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Correlative Imaging of the Female Reproductive System

Sanaz Katal¹, Akram Al‐Ibraheem², Fawzi Abuhijla³, Ahmad Abdlkadir², Liesl Eibschutz⁴, and Ali Gholamrezanezhad⁴

¹ Nuclear Medicine Fellow, Medical Imaging Department, St Vincent’s Hospital Melbourne, Australia

² Department of Nuclear Medicine, King Hussein Cancer Center, Amman, Jordan

³ Department of Radiation Oncology, King Hussein Cancer Center, Amman, Jordan

⁴ Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

Introduction

Gynecologic malignancies involve the female reproductive organs and are an important cause of morbidity and mortality worldwide. There are five main types of gynecologic cancer: vaginal, vulvar, cervical, endometrial, and ovarian. This chapter will primarily discuss the latter two malignancies, endometrial and ovarian. Endometrial cancer is the most prevalent gynecologic cancer, primarily affecting women over 50 years old [1]. The majority of endometrial cancer cases are detected early, with a history of abnormal vaginal bleeding reported as the most common symptom [2–5]. While ovarian cancer is the second most common gynecologic cancer, accounting for roughly 4% of all cancers among women, it is the leading cause of gynecologic cancer‐related death [6]. The high mortality rate associated with ovarian cancer can be attributed to delayed detection, as most ovarian cancer patients present in a later stage.

Background: Endometrial Cancer

The first section of this chapter will discuss endometrial cancer, a malignancy that begins in the endometrial lining of the uterus. Conditions that promote higher estrogen exposure are known to increase the risk of endometrial cancer development, including hormonal replacement therapy, obesity, tamoxifen usage, early menarche, late menopause, nulliparity, and polycystic ovarian syndrome history [7–9]. The main prognostic risk factors for endometrial cancer include histological grade, depth of myometrial invasion, cervical invasion, and lymph node status [10]. Histologically, endometrial cancer is subdivided into two subtypes: type I (80–85%) and type II (10–15%). Type I is estrogen‐dependent, affects younger women (pre‐menopausal or peri‐menopausal women), and is typically detected early with presentation of abnormal vaginal bleeding. Type I endometrial cancer is a grade 1–2 endometrioid adenocarcinoma with a favorable prognosis (5‐year survival rate of 80%). Type II endometrial cancer, on the other hand, affects older women (post‐menopausal), is frequently identified at an advanced stage (60%), and can proceed to peritoneal carcinomatosis. On a histopathological level, type II endometrial cancer encompasses grade 3 endometrioid adenocarcinomas, as well as other uncommon etiologies such as clear cell carcinoma, undifferentiated serous carcinoma, and carcinosarcoma. Type II endometrial carcinoma is known for its aggressive behavior, with an overall 5‐year survival rate of 40% [3, 5, 7].

Recent studies have introduced a variety of imaging modalities such as ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), and fluorodeoxyglucose (FDG) positron emission tomography/CT (PET/CT) to play a complementary role in the pre‐treatment assessment of endometrial cancers. This pre‐operative imaging not only plays a crucial role in the pre‐treatment evaluation of endometrial malignancies but also provides vital information post‐intervention. For instance, pelvic MRI is often employed to evaluate disease recurrence, and in certain scenarios FDG PET/CT can be utilized in post‐therapy surveillance due to its high diagnostic performance in identifying recurrent or residual disease.

By elucidating the role of correlative imaging (using US, CT, MRI, and FDG PET/CT) in women with endometrial cancers, clinicians can optimize decision‐making in these patients and better understand how and when diagnostic imaging modalities should be performed.

