Gynecology_Novak

Gynecology_Novak. Patterns of Metastatic Dissemination: Implications for Postoperative and Disease-Based Adjuvant Treatment was 94% for grade 1, 92% for grade 2, and 78% for grade 3 tumors (274). Therefore, patients with grade 3 tumors and a known propensity for deep myometrial invasion and lymph node metastasis may benefit from external-beam therapy. The decision to treat a patient who has endometrial cancer with radiation alone must involve a careful analysis of the relative risks and benefits of surgery. Although radiation alone can produce excellent survival and local control, it should be considered for definitive treatment only if the operative risk is estimated to exceed the 10% to 15% risk for uterine recurrence that is expected with radiation treatment alone.


Gynecology_Novak

Gynecology_Novak. Endometrial cancer is commonly diagnosed early in its natural history with approximately 80% of patients presenting with stage I disease. Nevertheless, approximately oneof every threewomen who die of endometrial cancer was considered to have early locoregional disease at primary diagnosis. The majority of treatment failures and the accompanying compromised longevity probably result from the failure to recognize sites of occult extrauterine dissemination at primary diagnosis. Traditional postoperative therapy (modality-based) for high-risk endometrial cancer is external-beam radiotherapy that is frequently supplemented with vaginal brachytherapy (278). This approach improves local control but not survival in early stage disease (135,155,279).


Gynecology_Novak

Gynecology_Novak. Understanding the different pathways of metastatic dissemination of endometrial cancer and their predictive factors allows the development of an individualized model for target-based therapeutic approaches to the predicted site(s) of failure. The natural history of epithelial corpus cancer includes fourpotential routes of metastasis: (i) contiguous extension (mainly to the vagina), (ii) hematogenous dissemination, (iii) lymphatic embolization, and (iv) exfoliation with intraperitoneal spread. On the basis of regression analysis, independent pathologic risk factors predictive of the four routes of metastatic spread were identified: 1. Contiguous extension: histologic grade 3 and lymphovascular space invasion are proven predictors of vaginal relapse in stage I endometrial cancer (280). 2. Hematogenous: deep myometrial invasion is the strongest predictor of hematogenous recurrence (>50% for all stages and ≥66% for stage I) (176,281). 3.


Gynecology_Novak

Gynecology_Novak. 2. Hematogenous: deep myometrial invasion is the strongest predictor of hematogenous recurrence (>50% for all stages and ≥66% for stage I) (176,281). 3. Lymphatic: lymphatic failure is more likely to occur when cervical stroma involvement or positive lymph nodes are present (182). 4. Peritoneal: predictors of peritoneal relapse are: (i) stage IV disease or (ii) stage II or III disease with twoor more of the following risk factors: cervical invasion, peritoneal cytologic results positive for endometrial cancer, positive lymph nodes, and nonendometrioid histologic findings (195).


Gynecology_Novak

Gynecology_Novak. Patients with the risk factors summarized in Table 35.10 account for 35% of the overall population with endometrial cancer, but 89% of the observed hematogenous, lymphatic, and peritoneal relapses. Importantly, 46% of the patients considered at risk subsequently experienced a recurrence in one or more of the three sites, compared with only 2% of patients not judged to be at risk based on these criteria (p <0.001). The identification of subgroups of patients at risk for the different patterns of recurrence would allow postoperative treatment targeted to the predicted areas of tumor dissemination. The recurrence sites predicted by risk factors would presuppose different adjuvant treatment strategies. Patients at risk for hematogenous or peritoneal recurrence would potentially benefit from systemic cytotoxic treatment,while patients at risk for lymphatic or vaginal recurrence would potentially benefit from radiation treatment directed at areas at risk.


Gynecology_Novak

Gynecology_Novak. Modalities of Postoperative Treatment Observation Patients with grades 1 and 2 lesions without myometrial invasion or any of the above risk factors (Table 35.10) have an excellent prognosis and require no postoperative therapy. In a GOG study, there were no recurrences and a 100% disease-free 5-year survival rate in the 91 patients in this category, 72 of whom received no additional treatment after hysterectomy (132). Other investigators reported equally favorable results with only surgical therapy in similar patients (282,283). Vaginal Vault Radiation Vaginal brachytherapy is an attractive alternative to externalradiation therapy (ERT).High-dose rate (HDR) brachytherapy is well tolerated with low rates of severe or chronic complications. Table 35.10 Rates of Recurrence at 5 Years According to the Different Risk Categories for 915 Patients


Gynecology_Novak

Gynecology_Novak. Table 35.10 Rates of Recurrence at 5 Years According to the Different Risk Categories for 915 Patients CSI, cervical stromal invasion. aCSI, nonendometrioid histologic subtype, positive lymph nodes, or positive result on peritoneal cytologic evaluation.bExcluding vaginal recurrences. cFor at least one of the three categories of recurrence (i.e. hematogenous, lymphatic, or peritoneal). From Mariani A, Dowdy SC, Keeney GL, et al. High-risk endometrial cancer subgroups: candidates for target-based adjuvant therapy. Gynecol Oncol 2004;95:120–126.


Gynecology_Novak

Gynecology_Novak. From Mariani A, Dowdy SC, Keeney GL, et al. High-risk endometrial cancer subgroups: candidates for target-based adjuvant therapy. Gynecol Oncol 2004;95:120–126. Vaginal control rates with the more convenient, better-tolerated HDR brachytherapy are comparable to control rates with the lengthier low-dose rate (LDR) brachytherapy. Pearcey and Petereit established the HDR dosing of 21 Gy to 5-mm depth in threefractions as the standard brachytherapy dose, providing local control rates of 98% to 100% (284). Additional retrospective data demonstrate 98% to 100% vaginal control rates with HDR in high risk early-stage endometrial cancer (285,286). Retrospective data suggestthat the vaginal relapse rate after brachytherapy averages 4% to 5% (Table 35.11) and this is similar to the 5-year vaginal failure rate of 3.5% reported among the highest-risk patients who received ERT in PORTEC-1 (135,282,285,287– 291).


