DOI: 10.1148/rg.281075134
RadioGraphics 2008;28:289-307
© RSNA, 2008
Oncodiagnosis Panel: 2006
Ovarian, Cervical, and Endometrial Cancer1
Akila N. Viswanathan, MD, MPH,
Barbara M. Buttin, MD, and
Anne M. Kennedy, MD
1 From the Department of Radiation Oncology, Brigham and Women’s Hospital/Dana-Farber Cancer Institute and Harvard Medical School, 75 Francis St, Boston, MA 02115 (A.N.V.); the Division of Gynecologic Oncology, Northwestern University Feinberg School of Medicine, Chicago, Ill (B.M.B.); and the Department of Radiology, University of Utah Health Sciences Center, Salt Lake City, Utah (A.M.K.). From the Oncodiagnosis Panel at the 2006 RSNA Annual Meeting. Received June 4, 2007; revision requested July 23; final revision received September 21; accepted September 24. All authors have no financial relationships to disclose.
Address correspondence to A.N.V. (e-mail: aviswanathan{at}lroc.harvard.edu).
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Introduction
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Gynecologic neoplasms contribute substantially to female mortality and morbidity in the United States. In 2006, uterine corpus cancer accounted for 41,200 new diagnoses, ovarian cancer for 20,180, and cervical cancer for 9,710 (1). 
Diagnostic imaging is critical in the staging of all gynecologic neoplasms and can help ensure that the proper therapy is administered. As part of the 2006 multidisciplinary Oncodiagnosis Panel, one case each of ovarian, cervical, and uterine cancer were presented to facilitate discussion of imaging, staging, and treatment of these malignancies. The cases were discussed by a radiation oncologist (A.N.V.), a gynecologic oncologist (B.M.B.), and a radiologist (A.M.K.).
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Case 1: Ovarian Cancer
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A 65-year-old woman presented to her family practitioner with the complaint of abdominal bloating. She had no family history of cancer, no postmenopausal bleeding, and no other symptoms. At examination, there was a palpable right adnexal mass but no other abnormal findings. The CA-125 level was 250 U/mL.
Diagnostic Radiologist’s View
What Is the Role of the Radiologist?—
The important points for the radiologist are to recognize clearly benign entities (thereby avoiding unnecessary surgery), recognize suspect lesions, recommend appropriate referral, and most importantly ensure that appropriate studies are performed to gather appropriate information and to identify patients who might be better served by first-line chemotherapy or radiation therapy rather than surgery. It is important to understand that microscopic metastases may be occult regardless of the imaging modality, and that we do not have a foolproof noninvasive method to determine lymph node involvement.
How Do We Image the Adnexal Mass?—
Ultrasonography (US), computed tomography (CT), and magnetic resonance (MR) imaging may all be used, with US being the most common initial imaging study in the nonemergent setting. Because the differential diagnosis for an adnexal mass is broad, an important role for the radiologist is recognition of benign entities such as a hemorrhagic cyst. Occasionally, a patient with acute pelvic pain will undergo CT as part of the initial assessment. MR imaging is helpful in evaluation of a complex adnexal mass, as the signal intensity characteristics can be used to make a specific diagnosis of benign entities such as endometrioma and mature cystic teratoma.
What Findings in the Imaging of an Adnexal Mass Increase Suspicion for Malignancy?—
Size is important. The normal volume of the premenopausal ovary is about 20 mL, while the postmenopausal ovary is about 10 mL; by the time a woman is over 70 years old, the ovaries should be about 2 mL total in volume. As a rule of thumb, if an ovary is more than twice the volume of its partner, suspicion is warranted (2).
Solid components are the most statistically significant finding in diagnosing an ovarian malignancy (3). Thick vascular septations thicker than 3 mm and papillary projections should also arouse suspicion; ascites and enlarged lymph nodes are also of concern. Although distant metastases confirm a neoplastic process, bilateral ovarian masses, ascites, and adenopathy can occur with other primary neoplasms (eg, gastrointestinal and breast cancers). In Figure 1, a US image of the ovary reveals a part cystic, part solid mass bigger than the transducer footprint, at least 9 cm in diameter. No ascites, lymphadenopathy, or distant lesions are seen sonographically. Recognition of the mass as a possible malignancy prompts the recommendation for referral to a gynecologic oncology surgeon.
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Figure 1. Ovarian cancer. Endovaginal US image shows a large (>9 cm), mixed cystic-solid mass with irregular vessels running in thick septa. The sonographic features are suggestive of a malignant neoplasm.
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What Is the Role of Radiology in Staging Ovarian Cancer?—
Radiologists need to be aware of the ways in which ovarian cancer spreads in order to recognize extensive disease and provide helpful staging information to oncologists and surgeons. The four mechanisms of spread are intraperitoneal dissemination, direct invasion of adjacent organs, hematogenous spread, and lymphatic spread to locoregional nodes and thence to the aortocaval nodes (4). Intraperitoneal dissemination produces a shower of malignant cells that implant on the omentum as well as on the serosa of the liver, spleen, and bowel. Extensive disease requires surgery by trained gynecologic oncology surgeons capable of omental and bowel resection. It is better for the patient to be aware of the extent of surgery required and to undergo one procedure by appropriately trained surgeons than to undergo one surgery for oophorectomy and a second debulking procedure later. Extensive disease in hard-to-reach places such as the porta hepatis or mesenteric root may also prevent adequate surgical debulking. Such patients are best served by first-line chemotherapy (Fig 2).