Staging/Pre‐operative Assessment

Currently, surgical staging of endometrial cancer is performed according to the International Federation of Gynecology and Obstetrics (FIGO) guidelines, along with the World Health Organization (WHO) criteria for histological classification [11]. The FIGO recommendation for standard surgical staging of endometrial cancer includes abdominal exploration, peritoneal cytology washing, hysterectomy, bilateral salpingo‐oophorectomy, pelvic and paraaortic lymphadenectomy, and biopsy of any suspicious lesions found during surgery. As accurate determination of the tumoral extent and lymph node status impacts the type and extent of surgical intervention, pre‐operative staging with noninvasive diagnostic methods is vital for identification of optimal treatment. In addition, patients with a medical contradiction for surgical staging, or those with an equivocal pelvic examination, will greatly benefit from these noninvasive techniques. In an effort to identify high‐risk patients, and pre‐operatively predict extrauterine extension, a multitude of imaging techniques have been evaluated, including conventional morphologic and novel molecular imaging tools. With the emergence of less invasive surgical techniques over recent decades, pre‐treatment imaging is now included in the updated FIGO staging system [12].

Although surgical staging is primarily utilized to evaluate endometrial cancer prognosis [13, 14], it is highly invasive and may only be advantageous in select patient populations. While full lymphadenectomy is oftentimes utilized in the surgical staging of uterine cancers, this technique remains controversial, particularly in patients with early‐stage disease [15]. In addition, surgical lymphadenectomy increases the likelihood of immediate and delayed complications. Thus, noninvasive detection of lymph node metastasis would enable us to tailor the extent of surgery and prevent unnecessary lymphadenectomy. Furthermore, pre‐surgical tools that accurately reveal distant metastases can assist in the development of adjuvant therapies.

The Role of Imaging

Transvaginal Sonography

As post‐menopausal bleeding (PMB) is the most commonly presenting symptom of endometrial cancer, a thorough investigation is essential in women presenting with this finding. The initial diagnostic step when working up PMB is transvaginal sonography (TVS), the modality of choice when evaluating endometrial thickness. This technique can reliably rule out endometrial cancer, particularly if a normal‐appearing endometrium with a thickness of less than 3 mm is visualized [16]. While the upper threshold value suggested for endometrial thickness in post‐menopausal women is 4 mm or 5 mm, cut‐off values in pre‐menopausal women might depend on many factors, such as the menstrual cycle [17]. Therefore, no standard specific values have been defined in this group yet.

In cases where the endometrial thickness is greater than 5 mm, the sonogram should be considered abnormal. A meta‐analysis reported that an endometrial thickness of 5 mm in post‐menopausal women could detect endometrial cancers with 96% sensitivity and acceptable specificity [18]. Moreover, a focal endometrial abnormality or indistinct endometrial margins in TVS of women with PMB should be considered abnormal, warranting tissue sampling or hysteroscopy with dilation and curettage (D&C) [19]. When TVS is unable to definitively characterize endometrial abnormalities, additional techniques such as transabdominal sonography and hysterosalpingography can be useful. Three‐dimensional (3D) sonography and color‐Doppler sonography have been suggested for evaluation of endometrial volume and tumoral vascular structures studies, predictors of endometrial cancer. However, there is no agreement on a certain cut‐off value for the time being [20].

Various scoring models have been proposed to predict the risk of endometrial cancer using TVS results [21]. TVS parameters of endometrial thickness, Doppler score, interrupted endo‐myometrial junction, and irregular surface on gel infusion sonography are among the most important features for predicting endometrial cancer. Ultimately, increased endometrial thickness and abnormal morphologic findings of the endometrium on sonography should raise the possibility of uterine malignancies in women presenting with PMB.

Another advantage of TVS is its ability to assess deep myometrial invasion with a moderate to high diagnostic accuracy in endometrial cancer [22, 23]. Some studies have reported that when performed by expert practitioners, TVS provides a diagnostic accuracy comparable to that of MRI in the pre‐operative local staging of endometrial cancers. Thus, while MRI is the gold standard technique for this purpose, TVS may be a feasible first‐line imaging modality in the assessment of women with suspected or proved endometrial cancer.

MRI

While TVS remains the preferred modality for screening and primary detection of endometrial cancer, pelvic MRI has emerged as an effective method for assessing disease status and treatment planning. Due to its excellent soft‐tissue resolution, MRI is considered the most accurate imaging tool in the pre‐operative evaluation of endometrial cancers [24].