Gynecology_Novak

Gynecology_Novak. PORTEC-2 randomized patients with apparent uterine-confined endometrial cancer at high risk for recurrence (>60 years of age with grade 1 or 2, stage IB and grade 3, stage IA; or any age, any grade IIA with <50% myometrial invasion), to pelvic ERT (46 Gy, in 23 fractions) versus vaginal brachytherapy (21 Gy in three HDR fractions or 30 Gy LDR, to a depth of 0.5 cm). At 3 years, there was no difference in vaginal failure rates (0.9% for vaginal brachytherapy, 2% for pelvic ERT; p = .97).There was a higher rate of nonvaginal pelvic relapse in the brachytherapy group (3.6 %) compared to the ERT group (0.7%; p = .03), however, the absolute difference was small and there was no difference in overall survival (292). The difference between nonvaginal pelvic recurrences may be a reﬂection of unrecognized lymph node metastases at the time of initial surgery treated with ERT. One concern regarding PORTEC-2 is that there was not a surgery-only control in the study. However, the highest risk


Gynecology_Novak

Gynecology_Novak. unrecognized lymph node metastases at the time of initial surgery treated with ERT. One concern regarding PORTEC-2 is that there was not a surgery-only control in the study. However, the highest risk endometrial cancer subgroup in PORTEC-1 (patients >60 years of age with grade 3 or deeply invasive grade 1 or 2, all stage I) was similar to the cohort included in PORTEC-2 and the locoregional recurrence rate in patients who did not receive adjuvant ERT in PORTEC-1 was 18% (135).


Gynecology_Novak

Gynecology_Novak. Table 35.11 Recurrence in High-Risk, Comprehensively Staged, Early-Stage Endometrial Cancer after Adjuvant Vaginal Brachytherapy Alone (No Pelvic ERT) ERT, external radiation therapy. Grade 3 histology and lymphovascular space invasion are proven predictors of vaginal relapse in stage I endometrial cancer. Patients with these risk factors are the most likely group to benefit from vaginal vault brachytherapy (280). Although vaginal recurrences can be successfully treated and controlled in up to 81% of cases,the addition of vaginal brachytherapy to the initial surgical intervention can significantly reduce the risk of such recurrences (293).


Gynecology_Novak

Gynecology_Novak. External Pelvic Radiation Radiation therapy traditionally was suggested to patients who were deemed to have intermediate or high risk of recurrence, according to grade and depth of myometrial invasion. Several retrospective studies and large, randomized trials did not show an overall survival benefit for intermediate-and high-risk patients with stage I endometrial cancer (or occult IIA endometrial cancer according to the 1988 FIGO staging) who received adjuvant pelvic radiotherapy.


Gynecology_Novak

Gynecology_Novak. The PORTEC trial tested the role of postoperative pelvic radiation therapy for presumed stage I endometrial cancer in 714 patients. Eligibility criteria were stage IB, grades 1 to 2, and stage IA, grades 2 to 3; patients with stage IA, grade 3, were only 10% of the study population, and lymph node biopsies and peritoneal cytology were not required. Local-regional recurrences developed in 14% of the surgery group, compared with 4% of the postoperative pelvic radiation group. Overall, the 5-year survival rate was no different between the two groups (85% vs. 81%, respectively) (135). These results were confirmed by GOG99, a prospective, randomized investigation of surgery alone (including lymphadenectomy to the level of the inferior mesentery artery in some patients) versus surgery plus adjuvant pelvic radiation in intermediate-risk endometrial cancer (stages IA to IIb occult). Of 392 patients accrued to the study, more than 80% were actually low-risk patients (90.6% stage I, 81.6%


Gynecology_Novak

Gynecology_Novak. adjuvant pelvic radiation in intermediate-risk endometrial cancer (stages IA to IIb occult). Of 392 patients accrued to the study, more than 80% were actually low-risk patients (90.6% stage I, 81.6% grades 1 to 2, 82% <50% myometrial invasion). Disease recurrence was reduced by 58% (p = 0.007) with the use of postoperative pelvic radiation. After 2 years, the cumulative recurrence rate was 12% in the group with no postoperative treatment compared with 3% in the group that received pelvic radiation. The pelvic failure rate was 8.9% in the surgery-alone group compared with 1.6% in the postoperative pelvic radiation group. Overall survival rates were not significantly improved in patients receiving postoperative pelvic radiation compared with those treated only with surgery (92% vs. 86%, respectively) (279). Recently, the intergroup ASTEC/EN.5 trial provided further confirmation that external-beam radiation therapy in patients at intermediate to high risk of recurrence has no significant


Gynecology_Novak

Gynecology_Novak. (279). Recently, the intergroup ASTEC/EN.5 trial provided further confirmation that external-beam radiation therapy in patients at intermediate to high risk of recurrence has no significant effect on overall survival (294).


Gynecology_Novak

Gynecology_Novak. Postoperative whole-pelvis external-beam radiation usually involves the delivery of 4,500 to 5,040 cGy in 180 cGy daily fractions over 5 to 6 weeks to a field encompassing the upper one-half of the vagina inferiorly, the lower border of the L4 vertebral body superiorly, and 1 cm lateral to the margins of the bony pelvis. The dose of radiation at the surface of the vaginal apex usually is boosted to 6,000 to 7,000 cGy by a variety of techniques. The most frequently reported side effects are gastrointestinal, usually abdominal cramps and diarrhea, although more serious complications such as bleeding, proctitis, bowel obstruction, and fistula can occur and may require surgical correction. The urinary system may be affected in the form of hematuria, cystitis, or fistula. The overall complication rate ranges from 25% to 40%; and the rate of serious complications requiring surgical intervention is about 1.5% to 3%.


Gynecology_Novak

Gynecology_Novak. External-beam pelvic radiation does not appear to impact survival in patients with high-risk stage I endometrial cancer. Patients with extrauterine pelvic disease, including adnexal spread, parametrial involvement, and pelvic lymph node metastases, in the absence of extrapelvic disease, are likely to benefit from postoperative pelvic radiation. Extended-Field Radiation Patients with histologically proven para-aortic node metastases and no other evidence of disease spread outside the pelvis should be treated with extended-field radiation. The entire pelvis, common iliac lymph nodes, and para-aortic lymph nodes are included within the radiation field. The para-aortic radiation dose is limited to 4,500 to 5,000 cGy. Extended-field radiotherapy appears to improve survival in patients with endometrial cancer who have positive paraaortic lymph nodes (132,295–298).


