Berna Degirmenci Polack
Uterine carcinoma is one of the most common cancers in women. In this chapter, endometrial and cervical cancers are discussed in detail with different perspectives such as epidemiology, diagnostic imaging methods, staging, therapy monitoring, and prognosis. Related up-to-date literature has been reviewed and summarized on this subject. The case examples are presented to facilitate learning. In parallel with increasing use of 18F-FDG PET or PET/CT imaging in oncology, the role of nuclear medicine has recently gained acceptance in management of patients with uterine endometrial and cervical carcinomas.
Endometrial cancer, a tumor of the endometrial lining of the uterus, is the most common genital tract cancer and the fourth most common malignancy in women in developed countries worldwide.1 According to the American Cancer Society’s reports, there will be approximately 49,560 new cases of and 8,190 deaths from endometrial cancer in the United States in 2013.2 Endometrial cancer is associated with excess estrogen levels, either from endogenous or exogenous sources. Obesity and diabetes are linked to increased levels of circulating unbound endogenous estrogen, and with the epidemic of obesity, the incidence of this cancer is expected to increase. Over 80% of endometrial cancer is typical adenocarcinomas and are also known as endometrioid. Other less common types of endometrial cancer are squamous cell and undifferentiated carcinoma. Endometrial cancer can be graded on the basis of its histopathologic characteristics: Grade 1 tumors have 95% or more of the cancerous tissue forming glands; grade 2 tumors have between 50% and 94% of the cancerous tissue forming glands; grade 3 tumors have less than half of the cancer forming glands. Grade 1 and 2 tumors are known as low-grade tumors; grade 3 tumors are known as high-grade tumors.
Diagnosis and Staging
The majority of endometrial cancer cases occur in postmenopausal women. Uterine bleeding is the most frequent clinical presentation of endometrial cancer causing early diagnosis of the patients. Well-differentiated endometrial (grade 1–2) cancers are generally localized to the surface of the endometrium, whereas poorly differentiated tumors (grade 3) show myometrial invasion. The diagnosis of endometrial cancer is made by endometrial biopsy or uterine dilatation and curettage (D&C), with or without hysteroscopy. These procedures are indicated if a woman complains of unexplained postmenopausal bleeding, has abnormal glandular cells on the patient’s Papanicolaou (Pap) smear, or an ultrasonogram shows a thickened endometrial stripe. A meta-analysis has shown that the 5-mm endometrial stripe as a threshold is 96% sensitive for detecting cancer, but has a 4% false-negative rate and a 50% false-positive rate.3
The patients who are diagnosed with endometrial cancer are staged according to International Federation of Gynecologist and Obstetricians (FIGO) staging system (Table 16.1).4 Staging is based on the extent of the primary tumor, regional lymph node (LN) involvement and the presence or absence of distant metastasis. In stage 1 disease, the tumor is confined to the corpus uteri with no, or less than half thickness, of myometrial invasion (stage IA), invasion equal to or more than half of the myometrium (stage IB). In stage II, tumor invades the cervical stroma, but does not extend beyond the uterus. Stage III indicates that the tumor spreads locally and the involvement of pelvic and para-aortic lymph nodes (PALNs). The likelihood of LN involvement is related to the histologic grade of the tumor, and the presence of deep myometrial and cervical invasion. Distant metastases most commonly involve the lungs, inguinal and supraclavicular nodes, liver, bones, brain, and vagina.
The vast majority of patients presents with early stage of disease and undergo hysterectomy and bilateral salpingo-oophorectomy. Ideally, staging should be done by total hysterectomy, bilateral salpingo-oophorectomy, as well as assessment and sampling of pelvic and PALNs. The tumor is generally confined to the uterus at the time of diagnosis, with only 10% to 20% of surgically staged patients having LN metastases at the time of surgery. In relatively older patients and those with comorbid diseases, unnecessary LN sampling may increase operation duration and may cause postoperational complications. For this reason, the patients who should undergo LN sampling should be chosen before their operation.
Imaging Modalities in Staging
Magnetic Resonance Imaging and Computed Tomography
Magnetic resonance imaging (MRI) appears to be superior imaging modality compared to computed tomography (CT) for the staging of endometrial cancer. The extent of myometrial invasion and LN metastases can be evaluated by MRI. Recent guidelines for the staging of endometrial cancer with MRI involve a protocol including at least two T2-weighted turbo spin echo (TSE) sequences with high resolution in the sagittal, transversal (short uterine axis) and coronal (long uterine axis) planes and the high resolution, contrast-enhanced T1-weighted sequences. To evaluate cervical invasion, an additional section perpendicular to the axis of endocervical channel is also recommended.5,6 The reported results for a contrast-enhanced MRI in the assessment of myometrial invasion ranged from 59% to 100% for accuracy, 33% to 100% for sensitivity, and 72% to 100% for specificity. The detection of cervical stroma invasion preoperatively is very important in selecting high-risk patients eligible for radical hysterectomy including pelvic lymphadenectomy. The reported accuracy, sensitivity, and the specificity values for MRI in the evaluation of cervical invasion of endometrial carcinomas ranged from 46% to 98% for accuracy, 19% to 100% for sensitivity, and 87% to 100% for specificity.7 Table 16.2 summarizes MRI findings in different FIGO stages of endometrial cancer.7 CT is more useful to evaluate stage IV patients with distant LN or solid organ metastases such as liver, lung, and bone than MRI.
