radiation or combined chemoradiation. The FIGO system has known inherent inaccuracies. Many important prognostic factors are excluded, such as tumor size, histologic grade, and local or retroperitoneal lymph node status. Para-aortic lymph node metastases are observed in approximately one-third of patients with locally advanced cervical cancer (FIGO stage IIB).10 Advanced imaging modalities such as PET/CT, CT, and MRI have been employed in attempts to overcome the limits of the traditional diagnostic methods and provide important prognostic information. In a multicenter clinical trial by the Gynecologic Oncology Group that included evaluation of tumor staging by imaging, the most significant prognostic factor in patients with stage I-IVA cervical cancer was the status of the para-aortic lymph nodes followed by tumor size Z3 cm.11 The National Comprehensive Cancer Network (NCCN) now recommends FDG-PET/ CT imaging as part of the pretreatment assessment in cervical cancer with clinical stage IB2 or higher.12 Knowledge of the pattern of tumor spread is always helpful for image interpretation and understanding the staging systems employed. The preinvasive stage of cervical cancer is mainly localized to the squamocolumnar junction. The cancer then invades the cervical stroma followed by direct invasion into the parametrium, uterus, and vagina. As the disease advances, the tumor spreads

P. Grant et al. through 3 lymphatic pathways: the lateral route along the external iliac vessels, the hypogastric route along the internal iliac vessels, and the presacral route along the uterosacral ligament. All 3 pathways ultimately drain into the common iliac lymph nodes, which then leads to involvement of the para-aortic nodes, lastly spreading to supraclavicular lymph nodes. Extrapelvic disease is rare. Only 12% of patients have metastases beyond the regional lymph nodes at the time of diagnosis.8 Hematogenous spread is even more rare at only 5% and is most commonly to the lungs, liver, and bones.13 Although it is possible to have distant organ disease at any stage, it is unlikely to occur in the absence of pelvic lymph node involvement.14-16

FDG-PET/CT for the Initial Treatment Strategy Diagnosis and Primary Lesion Evaluation Cervical cancer is primarily detected by the Papanicolaou screening test (Pap test). Cervical cancer typically has high levels of FDG uptake and the level of metabolic activity in the primary tumor has been reported to be higher in squamous cell histologies vs nonsquamous histologies as well as higher in poorly differentiated vs well-differentiated tumors.17 Despite this, FDG-PET/CT is not routinely used for the initial evaluation of the primary lesion itself, primarily because of limitations in identifying deep uterine parametrial involvement where MRI is considered the gold standard.18 FDG-PET/CT may also be falsely negative for smaller (ie, subcentimeter) and superficial infiltrative tumors that may be picked up on MRI because of higher spatial resolution.10 However, there are studies showing that the level and extent of metabolic activity in the primary cervical lesion provides prognostic information (Fig. 1). In 51 patients with newly diagnosed advanced cervical cancer, Miller and Grisby19 showed that tumor volumes r60 cm3 on PET, derived from regions of interest using a simple count thresholding method, were associated with better overall and progression-free survival compared with tumor volumes 460 cm3. Studies have also reported a worse prognosis with higher levels of metabolic activity in the primary cervical cancer, given by the maximum standardized uptake value (SUVmax), at baseline. The 5-year overall survival rates decreased with increasing SUVmax: 95% with SUVmax r 5.2, 70% with SUVmax 5.2-13.3, and 44% with SUVmax 4 13.3.20 Lee et al21 reported that high SUVmax was also an independent predictor of recurrence after surgical treatment. Initial Staging—Regional Lymph Node Evaluation Surgical staging is still advocated as the gold standard to assess for pelvic and para-aortic lymph node metastases. Kidd et al17 found a correlation between the SUVmax of the primary lesion at diagnosis and the presence of lymph node metastases on FDG-PET or FDG-PET/CT images. The sensitivity of FDGPET/CT for detecting para-aortic lymph node metastases has been reported to be as high as 95%.22,23 In patients with locally advanced disease, SUVmax Z 3.3 in para-aortic nodes was a strong negative prognostic factor and was associated with a

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Figure 1 Intense FDG uptake is seen in the primary cervical mass with SUVmax 19.8 (arrowheads). Intense but physiological FDG activity is seen in the bladder anterior to the cervical mass (arrows). No FDG-avid locoregional or distant metastases were identified. Higher levels of FDG uptake in the primary cervical mass have been associated with a worse prognosis.19,20

higher recurrence rate and lower survival rate compared with para-aortic nodes with SUVmax o 3.3.24 Furthermore, FDG-PET/CT has been found to be more accurate than contrast-enhanced CT and MRI for determining locoregional lymph node involvement and extrapelvic disease extension and subsequently for guiding laparoscopic staging procedures. The results of several meta-analyses comparing these imaging modalities are summarized in Table 1. The major limitations of these studies were a lack of histopathology as a gold standard, small study populations, and a lack of correlations with survival being performed.

Initial Staging—Distant Metastatic Evaluation An important site to evaluate for distant metastases in patients with cervical cancer is the left supraclavicular region. In 186 patients with newly diagnosed cervical cancer, Tran et al25 found 14 (8%) patients with occult supraclavicular lymph node involvement by FDG-PET/CT, all of which were pathologically confirmed. Of the patients in this study, 40% showed involvement of the para-aortic lymph nodes on FDGPET/CT, and the overall prognosis was poor.25 Grigsby et al26 retrospectively studied 101 patients and also found supraclavicular lymph node involvement in 8% of the patients.

