Presenter (Parul Barry): brief case description

An otherwise healthy woman in her 40s with a history of a stage IIIC-2 clear cell endometrial adenocarcinoma. She initially presented with menorrhagia, low back pain, and generalized pelvic discomfort in March 2012. Subsequent endocervical biopsy was concerning for adenocarcinoma. She was evaluated by gynecologic oncology and endocervical curettage in June 2012 returned endometrioid and clear cell endometrial adenocarcinoma. Upfront imaging was notable for enlarged endometrial mass with cervical/parametrial involvement as well as abnormal pelvic and para-aortic adenopathy. As such, she was clinically diagnosed with IIIC-2 clear cell endometrial cancer.

Pathologist (Rohit Bhargava)

Endocervical currettings performed in June 2012 were consistent with endometrioid and clear cell adenocarcinoma with papillary and glandular patterns, and extensive necrosis involving, in part, an endometrial polyp ( Figure 1 ). Benign endocervical tissue with squamous metaplasia was seen. There was loss of expression for MSH2 and MSH6 and preservation of MLH1 and PMS2. Genetic testing included analysis of MSH2, MSH6, and portions of EPCAM, for which no mutations were detected.

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Figure 1

Photomicrographs from pre-therapy biopsy shows the clear cell carcinoma component with strong nuclear staining for HNF1β (A) and negative estrogen receptor (B). Conversely, the endometrioid component shows weak nuclear staining for HNF1β (C) but strong estrogen receptor nuclear reactivity (D).

As such, she proceeded with pre-operative carboplatin/paclitaxel, followed by external beam radiation therapy to the pelvis and para-aortics and brachytherapy boost. Surgical staging with total abdominal hysterectomy, bilateral salpingoopherectomy, infracolic omentectomy, and sigmoid mesentery biopsies in November 2012 were notable for partial response to pre-operative therapy. Residual clear cell carcinoma of the endometrium was seen with extensive coagulative necrosis indicating completed response to chemoradiation ( Figure 2 ). The tumor invaded 0.4 cm of 1.0 cm (40%) myometrial thickness and invaded the stromal connective tissue of the endocervix. There was no lymphovascular space invasion. Endometrial adenomyosis and leiomyomata were appreciated. Omental and sigmoid biopsies showed benign fibroadipose tissue. Cancer antigen 125 (CA 125) in November 2012 was 20, 12.2 in February 2014, and 16.6 in April 2016.

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Figure 2

Restaging PET/CT ordered by medical oncology to assess disease stability (performed October 3, 2013).

The patient was asymptomatic and disease-free for approximately 1 year with no evidence of disease on exam. Unfortunately, restaging imaging in October 2013, incidentally performed by her local medical oncologist, demonstrated development of a positron emission tomography (PET)-avid oligometastatic common iliac lymph node in the prior radiation field. Biopsy was consistent with recurrent disease. The patient was seen by gynecologic oncology and her case reviewed at tumor board. Stereotactic body radiation therapy was favored over equally appropriate surgery, as it was felt to be a less morbid/invasive and equally effective local intervention. The patient was referred to radiation oncology for evaluation of salvage stereotactic body radiation therapy.

Radiologist (Ekta Maheshwari)

Surveillance PET/CT ordered by medical oncology in October 2013 was notable for a 1.3 cm retroperitoneal lymph node adjacent to the left common iliac artery with an SUVmax of 6.7 ( Figure 2 ). This was not present on prior PET/CT from May 2013, and was consistent with metastatic disease. No other sites of metastatic or recurrent disease were noted. Following completion of salvage stereotactic body radiation therapy in December 2013 ( Figure 3 ), a restaging PET/CT was obtained in February 2014. This was notable for an interval decrease in size and ¹⁸F-fluorodeoxyglucose (FDG) avidity of the metastatic lymph node adjacent to the left common iliac artery with no evidence of any additional recurrent or metastatic cancer ( Figure 4 ). The patient’s last set of restaging imaging with CT CAP (chest abdomen pelvis) in October 2015, MRI abdomen in March 2017, and MRI pelvis in February 2021 were without evidence of disease. No further imaging follow-up was recommended.