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Figure 2. Staging of ovarian cancer. Contrast-enhanced CT scan shows an extensive omental "cake," mesenteric nodularity, and ascites. In addition, there is diffuse enhancement of the entire mesenteric root (arrows). The mesenteric root involvement makes this case inoperable; therefore, the patient should receive chemotherapy as first-line treatment.
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Stage I disease is confined to the ovary; stage II is confined to the pelvis; stage III extends into the upper abdomen including serosal metastases to the liver and bowel; and stage IV implies distant metastases including the liver parenchyma. Careful evaluation of the bowel wall, liver and spleen capsules, and omental fat is important in detection of stage III and IV disease. Radiologic imaging of an ovarian mass with ascites carries a positive predictive value for malignancy of 72%–80% (5).
Gynecologic Oncologist’s View
Initial Discussion with the Patient.—
The most important point initially is to evaluate the likelihood of this being a malignant versus a benign process. Decision-making regarding surgery has to include discussions with the patient at the first opportunity to secure informed consent for all possible scenarios. The radiologic findings usually indicate how likely it is that we will find ovarian cancer versus a benign ovarian tumor. An elevated CA-125 level raises suspicions. In postmenopausal women, we should be very suspicious of a cancerous process when we find a CA-125 level greater than 35 U/mL, physical examination findings such as nodularity in the cul-de-sac, a mass that is fixed in the pelvis at vaginal examination, palpable ascites, or an omental mass (6).
During the consent process, we discuss the likelihood that the disease is cancer and the goal of surgery, to remove all visible disease. We explain that women with ovarian cancer who undergo debulking to minimal or no gross residual disease are also treated with intraperitoneal chemotherapy, which requires that we place an intraperitoneal port during surgery. It is important to point out that cytoreductive surgery improves gastrointestinal function, removes ascites and the associated discomfort, and relieves pressure symptoms and pain. Cytoreduction increases tumor perfusion by removing diseased tissue with poor vascular supply and improves cell kinetics, which then help us treat the tumor with chemotherapy. The smaller the amount of residual disease, the higher the chance of survival for a patient with ovarian cancer (7).
The patient may have an early-stage ovarian cancer, meaning an adnexal mass alone with frozen section diagnosis of cancer, without any obvious evidence of metastatic disease. However, in about 30% of such patients, there is microscopic evidence of metastatic disease (8). Most of those patients (when staging is accurate) have stage III disease. Therefore, even if a frozen section result is consistent with cancer, radical staging surgery is still required, including removal of the pelvic and paraaortic lymph nodes and the omentum, peritoneal biopsies of the diaphragm and peritoneal surfaces, and total abdominal hysterectomy with bilateral salpingo-oophorectomy.
Pictorial diagrams may help explain to patients the need for a large incision regardless of the location and spread of the tumor. A midline incision to the sternum is necessary, as there is a reasonable risk of tumor spread via lymphatics following the ovarian vessels all the way to the paraaortic lymph nodes near the renal veins. Also, these nodes are not always grossly involved; frequently there is microscopic metastatic involvement, which may be undetectable without nodal dissection. The fat pad next to the aorta may appear inconspicuous, but removal and pathologic review of the entire tissue will indicate whether lymph nodes are involved (Fig 3).
An argon beam coagulator for small tumor implants can be used on serosal and mesenteric surfaces. The goal is to reduce tumor volume to microscopic levels. Small implants may not necessarily appear at imaging but are visible during surgery (Fig 4). An argon beam coagulator is one way of ablating these lesions regardless of whether they are on the serosa of the bowel or liver or on the diaphragm. Radical surgery may also include large en bloc resections of tumor involving the pelvic organs, including the rectosigmoid colon, appendix, or right colon. Large bowel resections are often necessary to remove disease that has spread intraabdominally.
What Is the Current Chemotherapeutic Approach to Ovarian Cancer?—
The concept of intraperitoneal chemotherapy was first raised as early as the 1950s. In the 1960s, long-term peritoneal devices were first developed, and several studies performed on animals (dogs) in the 1970s showed that certain types of chemotherapeutic agents clear very slowly from the peritoneal fluid. In 1984, the feasibility of intermittent large-volume intraperitoneal chemotherapy was reported, and in 1996 an increased survival from intraperitoneal chemotherapy in ovarian cancer was reported (9,10). Drugs that are cleared slowly from the peritoneal cavity can expose any residual disease to a much higher concentration of chemotherapy than intravenous treatment alone.
However, most of the measurements were made by comparing the area under the curve of a drug such as cisplatin in the dialysate of the intraperitoneal fluid to that in the plasma, rather than the drug level within the tumor compared to that in the plasma (10). Tumor penetration is very superficial; hence the recommendation that intraperitoneal therapy benefits mainly patients with minimal residual disease. In addition, a good distribution of chemotherapy within the peritoneal cavity is required in order to cover all of the areas at risk for disease spread, which is difficult when patients have adhesions and other barriers to free distribution.
Three studies show a survival benefit for intraperitoneal chemotherapy compared to intravenous therapy (Table 1) (9,11,12). However, in GOG 172 (12), among women with optimally cytoreduced ovarian cancer (<1 cm of residual disease), the ideal comparison of intravenous to intraperitoneal chemotherapy was not made. In arm 1, the intravenous group received paclitaxel and cisplatin intravenously every 21 days in the standard fashion times six cycles. In arm 2, the intraperitoneal group received intravenous paclitaxel and intraperitoneal cisplatin, with intraperitoneal paclitaxel given 1 week later. The data show a significant survival advantage with an increased median overall survival of 16 months, resulting in an overall survival of 66 months in women with small-volume residual disease.