Primary detection: While the diagnostic performance of MRI and TVS for detecting endometrial cancer in PMB is roughly equivalent, MRI is time‐consuming, costly, and often only has limited availability. Thus, MRI should be considered as a second‐line imaging tool, particularly when TVS is not feasible or diagnostic, or when precise pre‐operative staging is needed [25].
Pre‐operative local staging: The American College of Radiology (ACR) recommends MRI to be the modality of choice in the pre‐treatment staging, evaluation of therapy response, and tumoral recurrence [26]. The National Comprehensive Cancer Network (NCCN) guidelines advocate MRI in the pre‐treatment evaluation of endometrial cancer type II and when cervical invasion is suspected [27]. This is primarily due to the ability of pre‐operative MRI to predict the extent of lymph node metastasis and assess disease stage, based on the depth of myometrial infiltration and cervical invasion. The results of pre‐operative MRI can then guide practitioners in triaging patients for neoadjuvant therapy or selecting the proper surgical techniques. Thus, MRI has proven to be the most effective imaging modality for this purpose due to its higher intrinsic resolution and multiplanar capability. To render the highest diagnostic accuracy for endometrial cancer local staging, clinicians should consider an integrated approach combining dynamic contrast‐enhanced (DCE) and diffusion‐weighted (DWI) MRI.
Endometrial cancer recurrence: While CT scanning is frequently utilized in the follow‐up of high‐risk patients to detect endometrial cancer recurrence or metastases, the vaginal vault, on the other hand, might be difficult to examine with CT. Thus, diffusion‐weighted and DCE MRI techniques may be useful in discriminating between soft‐tissue thickening after radiation therapy and inflammation or recurrent illness [9, 28]. In addition, MRI‐based techniques yield enhanced soft‐tissue resolution.
MRI versus other modalities: A large‐scale meta‐analysis on the performance of MRI, CT, and TVS in endometrial cancer staging [29] has found no significant differences in the overall performance; however, contrast‐enhanced MRI displayed a trend toward better results, particularly in the assessment of myometrial invasion. In another study by Savelli et al. [25], contrast‐enhanced MRI and TVS performed equally well in the assessment of myometrial invasion, whereas TVS displayed slightly better performance in the detection of cervical tumor spread. Consequently, these authors suggested TVS as a potential first‐line imaging modality in women with endometrial cancer, as recent sonographic technologies have allowed the development of transvaginal probes with high resolution. They also proposed that MRI should be applied only in cases with poor‐quality TVS results or if precise pre‐operative staging is crucial. However, other studies have proposed MRI as the best assessment tool for local staging of uterine carcinoma, as the MRI‐based assessment of nodal involvement or distant metastasis in uterine malignancies was comparable to CT scanning.
Abnormal MRI findings: Endometrial cancer is typically mildly hyperintense on T2‐weighted images compared to normal myometrium [7]. On noncontrast T1‐weighted images, endometrial carcinoma appears isointense with the normal endometrium and myometrium [30]. Disruption or irregularity of the junctional zone indicates an invasive malignancy, whereas a noninvasive cancer notes a normal or thickened endometrium, along with an intact junctional zone and a sharp tumor‐myometrium interface. Furthermore, cervical invasion is assumed when the cervical stroma with low‐signal intensity is thinned or disrupted by higher signal intensity endometrial cancer.

FDG PET/CT

For years, FDG PET/CT techniques have been successfully utilized in the evaluation of gynecologic malignancies as the combination of anatomic and metabolic information using hybrid FDG PET/CT allows this technique to overcome the limitations of morphological imaging alone. This technique can be used to establish a therapeutic strategy based on the diagnosis of distant metastases, as well as to diagnose recurrence after therapy, treatment response, and lymph node metastases. As a result, FDG PET/CT is being employed to enhance traditional diagnostic imaging modalities [31].