Gynecology_Novak

Gynecology_Novak. Five-year survival rates of 47% and 43% were reported for patients with surgically confirmed isolated para-aortic lymph node metastases and for those with para-aortic and pelvic lymph node metastases, respectively, using postoperative extended-field radiation. In one report, only one case of severe enteric morbidity occurred in 48 patients, a complication rate of 2% (295). In a GOG study, 37 of 48 patients with positive para-aortic nodes received postoperative para-aortic radiation, 36% of whom remained tumor free at 5 years (132). A comparison of patients with positive para-aortic nodes treated with megestrol acetate alone versus megestrol acetate and extended-field radiation showed that the survival rate in the patients receiving extended-field radiation was significantly better: 53% versus 12.5%, respectively (296). In another study of 18 patients with positive para-aortic nodes, 5-year survival rates were 67% for microscopic nodal disease and 17% for gross nodal disease (297).


Gynecology_Novak

Gynecology_Novak. Whole-abdomen radiation therapy is usually reserved for patients with stages III and IV endometrial cancer. It may be considered for patients who have serous or carcinosarcomas, which have a propensity for upper-abdominal recurrence (299–304). The recommended dose to the whole abdomen is 3,000 cGy in 20 daily fractions of 150 cGy, with kidney shielding at 1,500 to 2,000 cGy, along with an additional 1,500 cGy to the para-aortic lymph nodes and 2,000 cGy to the pelvis. Gastrointestinal side effects, including nausea, vomiting, and diarrhea, sometimes make it necessary to interrupt therapy, but it is rare for patients to discontinue treatment because of these symptoms. Hematologic toxicity can be expected to occur during whole-abdomen radiation, but it is usually mild. The incidence of late complications, mainly chronic diarrhea and small bowel obstruction, is low (5% to 10%).


Gynecology_Novak

Gynecology_Novak. In a series of 27 patients treated with surgical stage III endometrial cancer with whole-abdomen radiation, patients with spread to the adnexa, positive peritoneal cytology, or both had a 5year, relapse-free survival of 90%, whereas all patients with macroscopic disease beyond the adnexa had recurrence (298). Similar results were reported by others (300,301). Some advocated the use of adjuvant whole-abdomen radiotherapy for patients with high-risk stagesI and II endometrial carcinoma, including those with deep myometrial invasion, high-grade tumors, and serous histology, because of the high proportion of recurrences in the upper abdomen. A 5-year recurrence-free survival rate of 85% was reported (302,303). With whole-abdomen radiation in patients at increased risk for intra-abdominal metastatic disease, such as those with nonnodal extrauterine disease and serous histology, an actuarial 5-year relapse-free survival rate of 70% was reported, with no significant toxicity (304).


Gynecology_Novak

Gynecology_Novak. metastatic disease, such as those with nonnodal extrauterine disease and serous histology, an actuarial 5-year relapse-free survival rate of 70% was reported, with no significant toxicity (304). Similarly, others noted a 3-year disease-free survival rate of 79% in patients with stages III and IV endometrial adenocarcinoma treated with whole-abdomen radiation (305). Other reports of using adjuvant postoperative whole-abdomen radiation in early-stage uterine serous carcinoma suggest a reduction in recurrence rates (304– 306). Most recurrences are in the upper abdomen in all of these patients, despite use of this type of radiotherapy. After the publication of GOG122, demonstrating the superiority of chemotherapy over whole-abdominal radiotherapy in advanced endometrial cancer, the utilization of whole-abdominal radiotherapy is not common (see section on “Chemotherapy”) (307).


Gynecology_Novak

Gynecology_Novak. therapy attempted to reduce the risk of recurrence. This therapy is attractive because it provides systemic treatment and has few side effects. Unfortunately, several large randomized, placebo-controlled studies failed to identify a benefit for adjuvant progestin therapy (308–313). Chemotherapy Adjuvant cytotoxic chemotherapy was studied in a few trials. The GOG treated 181 patients who had poor prognostic factors with postoperative radiation and then randomly assigned patients to receive no further therapy or doxorubicin chemotherapy. After 5 years of observation, there was no difference in recurrence rates between the two groups (314).


Gynecology_Novak

Gynecology_Novak. In cases of advanced disease, chemotherapy is now standard treatment. The GOG122 trial compared whole-abdominal radiotherapy versus systemic chemotherapy (eightcycles of doxorubicin and cisplatin) in 388 patients with stage III or IV disease who underwent maximal surgical resection of disease to less than 2 cm. Its results showed a significant advantage of chemotherapy on 5-year survival (307). Patients who received chemotherapy had a 13% improvement in 2-year progression-free survival (50% vs. 46%) and an 11% improvement in overall 2-year survival (70% vs. 59%) compared with patients treated with whole-abdomen radiation. Although this study was the first to suggest an improvement in outcome for use of adjuvant chemotherapy compared with radiation, toxicity was more prevalent with chemotherapy; patients with gross residual disease were assigned to the radiation arm, almost guaranteeing failure; and overall, 55% of patients experienced a recurrence or progression during the study


Gynecology_Novak

Gynecology_Novak. patients with gross residual disease were assigned to the radiation arm, almost guaranteeing failure; and overall, 55% of patients experienced a recurrence or progression during the study period (315). GOG184 randomized 552 patients with advanced disease to sixcycles of cisplatin and doxorubicin with or without paclitaxel following surgical debulking and radiotherapy. Side effects were more pronounced with the three-drug regimen, and recurrence-free survival at 36 months was no different between arms (62% vs. 64% for the three-drug regimen). The investigation was closed to patients with stage IV disease during the trial, but subgroup analysis suggested a 50% reduction in recurrence or death in the 57 patients with gross residual disease who received cisplatin, doxorubicin, and paclitaxel (111).