STAGING OF ENDOMETRIAL CANCER
FIGO STAGES AND CORRESPONDING MRI FINDINGS IN ENDOMETRIAL CANCER
18F-FDG PET-CT in Endometrial Carcinoma
Primary endometrial cancer usually shows an increased 18F-FDG uptake. The reported mean SUVmax for primary tumors in the studies was between 4.5 and 17.6. The SUVmax of 18F-FDG PET/CT in endometrial cancer increases with FIGO grade, the expression of GLUT-1 transporters, and the maximum tumor size. Glucose consumption in endometrial cancer, as determined by 18F-FDG PET/CT, provides valuable information about tumor activity and histology. The higher primary tumor’s SUVmax of 18F-FDG PET/CT in endometrial cancer may be associated with aggressive biologic characteristics in endometrial cancer.8–10
Small malignant tumors or malignant tumors with low cellular density may have lower SUVmax values because of volume averaging and limited spatial resolution of the system. It is also important to be familiar with the variable physiologic uptake of 18F-FDG in the normal endometrium and benign endometrial lesions. Physiologic endometrial uptake can be seen around the time of the first 3 days of menstruation phase and the ovulatory phase of the menstrual cycle of the premenopausal women. Lerman et al.8 reported that the mean endometrial SUVs in premenopausal women were 5 ± 3.2 and 3.7 ± 0.9 during the menstruating and ovulating phases, respectively, and 2.6 ± 1.1 and 2.5 ± 1.1 during the proliferative and secretory phases, respectively. They also reported that the mean endometrial SUV of postmenopausal women receiving hormonal therapy was 1.7 ± 0.7 (range: 1.1 to 2.6) and that hormonal therapy in postmenopausal women was not associated with a significant alteration in endometrial 18FDG uptake. Increased 18FDG endometrial uptake in postmenopausal women may indicate the malignancy.
Benign endometrial lesions, such as uterine leiomyomas, adenomyosis, and endometrial hyperplasia generally show mild 18F-FDG uptake. Uterine leiomyomas sometimes may show intense 18F-FDG uptake. Chura et al.11reported leiomyomas showing very high SUVs in three patients: One case was an ordinary leiomyoma of 13 mm (SUVmax: 16), the second was a cellular leiomyoma of 33 mm (SUVmax: 9.3), and the third was a stromomyoma of 10 mm (SUVmax: 6). The exact mechanism responsible for high FDG uptake in leiomyomas is unclear. The FDG uptake in leiomyomas would be related to several factors including hormonal dependency, cellularity (the number of viable tumor cells), vascularity (microvessel density), tumor cell proliferation (the expression of growth factors such as basic fibroblast growth factor, transforming growth factor β, granulocyte-macrophage colony-stimulating factor, and Ki-67 and their receptors), expression of glucose transporter 1 (GLUT-1) and hexokinase, the existence of endometrial tissue, and the presence of inflammatory cells (12–14). Leiomyomas with FDG uptake are more common in premenopausal women than postmenopausal women. Nishizawa et al.12 reported that the incidence of 18FDG uptake in premenopausal women with leiomyomas (10.4% of 164 women) was higher than that in postmenopausal women with leiomyomas (1.2% of 338 women). They also reported that leiomyoma in premenopausal women tends to show higher uptake during a luteal phase than during menstrual flow and the follicular and per ovulatory phases. In their study, degenerated leiomyomas showing high signal intensity on T2-weighted MR images tend to show higher FDG uptake than nondegenerated leiomyoma showing low signal intensity on T2-weighted MR images. However, Kitajima et al.13 showed that nondegenerated leiomyoma can often show high uptake. Adenomyosis and endometrial hyperplasia generally show mild FDG uptake in premenopausal women. Higher 18F-FDG uptake during the menstruating and ovulating phases can be seen in adenomyosis.
Initial Staging with 18F-FDG PET or PET/CT
Compared to MRI, 18F-FDG PET/CT has a limited diagnostic role in the local staging of endometrial cancer. 18F-FDG PET/CT is a useful imaging modality in assessing LN involvement and distant organ metastases. In a recently published meta-analysis, it has been reported that the overall pooled estimates of sensitivity and specificity of FDG PET or PET/CT scan in the detection of pelvic lymph node (PLN) and/or PALN metastasis were 63% (95% confidence interval (CI), 48.7% to 75.7%) and 94.7% (95% CI, 90.4% to 97.4%), respectively. The positive likelihood ratio (LR+) was 10.465 (95% CI, 5.646 to 19.396) and the negative likelihood ratio (LR−) 0.399 (95% CI, 0.284 to 0.560). The overall diagnostic accuracy (Q* index) was 89.5%. The authors concluded that the high positive likelihood value confirms the reliability of a positive FDG PET or PET/CT to detect PLN and/or PALN metastasis in patients with untreated endometrial cancer. According to this meta-analysis, the surgeons may use FDG PET/CT when selecting appropriate patients on whom to perform lymphadenectomy.14
Kitajima et al. compared the three different imaging modalities such as contrast-enhanced 18FDG PET/CT scan with low-dose CT (ldCT), followed by full-dose CT with IV contrast, and contrast-enhanced CT (ceCT) in detecting PLN and/or PALN metastases in endometrial cancer patients. They investigated 358 LNs in 40 patients. They reported the sensitivity, specificity, and accuracy of PET/ceCT were 61.4%, 98.1%, and 93.6%, respectively, whereas those of PET/ldCT were 52.3%, 96.8%, and 91.3%, respectively, and those of enhanced CT were 40.9%, 97.8%, and 90.8%, respectively by region-based analysis. In this study, PET/ceCT had the best sensitivity among the three imaging modalities, a significant difference was observed only between PET/ceCT and enhanced CT. Although PET/ceCT had better sensitivity and accuracy than PET/ldCT, the differences between the two imaging methods did not reach statistical significance.15
MRI and PET/CT findings in 53 patients with endometrial cancer who underwent preoperative work up were compared by Park et al.16 They obtained T1-weighted spin-echo, T2-weighted transverse fast spin-echo, and contrast-enhanced MRI images. FDG PET/CT images were obtained using ldCT imaging protocol. In their study, they histopathologically examined all the primary tumors and 1,464 LNs from 137 LN areas. They found that for the primary tumors, MRI and 18FDG PET/CT showed no differences in sensitivity (91.5% versus 89.4%), specificity (33.3% versus 50.5%), accuracy (84.9% versus 84.9%), positive predictive value (PPV) (91.5% versus 93.3%), and negative predictive value (NPV) (33.3% versus 37.5%). 18FDG PET/CT had better sensitivity in detecting LN metastases than MRI but the significance did not reach the statistical significance. The sensitivity, specificity, accuracy, PPV, and NPV of MRI for detecting metastatic LNs on LN area-by-area analysis were 46.2%, 87.9%, 83.9%, 28.6%, and 94%, respectively; but the corresponding figures for 18FDG PET/CT were 69.2%, 90.3%, 88.3%, 42.9%, and 96.6%, respectively. In the study, 18FDG PET/CT showed high sensitivity, specificity, accuracy, PPV, and NPV for detecting distant metastases such as 100%, 93.8%, 92.5%, 62.5%, and 100%, respectively.