Table 1 Summary of Meta-Analyses for Initial Staging (Locoregional Lymph Node Metastases) for Cervical Cancer Reference

Choi et al149 Bipat et al150 Havrilesky et al43 Kang et al148 Selman et al151

No. of studies

PET or PET/CT

CT

Sensitivity (%)

Specificity (%)

Sensitivity (%)

Specificity (%)

Sensitivity (%)

Specificity (%)

41 57 20

82

95

92

95

56 60 54

91

84

50 43 47

10 72

34 75

97 98

58

92

56

93

MRI Sensitivity

96

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FDG-PET/CT for the Subsequent Treatment Strategy Detection of Recurrent Disease Recurrent cervical cancer is defined as tumor development at least 6 months after regression of the treated malignant lesion.27 The reported estimated recurrence rates have ranged as high as 28%-35% when patients with uterine parametrial invasion or para-aortic involvement or a combination of both are included.28,29 Locally recurrent cervical cancer occurs mainly in the vaginal vault but can subsequently extend to the parametrium and pelvic sidewall. Distant metastases are seen in 70% of patients with recurrent disease.30 Lymph node metastases occur most often in the para-aortic nodes (11%), abdominal cavity (8%), and supraclavicular nodes (7%). There is also hematogenous spread to the liver, adrenal glands (15%), lungs (21%), and bones (20%) (Fig. 2). Adrenal metastases may also occur with cervical adenocarcinomas.31-34 There is no universally accepted approach for the follow-up of patients with cervical cancer. Bodurka-Bevers et al35 retrospectively evaluated 133 patients and found that asymptomatic subjects with recurrent cervical cancer had higher overall survival (42 months) than symptomatic patients (11 months). These results suggest that diagnostic techniques that can detect early, asymptomatic recurrence may be of clinical benefit. FDG-PET/CT has advantages over other diagnostic techniques, including other imaging modalities, for detecting locally

recurrent cervical cancer. Pelvic examination as well as vaginal and cervical cytology have limited use because of postradiation changes.36 Blood tumor markers, such as carcinoembryonic antigen, CA-19.9, and CA-125, may help identify recurrence in asymptomatic patients; however, they are not disease specific and do not provide the site of relapse or the extent of disease. CT and MRI often have difficulty in discriminating areas of possible postsurgical or postradiotherapy scars from tumor recurrence. Sensitivity is high, but at the cost of specificity. CT and MRI are also limited for detecting disease in lymph nodes smaller than the size criteria to be considered abnormal.37 Conversely, metabolism is usually higher in recurrent malignancy than in posttreatment scarring, and FDG-PET and PET/CT have been shown to be effective in detecting recurrent tumor.38-41 The results of several of these studies are summarized in Table 2. The studies included different patient populations and a meta-analysis as well as different techniques (FDG-PET alone vs PET/CT). Overall, however, the studies reported relatively high sensitivity (90%-95%) of FDG-PET (/CT) for detecting recurrent cervical cancer, with specificities from 76%-93%, positive predictive values (PPVs) from 35%96%, and negative predictive values (NPVs) from 87%-98%. The large range of PPVs was related to a study investigating the use of FDG-PET for detecting early recurrence in patients without clinical evidence of recurrence, a setting in which one could postulate that a higher false-positive rate might be expected. In the study by Van der Veldt et al,38 the sensitivity

Figure 2 A 66-year-old woman with high-grade müllerian cervical adenocarcinoma, initially treated with chemotherapy and radiation. FDG-PET/CT for the subsequent treatment strategy revealed multiple bilateral FDG-avid pulmonary nodules. This patient never had biopsy-proven or FDG-avid pelvic or retroperitoneal lymph nodes and likely had predominately hematogenous spread of disease to the lung.

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Table 2 Cervical Recurrence Detection Reference

n

Modality

Population

SN (%)

SP (%)

Ryu et al39

249

FDG-PET (combined local and distant recurrence) FDG-PET (combined local and distant recurrence) FDG-PET/CT Local recurrence Distant recurrence

Asymptomatic

90

76

5

98

Equivocal clinical or imaging findings Asymptomatic and symptomatic Asymptomatic and symptomatic

92

93

96

87

93 96

93 95

86 96

96 95

95 90 82-100

87 76 78-100

Van der Veldt et al38

40

Mittra et al41

30

Meads, 201440

*

FDG-PET/CT Diagnostic CT MRI

PPV (%)

NPV (%)

SN, sensitivity; SP, specificity. *Meta-analysis of 15 studies.

was higher for local and regional recurrences (87%-100%) vs distant disease (75%). The specificity was similar regardless of the location of the recurrent disease.38 Diagnostic performance improved overall with combined FDG-PET/CT.41 Meads et al40 recently published a meta-analysis aimed to determine the added value of FDG-PET/CT to CT or MRI in 3 scenarios: routine follow-up of asymptomatic women with cervical cancer after treatment, detecting recurrence in symptomatic women, and detecting recurrence to define a treatment strategy. Only 15 studies were included in the final analysis, 9 included FDG-PET/CT and only 3 of these were direct comparisons of the imaging modalities. The pooled estimated sensitivities and specificities for detecting recurrence were higher for FDG-PET/CT than for CT and were unable to be determined for MRI (reported as range). Formal statistical analysis comparing diagnostic accuracy was not performed. Other limitations included older CT or MRI studies and overall poor quality studies. The study highlighted the paucity of good evidence-based literature to support the use of FDG-PET/CT in the evaluated settings.40 The current NCCN guidelines recommend FDG-PET/CT for the surveillance of cervical cancer only in the setting of symptoms suggestive of recurrence.12 The use of FDG-PET/CT at the time of recurrence has also been reported to have implications for therapeutic strategies. Chung et al42 showed that 40% of subjects with asymptomatic pelvic recurrence and no FDG-PET/CT evidence of distant metastases were cured with exenteration. Therapeutic strategies have been shown to change in approximately 25% of patients after FDG-PET/CT imaging.43,44 Monitoring Treatment Response Although not specific to cervical cancer, Nishiyama et al evaluated the role of FDG-PET for monitoring response to neoadjuvant therapy in patients with advanced stages of gynecologic cancers. The study showed an accuracy of 85% in predicting response to treatment, when the SUVmax of the primary tumor decreased by more than 65% after chemotherapy or chemoradiotherapy.45 Schwarz et al analyzed a prospective cohort of 92 subjects with cervical cancer who underwent external beam irradiation,

brachytherapy, and concurrent chemotherapy and were subsequently followed up by a postchemoradiation therapy FDGPET/CT examination at a median of 3 months following treatment. The posttreatment study results were classified as complete metabolic response, partial response, or appearance of new abnormal FDG-avid foci, and there was a significant difference in the 3-year survival rates of 78%, 33%, and 0%, respectively.46

FDG-PET/CT: Radiation Therapy Planning Chao et al47 showed the utility of FDG-PET/CT in assisting radiotherapy treatment planning for cervical cancer. As FDGPET/CT has been shown to have the best accuracy in detecting disease in lymph nodes and distant lesions, it was considered a useful tool for directing radiotherapists during intensitymodulated radiation therapy (IMRT).47 Inclusion of FDGPET/CT data in the IMRT plan allowed a decrease in the dose to surrounding healthy tissues as well as a dose escalation to the target. In other studies, IMRT led to significantly less grade 2 gastrointestinal toxicity and less use of antidiarrheal medication.48,49

Summary There is considerable growing evidence supporting the utility of FDG-PET/CT for the initial staging of patients with cervical cancer. This led the NCCN to recommend FDG-PET/CT imaging as part of the pretreatment assessment in cervical cancer with clinical stage IB2 or higher, and this is now a covered indication under the CMS. Although FDG-PET/CT has advantages for detecting recurrent disease and may detect disease earlier than standard imaging, the data regarding the use of FDGPET/CT in this setting are more variable and the largest utility seems to be in symptomatic patients with suspicion for recurrence. Further investigation is likely warranted. Finally, FDG-PET/CT has been shown to be helpful in guiding radiation therapy planning for cervical cancer.