Whether drug levels or the amount of drug given may have resulted in the advantage seen in the intraperitoneal group is unknown. In a trial of intravenous chemotherapy for ovarian cancer, patients randomized to carboplatin and paclitaxel had a median survival of 57.4 months, which was slightly longer than that seen with cisplatin and paclitaxel (13); although not a direct comparison study, the intraperitoneal arm of GOG 172 had a median survival of approximately 66 months, which was better than that of the best intravenous chemotherapy arm. As a result, the National Cancer Institute issued a clinical alert to draw our attention to the very significant survival advantage found for intraperitoneal therapy in multiple studies.
Unfortunately, toxicity is significant with intraperitoneal chemotherapy. In GOG 172, both hematologic and nonhematologic toxic effects were significantly stronger in the intraperitoneal arm. An interesting finding is that quality of life in the two arms differed significantly during treatment but was nearly identical 1 year after therapy (12).
How Are Intraperitoneal Ports Placed?—
Most intraperitoneal ports are not Tenckhoff catheters; rather, they are nonfenestrated, single-lumen venous access devices (Fig 5). Fenestrated ports have led to many bowel complications, adhesions, and increased rates of port occlusion (14). A preferred device is the Bard (Murray Hill, NJ) venous access catheter, which is a single-lumen silicone port (similar to the chest venous access port) that can be placed in multiple locations in the abdomen during surgery. Before closing the fascia, it is placed in a subcutaneous pocket made especially for the port, anywhere in the upper or lower quadrant of the abdomen. The port may be placed at the time of the original laparotomy or at a later time via laparoscopy or with interventional radiology.
Currently, no standard catheter or insertion technique exists, and managing complications can require a significant amount of expertise. Medical oncologists are more comfortable administering intravenous carboplatin and paclitaxel and therefore may not necessarily encourage patients with ovarian cancer to seek intraperitoneal treatment. In a 1991 overview from Memorial Sloan-Kettering Cancer Center, the total port complication rate was almost 20% (15). The majority of cases were related to inflow obstruction of Tenckhoff catheters, infections, and bowel perforations; inflow obstruction was the most common complication. However, the total port complication rate decreased to 10% over the next 10 years (16). Infection and bowel issues have significantly improved. Women who undergo extensive bowel resection, specifically a left colon resection at the time of surgical debulking, should not receive intraperitoneal chemotherapy immediately after surgery. Rather, they should receive the first one or two cycles intravenously, then have a port placed and switch to intraperitoneal therapy.
In GOG 172, the port complication rate was quite high. Only 42% of all women completed six cycles of intraperitoneal therapy. Nonetheless, the observed survival advantage means it may not be necessary that a patient complete all six cycles intraperitoneally. The rates of port complications in several other studies are comparable (Table 2) (14–16). Infection and bowel injuries represent significant toxic effects in intraperitoneal therapy.
Radiologist’s View
Is There a Role for Imaging in the Follow-up of Patients with Ovarian Cancer?—
Disease follow-up includes evaluation of complications of treatment as well as surveillance for local recurrence and the development of distant metastases. Recurrent disease manifests in much the same way as the primary tumor (Fig 6). Contrast-enhanced MR imaging may be more sensitive for recurrent disease and should be used if there is clinical suspicion of increasing tumor load without obvious findings at CT.
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Figure 6. Ovarian cancer in a patient with an elevated CA-125 level. Contrast-enhanced CT scan obtained for postoperative surveillance shows mesenteric nodules, retroperitoneal adenopathy (arrow), and metastases to the bowel serosa (arrowhead).
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Treatment complications can be early or late; pulmonary embolic disease, atelectasis, pneumonia, ileus, bowel or urinary tract obstruction, and bowel perforation can all occur acutely in any patient after abdominal surgery. Late complications include radiation-induced enteritis, cystitis, avascular necrosis of bone, and bowel obstruction secondary to stricture or adhesions. Urinary tract obstruction may also occur secondary to pelvic scarring. Most of these complications can be adequately evaluated with plain radiography and CT (Fig 7).
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Figure 7. Complications of treatment for ovarian cancer. Contrast-enhanced CT scan shows postoperative bowel perforation and peritonitis. There is oral contrast material (arrowhead) in the peritoneal space mixed with fluid bowel contents and gas. Note the large air-fluid level (arrow) in the peritoneal cavity. The perforation was repaired. An abscess formed subsequently and was treated with percutaneous drainage; ultimately, the patient recovered completely.
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In summary, the diagnosis of ovarian cancer in our 65-year-old patient was suggested by US findings, and she was referred to a gynecologic oncology surgeon. Surgical staging showed a stage III ovarian papillary serous carcinoma. She was treated with intraperitoneal and intravenous chemotherapy. Her follow-up was clinical with serial CT studies and measurements of CA-125 level.
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Case 2: Cervical Cancer
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A 36-year-old woman presented with heavy vaginal bleeding. At gynecologic examination, she had a 5-cm friable cervical mass with palpable nodularity that extended to the left parametrium. Therefore, she had a clinical stage IIB tumor, according to the International Federation of Gynecology and Obstetrics (FIGO) staging system, and was not considered a surgical candidate.