Gynecology_Novak

Gynecology_Novak. Other GOG studies and the PORTEC-3 trial are investigating the combination of chemotherapy and radiotherapy in advanced or high-risk endometrial cancer. Results of these trials await maturation. GOG258 is comparing chemoradiation followed by chemotherapy versus chemotherapy alone in advanced endometrial cancer. PORTEC-3 is investigating overall survival and failure-free survival of patients with high-risk and advanced stage endometrial carcinoma treated after surgery with chemoradiation followed by chemotherapy versus pelvic radiation alone.


Gynecology_Novak

Gynecology_Novak. Regarding the use of chemotherapy in high-risk populations with early stage endometrial cancer, the European Organisation for Research and Treatment of Cancer, along with the Nordic Society of Gynecologic Oncology, presented the results of a collaborative trial comparing external radiotherapy versus chemoradiotherapy in patients with stages I or II or IIIC1 (positive pelvic nodes only) and one of the following characteristics: grade 3 or myometrial invasion greater than 50%, DNA aneuploidy, or clearcell or serous histologic type. Performance of a systematic lymphadenectomy was optional. A total of 375 patients were enrolled over a 10-year period and the study was closed early because of slow recruitment. The hazard ratio for progression-free survival was 0.58 (95% CI, 0.34–0.99) in favor of chemoradiation after a median follow-up of 3.5 years (316).


Gynecology_Novak

Gynecology_Novak. The Japanese GOG randomized patients to pelvic radiotherapy versus platinum-based chemotherapy in patients with stage IB to IIIC endometrial cancer and myometrial invasion greater than 50%. Assessment of para-aortic nodal status was performed in only 29% of cases. The investigators found no differences between the twoexperimental arms in terms of progression-free survival and overall survival. A subgroup analysis of 120 patients with either (i) stage IB tumor and age greater than 70 years or grade 3 endometrioid adenocarcinoma or (ii) stage II or IIIA tumor (positive cytologic findings) showed that chemotherapy was associated with significantly improved disease-free and overall survival rates (317). The benefits achieved with combined chemoradiation, identification of the best chemotherapeutic regimen, and the identification of subgroups of patients who may benefit from these treatments deserves further investigation.


Gynecology_Novak

Gynecology_Novak. Clinical Stage II Endometrial cancer involving the cervix either contiguously or by lymphatic spread has a poorer prognosis than disease confined to the corpus (267,278,318–334). Preoperative assessment of cervical involvement is difficult. Endocervical curettage has relatively high false-positive (50% to 80%) and false-negative rates. Histologic proof of cancer infiltration of the cervix or presence of obvious tumor on the cervix is the only reliable means of diagnosing cervical involvement, although ultrasonography, hysteroscopy, or MRI may show cervical invasion. The relatively small number of true stage II cases in reported series and the lack of randomized, prospective studies preclude formulation of a definitive treatment plan. Three areas must be addressed in any treatment plan: 1. For optimal results, the uterus should be removed in all patients. 2.


Gynecology_Novak

Gynecology_Novak. For optimal results, the uterus should be removed in all patients. 2. Because the incidence of pelvic lymph node metastases is about 36% in stage II endometrial cancer, any treatment protocol should include treatment of these lymph nodes. 3. Because the incidence of disease spread outside the pelvis to the para-aortic lymph nodes, adnexal structures, and upper abdomen is higher than in stage I disease, attention should be directed to evaluating and treating extrapelvic disease. Two approaches usually were used in the treatment of clinical stage II disease: 1. Radical hysterectomy, bilateral salpingo-oophorectomy, and pelvic and paraaortic lymphadenectomy 2.


Gynecology_Novak

Gynecology_Novak. Two approaches usually were used in the treatment of clinical stage II disease: 1. Radical hysterectomy, bilateral salpingo-oophorectomy, and pelvic and paraaortic lymphadenectomy 2. An initial radical surgical approach to treatment of clinical stage II endometrial cancer has the advantage of collecting accurate surgical–pathologic information. Conversely, many patients with endometrial cancer are elderly and obese and have medical problems that make this approach unsuitable. Reported results are no better than those with combined radiation and less radical surgical therapy (267). The use of radical hysterectomy may be limited to patients with anatomic problems that prevent optimum dosimetry or other conditions that conﬂict with the use of radiation therapy. The most common, traditional approach to the management of clinical stage II endometrial cancer is to use external and intracavitary radiation followed by extrafascial hysterectomy.


Gynecology_Novak

Gynecology_Novak. The most common, traditional approach to the management of clinical stage II endometrial cancer is to use external and intracavitary radiation followed by extrafascial hysterectomy. This combined approach resulted in 5-year survival rates of 60% to 80%, with severe gastrointestinal or urologic complications occurring in about 10% of patients (319–327). Patients who have medically inoperable disease are usually treated with external-beam radiation and one or two intracavitary insertions. Compared with combined radiation and surgery, the results with radiation alone are diminished, but about 50% of patients are long-term survivors (279) (Table 35.9).


Gynecology_Novak

Gynecology_Novak. Another method of management of clinical stage II endometrial cancer that is gaining favor is an initial surgical approach followed by radiation. This method is based on the difficulty in establishing the preoperative diagnosis of cervical involvement in the absence of a gross cervical tumor, the evidence that radiation is equally effective when given after hysterectomy, and the high incidence of extrapelvic disease when the cervix is involved. Exploratory laparotomy with an extrafascial or modified radical hysterectomy, bilateral salpingo-oophorectomy, peritoneal washings for cytology, and resection of grossly enlarged lymph nodes are performed. These procedures are followed by appropriate pelvic or extended-field external and intravaginal radiation, depending on the results of surgical staging. Excellent results were reported using this treatment scheme (329–331).