18FDG PET/CT has moderate sensitivity, specificity, and accuracy in detecting primary tumors and LNs metastases in patients with endometrial cancer indicating that 18FDG PET/CT cannot replace surgical staging. In LN staging, the main reason for false-negative results is the size of the LNs. The sensitivity of detecting LNs metastases increases with the size of LNs. The LNs that are less than 5 mm in diameter can be missed by FDG PET/CT imaging. The major benefit of 18FDG PET/CT in staging endometrial cancer is to detect distant organ metastases which may alter subsequent patient management.
In Figures 16.1 and 16.2, 18F-FDG PET/CT demonstrated distant metastases which could not be found in MRI. The PET/CT findings changed the staging of these patients.
Recurrence Detection and Restaging with 18F-FDG PET or PET/CT
Although endometrial cancer is very common, there is still no consensus about the follow-up for patients after therapy. Most institutions have their own follow-up strategies such as physical examination, Pap smear, tumor marker assays, chest x-rays, CT, and MRI. The common sites of endometrial cancer recurrence are the vagina, pelvic and PALNs, the peritoneal cavity, and lungs. Other sites of hematogenous spread, such as bone, liver, and brain, can occur but are uncommon. Vaginal recurrence of this cancer is the most common site, occurring in approximately 7% of cases. Vaginal recurrence is detected by the occurrence of bleeding and is apparent on vaginal examination. Vaginal recurrence can be successfully treated in 50% to 75% of cases. Other sites of recurrence, with the exception of isolated PLNs, are rarely salvaged. To manage treatment in patients with recurrence, it is important to describe whether the recurrence is either local or disseminated. For the patient who has an isolated site of recurrence, surgery and/or radiotherapy may be curative or provide palliation, but with disseminated recurrent disease only palliative treatment can be considered. The early detection of recurrence of the tumor in especially asymptomatic patients may have a significant effect on survival.17–20
FIGURE 16.1. A 68-year-old woman with pathologically proven endometrial carcinoma. 18FDG PET/CT was performed to evaluate the stage of the disease. Computed tomography (CT) shows a large mass in the uterus and multiple pelvic lymph nodes (PLNs) which are less than 1 cm in diameter (A). Magnetic resonance imaging shows a uterine mass which is 7.5 × 4 cm in diameter causing distortion at cavity of the uterus and suspicious PLNs (arrows ) next to the uterus on the right side (B). 18FDG PET/CT demonstrates increased 18FDG in the mass of the uterus (arrowhead ) and pelvic multiple PLNs (arrows ) which are consistent with a malignant uterus mass and PLN metastases (C). (continued )
18F-FDG PET or PET/CT is a promising imaging modality in detecting recurrent disease in patients with endometrial cancer. There are published studies investigating the diagnostic role of 18F-FDG PET or PET/CT in detecting recurrent disease in the literature. Table 16.3 shows the summary results of the studies. The sensitivity, specificity, and accuracy of 18F-FDG PET or PET/CT to detect recurrent disease in endometrial cancer are all almost 90% and more. The 18F-FDG PET or PET/CT studies have an impact on clinical decisions in between 22% and 73% of the patients. Park et al.25 showed that 18F-FDG PET/CT especially revealed true positive studies in elevated tumor markers and negative CT findings. In this study, 18F-FDG PET/CT showed recurrence in 3 out of 64 asymptomatic patients without evidence of tumor recurrence. The rest of the patients showing no evidence of recurrent disease in FDG PET/CT images were free of recurrence. The sensitivity, specificity, accuracy, PPV, and NPV of FDG PET or PET/CT in asymptomatic patients without evidence of recurrence based on tumor markers and/or CT have been reported as 100%. The optimum time to image in the asymptomatic patients is still uncertain. Kitajima et al.26 compared contrast-enhanced FDG PET/CT (PET/ceCT) and low-dose nonenhanced FDG PET/CT (PET/ldCT) to evaluate the diagnostic value of the two tests in detecting recurrence disease. The sensitivity, specificity, and accuracy have been reported as 90%, 97% and 95% for PET/ceCT and 83%, 94% and 91% for PET/ldCT, respectively. Although there was no statistically significant difference between the two tests, four equivocal regions (local recurrence, pelvic LN metastasis, liver, and muscle metastasis) in PET/ldCT were correctly interpreted by PET/ceCT. Kitajima et al. claimed that PET/ceCT is an accurate imaging modality for the assessment of uterine cancer recurrence, and PET/ceCT reduces the frequency of equivocal interpretations.
FIGURE 16.2. A 48-year-old woman complaining of excessive bleeding from her uterus and pathologically proven endometrial carcinoma. Computed tomography (CT) shows thickening uterine wall and pelvic lymph nodes which are 1 cm in diameter (A). Magnetic resonance imaging (MRI) demonstrates a lesion starting from the endocervical channel and extending to the endometrium with a 3 cm in length (B). 18FDG PET/CT shows markedly increased 18FDG uptake in the lesion of uterus and bilateral external and internal iliac lymph nodes (C). Bilateral common iliac lymph nodes, left para-aortic lymph nodes, and left axillary lymph nodes (D, E). The patient was staged as IIIC1 for FIGO and N1 for tumor, node, metastases (TNM) with MRI. After PET/CT findings the patient was evaluated as stage IVB for FIGO and M1 for TNM staging.