Radiation Oncologist’s View
What Is the Role of Imaging in the Detection and Staging of Cervical Cancer?—
Underre-sourced countries have the highest incidence rates of cervical cancer. Because of the lack of MR imaging, positron emission tomography (PET), and CT facilities, staging in underresourced countries must rely primarily on clinical examination of the cervix and paracervical regions, including the parametrium, uterosacral ligaments, and vagina. Radiographic studies (chest radiography and skeletal radiography) are feasible worldwide and therefore are included in the FIGO clinical staging system. In the United States, studies not permitted in the FIGO staging system, including MR imaging, PET, and CT, are performed in order to detect distant metastatic spread and also to assist radiation oncologists in accurately delineating the cervical tumor volume.
Radiologist’s View
The detection of cervical cancer in the United States is primarily through Papanicolaou (Pap) smear screening programs. In third-world countries, patients often present with advanced disease and obvious clinical findings; imaging becomes more important for staging than for detection. MR imaging has been shown to be superior to clinical staging as well as to staging with FIGO criteria (17), but its lack of universal availability precludes its routine use in staging. However, given the availability of MR imaging, good evaluation techniques are vital in making the best use of the information it provides. The imaging radiologist should have a checklist of features to document in the report, including tumor size, depth of stromal invasion, presence of parametrial invasion, hydronephrosis, and lymphadenopathy.
Parametrial extension implies a stage IIB tumor, which is preferably treated with radiation therapy. Parametrial extension is best evaluated on images that show a true axial section through the cervix, the so-called doughnut view (Fig 8). On this view, the cervix is circular in cross-section, and the stroma is of very low signal intensity (dark) on T2-weighted images. Cervical cancer has intermediate signal intensity; therefore, it is possible to see whether the tumor is confined to the cervix or has breached the stroma and invaded the adjacent pelvic fat (Fig 9). MR imaging is excellent for assessment of local tumor extent, but for overall staging, PET/CT is rapidly becoming accepted as the best single test (18,19).
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Figure 8a. Correct imaging plane for evaluation of cervical cancer with MR imaging. (a) Sagittal T2-weighted image, obtained to localize the cervix, shows an imaging plane (dashed lines) that is axial to the cervix. (b) MR image obtained in the plane indicated by the dashed lines in a shows the cervix as a "doughnut" with the endocervical canal in the center. Normal cervical stroma is dark on T2-weighted images.
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Figure 8b. Correct imaging plane for evaluation of cervical cancer with MR imaging. (a) Sagittal T2-weighted image, obtained to localize the cervix, shows an imaging plane (dashed lines) that is axial to the cervix. (b) MR image obtained in the plane indicated by the dashed lines in a shows the cervix as a "doughnut" with the endocervical canal in the center. Normal cervical stroma is dark on T2-weighted images.
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Figure 9. Parametrial extension of cervical cancer. T2-weighted MR image shows that an intermediate-signal-intensity tumor has replaced all of the normal low-signal-intensity cervical stroma. Fingerlike projections of the tumor (arrows) extend into the parametrial fat.
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Radiation Oncologist’s View
What Is the Standard Treatment for Locally Advanced Cervical Cancer?—
In the United States, cervical cancer patients with tumors larger than 4 cm (stage IB2) or any pelvic spread (stage IIA–IVA) most commonly receive 5 weeks of daily external-beam radiation therapy followed by brachytherapy with concurrent cisplatin chemotherapy, typically 40 mg/m2 weekly, although other regimens are acceptable (20). External-beam radiation therapy covers the entire pelvic region, thereby encompassing all of the pelvic lymph nodes, the uterus, cervix, and vagina, and the supporting ligaments in their entirety. Figure 10 depicts standard pelvic radiation fields covering the internal and external iliac lymph nodes, which must be treated for postoperative or locally advanced (inoperable) cases. External-beam radiation therapy provides approximately 40–45 Gy, which is approximately half of the required dose for cure. The dose of external-beam radiation is limited by the tolerance of the normal tissues of the pelvis, including the bowel and bladder. After external-beam radiation therapy, internal brachytherapy is used to deliver radiation directly into the uterus and cervix while minimizing exposure of other pelvic organs.
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Figure 10. Standard four-field plan for external-beam radiation therapy to the pelvis. The plan was developed after CT simulation to depict the contours of the nodal regions, the central uterine cervix, and the vagina.
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Brachytherapy significantly increases both local control and survival, particularly in patients with advanced disease (21,22). The U.S. Patterns of Care study found that proper placement of an implant, as determined by reviewing plain radiographs after insertion, correlated with local control (23). An unacceptable implant (placed in an incorrect central position) resulted in decreased rates of local control and survival, indicating the critical role of brachytherapy as an adjunct to external-beam radiation therapy.
The most common applicator system used in the United States to deliver cervical cancer brachytherapy is called tandem and ovoids, where the tandem provides intrauterine radiation and the ovoids deliver radiation directly to the cervical surface. Figure 11 shows a typical low-dose-rate Fletcher-Suit-Delclos tandem and ovoid applicator. The radiation source may be either a high-dose-rate iridium 192 source or low-dose-rate cesium 137 source. Low-dose-rate radiation therapy typically requires inpatient hospitalization, whereas high-dose-rate radiation may be given over several outpatient visits (24). High-dose-rate radiation therapy has many applicator types, including a small applicator called a tandem and ring, which is localized just on the cervix (Fig 12). A tandem and ovoid covers more of the upper vagina than the ring applicator. In contrast, a tandem and cylinder treats the entire length of the vagina. For patients with a large volume of vaginal disease, involving the lower third of the vagina or with more than 5 mm of thickness, an interstitial implant is necessary.