Gynecology_Novak

Gynecology_Novak. Clinical Stages III and IV Clinical stage III disease accounts for about 7% to 10% of all endometrial carcinomas (335–340). Patients usually have clinical evidence of disease spread to the parametria, pelvic sidewall, or adnexal structures; less frequently, there is spread to the vagina or pelvic peritoneum. Treatment for stage III endometrial carcinoma must be individualized, but initial operative evaluation and treatment should be considered because of the high risk for occult lymph node metastases and intraperitoneal spread when disease is known to extend outside of the uterus into the pelvis. In the presence of an adnexal mass, the initial impetus for surgery is to determine the nature of the mass. Surgery is performed to determine the extent of disease and to remove the bulk of the disease if possible. This procedure should include peritoneal washings for cytologic examination, para-aortic and pelvic lymphadenectomy, biopsy or excision of any suspicious areas within the


Gynecology_Novak

Gynecology_Novak. of the disease if possible. This procedure should include peritoneal washings for cytologic examination, para-aortic and pelvic lymphadenectomy, biopsy or excision of any suspicious areas within the peritoneal cavity, and omentectomy and peritoneal biopsies. Except in patients with bulky parametrial disease, total abdominal hysterectomy and bilateral salpingo-oophorectomy should be performed. The goal of surgery is eradication of all macroscopic disease because this finding is of major prognostic importance in the management of patients with clinical stage III disease. Postoperative therapy can be tailored to the extent of disease.


Gynecology_Novak

Gynecology_Novak. Results of therapy depend on the extent and nature of disease. A 5-year survival rate of 54% was reported for all patients with stage III disease; however, the survival was 80% when only adnexal metastases were present, compared with 15% when other extrauterine pelvic structures were involved (335). Patients with surgical–pathologic stage III disease have a much better survival rate (40%) than those with clinical stage III disease (16%) (326). Patients who are treated with combined surgery and radiation fare better than patients who receive radiation therapy alone (340).


Gynecology_Novak

Gynecology_Novak. Stage IV endometrial adenocarcinoma, in which tumor invades the bladder or rectum or extends outside the pelvis, makes up about 3% of cases (340–344). Treatment of stage IV disease is patient dependent but usually involves a combination of surgery, radiation therapy, and systemic hormonal therapy or chemotherapy. One objective of surgery and radiation therapy is to achieve local disease control in the pelvis to provide palliative relief of bleeding, discharge, and complications involving the bladder and rectum. In one report, control of pelvic disease was achieved in 28% of 72 patients with stage IV disease treated with radiation alone or in combination with surgery, progestins, or both (342). Several reports noted a positive impact of cytoreductive surgery on survival, the median survival being about threetimes greater with optimal cytoreduction (18 to 34 months vs. 8 to 11 months, respectively) (342–344). Pelvic exenteration may be considered in the very rare patient in whom disease


Gynecology_Novak

Gynecology_Novak. being about threetimes greater with optimal cytoreduction (18 to 34 months vs. 8 to 11 months, respectively) (342–344). Pelvic exenteration may be considered in the very rare patient in whom disease is limited to the bladder, rectum, or both (345,346).


Gynecology_Novak

Gynecology_Novak. Recurrent Disease About one-fourth of patients treated for early endometrial cancer develop recurrent disease. More than one-half of the recurrences develop within 2 years, and about three-fourths occurs within 3 years of initial treatment. The distribution of recurrences is dependent in large part on the type of primary therapy: surgery alone versus surgery plus local or regional radiotherapy. In a GOG study of 390 patients with surgical stage I disease, vaginal and pelvic recurrences were noted to comprise 53% of all recurrences in the group treated with surgery alone, whereas only 30% of recurrences were vaginal or pelvic in the group treated with combined surgery and radiotherapy (132). Therefore, after combined surgery and radiotherapy (vaginal or external beam), 70% or more of patients with treatment failures have distant metastases, and most of these patients do not have evidence of local or pelvic recurrence. The most common sites of extrapelvic metastases are the lung,


Gynecology_Novak

Gynecology_Novak. patients with treatment failures have distant metastases, and most of these patients do not have evidence of local or pelvic recurrence. The most common sites of extrapelvic metastases are the lung, abdomen, lymph nodes (aortic, supraclavicular, inguinal), liver, brain, and bone. Patients with isolated vaginal recurrences fare better than those with pelvic recurrences, who in turn have a better chance of cure than those with distant metastases. Patients who initially have well-differentiated tumors or who develop recurrent cancer more than 3 years after the primary therapy also tend to have an improved prognosis.


Gynecology_Novak

Gynecology_Novak. In a 1984 report on 379 patients with recurrent endometrial cancer seen at the Norwegian Radium Hospital from 1960 to 1976, site of recurrence was local or regional in 190 patients (50%), distant in 108 patients (28%), and local and distant in 81 patients (21%) (347). The median time of recurrence was 14 months for patients with local recurrences and 19 months for patients with distant metastases. Of all recurrences, 34% were detected within 1 year, and 76% were detected within 3 years of primary treatment. At the time of diagnosis of recurrence, 32% of patients had no symptoms. Vaginal bleeding was the most common symptom associated with local recurrence, and pelvic pain was most often present with pelvic recurrence. Hemoptysis was the initial symptom in 32% of patients with lung metastases, but 45% of cases of lung metastases were asymptomatic and picked up on routine chest x-ray. Only 9% of patients with metastases at other sites did not have symptoms; most had pain (37%) or other


Gynecology_Novak

Gynecology_Novak. but 45% of cases of lung metastases were asymptomatic and picked up on routine chest x-ray. Only 9% of patients with metastases at other sites did not have symptoms; most had pain (37%) or other symptoms such as anorexia, nausea and vomiting, or ascites related to intra-abdominal carcinomatosis, neurologic symptoms such as seizures from brain metastases, or jaundice caused by liver metastases. Overall, only 29 (7.7%) of the 379 patients were alive without evidence of disease from 3 to 19 years. This included 22 patients (12%) with local or pelvic recurrence, 5 patients (5%) with distant metastases, and 2 patients (2%) with both local and distant recurrences. The best results were obtained in the 42 patients with vaginal vault recurrences who were treated with radiotherapy, resulting in a 24% survival rate. None of the 78 patients with pelvic soft tissue recurrence survived. Three patients (7%) with only lung metastases treated with progestins, two patients with lymph node metastases


Gynecology_Novak

Gynecology_Novak. 24% survival rate. None of the 78 patients with pelvic soft tissue recurrence survived. Three patients (7%) with only lung metastases treated with progestins, two patients with lymph node metastases treated with combined radiotherapy and progestins, and two patients with local recurrence and lung metastases treated with radiotherapy, surgery, and progestins survived.