THE VALIDITY AND CLINICAL IMPACT OF 18F-FDG PET OR PET/CT IN POSTTHERAPY SURVEILLANCE OF ENDOMETRIAL CANCER
Figure 16.3 shows a patient who was diagnosed as stage IIIA endometrial carcinoma. 18F-FDG PET/CT was used to restage and monitor the treatment of the patient. In this particular case, 18F-FDG PET/CT demonstrated metastatic focus in the abdomen of the patient. 18F-FDG PET/CT also showed the inefficacy of the chemotherapy at the early phase of chemotherapy and caused a change to the chemotherapy regime. After changing chemotherapy regime, the patient showed complete response to treatment. In this patient, 18F-FDG PET/CT has played a very important role in the patient management.
Prediction of Prognosis of Endometrial Carcinoma with 18F-FDG PET/CT
The most important factors in predicting recurrence and death in patients with endometrial cancer are
• advanced FIGO surgical stage
• a nonendometrioid surgical subtype
• poorly differentiated histology
• invasion of more than half of the myometrium
• larger tumor size
• presence of LN metastasis
• lymphovascular space invasion
These parameters are dependent on comprehensive surgical staging of the patients. Preoperative prediction of tumor aggressiveness and prognostic information about the patients are useful in patient management.
18F-FDG PET/CT might be useful noninvasive imaging modality in predicting recurrence of the endometrial cancer in preoperative phase of the patients. Kitajima et al.27 evaluated the prognostic value of SUVmax of primary endometrial cancer in 57 patients with stage I–IV endometrial cancer. In their study, a total of 57 patients with stage I–IV endometrial cancer were included. The median follow-up period was 33 months. They found that SUVmax in primary tumor was statistically higher in patients with higher FIGO stage, higher tumor histologic grade, myometrial invasion, LN metastasis, and larger tumor size. Univariate analyses of the data showed that SUVmax in primary tumor, FIGO stage, histologic grade, myometrial invasion, LN metastasis, and larger tumor size are associated with the recurrence of the disease. However, multivariate analysis showed that only SUVmax in primary tumor was significantly related to tumor recurrence. In this study, the patients with a high SUVmax (≥12.7) had a significantly lower disease-free survival (DFS) rate than those with a low SUVmax (<12.7). Nakamura et al.28 also showed that the DFS and overall survival (OS) of patients who have high SUVmax in the primary tumors were significantly lower than those of patients who have low SUVmax. Even in the advanced FIGO stage patients, DFS and OS were significantly lower in the patients who have high SUVmax in the primary lesion than those of the patients who have low SUVmax. In Nakamura’s report, SUVmax was an independent factor for OS in the patients with endometrial cancer. Chung et al.29 reported on the prognostic value of SUVmax in 61 patients who had prior surgery and/or chemoradiotherapy. Posttreatment SUVmax and serous adenocarcinoma histology were significantly associated with the recurrence and inversely correlated with DFS.
Carcinoma of the cervix is the third most common cancer of gynecologic malignancies. According to American Cancer Society Statistics, 12,340 new cases of invasive cervical cancer will be diagnosed and about 4,030 women will die from cervical cancer in 2013.30 Cervical cancer was once one of the most common causes of cancer death in American women. The death rate declined up to 2003 with increased use of Pap test as screening procedure. The most important risk factor for cervical cancer is infection by Human Papilloma virus (HPV). Certain types of HPV such as HPV16, HPV18, HPV31, HPV33, and HPV45 are high-risk types because they are strongly linked to cervical cancer. Smoking, immunosuppression, chlamydia infection, long-term oral contraceptive usage, family history of cancer, multiple full-term pregnancies, low fruit and vegetable diet, diethylstilbestrol exposure, increased number of sexual partners, early age of first coitus, and low socioeconomic status are the other risk factors for cervical cancer.
The most common histologic subtype of cervical carcinoma is squamous cell carcinoma which occurs in 90% of cases. Squamous cell carcinomas arise from the squamocolumnar junction near the external orifice of cervix in younger patients, resulting in exophytic lesions. As the squamocolumnar junction migrates toward the uterine body in older women, these tumors grow from the endocervix and may become quite large before they are diagnosed. Adenocarcinoma and adenosquamous carcinoma account for about 10% of cervical cancer cases; sarcoma and lymphoma are quite rare.
Diagnosis and Staging
Clinical, vaginal, and colposcopic examinations of the cervix, bimanual palpation of the parametrial area, cytologic smears, and biopsies are mandatory in diagnosing cervical cancer. Following a preinvasive stage, the cancer invades the cervical stroma and then spreads by direct invasion into the parametrium, uterus, and vagina. Adjacent organs in the pelvis such as the bladder and rectum may be involved in more advanced disease. As the disease advances, the tumor spreads via lymphatic channels toward the pelvic, para-aortic, and supraclavicular LNs. Hematogenous spread to the lungs, liver, or any other distant organ may occur at any stage, but it is unlikely to occur in the early stages of the disease.
FIGURE 16.3. A 61-year-old woman who was operated on 4 years ago because she had grade 2 endometrium cancer. The patient was staged as IIIA pathologically. During the follow-up, she had a history of pulmonary metastases 2 years after the diagnosis. Pulmonary metastases were resected and she underwent chemotherapy. On the follow-up after chemotherapy, tumor markers of the patient increased 1 year after the completion of chemotherapy. The patient was referred to our nuclear medicine department to evaluate recurrence/metastatic disease. Computed tomography (CT) shows a lesion 1 cm in diameter in her abdomen in the pericecal region (arrow) (A). 18FDG PET/CT demonstrates increased 18FDG uptake at the lesion which is consistent with a metastatic disease (B). The patient once again received chemotherapy. However, because she had multiple infectious episodes, the chemotherapy could not have been given to the patient precisely according to chemotherapy scheme. 18FDG PET/CT was performed to evaluate chemotherapy response and shows progression of the lesion in terms of size and metabolic activity (C and D). After 18FDG PET/CT findings, her chemotherapy regime was changed. The last 18FDG PET/CT was performed to evaluate the efficiency of the new chemotherapy after the chemotherapy was completed. At this time, 18FDG PET/CT shows no evidence of metastatic disease (E).