US during tandem insertion can show whether the uterus is perforated by the tandem or whether the tumor is eccentrically located. The posterior cervicouterine junction is the most common site of perforation. Figure 13 depicts improper placement of the tandem into the posterior myometrium, but not causing a uterine perforation. US was used to reposition the tandem into the center of the uterine canal. If the applicator is properly repositioned before initiation of radioisotope therapy, outcomes are not affected.
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Figure 13a. Improper placement of a radiation therapy applicator. (a) US image shows an intrauterine tandem that is displaced into the posterior myometrium but does not perforate the serosa. The applicator was removed and repositioned with US guidance. (b) US image shows proper positioning of the applicator.
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Figure 13b. Improper placement of a radiation therapy applicator. (a) US image shows an intrauterine tandem that is displaced into the posterior myometrium but does not perforate the serosa. The applicator was removed and repositioned with US guidance. (b) US image shows proper positioning of the applicator.
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How Is Imaging Used for Radiation Treatment Planning?—
From a radiation oncologist’s perspective, the use of MR imaging, PET, and CT provides several advantages over plain radiography for diagnosis and treatment planning. Fluorodeoxyglucose PET is very useful in the diagnostic and staging work-up of cervical cancer. PET shows the location of the primary tumor, involved lymph nodes, and distant metastases and allows targeting of these involved sites during radiation treatment planning. PET may demonstrate skip metastasis to the paraaortic or supraclavicular lymph nodes (Fig 14). For supraclavicular metastases, fine-needle aspiration or needle biopsy is needed to confirm the presence of malignant cells. However, PET may not allow accurate identification of cancer measuring less than 1 cm. Despite the cost and time involved to obtain the scan, the advantages of better staging and accuracy in treatment administration have made PET the standard diagnostic staging test in the United States.
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Figure 14. PET image shows uptake in the supraclavicular region (arrow), a known site of skip metastases from cervical cancer. PET depicts distant nodal disease that would not be evident at clinical examination.
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Studies of preoperative sensitivity and specificity indicate that PET may be more accurate than MR imaging in diagnosis of cervical cancer (25). However, MR imaging is superior to PET in delineation of primary tumor local disease extension, including to the parametrium, uterosacral ligaments, pelvic sidewall, or vagina. T2-weighted images show bright areas of tumor enhancement within the cervix. One advantage of MR imaging to a radiation oncologist in treatment planning is the ability to view the tumor in sagittal, coronal, and axial planes. Determination of the degree of ante- or retroversion of the uterus assists with proper selection of the intrauterine tandem for brachytherapy. MR imaging may reveal vaginal extension, which can guide proper applicator selection, including the use of interstitial needles instead of ovoids. Recent guidelines for use of MR imaging during cervical cancer brachytherapy have been published (26). Difficult cases clearly benefit from imaging, in particular during the insertion process. For interstitial cases, the needles should be spaced 1 cm apart to obtain a homogeneous distribution. Figure 15 is an example of the isodose curves around an interstitial implant, showing how well interstitial therapy conforms to the very irregular volume close to the bone, yet spares the urethra, bladder, and rectum.
The most commonly used three-dimensional imaging modality in radiation oncology in the United States is CT at the time of simulation. Images from the simulation CT scan may be fused into treatment planning software, which allows the radiation oncologist to contour the involved sites. Thus, treatment plans are generated that allow coverage of the contoured volumes by various angles of radiation beams. The ideal plan maximizes coverage of the tumor and minimizes dose to the normal tissues. Fusion of the CT data with either the diagnostic PET or MR imaging data is feasible, although patients must be imaged in the same position to ensure proper alignment of internal organs. Treatment planning with CT-based brachytherapy is feasible, particularly to generate normal tissue dosimetry (27). PET/CT fusion may accurately delineate the primary nodes and allow identification of the involved nodes (Fig 16). If no grossly enlarged nodes are detected, contouring of pelvic vessels approximates the location of the pelvic nodes. Contours of the bladder, rectum, and sigmoid allow sparing of these normal tissues.
Concurrent chemo- and radiation therapy sterilizes any potential pelvic nodal disease that the brachytherapy implant does not treat and also shrinks the cervical mass so that the brachytherapy implant covers the full extent of disease spread. However, if the brachytherapy is given too early in the course of external-beam radiation therapy, the lateral extension of tumor may not receive an adequate dose. If the patient has locally advanced cervical cancer and undergoes a hysterectomy instead of primary radiation therapy, inevitably the margins will be positive, resulting in a significantly increased risk of tumor relapse, and the option of intrauterine brachytherapy is lost (28). The patient will need external-beam therapy after surgery, but this can mean increased risk of bowel, bladder, and bone complications compared to the combination of chemo- and radiation therapy alone (29). Complications of brachytherapy result from a very high dose being delivered to a very small volume of tissue and may include bleeding, ulceration, and fistula. Delivery of a moderate dose to a very large volume may result in long-term complications of stricture, fibrosis, and bladder contracture (30).
Radiologist’s View
How Do You Image the Complications of Treatment?—
As with ovarian cancer, postoperative complications and disease recurrence can be easily evaluated with cross-sectional imaging by using CT (Fig 17). Many complications are clinically apparent and do not require a specific imaging work-up. Local recurrence may be difficult to distinguish clinically from postoperative scarring and fibrosis; MR imaging may be helpful in this regard (Figs 18, 19).