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Ovarian cancer is the second most common gynecologic malignancy and the sixth most common malignancy in women worldwide. It has the highest mortality of all gynecologic cancers, despite representing only 3% of all cancers in women.50 The incidence has decreased slightly over the past 30 years. Approximately 10% of ovarian cancers are autosomal inherited forms with 90% caused by BRCA-1 and BRCA-2 gene mutations and approximately 10% caused by Lynch syndrome (hereditary nonpolyposis colon cancer syndrome).51 By the age of 70 years, 18%-54% of BRCA-1 mutation carriers and 2.4%-19% of BRCA-2 mutation carriers are diagnosed with ovarian cancer. Lynch syndrome has a lifetime risk for ovarian cancer of up to 10%-15%.52 Other commonly known risk factors for ovarian cancer are age (greater than two-third of patients present during the postmenopausal period), family history, nulliparity, early menarche, and late menopause. Reported protective factors are oral contraceptive use, parity, and bilateral oophorectomy. Ovarian cancer often presents as advanced disease resulting in a high mortality. The typical signs and symptoms are abdominal pain, menstrual irregularities, and dyspepsia. As the disease progresses, abdominal distention can occur, and there are respiratory symptoms due to the increased intra-abdominal pressure caused by ascites.53 Histologically, ovarian cancers are differentiated by the cell of origin. Most (90%) are epithelial tumors, and the remaining 10% are of stromal, germ, or mixed cell origin. Epithelial tumors are subdivided into serous, mucinous, endometrioid, clear cell, and undifferentiated histologies. Epithelial serous carcinoma represents approximately 80% of all ovarian cancers and is graded as low, which arises from borderline tumor, or high, with no definite precursor lesion and a poorer prognosis.54,55 The standard primary treatment for ovarian cancer includes optimal debulking surgery followed by chemotherapy, typically administration of paclitaxel and platinum-based cytotoxic chemotherapy.56 Patients diagnosed at an early stage (stage I) have a significantly better prognosis compared with those diagnosed at a later stage (stages III and IV), with the 5-year survival rates estimated at 90% and 25%, respectively.57

CA-125 levels, and imaging consisting of contrast-enhanced CT, MRI, and FDG-PET/CT evaluations.58 The FIGO staging system for ovarian cancer is summarized in Table 3. Up to 75% of cases are diagnosed at an advanced stage (FIGO stage III or IV).59 This is likely because of the lack of specific early signs and symptoms and the absence of effective screening programs. Unlike cervical cancer, ovarian cancer usually spreads directly into the peritoneal cavity. Lymphatic and hematogenous spread are less common. The usual pathway consists of penetration of the ovarian capsule with direct invasion of contiguous organs or pelvic peritoneum. Tumor spreads to the contralateral ovary, uterus, and peritoneum. Cells can then be carried up into the abdomen by the peritoneal fluid. This spread involves normal circulation from the pelvis to the abdomen along a clockwise pathway; initially to the right paracolic gutter, then the right upper quadrant around the liver and diaphragm, and thereafter to the greater omentum and left paracolic gutter. Implants are usually found in the paracolic and subphrenic spaces, in the greater omentum, and on the surfaces of the liver, bowel, and spleen. Following peritoneal carcinomatosis, transdiaphragmatic spread to the pleura is common.51,55,60-63 Serous papillary carcinoma and poorly differentiated adenocarcinoma are the most common histologic subtypes of peritoneal carcinomatosis (Fig. 3).64,65 Lymphatic spread to the pelvic lymph nodes occurs via the broad ligament and to the para-aortic nodes along the gonadal vessel. The spread of disease from the retroperitoneal lymph nodes through the lymphatic channels into the diaphragm can lead to distribution to the supraclavicular lymph nodes and rarely to the internal mammary lymph nodes. There is also the rare spread to the Sister Mary Joseph nodules (umbilical metastases), which is usually a sign of widespread intraabdominal disease and most commonly occurs with serous papillary carcinoma.55 Lymph node involvement at primary surgery has a reported incidence of 25% in patients with stage I disease, 50% in stage II disease, and 74% in stage III-IV disease.66 Hematogenous metastases at the time of diagnosis are uncommon, but most commonly occur in the liver (Fig. 4), lung, and pleura.55,62 Only 2%-3% of patients have pulmonary or hepatic metastases at diagnosis. Pleural effusion, followed by parenchymal liver metastases is the most common finding of stage IV disease.62

Clinical Staging and Pattern of Spread

FDG-PET/CT for the Initial Treatment Strategy

Ovarian cancer has often been staged surgically. The NCCN guidelines recommend staging studies to include regular physical and pelvic examinations, measurement of serum

Diagnosis and Primary Lesion Evaluation Ultrasound (US) is the primary screening method for ovarian cancer. The tumor marker CA-125 is often used for early

Ovarian Epidemiology, Clinical Presentation, and Prognosis

Table 3 Summary of FIGO Staging System for Cervical and Ovarian Cancer Stage I Stage II Stage III Stage IV

Cervical Cancer

Ovarian Cancer

Confined to uterus Invades beyond the uterus Extends to pelvic wall or involves lower third of vagina or both Distant metastases

Limited to ovaries Extends to pelvis Microscopic or macroscopic peritoneal metastases or regional lymph node beyond the pelvis or both Distant metastases

Gynecologic oncologic imaging with PET/CT

Figure 3 A 65-year-old woman with poorly differentiated papillary serous carcinoma presented for a PET/CT scan for the subsequent treatment strategy that demonstrated FDG-avid peritoneal carcinomatosis and inguinal and right-sided axillary lymphadenopathy (red arrows). There is also physiological uptake in the brown fat (black arrows) and a single left-sided kidney with increased uptake because of a ureteral stent (arrowhead).