Gynecology_Novak

Gynecology_Novak. Surgery A small subset of patients with isolated recurrent endometrial cancer may benefit from surgical intervention. A search for distant recurrences prior to treatment is obligatory as such patients are best treated with chemotherapy. In one small series, upper-abdominal disease was found at laparotomy in three(37.5%) of eightpatients with presumed localized pelvic recurrence. Presence of subclinical extrapelvic metastases was associated with larger pelvic tumor size (>2 cm) and elevated serum CA125 levels (348). As discussed in the next section, isolated vaginal recurrence in patients who have not received prior pelvic radiation is best treated with external radiation plus some type of brachytherapy.


Gynecology_Novak

Gynecology_Novak. Treatment of patients with pelvic recurrence (generally located on the pelvic sidewall secondary to lymphatic failure) is more complex. Althoughthe study by Aalders et al. reviewed above showed no survivors in patients with pelvic recurrences, there is evidence that a multimodality approach consisting of radiotherapy followed by radical surgical resection and intraoperative radiotherapy (IORT) will cure some patients (347). A retrospective investigation at Mayo Clinic of 25 heavily pretreated patients with recurrent endometrial cancer demonstrated a survival of 71% in patients with complete surgical resection (349). Over 50% of these patients underwent radiation as primary therapy and one-half of those treated with radiationalso received chemotherapy or an attempt at surgical resection at the time of recurrence. Radical procedures performed at the time of IORT included resection of the pelvic sidewall en bloc with the obturator nerve, external iliac vein, psoas, iliacus, or obturator


Gynecology_Novak

Gynecology_Novak. the time of recurrence. Radical procedures performed at the time of IORT included resection of the pelvic sidewall en bloc with the obturator nerve, external iliac vein, psoas, iliacus, or obturator internus muscles, ureter, or boney ileum (Fig. 35.7). Seven patients required exenteration in combination with resection of the pelvic sidewall. Two patients with isolated para-aortic recurrences were alive and diseasefree at 54 and 71 months. Althoughsurvival in this cohort was impressive, the complication rate was similarly impressive at 64%. The most common complication was neuropathy; other complications included functional ureteral obstruction and fourpatients developed fistulas. Until more active agents are developed, radical multimodality treatment remains the only viable alternative for patients with pelvic recurrences. Memorial Sloan-Kettering Cancer Center reported on 36 patients with isolated central pelvic recurrence who underwent pelvic exenteration for recurrent endometrial


Gynecology_Novak

Gynecology_Novak. patients with pelvic recurrences. Memorial Sloan-Kettering Cancer Center reported on 36 patients with isolated central pelvic recurrence who underwent pelvic exenteration for recurrent endometrial carcinoma. Seventy-five percent died of their cancer within 1 year of operation, and 14% were alive after 5 years (349).


Gynecology_Novak

Gynecology_Novak. Radiation Therapy Radiotherapy is the best treatment option for patients with isolated local or regional recurrences who are unable or unwilling to undergo radical pelvic resection (350–356). The best local control and subsequent cure are usually achieved by a combination of ERT followed by a brachytherapy boost to deliver a total tumor dose of at least 6,000 cGy. Women with low-volume disease limited to the pelvis have the best outcome. For patients with isolated vaginal recurrence treated with radiation, reported 5-year survival rates range from 24% to 45%. The reclamation rate was 81% in one multi-institutional series that was limited to stage I patients with isolated vaginal failures (357). Conversely, for those patients who undergo radiation for the pelvic extension of their disease, lower survival rates (0% to 26%) are reported. Factors associated with improved survival and control of pelvic disease in patients with locally recurrent endometrial cancer include initial


Gynecology_Novak

Gynecology_Novak. disease, lower survival rates (0% to 26%) are reported. Factors associated with improved survival and control of pelvic disease in patients with locally recurrent endometrial cancer include initial endometrial cancer grade 1, younger age at recurrence, recurrent tumor size 2 cm or less, time from initial treatment to recurrence of more than 1 year, vaginal versus pelvic disease, and use of vaginal brachytherapy.


Gynecology_Novak

Gynecology_Novak. Hormonal Therapy The use of progestational agents for treatment of metastatic endometrial cancer was first described in 1961 when researchers observed an objective response rate of 29% in 21 patients (358). In a report from 1974, a beneficial response was observed in 35% of 308 patients (359). Subsequent reports noted somewhat less optimistic response rates, probably as a result of more strictly applied criteria for objective responses (359–362) (Table 35.12). Reports from Roswell Park Cancer Center and the Mayo Clinic observed objective response rates of 16% and 11%, respectively, with an additional 15% to 40% of patients exhibiting stable disease for at least 3 months (358,363). In 1986, the GOG reported on the use of oral medroxyprogesterone acetate for treatment of patients with advanced or recurrent endometrial cancer (361). Of 219 patients with measurable disease, 8% had a complete response, 6% had a partial response, 52% had stable disease, and 34% developed progressive disease


Gynecology_Novak

Gynecology_Novak. or recurrent endometrial cancer (361). Of 219 patients with measurable disease, 8% had a complete response, 6% had a partial response, 52% had stable disease, and 34% developed progressive disease within 1 month. The mean survival time for the entire group was 10.4 months. In a follow-up study comparing


Gynecology_Novak

Gynecology_Novak. Table 35.12 Response to Progestin Therapy in Advanced or Recurrent Endometrial Cancer HPC, hydroxyprogesterone caproate (Delalutin); MPA, medroxyprogesterone acetate (Provera, Depo-Provera); MA, megestrol acetate (Megace); IM, intramuscular; PO, oral. two different doses of oral medroxyprogesterone acetate, similar response rates were achieved (26% for 200 mg per day and 18% for 1,000 mg per day) (362). The type, dosage, and route of administration of the progestin seemed to have no effect on response in these studies.


