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ORIGINAL RESEARCH |
From the Gynecology Service, Department of Surgery, and Departments of Radiation Oncology, Biostatistics, and Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York; Departments of Gynecologic Oncology, Radiation Oncology, and Pathology, MD Anderson Cancer Center, Houston, Texas; and Department of Obstetrics, Gynecology, and Reproductive Sciences, UMDNJ–Robert Wood Johnson Medical School, New Brunswick, New Jersey.
Address reprint requests to: Richard R. Barakat, MD, c/o Gynecology Service Academic Office, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Room MRI-1027, New York, NY 10021; E-mail: gynbreast{at}mskcc.org.
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ABSTRACT |
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METHODS: We conducted a retrospective chart and pathology review on patients diagnosed with endometrial cancer between 1976 and 2000 who had previously received definitive radiation treatment for cervical cancer. Abstracted data included patient demographics, type of radiation therapy, histological grade, histological subtype, and stage of endometrial cancer.
RESULTS: The mean age at endometrial cancer diagnosis was 64.4 years (range 53–80), and the average latency period from initial therapy to development of endometrial carcinoma was 14 years (range 6–27). Distribution by stage, grade, and histology was as follows: stage I, five (22%); stage II, one (4%); stage III, nine (39%); stage IV, seven (30%); unknown stage, one (4%); grade 1, one (4%); grade 2, three (13%); grade 3, 17 (74%); unknown grade, two (9%); carcinosarcoma, eight (35%); endometrioid, four (17%); papillary serous, six (26%); clear cell, one (4%); mucinous, one (4%); undifferentiated, one (4%); and unknown histology, two (9%). The median survival was 24 months, and the 2- and 5-year survival rates were 50% (95% confidence interval [CI] 31.4%, 78.9%) and 21% (95% CI 8.1%, 56.3%), respectively.
CONCLUSION: Patients treated with definitive radiation therapy for invasive cervical cancer may still have viable endometrium at risk for neoplasia. Endometrial cancers that develop after radiation treatment have a preponderance of high-risk histological subtypes and, consequently, a poor prognosis.
Radiation therapy is the standard treatment for most patients with stages IIB–IVA cervical cancer. Recent randomized trials demonstrating improved survival rates when concurrent chemotherapy is added to radiation have led to the adoption of chemoradiation as the standard of care in locoregionally advanced cervical cancer. This includes patients with stages IB2–IVA cervical cancer treated with primary radiation therapy and women with stages I–IIA disease noted to have poor prognostic factors (metastatic disease in pelvic lymph nodes, parametrial disease, or positive surgical margins) at time of primary surgery.1–5 However, radiation can damage normal tissues, including the uterine corpus. Because these patients are often cured of their cervical cancers, the development of second malignancies must be considered. The risk of developing endometrial carcinoma is not well established. Furthermore, early reports of endometrial carcinomas arising after radiation therapy for cervical cancer have suggested that many of these cancers are poorly differentiated and are diagnosed at an advanced stage, resulting in poorer prognoses. Because these cases are rare and most reports have included few patients, we are reporting the combined Memorial Sloan-Kettering Cancer Center and MD Anderson Cancer Center experience with patients who developed endometrial carcinoma after definitive radiation therapy for invasive cervical cancer.
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MATERIALS AND METHODS |
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RESULTS |
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outlines the basic clinical characteristics of the 23 patients studied. The mean age at diagnosis of the initial cervical cancer was 52 years (median 51, range 35–67). Of the 23 patients, 17 were white and six were black. Four of 23 patients had a history of smoking. Two patients had additional malignancies, one had both colon and breast cancer, and another patient had breast cancer only. All 21 patients for whom radiation treatment data were available had received definitive radiation therapy for cervical cancer: 19 (83%) received both external beam and brachytherapy, one (4%) received external beam irradiation only, and one (4%) received brachytherapy only. None of the patients received concurrent chemotherapy with radiation for their cervical cancer.
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The mean age of patients diagnosed with endometrial cancer was 64.4 years (median 64, range 53–80). The mean latency period from the initial diagnosis of cervical carcinoma to the development of endometrial carcinoma was 14 years (range 6–27). The most common presenting symptom was abdominal pain or cramping, which was noted in six patients, with the duration of symptoms ranging from 1 week to 12 months. Preoperative imaging with either ultrasound or computed tomography scan revealed a pelvic mass or enlarged uterus in 12 of 20 cases. Retrospectively applying 1988 International Federation of Gynecology and Obstetrics criteria, five patients (22%) had stage I disease, one (4%) had stage II, nine (39%) had stage III, seven (30%) had stage IV, and one (4%) had disease of unknown stage. With respect to grade, 17 (74%) had grade 3 cancer, three (13%) had grade 2, only one patient (4%) had grade 1, and two cases (9%) were not available for review. The histological type was carcinosarcoma in eight (35%), endometrioid in four (17%), papillary serous in six (26%), clear cell in one (4%), mucinous in one (4%), and undifferentiated in one (4%); two cases (9%) were not available for review. The two patients whose specimens were not available for rereview were said to have grade 3 endometrioid carcinomas on initial interpretation. Nineteen of the 23 patients in this study had an exploratory laparotomy after initial diagnosis; of these, 14 had total abdominal hysterectomy and bilateral salpingo-oophorectomy and five had supracervical hysterectomy and bilateral salpingo-oophorectomy. Four patients had only a diagnostic dilation and curettage because of advanced disease at presentation. Among the group, five patients had their surgery for endometrial cancer elsewhere, and intraoperative complications were unavailable. Intraoperative complications included one patient with a posterior cystotomy due to the bladder densely adhering to the cervix, one patient with an enterotomy, and another patient with a venotomy. Additionally, in five patients a supracervical hysterectomy was performed secondary to dense scarring due to previous radiation therapy for cervical cancer. In terms of postoperative complications, two patients had postoperative fever and wound seromas, whereas one patient had an ileus, abscess, and wound separation.