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Figure 17. Radiation enteritis in a patient who was treated for cervical cancer. Contrast-enhanced CT scan shows thick-walled small bowel loops of increased permeability, hence the ascites.
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Figure 18. Local recurrence after hysterectomy for cervical cancer. T2-weighted MR image shows a mass in the anterior vaginal wall (arrow), a finding that represents a local recurrence of cervical cancer. The vagina is distended with surgical lubricant, which allows better delineation of the walls.
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Figure 19a. Complications of external-beam radiation therapy for cervical cancer. (a) CT scan shows avascular necrosis of the right femoral head (arrowhead) and a soft-tissue mass along the right pelvic sidewall (arrow). (b) MR image shows abnormal signal intensity in the presacral space and piriformis muscle. Biopsy results were negative, and the signal intensity changes were attributed to inflammatory changes after radiation therapy.
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Figure 19b. Complications of external-beam radiation therapy for cervical cancer. (a) CT scan shows avascular necrosis of the right femoral head (arrowhead) and a soft-tissue mass along the right pelvic sidewall (arrow). (b) MR image shows abnormal signal intensity in the presacral space and piriformis muscle. Biopsy results were negative, and the signal intensity changes were attributed to inflammatory changes after radiation therapy.
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In summary, our patient was a 36-year-old woman with menorrhagia. Clinical examination revealed a 5-cm cervical mass, clinically FIGO stage IIB. PET/CT was performed for more accurate staging. Treatment was with daily external-beam radiation therapy with five weekly cycles of concurrent cisplatin-based chemotherapy, followed by tandem and ovoid brachytherapy.
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Case 3: Uterine Cancer
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A 70-year-old woman presented to her gynecologist with postmenopausal bleeding. She was not taking hormone replacement therapy. The uterus felt normal in size, and no adnexal masses were palpated. An endometrial biopsy revealed endometrioid adenocarcinoma. Pathologic review of the uterus after a total abdominal hysterectomy with bilateral salpingo-oophorectomy and lymph node dissection revealed endometrioid adenocarcinoma, grade 3, with 75% myometrial invasion. Lymphovascular invasion was also detected. Three left and six right pelvic lymph nodes were removed, and all were negative. The patient was referred for postoperative radiation therapy.
Radiologist’s View
What Is the Best Imaging Test to Determine the Cause of Postmenopausal Bleeding?—
In 2001, the Society of Radiologists in Ultrasound issued a consensus statement that transvaginal US was an acceptable modality for first-line assessment of postmenopausal bleeding (31). They established the threshold endometrial thickness for intervention at 5 mm, which confers 96% sensitivity for detection of endometrial cancer. A subsequent meta-analysis of studies of transvaginal US by Smith-Bindman et al (32) confirmed the 5-mm threshold. They noted that a 4-mm threshold not only failed to improve sensitivity, but also decreased specificity due to the higher number of false-positive results.
As with other imaging in gynecologic oncology, good technique is vital. In a good study, the entire endometrial echo complex can be visualized. However, in 5%–10% of women this is technically impossible because of fibroids, adenomyosis, body habitus, or inability to tolerate endovaginal transducer placement. If transvaginal US fails but the patient can tolerate the transducer, sonohysterography is the next step (33). It is a more invasive procedure, as a catheter is placed in the cervix and sterile saline is injected to distend the uterine cavity. No sedation or analgesia is required, and it is performed as an outpatient study. The transducer is "swept" from side to side and front to back of the distended cavity, allowing complete sonographic evaluation of the endometrial surface.
In patients with homogeneously thick endometrium, a "blind" office biopsy is acceptable, whereas those patients with a focal thickening or polypoid excrescence require a hysteroscopic biopsy with direct visualization of the abnormality. Other indications for sonohysterography in the evaluation of postmenopausal bleeding include abnormal US results with negative blind biopsy results and persistent bleeding despite negative suction biopsy results and apparently normal transvaginal US results. Sonohysterography may reveal small focal abnormalities that are missed at conventional transvaginal US. This is important, as up to 10% of women with postmenopausal bleeding have endometrial cancer; when it is diagnosed at an early stage, treatment is very successful (34).
What Is the Role of Imaging in the Staging of Endometrial Cancer?—
The main role of radiology in endometrial cancer is detection, and US is the best modality. As with ovarian cancer, microscopic metastases and lymph node metastases may be occult with all imaging modalities, requiring surgery for accurate staging.
MR imaging and CT can be used to assess the extent of endometrial cancer especially in locally advanced cases, which might best be treated with first-line chemotherapy or radiation therapy (35). The superior soft-tissue contrast of MR imaging makes it preferable to CT for this indication. Our patient underwent pelvic US (Fig 20), which showed a 13.6-mm endometrial echo complex with an irregular endometrial-myometrial interface, inhomogeneous internal echogenicity, and abnormally branching blood vessels, all of which raise suspicion for endometrial carcinoma. This was confirmed at endometrial biopsy, and she was referred to gynecologic oncology for hysterectomy and surgical staging.
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Figure 20a. Pelvic US of endometrial cancer. (a) Gray-scale US image shows focal thickening of the endometrium (arrow), which has heterogeneous echogenicity. (b) Color Doppler image shows irregular vessels (arrow) within the area of endometrial thickening.
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Figure 20b. Pelvic US of endometrial cancer. (a) Gray-scale US image shows focal thickening of the endometrium (arrow), which has heterogeneous echogenicity. (b) Color Doppler image shows irregular vessels (arrow) within the area of endometrial thickening.