Primary diagnosis: As the research regarding the use of FDG PET/CT in the primary detection of endometrial cancer is limited, this technique has a limited role in detection and local staging in pre‐ and peri‐menopausal women [32]. Although higher grade endometrial cancers have a high FDG avidity due to increased tumor glucose metabolism, benign entities such as uterine bleeding and uterine myomas can present similarly, thus limiting the accuracy of this technique.
Pre‐operative local staging: As a recent meta‐analysis indicated that FDG PET/CT imaging has an overall pooled sensitivity, specificity, and accuracy of 72.0, 94.0, and 88.0%, respectively, for detecting lymph node metastasis in endometrial malignancy, the role of this technique in endometrial cancer is evolving [33]. Although the overall sensitivity of FDG PET/CT for the diagnosis of lymph node metastasis is modest, it compares favorably to the reported sensitivities for conventional techniques such as MRI and CT. However, roughly 45% of endometrial cancers are grade 1 and express low FDG avidity, thus FDG PET/CT is not indicated for regular pre‐operative staging in early‐stage illness. Thus, this imaging technique may only be employed in certain cases that have equivocal findings on other imaging modalities or when clinical suspicion of nodal or distant metastases is eminent (as shown in Figure 20.1) [34, 35].
Lymph node metastasis: Recent studies have evaluated the performance of FDG PET/CT in the pre‐operative detection of lymph node metastasis. Bollineni et al. described a high diagnostic ability for FDG PET/CT in evaluating lymph node metastasis pre‐operatively (with sensitivity and specificity of 72% and 95%, respectively) [33] (as shown in Figure 20.1). Although up to 25% of nodal metastasis (e.g. micro‐metastasis) might still be missed on FDG PET/CT imaging, the reported sensitivity compares favorably to other techniques such as MRI and CT. However, a study by Grigsby et al. [36] demonstrated 60% sensitivity and 98% specificity for the detection of pelvic and para‐aortic lymph node metastasis utilizing FDG PET/CT. Similar results were found by Suzuki et al. [37]. Thus, it is evident that FDG PET/CT cannot replace lymphadenectomy in most women with endometrial cancer. However, this technique is still useful for guiding systemic adjuvant therapies in patients who are poor surgical candidates and has the potential to unlock uncommon sites of metastasis (as shown in Figure 20.2).
Distant metastasis: The ability of FDG PET/CT to detect distant metastasis (as shown in Figure 20.3) makes it an excellent tool for pre‐operative staging of endometrial cancer in high‐risk patients. A study by Picchio et al. [38] noted that FDG PET/CT can accurately detect distant metastases in the abdomen and extra‐abdominal regions (with sensitivity and specificity of 100% and 96%, respectively). Therefore, FDG PET/CT will be able to add beneficial information regarding planning the treatment course in selected patients, particularly those with high‐risk endometrial cancer.
Post‐therapy assessment: To date, several studies have discussed the role of FDG PET/CT in detecting recurrent/residual disease post‐therapy or post‐surgery with curative intent and note a high diagnostic accuracy in these settings [39, 40]. This is primarily due to the ability of FDG PET/CT to identify areas of interest even when anatomical landmarks are no longer present. Thus, FDG PET/CT may play a promising role as a diagnostic tool for suspected recurrence. In addition, this technique can evaluate therapeutic response, yield important information regarding response to therapy, and predict patient outcome [41]. However, special caution should be taken when using FDG PET/CT early in post‐treatment settings, as patients who received radiation therapy, external beam radiotherapy (EBRT) and or intracavitary brachytherapy (ICBT) may have residual radiotherapy‐related inflammatory changes at this time point [42]. Ultimately, further research is necessary to identify the exact role of FDG PET/CT technologies in endometrial cancer patients.