The median survival of 23 patients was 24 months (lower confidence limit 19.8 months, upper confidence limit not estimable because of lack of follow-up and censored data). When patients were analyzed based on low stage (I and II) versus high stage (III and IV), there was no difference in survival: 30.5 versus 32.7 months, respectively (P = .37), using the log-rank test (Figure 1). The 2-year survival probability was 50% (confidence interval [CI] 31.4%, 78.9%), and the 5-year survival probability was 21% (CI 8.1%, 56.3%) (Figure 2).
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DISCUSSION |
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A number of factors may contribute to this poor outcome. In our series, 73% of patients were diagnosed with stages II–IV disease. Rodriguez and Hart9 also found that 80% of their patients were diagnosed with advanced disease. Delays in diagnosis may contribute to this. Radiation-induced cervical stenosis may prevent early symptoms and complicate efforts to obtain a diagnosis. Unlike other patients with endometrial cancer, whose first symptom is typically vaginal bleeding, the patients in this series usually presented with symptoms of an enlarged uterus and pelvic pain, indicating relatively advanced disease. Although median survivals in our series did not differ between low and high stages (P = .37), the numbers were small in this statistical comparison.
Patients who develop endometrial cancer after radiation are also much more likely to have aggressive histological subtypes of adenocarcinoma. In our series, 74% had grade 3 disease, 35% had carcinosarcomas, and 30% had papillary serous or clear cell carcinomas. Papillary serous and clear cell histological types are usually found in less than 15% of spontaneous endometrial cancers, and carcinosarcoma occurs in less than 4%.10 Others have reported similar findings: Rodriguez and Hart9 found a high incidence of poorly differentiated tumors (80%) and carcinosarcoma (33%), and Prakash and Carcangiu11 reported six cases of uterine papillary serous carcinomas that developed after radiation therapy for cervical carcinoma, implicating radiation as a carcinogenic factor in the development of this aggressive histological subtype. The long latency period observed in many of these cases would be consistent with the hypothesis that radiation contributes to the genesis of these cancers.
Endometrial tissue can persist after radiation therapy for cervical cancer and undergo neoplastic transformation. According to Barnhill et al,12 in patients treated with high-dose radiation therapy for cervical cancer, ten of 16 patients had active endometrium. These patients received unopposed estrogen therapy and developed vaginal bleeding after radiation therapy. Endometrial biopsy revealed seven cases of proliferative endometrium, one cystic hyperplasia, one atypical adenomatous hyperplasia, and one endometrial adenocarcinoma. An increased risk of endometrial cancer has been associated with prolonged, unopposed estrogen,13 whereas combined estrogen and progesterone therapy prevents this increased risk.14 Thus, in young women treated with radiation for cervical cancer who receive hormone replacement therapy, combined estrogen and progesterone therapy should be considered. This may reduce the incidence of endometrioid adenocarcinomas, but there is no evidence that adding progesterone will reduce the incidence of carcinosarcomas or papillary serous tumors.
It is still unclear whether radiation induces a carcinogenic effect on the endometrium and leads to cancer. Endometrial carcinoma can develop as a result of unopposed estrogen exposure or be attributable to inherited genetic defects in the mismatch repair genes in hereditary nonpolyposis colorectal cancer families. However, given the age at diagnosis, latency interval, and the preponderance of high-risk histological subtypes, radiation may be the likely cause. This points to the importance of careful surveillance in these patients, probing for atypical signs and symptoms of endometrial cancer development, such as abdominal pain, cramping, or an enlarged uterus, in addition to the typical symptom of vaginal bleeding. Patients should be observed closely with an examination and Papanicolaou test every 3 months for the first 2 years, then every 6 months for 3 additional years, and then annually thereafter. It is important to continue careful annual surveillance even if the patient has been free of disease for many years, as the mean latency to developing endometrial carcinoma was 14 years.
Furthermore, it is important to consider that young women treated with radiation for cervical cancer will have ovarian function ablated and may require hormone replacement therapy. In these patients it is important to note that the endometrium may not be fully ablated and can remain viable. Therefore, it is imperative that clinicians recognize that endometrial cancer can develop in patients with cervical cancer who have been treated with definitive radiation. Furthermore, it is important to recognize that patients developing endometrial cancer after radiation may have a poor prognosis secondary to high grade and a preponderance of high-risk histological subtypes. Further research to understand the molecular genetic alterations in these tumors is needed.
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Footnotes |
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Received July 3, 2002. Received in revised form November 25, 2002. Accepted December 4, 2002.
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REFERENCES |
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2. Morris M, Eifel PJ, Lu J, Grigsby PW, Levenback C, Stevens RE, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999;340: 1137–43.
3. Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999;340:1144–53.
4. Keys HM, Bundy BN, Stehman FB, Muderspach LI, Chafe WE, Suggs CL 3rd, et al. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 1999;340:1154–61.
5. Peters WA 3rd, Liu PY, Barrett RJ 2nd, Stock RJ, Monk BJ, Berek JS, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000;18: 1606–13.
6. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53: 457–81.
7. Fehr PE, Prem KA. Malignancy of the uterine corpus following irradiation therapy for squamous cell carcinoma of the cervix. Am J Obstet Gynecol 1974;119:685–92.[Medline]
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12. Barnhill D, Heller P, Dames J, Hoskins W, Gallup D, Park R. Persistence of endometrial activity after radiation therapy for cervical carcinoma. Obstet Gynecol 1985;66: 805–8.
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14. Jick SS. Combined estrogen and progesterone use in endometrial cancer. Epidemiology 1993;4:384.[Medline]
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