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Figure 3

Salvage stereotactic body radiotherapy plan for 40 Gy in five fractions every other day (treatment delivered from December 3, 2013 to December 13, 2013).

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Figure 4

Restaging PET/CT to evaluate response to stereotactic body radiotherapy and assess disease stability (performed on April 24, 2014).

Discussants: Sushil Beriwal and William Small Jr

Endometrial cancer is the fourth most common cancer diagnosed and sixth most common cause of cancer death in American women with approximately 66 570 and 12 940 cases each year, respectively. 1 While approximately 80% present with stage I disease, unfortunately 25–30% of women with endometrial cancer develop disease recurrence. The current recommendations from the National Comprehensive Cancer Network (NCCN) dictate that women undergo routine follow-up with history and physical exam with their gynecologic and radiation oncologists for at least 5 years, as the majority of recurrences are detected within the first 3 years after treatment. Surveillance imaging is currently reserved for those who are symptomatic. However, with the rate of endometrial cancer on the rise, clinicians will find more patients with recurrent endometrial cancer in their practice. 2 Furthermore, the publication of Gynecologic Oncology Group 258 (GOG 258), which did not show improvement in relapse-free survival with chemoradiotherapy compared with chemotherapy alone, resulted in reduced use of pelvic radiation for advanced endometrial cancer despite higher rates of local recurrences seen with the omission of radiation therapy.2

Current imaging recommendations

Following definitive oncologic therapy, patients are followed closely by both gynecologic and radiation oncologists with history and physical exam, as approximately 25–30% are at risk of developing disease recurrence and metastasis. 3 4 NCCN guidelines recommend that endometrial cancer patients are followed every 3 to 6 months for the first 2 to 3 years after treatment, every 6 months for years 4 and 5, and then on a yearly basis.4

NCCN notes that surveillance imaging is not indicated unless there is clinical suspicion of recurrent or metastatic disease. This includes the following: disease noted on pelvic exam, palpable mass or adenopathy, and/or new pelvic, abdominal, or pulmonary symptoms. It is thought that history and physical exam detect 70–80% of recurrent or metastatic disease in endometrial cancer but do not impact survival. 3 American College of Radiology (ACR) guidelines generally support these recommendations with an important caveat: in those with high-risk endometrial cancer, imaging may be appropriate. 5 In this case, our patient would not have qualified for surveillance imaging based on the published guidelines from NCCN but would qualify based on ACR guidelines. The authors agree that routine surveillance imaging is not indicated for low- or intermediate-risk endometrial cancer, and that restaging imaging with CT, PET/CT, and/or MRI may be required for suspected recurrent and/or metastatic disease. However, the authors note that CT of the abdomen and pelvis, with or without CT or radiography of the chest, may be appropriate for asymptomatic patients with high-risk endometrial cancer. It is clear that our patient benefited from surveillance imaging, which has resulted in durable control of her disease and offered her a second opportunity for cure.

While current guidelines do not recommend routine surveillance imaging in high-intermediate, high-risk, and locally advanced endometrial cancer patients, this may soon become outdated. Post-operative surveillance imaging has been integrated into modern clinical trials. In GOG 249, which randomized stage I/II endometrial cancer patients to receive either adjuvant carboplatin/paclitaxel chemotherapy and vaginal cuff brachytherapy or adjuvant pelvic radiation, patients were followed with abdominopelvic imaging (CT or MRI) and chest X-ray within 4 weeks after study therapy, every 6 months for 2 years, then annually for 3 years. 6 GOG 258, which randomized stage III-IVA patients to receive either chemoradiation or chemotherapy alone, evaluated patients with CT of the abdomen and pelvis and chest radiography at baseline, at the end of treatment, every 6 months for the first 2 years, and then annually up to 5 years.2