Schematic illustration of FDG PET MIP image of a 61-year-old female patient presenting with a suspected uterine mass (left). FDG PET/CT scan showed intensely hypermetabolic uterine mass lesion suggestive of primary tumor (as shown in image A below) as well as hypermetabolic borderline sized left para-iliac and retroperitoneal lymph nodes (arrows in image B) and left supraclavicular lymph node (arrows in image C), which were confirmed to be metastasis. — **Figure 20.1** FDG PET MIP image of a 61‐year‐old female patient presenting with a suspected uterine mass (left). FDG PET/CT scan showed intensely hypermetabolic uterine mass lesion suggestive of primary tumor (as shown in image a below) as well as hypermetabolic borderline sized left para‐iliac and retroperitoneal lymph nodes (arrows in image b) and left supraclavicular lymph node (arrows in image c), which were confirmed to be metastasis.

Schematic illustration of a 70-year-old woman who proved to have endometrial cancer after total abdominal hysterectomy and bilateral salpingo-oophorectomy. — **Figure 20.2** A 70‐year‐old woman who proved to have endometrial cancer after total abdominal hysterectomy and bilateral salpingo‐oophorectomy. While her staging CT scan only showed a small nonspecific left inguinal lymph node by the CT criteria (as shown in a), the patient had an FDG PET/CT which revealed a hypermetabolic left inguinal lymph node (as shown in b and c), suggesting a metastasis, which was confirmed by histopathology.

Schematic illustration of a 53-year-old female patient who proved to have endometrial cancer after total abdominal hysterectomy. — **Figure 20.3** A 53‐year‐old female patient who proved to have endometrial cancer after total abdominal hysterectomy. Her staging work‐up showed multiple small bilateral pulmonary nodules of indeterminant significance on CT scan (as shown in a). FDG PET/CT depicted the hypermetabolic status of these lung nodules despite their small volume and correctly denoted them as metastases (as shown in b). In addition, FDG PET/CT detected para‐iliac and retroperitoneal hypermetabolic lymph node metastases.

Schematic illustration of a before treatment photograph of a 53-year-old female endometrial cancer patient. — **Figure 20.4** A 53‐year‐old female endometrial cancer patient who had a hypermetabolic enlarged right common iliac lymph node on FDG PET/CT (as shown in a, b, c). After receiving radiotherapy, this lymph node completely resolved (as shown in d, e, f). This is an example of FDG PET/CT utilization in a post‐therapy setting.

Schematic illustration of the before treatment PET image of a 66-year-old female patient with endometrial cancer. — **Figure 20.5** A 66‐year‐old female patient with endometrial cancer as shown in axial CT, PET, and FDG PET/CT images before treatment (as shown in a, b, c). After undergoing an abdominal hysterectomy and bilateral salpingo‐oophorectomy, follow up CT images showed a questionable soft tissue thickening in the right side of the pelvis with no definite metastasis (as shown in d). In addition, the patient had an FDG PET/CT that demonstrated a lesion with abnormal FDG uptake in the ride side of the pelvis, suggesting local recurrence along with hypermetabolic pelvic lymph nodes confirming the presence of regional metastatic process (as shown in e, f). This clinical picture reflects the vital role of FDG PET/CT in detecting disease recurrence postoperatively when anatomical landmarks are distorted.

Current research is focused on improving the overall quality of PET scanning, primarily through the utilization of novel agents such as methionine and choline, as well as tracers other than ¹⁸F (¹¹C, ¹³N, ¹⁵P) [43]. Combining tracers may ultimately help elucidate the molecular basis behind malignancies, allowing for more accurate differential diagnosis and personalized treatment [31]. A recent study by Tsujikawa et al. focused on conducting PET scans using 16‐[¹⁸F] fluoro‐17‐estradiol (FES) and FDG to evaluate estrogen receptor (ER) expression and FDG uptake [43]. As FES is an ¹⁸F‐labeled estradiol compound with the highest physiological activity among estrogens, it is anticipated to be beneficial for diagnosing estrogen‐dependent disorders and assessing the effectiveness of hormonal therapy. These authors ultimately identified a direct correlation between the FDG to FES accumulation ratio and the aggressiveness of the endometrial cancer [43]. Other studies have noted similar findings, with semi‐quantification of tumor FDG and FES uptake as standardized uptake values (SUV) revealing that an FDG to FES uptake ratio of ≥2 has a 91.3% accuracy in detecting uterine sarcoma [44].