467 detection; however, CA-125 is neither specific for ovarian cancer nor sensitive for small-volume disease. Approximately 20% of all ovarian cancers do not show increased CA-125 expression.68 Most ovarian masses in premenopausal women are benign. A mass that does not resolve or regress is of considerable concern for cancer and requires further workup. Conversely, ovarian masses in postmenopausal women are commonly malignant. The combination of a postmenopausal adnexal mass with an elevated CA-125 level greater than 200 IU/mL was found to have a PPV of 97% for ovarian cancer.69 Several authors have evaluated FDG-PET/CT for differentiating benign vs malignant ovarian masses. Nam et al70 performed a prospective study comparing the diagnostic performance of FDG-PET/CT, CT, or MRI and US with surgery used as the gold standard in 133 patients with suspected ovarian cancer. The accuracy of FDG-PET/CT tended to be higher than that of pelvic US, CT, or MRI at all cutoff levels evaluated for distinguishing benign or borderline and malignant tumors.70 Castellucci et al used SUVmax to try to discriminate between benign and malignant ovarian lesions with focal SUVmax of 3 or higher in the ovary considered as positive for ovarian malignancy and 2.7 or lower considered as benign. This yielded a sensitivity of 87% and specificity of 100%.71 Despite this, FDG-PET/CT is not primarily indicated for the screening or diagnosis of the primary ovarian malignancy because of the false-positive and false-negative cases that can occur. In one series,72 19 of 91 cases (21%) of benign ovarian masses had abnormal FDG uptake, including cystadenoma, endometrioma, hydrosalpinx, benign germ cell tumors,

Figure 4 A 77-year-old woman with ovarian müllerian adenocarcinoma presented for a restaging study following cytoreductive surgery and chemotherapy. There is increased FDG uptake in a hepatic dome hypodensity most consistent with a hematogenous metastasis.

468 cholesterol granuloma, abscess, and thecomas. Increased FDG uptake has also been described in endometriosis, which is important because the ovaries are the most frequent anatomical location for endometriosis.73 The specificity of FDG-PET/CT can be improved when combined with postmenopausal status and elevation of CA125 level. Risum et al evaluated the use of FDG-PET/CT in 101 menopausal women with elevated serum CA-125 levels and an ovarian mass on US. FDG-PET/CT was 100% sensitive and 92% specific for differentiating malignant and benign or borderline tumors.74 Therefore, FDG-PET/CT can have an important role in confirming the diagnosis of malignancy in cases with higher clinical suspicion or in high-risk surgical cases. FDG-PET/CT can be falsely negative in small, necrotic, mucinous, cystic, or low-grade tumors.75 Another limitation is the ability of FDG-PET/CT to identify lesions less than 1 cm, in particular, those smaller than 5 mm. In the study by Castellucci et al,71 3 of the 4 FDG-PET/CT scans with false-negative findings had primary tumors measuring less than 5 mm. Initial Staging Studies investigating the value of a preoperative FDG-PET/CT scan are ongoing. The scan could estimate the likelihood of achieving optimal debulking. This includes analyzing the extent of localized ovarian cancer and helping with the determination of initial treatment planning (often including debulking surgery). FDG-PET/CT has been shown to increase the pretreatment staging accuracy to 69%-75% compared with that of 53%55% for CT alone.71 Nam et al70 prospectively evaluated 91 patients before surgical staging. In 16% of the patients, PET/CT imaging found extra-abdominal lymph node metastases that surgical staging did not identify. In addition, they found secondary malignancies in 5 other patients (including thyroid, breast, and pancreatic neuroendocrine), further adding to the potential usefulness of FDG-PET/CT imaging for the initial treatment strategy in patients with ovarian cancer.70

FDG-PET/CT for the Subsequent Treatment Strategy Detection of Residual and Recurrent Disease Up to 75% of patients with ovarian cancer have a disease relapse76 primarily in the peritoneal cavity and retroperitoneal lymph nodes. Currently, there is no definitive timetable for follow-up examinations and, more importantly, no definitive consensus on what type of examination should be used. Serum CA-125 assay, physical examination, and anatomical imaging have all been widely used. There have been numerous studies evaluating the use of FDG-PET and PET/CT for detecting recurrent ovarian cancer. Although the studies regarding design (retrospective vs prospective), patient population, and technique have been mixed, they can largely be divided into evaluating the utility of FDGPET/CT compared with that of evaluation of CA-125 level and other imaging modalities and the utility of FDG-PET/CT in the

P. Grant et al. “suspected recurrence” and “disease-free” settings. There is a nice recent review on this specific topic by Son et al.77 The Gynecologic Cancer Intergroup's definition for a positive result on CA-125 evaluation, even in the absence of clinical or radiologic findings, is a level that is twice the upper limit of normal (35 U/mL) for patients who have normalized CA-125 level after initial therapy or twice the nadir value if the levels did not normalize.78 CA-125 evaluation has a high PPV (95%), but its NPV is low (50%-60%).79 Another disadvantage of CA-125 evaluation is that it does not give any information about the extent or location of recurrence. In a meta-analysis, Gu et al80 reported higher pooled sensitivity for FDG-PET/CT (91%) compared with CA-125 evaluation (69%), but the pooled specificity was higher for CA-125 evaluation (93% vs 88% for FDG-PET/CT). In the same meta-analysis, pooled sensitivity and specificity were both higher for FDG-PET and PET/CT compared with CT and MRI.80 Sebastian et al81 reported better diagnostic accuracy and interobserver variability for detecting recurrent ovarian cancer with FDG-PET/CT compared with CT alone. Kim et al82 compared MRI and FDG-PET/CT for detecting recurrent ovarian cancer in 36 patients with suspected recurrence, 20 of whom underwent staging laparotomy 2-35 days after the imaging procedures. For the patient-based analysis, overall sensitivity for detecting recurrence was higher for MRI vs FDG-PET/CT (91% vs 73%, P o 0.05), with similar specificity, NPVs and PPVs. However, lesion-based analysis revealed that the superior sensitivity of MRI was likely because of better detection of peritoneal lesions. FDG-PET/CT had higher sensitivity for lymph node metastases; however, the number of overall lesions in this group was very small.82 Combining CA-125 assay with imaging (CT, MRI, and FDG-PET/CT) is now commonly performed when there are signs or symptoms suggestive of recurrent disease. Despite the results obtained by Kim et al,82 others have reported challenges of using CT and MR for detecting small-volume deposits on visceral surfaces as well as after debulking surgery owing to altered anatomy.83 Although FDG-PET/CT also has limitations for detecting small lesions and military or diffuse peritoneal involvement (Fig. 5A and B),77 some small lesions can be very FDG avid (Fig. 5C). For detecting suspected recurrence, the reported sensitivity of FDG-PET/CT ranges from 65%-100%, specificity from 60%-100%, PPV from 85%-100%, and NPV from 67%-100%.67,84-87 Risum et al84 prospectively investigated 60 patients with a 3-month or more remission after primary therapy and suspected recurrent ovarian cancer on physical examination or US or increasing CA-125 levels and found higher sensitivity (P o 0.001) for FDG-PET/CT (97%) vs US (66%) and CT (81%). Several authors and reviews have reported that the best evidence for FDGPET/CT is in the setting of rising CA-125 level and unremarkable or equivocal findings on CT or MRI.67,77,85 In a study by Mangili et al,86 the findings on FDG-PET/CT were positive in a larger percentage of patients with suspected recurrence compared with those on CT (91% vs 63%). In 12 of 32 patients with unremarkable findings on CT scans,