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Gynecologic Oncologist’s View
Is Surgical Staging Necessary for All Endometrial Cancer Patients?—
Surgical staging is necessary unless the patient is not a surgical candidate; that is, if the performance status is so poor that the patient could not withstand a laparotomy. Benefits of surgical staging include improved survival through removal of microscopically or macroscopically involved lymph nodes. Furthermore, the pathologic findings direct the use of adjuvant therapy. Risks are fairly minimal as long as the procedure is performed by surgeons with lymphadenectomy experience, with an average increase in operating room time of approximately 1 hour. There is a slightly increased complication rate, but the most frequent complications are lymphoceles and increased blood loss.
Lymph node palpation or any other kind of intraoperative assessment of lymph nodes is crude and unreliable (36). Many patients with endometrial cancer seen intraoperatively have diffusely enlarged lymph nodes, all of which are negative. Conversely, many patients with endometrial cancer have normal-appearing lymph nodes, but after removal two or three will show microscopic involvement with tumor; there is no accurate way of estimating preoperatively or intraoperatively whether the patient has positive nodes without removing them. Data from a retrospective study at the University of Alabama showed a survival advantage for patients with endometrial cancer who underwent extensive lymphadenectomy versus those who underwent no lymphadenectomy (37). The patients in the study were divided into low-risk and high-risk groups based on routine pathologic factors such as depth of invasion, vascular space invasion, and grade of tumor.
Preoperative imaging with US and MR imaging shows only the size of the lymph nodes, and often size does not correlate with disease. Grossly involved lymph nodes will be visible in a small number of patients. Intraoperative pathologic assessment is both unreliable and time-consuming. Most importantly, surgical staging improves treatment planning. It includes the routine total abdominal hysterectomy, bilateral salpingo-oophorectomy, and then removal of all of the pelvic and paraaortic lymph nodes, ideally up to the level of the renal veins but at least to the level of the inferior mesenteric artery. The lymphatic tissues surrounding the obturator, iliac, and paraaortic regions are cleared. Figure 21 illustrates the appearance of the retroperitoneum after lymph node dissection and stripping the vessels of all lymphatic tissue.
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Figure 21a. (a) Photograph shows the left pelvic retroperitoneum after lymph node sampling. The view is from the right side looking toward the feet. (b) Photograph shows the vena cava after the removal of lymph nodes. (Case courtesy of Julian Schink, MD.)
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Figure 21b. (a) Photograph shows the left pelvic retroperitoneum after lymph node sampling. The view is from the right side looking toward the feet. (b) Photograph shows the vena cava after the removal of lymph nodes. (Case courtesy of Julian Schink, MD.)
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Randomized trials in early-stage endometrial cancer show that radiation therapy after surgery significantly decreases local recurrence rates in endometrial cancer. Radiation therapy did not affect overall survival in these studies, though no study has had sufficient statistical power to detect a difference if it existed. A large number of patients and a long duration of follow-up would be necessary to truly detect a survival difference in a low-risk population.
GOG 99 compared surgical staging alone to surgical staging followed by whole pelvic radiation therapy in patients with intermediate-risk endometrial cancer (38). Eligible patients included those with stage IB or IC and occult stage IIA or IIB disease without clinically apparent cervical involvement. Surgical treatment required lymph node dissection, although selective pelvic and paraaortic lymph node sampling was also allowed; however, there had to be nodes present from each nodal basin. Dissection was followed in the radiation arm by standard external-beam whole pelvic radiation therapy without brachytherapy. The population in this study was more low-risk than intermediate-risk and therefore did not show dramatic or significant survival advantage in either group. Nonetheless, it was noted that pelvic radiation therapy significantly decreased recurrence rates, specifically the local recurrence rate, meaning vaginal and pelvic recurrences, with 12% in the surgery alone group versus 0.5% in the surgery and adjuvant radiation therapy group (Table 3).
Patients with grade 1 tumor at biopsy or dilation and curettage and no evidence of invasion or risk of lymph node involvement, according to the GOG 99 study, should have an approximately 0%–3% risk of metastases (39). However, from a surgeon’s perspective, the 3% risk of remaining positive nodes generally outweighs the risk of additional surgery; therefore, extensive surgery with full lymphadenectomy is recommended, particularly if the tumor measures at least 2 cm (40).
Surgical staging helps identify patients who do not need adjuvant radiation therapy, thereby avoiding the risk of toxic effects. A subanalysis within GOG 99 showed that the majority of those who benefited were in the "high-intermediate risk group," who had certain high-risk factors (including depth of invasion greater than 66%, grade 2 or 3 endometrioid adenocarcinoma, lymphovascular invasion, and older age). Without those risk factors, the majority of low-stage, intermediate-and high-grade cases benefit from vaginal cuff brachytherapy on the basis of retrospective studies, whereas whole pelvic radiation therapy may be indicated for some uterine cancers with either grade 3 disease or stages IC and above.
Radiation Oncologist’s View
What Are the Indications for Radiation Therapy in Endometrial Cancer?—
GOG 99 was a pivotal study in the management of early-stage endometrial cancer, as all patients were required to undergo surgical lymph node dissection. The definition of high-risk features identifies which patients to treat with radiation. High-risk features included depth of myometrial invasion, grade 2 or 3 disease, older age, and lymphatic-vascular space invasion. The external-beam component of treatment was reserved for patients with deep invasion or high grade and all patients with stage IC grade 3 disease, regardless of whether lymph nodes had been adequately dissected. For all patients with surgical assessment of lymph nodes, the highest risk of recurrence was in the vaginal cuff.