When combined with glucose metabolism evaluation by FDG PET, FES PET techniques can identify estrogen‐dependent activity and differentiate benign and malignant uterine tumors. This is due to the fact that gynecological malignancies like endometrial cancer and uterine sarcomas have high glucose metabolism and low ER expression, whereas benign tumors like endometrial hyperplasia and uterine leiomyomas have low glucose metabolism and high ER expression [43].

PET/MRI

Although limited data exists regarding this technique, PET/MRI has potential diagnostic utility in endometrial cancer patients when compared to the traditional modalities of CT, MRI or FDG PET/CT. A study conducted by Tsuyoshi et al. [45] discussed the high diagnostic value of this technique, which is comparable to MRI for assessing the primary tumor, and akin to CT for assessing nodal and distant metastasis. In addition, PET/MRI imaging systems can yield high resolution soft tissue images as well as improved anatomic assessment of cancers [46]. Thus, PET/MRI could be implemented as an alternative to traditional imaging modalities for pre‐operative endometrial cancer staging [45].

Further advancements in PET/MRI technology, as well as the development of additional positron tracers and expanded availability, are expected to make PET/MRI an increasingly significant tool in the pre‐operative staging and surveillance of patients with endometrial cancer. A recent study found that fusing PET and MRI enhances the individual benefits of MRI and PET, and aids in the assessment of the primary endometrial carcinoma and overall lymph node staging [47]. By combining the advantages of PET in staging nodal and distant metastatic disease with the advantages of MRI in local staging, endometrial cancer patients can receive more accurate staging results. However, this novel technology was just recently launched into the clinical arena, thus the diagnostic value of PET/MRI for recurrent endometrial cancer and ability to assess treatment response is still unclear.

The Role of Imaging in Radiation Therapy

Prior to beginning radiation therapy, imaging is necessary to make informed treatment decisions. Radiation therapy is currently used for the management of endometrial cancer, as neoadjuvant or adjuvant therapy in relation to surgery [48]. Postoperatively, imaging plays a primary role in post‐treatment evaluation.

CT Simulation

Prior to initiating radiation therapy for endometrial cancer, CT scanning is often utilized to generate an overall treatment plan. This includes 3D model generation of the abdomino‐pelvic region for target definition and dose calculation. The organs at risk within the radiated area are also contoured to ensure the dose limit is not exceeded for these structures. For endometrial cancer, the radiation volume usually includes regional nodal chains in addition to the tumor bed and upper vagina. In addition to CT scanning, other imaging modalities as MRI and or FDG PET/CT can also be used for target guidance when fused with CT simulation scans [49].

Image Guidance

Since EBRT is primarily given over 25–30 fractions for endometrial cancer, routine images are obtained to monitor regional anatomical shifts and ensure adequate patient positioning. In addition, kilovoltage and megavoltage images aid visualization of the pelvic bony landmarks for endometrial radiation therapy. More advanced imaging forms, such as cone‐beam CT (CBCT), aid visualization of pelvic soft tissue structures and assessment of vaginal vault motion due to changes in bladder and rectal filling during therapy, particularly when sophisticated radiation techniques are used as inverse modulated radiation therapy (IMRT) [50].

Imaging in Brachytherapy

Based on pathological findings, brachytherapy can be given as monotherapy or in combination with EBRT after surgery for endometrial cancer. Imaging modalities are used for ICBT planning (as shown in Figure 20.6) using C‐arm X‐ray for two‐dimensional planning. In unresectable or recurrent endometrial cancer, US imaging oftentimes guides brachytherapy applicator insertion, and CT and MRI are utilized for three‐dimensional planning and proper dose adjustment for recurrent disease (as shown in Figure 20.7) [51, 52].