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Figure 5 (A) A 59-year-old woman with ovarian cancer and rising CA-125 level. FDG-PET/CT shows mild but diffuse uptake throughout the abdomen, which is greater than just a bowellike pattern (maximum intensity projection image) and corresponds to ascites and diffuse peritoneal disease on CT. FDG-PET/CT can be limited for the detection of diffuse peritoneal carcinomatosis. (B) A 54-year-old woman with serous ovarian adenocarcinoma presented for PET/CT for the subsequent treatment strategy because of rising CA-125 level. There is no abnormal FDG uptake within the two 5-mm soft tissue implants along the left lateral fascia, which was considered most likely to be related to their small size. (C) A 49-yearold woman with mucinous ovarian adenocarcinoma after debulking therapy and chemotherapy. PET/CT showed a FDGavid small visceral deposit (red arrow). The CA-125 level was 954 IU/mL and the diagnostic CT performed 1 week prior showed no remarkable findings.

FDG-PET/CT findings were positive in 10. FDG-PET/CT also found more lesions in 8 of 25 patients with a single site of disease detected on CT while the opposite was true in only 1 of 5 patients. The major limitation in this study was the lack of a histopathologic gold standard. FDG-PET/CT tends to identify more lesions than other imaging modalities88 and Fulham et al89 found that FDG-PET/CT evidence of recurrent ovarian cancer can precede CT findings by 6 months.

Treatment for recurrent ovarian cancer may be altered on the basis of FDG-PET/CT findings in as many as 37%-63% of patients.86,89-91 These studies are in line with the results reported from the US National Oncologic PET Registry that included more than 3000 patients with ovarian or uterine cancers. A change in the management, defined as different treatment options (surgery, chemotherapy, or radiation), or switching to a nontreatment plan (observation, alternative

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470 imaging, or other noninvasive therapy, biopsy, or supportive care) occurred 38%-45% of the time in those patients after restaging FDG-PET/CT.1 Some authors evaluated the use of FDG-PET/CT for planning second-look surgery after first-line treatment. Overall, FDG-PET/CT detects clinically occult residual disease and can be helpful for surgical planning; however, the major limitation is the detection of additional microscopic disease that is found only during surgery.67 Surveillance The role of FDG-PET/CT in the surveillance setting for ovarian cancer is less well defined and is not routine clinical practice.85,88 Garcia-Velloso et al retrospectively evaluated FDGPET/CT scans in 31 patients who were clinically disease free. This surveillance scanning was found to have sensitivity, specificity, PPV, NPV, and accuracy of 55%, 88%, 78%, 71%, and 73%, respectively.85 Therapy Response There have been relatively few studies in a small number of patients and different settings evaluating FDG-PET/CT for monitoring the response of ovarian cancer to therapy, thus limiting its current role. Avril et al92 prospectively evaluated the correlation between FDG-PET/CT response and overall survival in 33 patients with advanced-stage ovarian cancer (stage IIIC-IV) receiving neoadjuvant carboplatin-based chemotherapy before cytoreductive surgery. There was a statistical correlation observed between overall survival and the FDG-PET/CT metabolic responses after the first (threshold of 20% decline in SUVmax) and third cycle of chemotherapy (threshold of 55% decline in SUVmax). The median overall survival was 38.3 months in patients who demonstrated a metabolic response to therapy compared with 23.1 months in patients who demonstrated no metabolic response. No correlation was found for clinical or CA-125 response and overall survival.92 Nishiyama et al45 evaluated the role of FDG-PET for monitoring neoadjuvant therapy in patients with advanced stages of gynecologic cancers and 8 of 21 had ovarian cancer. Using an arbitrary SUVmax cutoff of 3.8 after therapy, PET had a sensitivity of 90%, specificity of 64%, and accuracy of 76% for differentiating responders from nonresponders by histopathology. The specificity and the accuracy were further improved to 82% and 86%, respectively, if an arbitrary percentage change threshold (decline in SUVmax of 65%) was applied rather than an absolute floor. Although these results are promising, additional larger and prospective studies are needed before FDG-PET/CT is implemented more routinely in this setting.

Summary Currently, there is no established role for FDG-PET/CT imaging in screening for ovarian cancer. Although studies demonstrated that FDG-PET/CT has a high sensitivity for

detecting primary ovarian cancer, there are limitations owing to false-positive and negative findings. In the initial treatment strategy setting, FDG-PET/CT is probably most useful for confirming a diagnosis with high clinical suspicion, evaluating extent of disease to optimize debulking surgery, and predicting the odds of overall survival. The most established indication for FDG-PET/CT is in patients with clinical suspicion of recurrent ovarian carcinoma, especially in those with rising CA-125 levels (more than 35 U/mL or doubling of the nadir after primary treatment) and unremarkable or equivocal diagnostic imaging findings. There are data showing FDG-PET/CT to be consistently superior to CT alone in the detection of recurrent ovarian cancer. Many retrospective studies continue to demonstrate the limited ability of FDG-PET/CT imaging to detect lesions less than 5-10 mm in maximum diameter. The roles of FDG-PET/CT imaging in ovarian cancer treatment response are less well explored, and although initial data are promising, more evidence is needed in this setting for routine implementation.