The most important parameter of staging in patients with cervical cancer is to evaluate parametrial spread. Once a diagnosis of invasive cervical cancer is made, accurate staging is of great importance for treatment planning. When the tumor is confined to the cervix and the overall tumor volume is small, surgical management can be curative and radical hysterectomy is typically performed. As tumor size increases and spread beyond the cervix into the parametrial tissues occurs, definitive radiotherapy and chemotherapy are generally used. FIGO staging has been used for the staging of patients with cervical cancer.31 Table 16.4 shows FIGO and TNM staging for cervical cancer.
THE FIGO AND TNM STAGING AND CORRESPONDING MRI FINDINGS FOR CERVICAL CANCER
Imaging Modalities in Cervical Cancer
Imaging is an important tool in the evaluation of tumor size, detection of parametrial invasion, and assessment of the involvement of the pelvic sidewall and adjacent organs, as well as the assessment of nodal involvement and distant metastasis. Nodal involvement is not part of the FIGO staging classification. Nevertheless, nodal stage has marked prognostic implications and may alter the extent of radiotherapy field. Tumor grade and histologic subtype, patient age, intratumoral oxygenation, tumor vascularity, DNA ploidy, distant metastasis, and the presence of HPV infection are additional prognostic factors.32
Magnetic Resonance Imaging
Although transvaginal and abdominal ultrasonography can be used for diagnosis and staging, because of its superior soft tissue delineation and multiplanar capability, MRI is the ideal diagnostic imaging tool in patients with cervical cancer. MRI protocols vary from institution to institution but the recommended standard protocol in MRI includes T2-weighted TSE sequences with high spatial resolution (matrix 512) in the sagittal and transversal oblique (short cervical axis) planes in addition to a T1-weighted TSE sequence in the transversal plane.31 Dynamic multiphase contrast-enhanced MRI (DCE-MRI), which is a T1-weighted sequence, may improve detection of small tumors and distinguishing recurrent tumors from radiation necrosis.33,34 The sensitivity of DCE-MRI has been reported 92% compared to 23% with T2-weighted MRI in detecting small lesions with depth stromal invasion between 3.1 and 5 mm.
The overall staging accuracy of MRI ranges from 77% to 90%.35–39 MRI performance has been reported better than CT in the depiction of parametrial invasion and overall staging accuracy. A recent prospective multicenter study performed by the ACR Imaging Network (ACRIN) and the Gynecologic Oncology Group (GOG) comparing MRI with CT in patients with early invasive cervical cancer reported that MRI was equivalent to CT for overall preoperative staging. However, MRI performed significantly better for visualization of the primary tumor and detection of parametrial invasion. In addition, CT had much greater interobserver variability when compared with MRI.39Table 16.4 shows FIGO and TNM staging and corresponding MRI findings in cervical cancer.
18F-FDG PET or PET/CT in Cervical Cancer
Almost all the primary tumors greater than 0.7 cm in diameter demonstrate increased 18F-FDG uptake. In cases of tumor extension superiorly to the uterus and inferiorly to the vaginal cuffs, 18F-FDG PET/CT may be helpful in delineation of the tumor margins. However, MRI is more effective than 18F-FDG PET/CT to evaluate primary tumor size and extensions. Integrated PET/MRI technique may well become the preferred method to evaluate primary tumor and extension, but at present there is no sufficient data.
The evaluation of LN involvement is an important parameter for defining prognosis and therapy in cervical cancer. MRI and CT have poor diagnostic accuracy in evaluating LN metastasis because LN metastasis is basically based on the enlargement of size in both the imaging techniques. Using the size criteria, the sensitivity of MRI detecting LN metastasis ranges from 29% to 86%.40 A meta-analysis comparing the diagnostic efficiency of CT, MRI, and PET or PET/CT showed that PET or PET/CT has the highest pooled sensitivity (82%) and specificity (95%), whereas CT has 50% and 92%, MRI has 56% and 91%, respectively in patient data analyses. In region- or node-based data analysis, sensitivities of CT (52%) and PET or PET/CT (54%) were higher than that of MRI (38%), respectively, whereas specificities of MRI (97%) and PET or PET/CT (97%) were higher than that of CT.41
The diagnostic value of 18F-FDG PET/CT in detecting LN metastases in cervical cancer should be discussed in two different groups of patients with cervical cancer. The first group is early stage cervical cancer patients. In this particular patient group, the treatment is radical hysterectomy and pelvic lymphadenectomy (RH-PLND). The diagnostic role of 18F-FDG PET/CT to determine PLN involvement in early stage cervical cancer is still controversial. Signorelli et al. investigated the effectiveness of 18F FDG PET/CT in patients with early stage disease. In this study, they included the patients with stage IA–IIA, <4 cm cervical cancer. Overall patient-based sensitivity, specificity, PPVs, and NPVs of 18F-FDG PET/CT for detection of PLN disease were 32.1%, 96.9%, 69.2%, and 87%, respectively.42 The low sensitivity in this group of patients was probably because of nodal micrometastasis which is typical in the early stage of cervical cancer. Micrometastasis, less than 5 mm could not be detected with FDG PET/CT because of its limited spatial resolution. Other 18F-FDG PET/CT studies in patients with early cervical cancer showed the low (10% to 73%) sensitivity in detecting PLN involvement.43–48 Table 16.5summarizes the results of the studies in early stage of cervical cancer. Although NPVs are good at depicting LN metastasis in patients with early stage cervical cancer, 18F-FDG PET/CT seems to have minimal clinical impact on patient management. The benefit gained is limited from additional 18F-FDG PET/CT after negative MRI/CT at primary staging in patients with early stage cervical cancer.