Gynecology_Novak

Gynecology_Novak. The response of metastatic endometrial carcinoma to progestin therapy is related to several clinical and pathologic factors. Higher response rates are observed in well-differentiated tumors. A 20.5% response in low-grade tumors and only 1.4% response in high-grade tumors are noted (360). Likewise, the probability of an objective response to progestin therapy is about 70% for tumors that are estrogen-and progesterone-receptor positive, compared with about 5% to 15% for tumors that are negative for both receptors. A longer disease-free interval is associated with higher response rates to progestins. The response rate to progestinsranged from 6% in patients with an interval from primary treatment to recurrence of less than 6 months to 65% in patients in whom disease recurred more than 5 years after initial treatment (359). Other observed but less well-documented factors that may have an adverse effect on response to progestins are disease recurrence within a prior radiation field, large


Gynecology_Novak

Gynecology_Novak. after initial treatment (359). Other observed but less well-documented factors that may have an adverse effect on response to progestins are disease recurrence within a prior radiation field, large tumor burden, and advanced primary versus recurrent disease (360, 363).


Gynecology_Novak

Gynecology_Novak. A phase II investigation of the aromatase inhibitor anastrozole showed minimal activity in an unselected subset of patients with advanced or recurrent endometrial cancer (364).


Gynecology_Novak

Gynecology_Novak. Tamoxifen, a nonsteroidal antiestrogen with some estrogenic properties, was evaluated for treatment of metastatic endometrial carcinoma based on experience in using this agent in breast cancer treatment. Its use as either a single agent or in combination with a progestin is related to its ability to inhibit the binding of estradiol to the estrogen receptor and to increase progesterone-receptor expression. In a review of eight studies using tamoxifen, 20 to 40 mg per day, in patients with metastatic endometrial carcinoma, the overall response rate was 22%, with a range of 0% to 53% (365). Responses to tamoxifen were more likely to be observed in patients with low-grade, hormone receptor–positive tumors who had a prior response to progestin therapy. In an attempt to reverse the hormone receptor down-regulation seen with progestin therapy, tamoxifen was given along with progestins, but the overall responses to combined tamoxifen and progestin therapy were similar to those noted for


Gynecology_Novak

Gynecology_Novak. receptor down-regulation seen with progestin therapy, tamoxifen was given along with progestins, but the overall responses to combined tamoxifen and progestin therapy were similar to those noted for single-agent progestin therapy.


Gynecology_Novak

Gynecology_Novak. Progestins are recommended as initial treatment for all patients with recurrent endometrioid tumors with hormone receptor–positive tumors. Radiation therapy, surgery, or both should be used whenever feasible for treatment of localized recurrent cancer such as vaginal, pelvic, bone, and peripheral lymph node disease; however, these patients should also be given longterm progestin therapy unless they are known to have a progesterone-receptor–negative tumor. Patients with nonlocalized recurrent tumors, especially if progesterone receptors are known to be positive, are candidates for progestin therapy, either megestrol acetate, 80 mg twice daily, or medroxyprogesterone acetate, 50 to 100 mg three times daily. Progestin therapy should be continued for at least 2 to 3 months before assessing response. If a response is obtained, the progestin should be continued for as long as the disease is static or in remission. In the presence of a relative contraindication to high-dose progestin therapy


Gynecology_Novak

Gynecology_Novak. If a response is obtained, the progestin should be continued for as long as the disease is static or in remission. In the presence of a relative contraindication to high-dose progestin therapy (e.g., prior or current thromboembolic disease, severe heart disease, or inability of the patient to tolerate progestin therapy), tamoxifen, 20 mg twice daily, is recommended. Failure to respond to hormonal therapy is an indication for initiating chemotherapy.


Gynecology_Novak

Gynecology_Novak. Chemotherapy Several chemotherapeutic agents or combinations of agents are capable of inducing objective responses and even remissions in patients with metastatic endometrial carcinoma, but all cytotoxic therapy should be considered palliative because response and survival times are short (365–368). The most active chemotherapeutic agents are doxorubicin, the platinum compounds cisplatin and carboplatin, and paclitaxel (Taxol). Doxorubicin, 50 to 60 mg/m2 every 3 weeks (366–368); cisplatin, 60 to 75 mg/m2 every 3 weeks; and carboplatin, 350 to 400 mg/m2 every 4 weeks are associated with response rates of 21% to 29%. Paclitaxel, 250 mg/m2 as a 24-hour infusion with granulocyte colony-stimulating factor support, or 175 mg/m2 as a 3-hour infusion every 3 weeks, produced response rates of about 36% (369–371). Alkylating agents such as cyclophosphamide and melphalan, 5-ﬂuorouracil, altretamine (hexamethylmelamine), liposomal doxorubicin, and topotecan show activity against endometrial


Gynecology_Novak

Gynecology_Novak. about 36% (369–371). Alkylating agents such as cyclophosphamide and melphalan, 5-ﬂuorouracil, altretamine (hexamethylmelamine), liposomal doxorubicin, and topotecan show activity against endometrial cancer (371–374). Most responses obtained with use of these agents were partial, averaging only 3 to 6 months, with the median survival time ranging from 4 to 8 months.


Gynecology_Novak

Gynecology_Novak. Combination chemotherapy regimens employing doxorubicin and cisplatin; cyclophosphamide, doxorubicin, and cisplatin; paclitaxel and cisplatin with or without doxorubicin; and carboplatin and paclitaxel resulted in response rates ranging from 38% to 76% (375– 390). Despite these fairly impressive response rates, most responses are partial, with durations of 4 to 8 months, and the median survival time is less than 12 months. Response to chemotherapy in patients with metastatic endometrial cancer does not appear to be affected by prior or concurrent progestin therapy. Metastatic site, age, disease-free interval, histology, and tumor grade appear to have no effect on chemotherapy response. Patients with long disease-free intervals and better performance status may live longer.