Salvage of asymptomatic recurrences

While 95% of patients present with early-stage endometrial cancer, women who develop recurrent or metastatic disease will find their treatment options limited and survival poor. 1 Even though vaginal recurrences can be detected clinically, regional nodal and distant recurrences are difficult to assess without imaging. With the publication of GOG 258, there may have been a decline in the use of pelvic irradiation for locally advanced endometrial cancer, as no improvement in relapse-free survival was seen with the addition of radiation to chemotherapy. 2 In this study, women who did not receive radiation therapy experienced a higher nodal recurrence rate than those who did (20% vs 11%, respectively). Further, in GOG 249, the omission of pelvic radiation in favor of chemotherapy and vaginal cuff brachytherapy similarly resulted in a higher regional nodal recurrence rate of 9% versus 4%, respectively. 6 As noted above, both studies integrated surveillance imaging into patient follow-up. This furthered our understanding of patterns of local regional recurrence as earlier endometrial cancer clinical trials lacked routine surveillance imaging follow-up.

Patients who develop recurrent endometrial cancer may benefit from salvage radiation therapy, as our patient did, which is often less morbid than either single-modality surgical or chemotherapeutic approaches for those with limited disease. McAlarnen et al evaluated patients with endometrial cancer who developed nodal, pelvic, or peritoneal cavity recurrences. 7 In this series, 59% were pelvic/para-aortic lymph nodes and 41% were abdominal recurrences with a median time to diagnosis of 16 months. Treatment included surgical resection (with or without chemotherapy or external beam irradiation), non-surgical intervention (chemotherapy and/or external beam irradiation), or multi-modality therapy (combination surgical resection, chemotherapy, external beam irradiation ± vaginal brachytherapy). For all patients, 2-year overall survival was estimated at 69%. In the multi-modality and surgical cohort it was 68% and 67%, respectively. In the non-surgical cohort it was 53%. Two-year progression-free survival was 62% in the multi-modality cohort compared with about 40% in both the surgical and non-surgical cohorts. Toxicity was acceptable within the series. Advancements in treatment techniques and delivery have allowed oncologists to deliver salvage therapy with stereotactic body radiation therapy resulting in tumor ablation and minimal toxicity. Further study of patients with gynecologic malignancies (including endometrial cancer) with both nodal and distant oligometastases show excellent local control rates of 60–100% with salvage. 8

Furthermore, survival rates for women with asymptomatic recurrences are improved compared with those who are symptomatic. Ueda et al found that for those with stages I-IV endometrial cancer with recurrent disease, those with asymptomatic recurrences had improved progression-free survival (9 vs 2 months, p=0.017), but no difference in overall survival (37 vs 20 months, not significant). 9 Jeppesen et al evaluated early-stage endometrial cancer patients in Denmark with the goal of mitigating lead time bias as much as possible. The authors found that 3-year survival rates for those with asymptomatic endometrial cancer recurrences were 80.3% versus 54.3% with symptomatic recurrences. 10 Asymptomatic vaginal vault recurrences had improved 3-year survival (99.9%) compared with symptomatic ones (69.6%). Unfortunately, only 2.3% of women were found to have asymptomatic recurrences – a number that likely could increase with surveillance imaging. Furthermore, symptomatic lesions could be symptomatic due to increased aggressiveness, complicating length-time bias.

Summary

The addition of surveillance imaging to routine history and physical exam would improve the detection of asymptomatic recurrent endometrial cancer. Modern clinical trials currently incorporate surveillance imaging in high-risk patients. For those who did not receive external beam radiotherapy pelvic radiation, elevated risks of regional nodal recurrences were found at short-interval follow-up. The decline in use of pelvic radiation therapy following the publication of GOG 258 is especially concerning as 20% of patients experienced locoregional recurrence without radiation.2 Patients with high-risk or locally advanced endometrial cancer benefit most from surveillance imaging as they benefit most from radiation in reducing their risk of pelvic and para-aortic nodal recurrence. Should surveillance imaging find recurrent disease, such patients may benefit from salvage therapy with targeted intensity modulated radiation therapy, stereotactic body radiation therapy, or brachytherapy, which is in contrast to the currently recommended palliative standard treatment with platinum-doublet chemotherapy. We recommend surveillance imaging in high-risk endometrial cancer as it may provide a window for cure that closes as the disease progresses to symptomatic state.