The second group includes patients with locally advanced cervical cancer. In this group of patients, determining PALN involvement is a very important prognostic parameter because the patients with PALN have lower OS, DFS, and survival after recurrence.49–52 Accurate assessment of PALNs metastasis is also crucial to determine radiotherapy field planning because PALNs are beyond the standard radiotherapy planning field. Therefore, surgical staging has been recommended as a gold standard procedure to evaluate PALN involvement. The routine use of surgical staging before radiotherapy in locally advanced cervical cancer patients increases adverse effects and morbidities resulting from surgery. Imaging methods in this group of patients, therefore, are useful to evaluate PALNs metastases. A meta-analysis indicates that both CT and MRI have low sensitivity (57.5% and 55.5%, respectively). Both MRI and CT had an LR− greater than 0.5, meaning these tests cannot be used to confirm the absence of nodal metastasis.52 Kang et al. published a meta-analysis investigating the diagnostic value of 18F-FDG PET for evaluation of PALN metastases in patients with cervical carcinoma. They analyzed data from 385 patients in 10 studies. The overall sensitivity, specificity, LR+, and LR− were 34%, 97%, 12.49, and 0.68, respectively. When the studies were divided into two different prevalence groups such as low (≤15) and high (>15) prevalence of PALN metastases, the sensitivity of the 18F-FDG PET decreased in low-risk group up to 5%, but it increased to 73% in high-risk group. In both low- and high-risk groups, specificity were 99% and 93%, respectively. The LR− was 0.95 in low-risk group, whereas it was 0.29 in high-risk group. Nevertheless, Kang et al. suggested that in the low prevalence group, PALNs showing high 18F-FDG uptake should be histologically confirmed in terms of metastases because the false-positive rate was 21.9% in this group. However, when 18F-FDG PET or PET/CT is positive for PALN metastases in high-risk group, the finding is likely indicative of metastatic involvement.53
LITERATURE REVIEW OF THE DIAGNOSTIC ACCURACY OF 18F-FDG PET OR PET/CT IN DETECTING LYMPH NODE INVOLVEMENT IN EARLY STAGE OF CERVICAL CANCER
Leblanc et al. recently reported a study that included 125 patients with locally advanced cervical cancer (stage IB2 and IVA). The sensitivity, specificity, PPV, and NPV of the PET/CT for the detection of microscopic PALN metastases were 33.3%, 94.2%, 53.8%, and 87.5%, respectively. These results were greatly influenced by the size of metastatic node; for metastasis ≥5 mm, the sensitivity and PPV were 42% and 38%, respectively. But the sensitivity and PPV decreased to 22% and 15% when metastasis size was <5 mm. When PLN and PALN were negative in 18FDG PET/CT, they found a 10% false-negative rate for detection of PALN microscopic metastases. By contrast, PLN was positive, but PALN was negative in 18FDG PET/CT, PALN metastases were confirmed histopathologically in 20% of the patients. When PLN is positive in 18FDG PET/CT, the probability of microscopic metastases of PALN increases.54 They concluded that laparoscopic staging is necessary in patients with locally advanced cervical cancer with negative 18FDG PET scan who are candidates for definitive concurrent chemoradiotherapy or pelvic exenteration. Similar findings were reported by Ramirez et al.55 in an analysis of 60 patients with locally advanced cervical cancer. They performed laparoscopic extraperitoneal lymphadenectomy from the common iliac vessels to the left renal vein. Given the results of the study, 14 (23%) patients had histopathologically positive para-aortic nodes. Of the 26 patients with negative PLN and PALN on PET/CT, 3 (12%) had positive PALN on histopathology. Of the 27 patients with positive PLN but negative PALN on PET/CT, 6 (22%) had histopathologically positive PALN. The sensitivity and specificity of 18FDG PET/CT in detecting positive PALN when nodes were negative on CT or MRI were 36% and 96%, respectively. Eleven (18.3%) patients had treatment modifications based on surgical findings. The authors concluded that laparoscopic extraperitoneal para-aortic lymphadenectomy should be discussed with patients with locally advanced cervical cancer scheduled to undergo chemoradiation, particularly if preoperative 18FDG PET/CT shows positive pelvic nodes and negative PALN as a safe and feasible surgery method.
Two case examples are presented in Figures 16.4 and 16.5. These two patients had locally advanced cervical carcinoma and positive PLN but negative PALN in 18FDG PET/CT. After chemoradiotherapy, both patients showed complete response to treatment with a 2-year follow-up without recurrence or metastatic disease.
Pretreatment Prognostic Value of 18F-FDG PET/CT in Cervical Cancer
Although increased 18FDG uptake has been found to correlate positively with tumor aggressiveness in many cancers, the prognostic value of PET is still under investigation. Miller and Grigsby56 reported that the three-dimensional volume of the primary tumor by 18FDG PET was predictive for both progression-free survival (PFS) and OS in patients with advanced cervical cancer. The presence of SUVmax of more than 3.3 in PALNs was significantly associated with both 5-year disease recurrence (Hazard Ratio [HR] = 4.52, 95%, CI 1.7 to 11.8) and 5-year mortality (HR = 6.04, 95%, CI 1.97 to 18.57). Xue et al.57 reported that a pretreatment baseline SUVmax less than 10.2 in primary cervical cancers was associated with a better prognosis in patients receiving definitive radiotherapy than in patients whose tumors had higher values.
Kidd et al.58 assessed pretreatment SUVmax and its association with treatment response and prognosis in 287 patients with stage IA2 through IVB cervical cancer. Three prognostic groups were established using SUVmax, which was demonstrated to be a sensitive biomarker of treatment response and prognosis for patients with cervical cancer. The OS rates at 5 years were 95% for an SUVmax 5.2, 70% for an SUVmax ranging from 5.2 to 13.3, and 44% for an SUVmax more than 13.3 (p < 0.0001). Increasing SUVmax was associated with persistent abnormal FDG uptake in the cervix on 3-month FDG PET studies in 238 patients who received curative chemoradiation.
Yen et al.59 analyzed 70 patients with untreated squamous cell cervical cancer and PLN or PALN metastasis detected by CT/MRI. All patients had 18FDG PET for primary staging. SUVmax greater than 3.3 at a PALN is predictive of poor outcome in patients with primary squamous cervical carcinoma and LN metastasis on CT/MRI as measured by adverse 5-year recurrence-free survival (HR = 4.52, 95% CI, 1.73 to 11.80) and 5-year OS (HR = 6.04, 95% CI, 1.97 to 18.57).