Endometrial Epidemiology, Clinical Presentation, and Prognosis Endometrial cancer is the most common invasive gynecologic malignancy.50 There are 2 main subtypes, endometriod (80%90%) and nonendometrioid.93 The most common histology is adenocarcinoma, usually well or moderately differentiated. The less common nonendometrioid subtypes, serous and clear cell, have a poor prognosis. Unlike ovarian cancer, up to 25% of cases occur in premenopausal patients.94 The main risk factor is increased unopposed estrogen, which is associated with menopause, nulliparity, obesity, anovulation, and polycystic ovarian syndrome. Patients with Lynch syndrome also have an increased risk for developing endometrial cancer. In postmenopausal patients, dysfunctional bleeding is usually detected early. Owing to the early detection, more than 70% of patients have stage I disease at presentation.8 Serous and clear cell carcinoma have a high tendency for myometrial invasion, vascular invasion, and peritoneal carcinomatosis.95 Prognosis is related to the stage and grade of tumor at diagnosis, with a 5-year overall survival of 80%-90% for stage I disease, 70%-80% for stage II disease, and 20%-60% for stage III-IV disease.96,97

Clinical Staging and Pattern of Spread FIGO staging is usually performed surgically by exploratory laparotomy, total abdominal hysterectomy, bilateral salpingooophorectomy, and peritoneal lavage. Lymphadenectomy is also advised with high-risk stage I disease and in patients with serous or clear cell cancer78 to help assess the need for adjuvant chemotherapy. Clinical staging may understage up to 22% of patients98 and imaging may be able to assist in planning the optimal course of treatment.

Gynecologic oncologic imaging with PET/CT The initial spread is by invasion of the myometrium into the cervix or from the fallopian tubes into the ovaries. Then, there is local invasion to other organs of the pelvis. The likelihood of nodal spread increases as the depth of myometrial invasion increases. Nodal disease is also linked to tumor histologic grade. Tumors from the middle and inferior uterus drain to the parametrial and obturator nodes. Tumors from the proximal body and fundus drain to the common iliac and para-aortic nodes.99 The literature on the role of FDG-PET/CT specifically in endometrial cancer is limited but summarized in the following section.

FDG-PET/CT for the Initial Treatment Strategy US and MRI are the primary modalities for the diagnosis of endometrial cancer. In patients with postmenopausal bleeding, a threshold of 5 mm was found to have a diagnostic sensitivity of 96% by the Society of Radiologists in Ultrasound.100 MRI is considered the most accurate imaging technique for preoperative assessment of myometrial invasion.101 Owing to limitations of spatial resolution, FDG-PET/CT is unlikely to replace US or MRI. The major roles of FDG-PET/CT for the initial treatment strategy in endometrial cancer are to exclude the presence of lymph node metastases and identify distant metastases. This allows the avoidance of surgical staging in poor candidates. Suzuki et al102 found a sensitivity of 83.3% for FDG-PET in the detection of distant metastases vs only 66.7% for CT and MRI. As in other malignancies, the sensitivity of PET/CT

471 decreases with decreasing tumor size. Kitajima et al103 found FDG-PET/CT to be 93.3% sensitive for detecting tumors greater than 10 mm in the lymph nodes, but this decreased to 66.7% for lesions between 5 and 9 mm and to 16.7% for lesions smaller than 4 mm.

FDG-PET/CT for the Subsequent Treatment Strategy The other major contribution of FDG-PET/CT for the assessment of endometrial cancer is in the early assessment of disease recurrence after therapy. Patients may present with vaginal spotting, as local recurrence usually occurs at the vaginal apex. Similar to other malignancies, CA-125 evaluation and CT have been used in the posttherapy follow-up of patients, but again CA-125 evaluation is not specific and posttherapeutic changes are difficult to differentiate from recurrent disease on anatomical imaging alone. FDG-PET/CT detected recurrent endometrial cancer (Fig. 6) and was found to have sensitivity and specificity ranging from 93%-100% and 78%-93%, respectively, for the detection of recurrent disease (Table 4).104-106 In another study, Park et al107 showed that FDG-PET/CT findings resulted in a change in clinical management in 21.9% of 64 patients with recurrent disease. Whether the changes in clinical management ultimately affected patient outcome was not described.

Other Gynecologic Cancers The gynecologic cancers outside of the main 3 discussed so far are reasonably rare in comparison. Owing to the

Figure 6 A 72-year-old woman with endometrioid-type endometrial carcinoma had a rising CA-125 level. There were 2 FDG-avid bilateral external iliac lymph nodes and an FDG-avid perisplenic nodule (arrows) which were only borderline abnormal size on diagnostic CT.

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472 Table 4 Endometrial Recurrence Detection Reference

n

Population

Belhocine104 FDG-PET Distant recurrence

34

Asymptomatic

SN (%)

SP (%)

PPV (%)

NPV (%)

96

78

89

91

105

Saga FDG-PET CT or MRI CA-125 Kitajima, 2008103 FDG-PET FDG-PET/CT

21

Asymptomatic

100 85 100

88 86 71

30

Symptomatic

80 93

80 93

SN, sensitivity; SP, specificity.

infrequent diagnoses of uterine sarcoma and vaginal and vulvar cancers, there is a scarcity of information regarding the value of FDG-PET/CT imaging for these specific malignancies.