Therefore, the recommendation regarding treatment for stage I endometrial cancer can be either (a) external-beam therapy with vaginal brachytherapy, (b) external-beam therapy alone, or (c) vaginal cuff brachytherapy alone. Patients with no myometrial invasion and grade 1 or 2 disease (ie, stage IA1 or IA2) are candidates for observation only. Patients with stage IB1 endometrial cancer with no evidence of lymphovascular invasion may also be closely monitored. Patients with stage IB2 endometrial cancer are typically treated with vaginal cuff brachytherapy alone, as are patients with stage IC grade 1 and 2 disease who have undergone complete lymphadenectomy. Patients with grade 3 disease typically receive pelvic external-beam radiation therapy to the postoperative pelvis with 45 Gy to the pelvis over 5 weeks followed by a high-dose-rate vaginal cuff brachytherapy boost. Figure 22 shows anterior and lateral views of pelvic radiation fields in the postoperative setting.
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Figure 22. Treatment planning in endometrial cancer. Anterior (left) and lateral (right) simulation images of the postoperative pelvis show the radiation fields for external-beam radiation therapy. The contoured volumes include the pelvic lymph nodes and the vagina.
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How Is Vaginal Cuff Brachytherapy Delivered?—
A vaginal cylinder is inserted and stabilized by using the brachytherapy board. We measure the vaginal length and ensure that the cylinder is placed to the vaginal apex. Several publications provide recommendations about the acceptable number of fractions for vaginal brachytherapy, all with equal efficacy. A randomized trial of brachytherapy alone comparing four and six fractions showed that six fractions decreased the rate of vaginal stenosis (41). All patients receive a vaginal dilator in follow-up to prevent vaginal stenosis.
What Are Survival Rates for Patients with a Vaginal Cuff Recurrence?—
Notwithstanding the significant psychological anxiety induced by a recurrence, the likelihood of cure after a recurrence is approximately 50% at 5 years, though not as high as with up-front comprehensive management at diagnosis (42). It is important to note that endometrial cancer has a long natural history: a patient must be followed up for at least 5 years. The PORTEC randomized trial (43) compared surgery alone to surgery and external-beam radiation therapy. The surgery did not require a lymph node dissection. For patients who had relapse, the 2-year and 5-year disease-specific survival rates were 80% and 65%, respectively, for patients with a solitary vaginal cuff recurrence (44).
How Are Isolated Vaginal Cuff Recurrences Treated?—
All patients should be evaluated for radiation therapy after biopsy-confirmed recurrence. After external-beam therapy, vaginal recurrences of endometrial cancer are treated with brachytherapy. For lesions less than 5 mm in depth, a vaginal cylinder is adequate; deeper lesions require an interstitial implant. Placement with image guidance ensures proper coverage of the tumor volume with minimal dose to the bladder, rectum, and sigmoid (45) (Fig 23).
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Figure 23. MR imaging–guided interstitial brachytherapy of a recurrent endometrial cancer of the vaginal cuff, which was treated with curative radiation therapy. The addition of imaging-guided interstitial brachytherapy after external-beam therapy results in sparing of the bladder, rectum, and sigmoid colon.
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Radiologist’s View
What Is the Role of Imaging in Follow-up of Patients with Endometrial Cancer?—
As for other gynecologic malignancies, postoperative complications can be assessed with plain radiography and CT. Endometrial carcinoma tends to occur more frequently in obese women, in whom body habitus compromises both clinical and sonographic assessment. The difficulties are further compounded in the postoperative patient, as bowel loops move into the pelvis, limiting the ability to image soft-tissue masses and adenopathy. CT is useful for routine surveillance and can demonstrate ascites, adenopathy, and distant metastases. MR imaging is much less compromised by body habitus than is US and allows easy differentiation of soft-tissue masses from bowel, incisional hernia, and hypertrophic scar (Fig 24).
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Figure 24. Tumor recurrence in a patient who underwent hysterectomy for endometrial cancer. The patient experienced pelvic pain for several months after surgery; because palpation was compromised by body habitus, MR imaging was performed to evaluate for recurrence. Sagittal MR image shows implantation of endometrial cancer (arrowhead) in the hysterectomy scar. The large abdominal wall mass was successfully resected with resolution of the patient’s pain.
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In summary, our patient was a 70-year-old woman with postmenopausal bleeding. The diagnosis of endometrial cancer was suggested at US and confirmed at endometrial biopsy. She was treated and staged surgically. The final stage was FIGO stage IC grade 3 with lymphovascular invasion. After a complete lymph node dissection, she underwent external-beam radiation brachytherapy followed by vaginal cuff brachytherapy.
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Conclusions
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Imaging is crucial in gynecologic malignancies, both for diagnosis and to guide radiation therapy and other treatment modalities. Accurate imaging allows individualized, noninvasive radiation therapy and can also help direct invasive therapy. Future advances in image-guided evaluation and treatment may ultimately increase patient survival.
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Acknowledgments
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The authors thank Shannon Dickson for transcription, Paul Guttry for editorial assistance, and Jorgen Hansen for assistance with images.
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Footnotes
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Abbreviations: FIGO = International Federation of Gynecology and Obstetrics, GOG = Gynecologic Oncology Group
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References
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Introduction
Case 1: Ovarian Cancer