Recently, Chung et al.60 studied with a metabolic tumor volume (MTV) measured by 18F-FDG PET/CT to determine its prognostic value in patients with cervical cancer primarily with radical hysterectomy. They enrolled 63 patients with stage IB to IIA and evaluated the relationship of MTV to DFS in this study. MTV was found to be correlated with LN metastasis, parametrium involvement, FIGO stage, and SUVmax. In univariate analysis, MTV ≥23.4 mL (HR 1.017, 95% CI 1.005 to 1.029, p = 0.004), SUVmax ≥9.5 (HR 5.198, 95% CI 1.076 to 25.118, p = 0.04), LN metastasis (HR 12.338, 95% CI 1.541 to 98.813, p = 0.018), parametrium involvement (HR 14.274, 95% CI 1.785 to 114.149, p = 0.012), and lymphovascular space invasion (HR 8.871, 95% CI 1.104 to 71.261, p = 0.04), were related to DFS. In multivariate analyses, age (HR 0.748, 95% CI 0.587 to 0.952, p = 0.018) and MTV ≥23.4 mL (HR 49.559, 95% CI 1.257 to 1953.399, p = 0.037) were determined to be independent prognostic factors of DFS.
18F-FDG PET/CT in Monitoring the Response to Treatment and Detection Recurrence Disease in Cervical Cancer
Recurrence may occur in approximately one-third of cervical cancer patients. The majority of the recurrence occurs within first 2 to 3 years after completion of therapy. The amount of tumor regression during the course of extension beam radiotherapy is an important predictor factor for both local recurrence and survival. Lin et al.61 analyzed the physiologic tumor volume response, using 18FDG PET, during radiotherapy and brachytherapy treatment in 32 patients with cervical cancer. Patients with no residual 18FDG uptake at 3-month posttreatment had better 5-year recurrence-free survival (83%) than the patients with evidence of 18FDG PET residual disease within the cervix. Grigsby et al.62 reported similar results to this study. In this retrospective study of 152 patients, posttherapy 18FDG PET was performed 1 to 12 months (mean: 3 months) after completion of treatment. Five-year cause-specific survival was 80% for patients with no abnormal 18FDG uptake, 32% for those with persistent uptake, and 0% for those with new uptake on posttreatment imaging.
Schwarz et al.63 demonstrated that 3-month posttherapy 18FDG uptake was predictive of survival of 92 patients who were treated with external irradiation, brachytherapy, and concurrent chemotherapy. Posttherapy whole-body 18FDG PET was performed 2 to 4 months (mean: 3 months) after completion of treatment, showing a complete metabolic response in 65 patients (70%), a partial metabolic response in 15 (16%), and progressive disease in 12 (13%). The 3-year PFS rates were 78%, 33%, and 0%, respectively. The HR for risk of recurrence based on the posttherapy metabolic response showing progressive disease was 32.57 (95% CI, 10.22 to 103.82). A partial metabolic response had an HR of 6.30 (95% CI, 2.73 to 14.56).
Chung et al.64 recently demonstrated the diagnostic accuracy of posttherapy 18F-FDG PET/CT to detect recurrent disease and prognosis of the 276 patients with cervical cancer in a retrospective study. 18F-FDG PET/CT scans were performed under several circumstances.
FIGURE 16.4. A 55-year-old woman with pathologically proven squamous cell carcinoma of the cervix. 18FDG PET/CT was performed for staging of the disease. A cervical mass invading the rectum showed markedly increased 18FDG uptake as seen in CT and PET/CT images (A and B). There was also left internal iliac lymph node showing increased 18FDG uptake which is consistent with metastatic disease (arrow) (C). The patient was evaluated as having locally advanced cervical cancer. Radiotherapy and chemotherapy were applied. After 6 months of completion of a therapy regimen, the patient was imaged with 18FDG PET/CT for therapy evaluation. 18FDG PET/CT shows marked regression of the lesion both in size and metabolic activity (D). The internal iliac lymph node is not visible at this time (E). The findings were evaluated as a complete therapy response.
• Patients had symptoms suspecting recurrence
• A new lesion in other surveillance imaging studies
• Elevated tumor markers with or without abnormal imaging studies
• Abnormal physical examination findings
• Clinician concern for unspecified reasons
The overall sensitivity, specificity, PPV, NPV, and accuracy of posttreatment 18FDG PET/CT to detect recurrent disease were 94.7%, 87.8%, 80.4%, 97%, and 90.2%, respectively. The 18FDG PET/CT scan modified both the diagnostic or treatment plan in 67 patients (24.3%). The patients were divided into two groups based on SUVmax value established on the basis of ROC analysis (<5.25 versus ≥5.25). They found a significant difference in OS between groups (p = 0.001). They reported that the 5-year PFS and OS rates of patients with a negative PET/CT scan for recurrence were significantly better than those with a positive PET/CT (98.62% versus 17.83%, p < 0.0001 for PFS, 99.31% versus 85.38%, p = 0.0015 for OS).
FIGURE 16.5. A 72-year-old woman with biopsy proven squamous cell cervical carcinoma. Magnetic resonance imaging (MRI) shows a 6 × 3 cm in diameter lesion starting from cervix and extending halfway through the uterus (A). There was no suspicion of metastatic disease in MRI. 18FDG PET/CT was performed for initial staging. There was markedly increased 18FDG uptake in the lesion (B). 18FDG PET/CT images show a tiny right internal iliac lymph node showing moderate FDG uptake with SUVmax: 3.1 which is suspicious of metastatic involvement of the lymph node (arrow) (C). The patient was treated with radiotherapy which was planned to cover primary lesion of cervix and suspicious lymph node. Six months after radiotherapy, 18FDG PET/CT was performed to evaluate the response of the treatment. 18FDG PET/CT shows no evidence of residual and metastatic disease (D and E). MRI also confirmed no residual disease at the cervical region (not shown). With these findings, the patient was accepted as a complete response to treatment.