Uterine Sarcoma Uterine sarcomas are aggressive, but rare, tumors representing approximately 2%-8% of uterine malignancies.108,109 Uterine sarcomas are categorized into 3 subtypes—carcinosarcoma, leiomyosarcoma, and endometrial sarcoma—and have a wide range of histologic appearances, including myomatous, osteous, and stromal.108 The tumor markers commonly used to follow these patients are lactate dehydrogenase and CA-125. Clinically, the disease often appears confined to the uterus. However, Yamada et al110 retrospectively upstaged up to 61% of the 62 patients following surgery. The spread of disease is felt to be hematogenous, which is similar to that seen in endometrial cancer.110 The prognosis is poor, and uterine sarcomas are responsible for a large number of deaths in women with uterine cancer. Regarding imaging evaluation for uterine sarcoma, they do accumulate FDG (SUVmax reported between 3 and 6.3 in a study), but the use of FDG-PET/CT is not well defined.111 The possible utilities of FDG-PET/CT for uterine sarcomas are differentiating between low-grade and high-grade tumors and evaluating for response and residual disease after therapy. This is based on data in other types of bone and soft tissue sarcomas.112-115 FDG-PET/CT has been reported to have a higher detection rate compared with CT alone for the detection of extrapelvic recurrence. The sensitivity of PET/CT was 100% compared with 85.7% for CT.116,117 Park et al118 evaluated 36 patients and found FDG-PET/CT to have a sensitivity, specificity, accuracy, PPV, and NPV of 92.9%, 100%, 94.4%, 100%, and 80%, respectively, in symptomatic patients and 87.5%, 95.5%, 93.3%, 87.5%, and 95.5%, respectively, in asymptomatic patients. They also found that FDG-PET/CT altered the treatment plan in 33.3% of the patients with suspected recurrence.118

Vaginal Carcinoma Vaginal carcinoma accounts for less than 3% of all gynecologic malignancies,119 and the squamous cell carcinoma histology accounts for close to 80% of the reported cases.120 The risk factors for these include early coitus, multiple sexual partners, smoking, diethylstilbestrol exposure while in utero, and HPV.121-123 Tumor spread is typically by local invasion. Hematogenous spread to the lungs and lymphatic spread can also occur. The lymph node drainage pattern varies, depending on the location of tumor. Tumor in the upper third of the vagina generally drains to the obturator and internal and external iliac lymph nodes. Primary tumors in the lower third of the vagina often drain to the femoral and inguinal lymph nodes.124 Isolated studies using FDG-PET/CT in vaginal cancer are limited. Lamoreaux et al125 compared CT alone with FDGPET/CT in 23 patients. FDG-PET/CT had a sensitivity of 100% for the detection of the primary tumor, whereas CT was only 43% sensitive. FDG-PET/CT also detected metastatic lymph nodes in 35% of patients compared with 17% detected by CT.125

Vulvar Carcinoma Vulvar carcinoma accounts for around 4% of all gynecologic malignancies and most have a squamous cell histology.126,127 The typical pattern of spread involves lymphatic dissemination, draining primarily to the ipsilateral inguinal lymph nodes. If there is tumor extension to the midline or clitoris, the bilateral inguinal lymph nodes can be involved. Following the inguinal lymph nodes, the tumor spreads to the pelvic nodes.128 There is a high rate of lymph node involvement even with small tumors; for example, tumors that are 5 mm or less can be associated with lymph node metastases in up to 20% of cases.127 Lymph node metastases are an important prognostic factor in vulvar cancer. Upstaging from stage I (no lymph node involvement) to stage III (nodal involvement) decreases the 5-year overall survival from 97%-50%.129 The use of FDG-PET/CT in patients with vulvar cancer is unclear. It may be used in the staging of invasive vulvar tumors owing to the high prevalence of regional metastases. The

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473

rationale for using FDG-PET/CT is that vulvar cancers have the same histology as cervical squamous cell carcinoma; therefore, metabolic activity should perform in a similar manner (Fig. 7). While researching this topic, no studies evaluating vulvar cancer with FDG-PET/CT imaging were discovered.

Additional Challenges in FDGPET/CT Interpretation in Gynecologic Malignancies Although both nonmalignant and physiological processes in the pelvis can make the interpretation of FDG-PET/CT findings in this region challenging,75,130-132 knowledge of these entities and patterns can avoid misinterpretation. Some of the most common findings are related to the cyclic changes that occur as part of the menstrual cycle in premenopausal women. The endometrial uptake of FDG is cyclical, increasing in the ovulatory and menstrual phases.131 This is typically seen as a linear uptake fusing to the midline uterus or endometrial cavity (Fig. 8). In a premenopausal woman with cervical cancer, uptake in the endometrium does not necessarily mean uterine invasion, but in a postmenopausal women, it is very concerning. Unilateral or bilateral FDG uptake can also be seen in the ovaries, particularly in the late follicular to early luteal phase of the menstrual cycle (Fig. 9).133 In a study, physiological uptake was seen in 33% of premenopausal women during the late follicular to early luteal phase.134 Follicular uptake was described as typically spherical and less intense than the discoid uptake of a corpus luteal cyst. A postulated mechanism is increased Glut-3 expression and glucose metabolism in the ovaries in the preovulatory phase of the menstrual cycle.135 Knowledge of the timing of the patient's menstrual status and timing of the FDG-PET/CT during the cycle is helpful for interpretation.131 Increased FDG uptake in the ovaries of postmenopausal woman is abnormal and warrants further investigation. Furthermore, in a cancer population, fertility preservation is a common pretherapy intervention and can yield false-positive results. This involves the banking of mature oocytes or embryos after gonadotropin stimulation. The hyperstimulated ovaries have been reported to demonstrate increased FDG uptake.136 The menstrual and ovulatory phases can also cause increased FDG uptake in uterine fibroids.131 Many patients

Figure 8 A 39-year-old premenopausal woman presented for FDGPET/CT for the evaluation of thyroid carcinoma. The focal FDG uptake, just left of midline in the uterus, was physiological in the endometrium related to the patient's menstrual cycle as the patient reported menstruating at the time of the PET/CT scan.

undergoing FDG-PET/CT have benign uterine leiomyomas. FDG uptake is generally higher in degenerated leiomyoma compared with nondegenerated leiomyomas.137 However, there is substantial overlap between malignant transformation, degenerated leiomyoma, and nondegenerated leiomyomas, making differentiation at a single imaging time difficult (Fig. 10). It is sometimes difficult to distinguish physiological excretion of FDG in the ureters and bladder from primary or recurrent malignancy in the pelvis, particularly after undergoing surgery or radiation or both. Detection of invasion into the bladder wall and small bladder wall lesions may be obscured, but they should be suspected if there is effacement of perivesical or perirectal fat. Some have advocated for catheterization of the urinary bladder during the study,75,130-132 but it is not routinely done in many institutions. In our experience, delayed imaging of the

Figure 7 Intensely FDG-avid invasive squamous cell carcinoma of the vulva seen on an initial staging PET/CT scan.