Figure 16.6 shows a patient who had disseminated metastatic disease as documented by 18F-FDG PET/CT after 18 months of radical chemotherapy and brachytherapy. In this case, metastatic LNs and bone metastases are well documented with 18F-FDG PET/CT.
According to the literature, posttreatment PET/CT scan is a sensitive and accurate surveillance modality, and provides prognostic information in cervical cancer. Optimum time for PET/CT scan after completion of treatment is still controversial. In most studies, the median follow-up FDG PET/CT scan is 3 months after completion of therapy. In some studies, a 6-month interval is recommended especially after radiotherapy to decrease false-positive identification of an inflammatory reaction.
Pitfalls and Limitations of 18F-FDG PET or PET/CT in Imaging of Endometrial and Cervical Cancer
Physiologic accumulation of 18FDG in bowel and urinary bladder may interfere with evaluation of the primary tumor and LN involvement. These issues should always be kept in mind; careful review and clinical correlation are required for accurate interpretation. To avoid the bladder problem, patients are asked to empty off their bladder at the beginning of the examination; alternately, a urinary catheter can be placed in the bladder to drain bladder activity continuously or using hydration with 1 L of intravenous normal saline along with diuretics.65
FIGURE 16.6. A 51-year-old woman with stage IIB cervical cancer. She had radical chemotherapy and brachytherapy. Eighteen months after her treatment was completed, a full-dose contrast-enhanced thorax computed tomography (CT) showed pleural thickening and pleural nodules, enlarged lymph nodes in mediastinum, bilateral hilum, and bilateral para-aortic region. 18FDG PET/CT was performed to restage the patient. 18FDG PET/CT shows increased FDG uptake in the lymph nodes of the bilateral cervical chain of the neck, multiple stations of the mediastinum and bilateral hilum. Para-aortic lymph nodes and pelvic lymph nodes also showed high 18FDG uptake (A and B). There is also increased 18FDG uptake in the corpus and pedicle of the ninth vertebra which is consistent with metastatic bone disease (C).
One of the other limitations of 18FDG PET/CT imaging in cancer imaging is the accumulating of 18FDG in inflammatory lesions. This may cause false-positive interpretations of the lesions, especially in differentiating recurrence lesions from postoperative changes. This problem may be solved by as PET/MRI becomes available.
18F-FDG PET/CT has a limitation to identify the lesions <1 cm and especially in lesions smaller than 5 mm because of the limited spatial resolution leading to false-negative evaluation of the LN metastases. 18F-FDG PET/CT can also detect lesions with a certain amount of malignant cells sufficient to change glucose metabolism, but neither of the imaging methods can detect such tiny lesions. The recent introduction of instrumentation with greater sensitivity, however, may alter these limitations somewhat.
FUTURE PERCEPTIONS AND RESEARCH AREAS OF PET IN ENDOMETRIAL AND CERVICAL CANCER
Other PET Tracers
Although 18F-FDG is the most commonly used tracer in oncology imaging, tracers other than 18FDG are under investigation. These new tracers that potentially address the complexities of tumor biology may provide information that will result in patient-specific treatment and reliable prognostic information. Tracers other than 18F-FDG are needed because tumor glucose metabolism is a nonspecific biomarker.
Lapela et al.66 imaged 14 patients (eight patients with endometrial cancer and six patients with cervical cancer) with 11C-labeled amino acid methionine. One of the advantages of 11C methionine is the absence of significant renal excretion. Because there is little or no radioactivity in the urinary bladder as seen with 18FDG imaging, 11C-methionine is better suited to image the pelvic area. All primary uterine tumors showed increased uptake with a mean SUVmax of 8.4 for tumor, compared to a mean SUVmax of 4.6 for normal endometrium.
Cu-60 diacetyl-bis-N(4)-methylthiosemicarbazone (Cu-ATSM) is a hypoxia tracer. It has been evaluated to predict response to therapy in patients with cervical cancer. Tumor uptake of Cu-ATSM was inversely related to PFS and OS. The rate of regional LN metastases was higher in patients who had hypoxic tumor.67
Tsujikawa et al. compared 16a-[F18] fluoro-17b-oestradiol (FES) and 18FDG PET in 38 patients with benign and malignant uterine tumors to determine differences in tracer accumulation. FES uptake were higher in benign lesions, whereas malignancies were more FDG avid. In another study, Tsujikawa reported that high-risk carcinoma (FIGO ≥ IC or histologic grade ≥2) showed a significantly greater FDG to FES ratio (3.6 ± 2.1) than did low-risk carcinoma (FIGO ≤ IB and histologic grade 1; 1.3 ± 0.5).68,69
PET/MRI in Endometrial and Cervical Carcinoma
Recently, there has been growing interest in the development of PET/MRI hybrid imaging systems. PET/MRI has advantages especially in endometrial and cervical carcinoma such as improved soft tissue contrast, the possibility of performing real-time simultaneous imaging, availability of the imaging techniques of MRI (functional MRI, diffusion and perfusion imaging, and spectroscopy). Information obtained from 18FDG PETMRI and FDG PET is likely to be in staging therapy response and prognosis in uterine cancer.
Multimodality imaging is clinically important to effectively manage the patients with cervical and endometrial cancer. MRI currently has a prominent role of the initial staging of pelvic disease and therapy monitoring because it has better tumor delineation in the entire pelvis, superior tissue contrast, and additional information concerning accompanying pathologies which can be helpful for further therapy planning. However, MRI has also some limitations in evaluating extra PLNs and distant tissue metastasis, detecting recurrence diseases and obtaining prognostic information about the patients. 18FDG PET/CT is a useful imaging modality in staging especially in extra pelvic diseases, monitoring to treatment, obtaining prognostic information and detecting recurrent disease in endometrial and cervical cancer. Advances in imaging technology such as hybrid imaging systems like PET/MRI with a better spatial resolution is likely to have a very important diagnostic role for patients with cervical and endometrial cancers. The other promising area is the development of new radiopharmaceuticals which will allow imaging molecular biology of tumor microenvironment more specifically.
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