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Figure 9 A 37-year-old premenopausal woman undergoing her FDG-PET/CT scan during the late follicular phase of her menstrual cycle. There is intense but physiological uptake in the right ovary.

pelvis, after voiding, can also be helpful for distinguishing tumor uptake from physiological uptake in the ureter or bladder. Tumor uptake typically remain in the same place or increases whereas urine uptake may be expected to move or clear. As with all tumor types, inflammatory and infectious process can also have increased FDG uptake. The history and patterns of uptake are often the most helpful for coming to the correct interpretation. FDG uptake along the surgical bed or postradiation site can be seen at various points following the procedures,132 but it may be accompanied by typical postsurgical changes on the accompanying CT, for example, linear scarring. Finally, metallic prosthetic implants such as hip replacements, intrauterine devices, or surgical clips can cause beam hardening on CT, which consequently can result in attenuation correction artifacts on the PET component of the study.132

cancer, and 60Cu-ATSM and 64Cu-ATSM PET for the assessment of tumor hypoxia in cervical carcinoma. These agents are still investigational and have not been used in routine clinical practice. 11

C-methionine

Unlike FDG-PET, 11C-methionine is not renally excreted, resulting in little or no activity in the urinary bladder. This obviously helps in the evaluation of gynecologic malignancies. Lapela et al evaluated 14 patients with cervical or endometrial carcinoma. All primary tumors showed increased 11Cmethionine uptake, with a mean SUV of 8.4.138 The mean SUV for the normal endometrium was 4.6. The study also demonstrated that moderate or poorly differentiated tumors showed greater 11C-methionine uptake than well-differentiated tumors did.138 11

Non–FDG-PET/CT Several other radiopharmaceuticals besides FDG have been studied for gynecologic malignancies, including 11C-choline for cervical and endometrial cancer, 11C-methionine for cervical, ovarian, and endometrial cancer, FES for endometrial

C-choline

Torizuka et al139 compared FDG with 11C-choline in 18 patients with gynecologic malignancies. The primary tumor was detected by 11C-choline in 16 of 18 patients, as compared with 14 of 18 by FDG. Although primary lesion detection appeared promising, there were several limitations of using

Figure 10 A 66-year-old postmenopausal women referred for FDG-PET/CT to evaluate for lymphoma. There is intense FDG uptake in an enlarged uterus, which was subsequently found to be related to a degenerating uterine fibroid. FDG uptake is generally higher in degenerated leiomyoma compared with nondegenerated leiomyomas.137 However, there is substantial overlap of FDG uptake between malignant transformation, degenerated leiomyoma, and nondegenerated leiomyomas, making differentiation at a single imaging timepoint difficult.

Gynecologic oncologic imaging with PET/CT 11

C-choline, including lower SUVs compared with FDG, false positives in pelvic inflammatory disease and atypical hyperplasia of the endometrium, and inability to distinguish iliac lymph node metastases because of adjacent intense physiological intestinal activity.139

18

F-fluoro-17-beta-estradiol

18

F-FES-PET has been evaluated in endometrial cancer for imaging the estrogen receptor, and 18F-FES uptake can be visualized in endometrial hyperplasia as well as endometrial cancer, but to a lesser degree.140-143 This pattern of uptake is opposite that of FDG, which is typically higher in carcinoma than hyperplasia. Studies have suggested that FES-FDG ratios provide the most useful information for differential diagnosis and prognosis.142,143 Higher FDGFES ratios were reported for endometrial carcinoma than for endometrial hyperplasia.142 In a study, Tsujikawa et al143 reported a higher FDG-to-FES ratio (3.6) in high-risk carcinoma than in low-risk carcinoma (1.3) and hyperplasia (0.3). Using the optimal cutoff value of 2.0 for the FDG-to-FES ratio employing receiver operating characteristic analysis, the sensitivity was 73%, specificity 100%, and accuracy 86% for predicting high-risk vs low-risk carcinoma. This was higher than the 77% accuracy for MRI. Using a ratio of 0.5 had an accuracy of 100% for the correct diagnosis of carcinoma vs hyperplasia. The authors concluded that endometrial carcinoma reduces estrogen dependency with increased glucose metabolism as it progresses to a higher stage or grade.143

64

Cu-ATSM and 60Cu-ATSM

Grigsby et al144 prospectively investigated the use of 60CuATSM-PET for separating hypoxic vs nonhypoxic phenotypes in 15 patients with cervical cancer. The 4-year overall survival was better for the 9 patients with nonhypoxic tumors (75%) than for the 6 with hypoxic tumors (33%). Dehdashti et al prospectively evaluated 14 patients with locally advanced cervical carcinoma. They assessed whether pretherapy 60Cu-ATSM imaging could predict response to radiation and chemotherapy. Tumor uptake of 60Cu-ATSM was inversely related with progression-free and overall survival. In addition, the frequency of locoregional nodal metastases was greater in hypoxic tumors. FDG uptake did not correlate with 60 Cu-ATSM uptake. There was no significant difference in FDG uptake between hypoxic and nonhypoxic tumors.145 They also prospectively evaluated another 24 patients. In this study, the 60Cu-ATSM uptake was inversely related to progression-free survival. The 3-year progression-free survival was 71% in patients with nonhypoxic tumors and 28% in patients with hypoxic tumors.146 In a more recent study, Lewis et al prospectively studied 10 patients with cervical carcinoma. They concluded that the image quality obtained with 64Cu-ATSM was better than that with 60Cu-ATSM because of lower noise.147

475

Conclusions FDG-PET/CT has been evaluated in a variety of gynecologic malignancies in a variety of settings and is approved by the CMS for the initial and subsequent treatment strategies of these malignancies. In cervical cancer, FDG-PET/CT appears to be most valuable for initial staging, radiation therapy planning, and detection of recurrent disease. For ovarian cancer, the most value of FDG-PET/CT appears to be for detecting recurrent disease in the setting of rising CA-125 level or with unremarkable or equivocal anatomical imaging findings. Initial studies evaluating response to therapy are promising and further work in this area is needed. As new tracers are being developed, comparisons with patient outcomes and standards of care (eg, FDG-PET/CT) will be needed.

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CT.

FDG-PET/CT has been evaluated in a variety of gynecologic malignancies in a variety of settings and is approved by the Centers for Medicare & Medicaid...
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