Gynecology_Novak

Gynecology_Novak. Treatment Results Comprehensive survival data for endometrial cancer are provided by the FIGO (391). Survival in relation to the old clinical and surgical stage is shown in Table 35.13 and in relation to surgical stage and grade in Table 35.14. The overall 5-year survival rate was 76%. Patients who underwent surgical staging had much better 5-year survival rates than those staged clinically across all stages (respectively): stage I, 87% versus 54%; stage II, 76% versus 41%; stage III, 57% versus 23%; stage IV, 18% versus 12%. Survival in surgical stage I disease ranged from more than 90% for patients with grade 1 and 2 tumors without myometrial invasion to 63% for stage IB grade 3. Table 35.13 Carcinoma of the Endometrium: Stage Distribution and Actuarial Survival by Stage (Surgical and Clinical) Surgical I 3,996 70 92 87 II 70912 82 76 III 758 13 66 59 IV 231 423 18 Total 6,260 100 82 76


Gynecology_Novak

Gynecology_Novak. Surgical I 3,996 70 92 87 II 70912 82 76 III 758 13 66 59 IV 231 423 18 Total 6,260 100 82 76 Adapted from Creasman WT, Odicino F, Maisonneuve P, et al. Carcinoma of the corpus uteri. FIGO Annual Report on the results of treatment in gynecological cancer. J Epidemiol Biostat 2001;6:45–86, with permission. Table 35.14 Surgically Staged Endometrial Cancer: Actuarial 5-Year Survival Rate (%) by Histologic Grade and Stage (1988 staging criteria) Adapted from Creasman WT, Odicino F, Maisonneuve P, et al. Carcinoma of the corpus uteri. FIGO Annual Report on the results of treatment in gynecological cancer. J Epidemiol Biostat 2001;6:45–86, with permission.


Gynecology_Novak

Gynecology_Novak. History and physical examination remain the most effective methods of follow-up in patients treated for endometrial cancer (392–394). Patients should be examined every 3 to 4 months during the first 2 years and every 6 months thereafter. About one-half of patients discovered to have recurrent cancer have symptoms, and 75% to 80% of recurrences are detected initially on physical examination. Particular attention should be given to peripheral lymph nodes, the abdomen, and the pelvis. Very few asymptomatic recurrences are detected by vaginal cytology. Chest x-ray every 12 months is an important method of posttreatment surveillance. Almost one-half of all asymptomatic recurrences are detected by chest x-ray. Other radiologic studies, such as CT scans, are not indicated for routine follow-up of patients who do not have symptoms.


Gynecology_Novak

Gynecology_Novak. Serum CA125 measurement was suggested for posttreatment surveillance of endometrial cancer (392–394). Elevated CA125 levels were documented in patients with recurrent tumor, and these levels correlated with the clinical course of disease. However, CA125 levels may be normal in the presence of small recurrences, making the utility of CA125 measurements for follow-up of patients after treatment of early-stage disease suspect. Determinations of CA125 should be obtained in patients with elevated levels at the time of diagnosis or with known extrauterine disease.


Gynecology_Novak

Gynecology_Novak. Twenty-five percent of women with endometrial cancer are premenopausal and 5% are under the age of 40, indicating that interest in ovarian preservation or postoperative estrogen replacement is not uncommon (395). Isolated investigations suggest that premenopausal women have a much higher likelihood (23%) of a synchronous ovarian cancer (396). If both ovaries appear grossly normal, the risk of adnexal malignancy decreases to less than 1% (397).Careful inspection of the adnexa is imperative when ovarian preservation is considered (23,396–398).


Gynecology_Novak

Gynecology_Novak. Most endometrial cancers are associated with excess estrogen exposure, calling into question the appropriateness of estrogen therapy for premenopausal patients with endometrial cancer following hysterectomy and bilateral salpingo-oophorectomy. In 1986, Creasman et al. and others reported that estrogen therapy appeared safe with no documented increase in the risk of recurrence following surgical treatment for endometrial carcinoma (397,399,400). Some investigations reported higher intercurrent death rates, such as from myocardial infarction, in the group in which estrogen was withheld (397,401). A randomized, double-blind, placebo-controlled study was designed to determine whether estrogen replacement increased rates of disease recurrence in women with stage I or II endometrial cancer. This investigation closed early because of a fall off in accrual after the findings of the Women’s Health Initiative were made public in 2002. At the time of closure, the enrollment of over 1,200


Gynecology_Novak

Gynecology_Novak. This investigation closed early because of a fall off in accrual after the findings of the Women’s Health Initiative were made public in 2002. At the time of closure, the enrollment of over 1,200 patients in the study was insufficient, given the exceptionally low recurrence rate is this low-risk group (399). Although the safety of estrogen therapy in patients with endometrial cancer was not verified with level 1evidence, this investigation provided sufficient reassurance to justify the practice of offering estrogen therapy to patients with low-grade, FIGO 2009 stage IA disease in the absence of other contraindications. The American College of Obstetricians and Gynecologists issued a committee opinion recommending that providers should take into consideration prognostic indicators such as depth of invasion, grade, and stage when deciding to administer estrogen therapy to these patients (402).


Gynecology_Novak

Gynecology_Novak. For women who decline systemic estrogen replacement, symptoms of vaginal dryness and dyspareunia may be judiciously treated with topical estrogen alone. Symptomatic relief of hot ﬂashes can be achieved by prescribing progestins such a medroxyprogesterone acetate, 10 mg orally daily or 150 mg intramuscularly every 3 months, or nonhormonal agents such as Bellergal, clonidine, and venlafaxine. Uterine sarcomas are relatively rare tumors of mesodermal origin. They constitute 2% to 6% of uterine malignancies (403–405). There is an increased incidence of uterine sarcomas after radiation therapy to the pelvis for either carcinoma of the cervix or a benign condition. The relative risk of uterine sarcoma after pelvic radiotherapy is estimated to be 5.38, with an interval of 10 to 20 years (405). Uterine sarcomas are, in general, the most malignant group of uterine tumors and differ from endometrial cancers with regard to diagnosis, clinical behavior, pattern of spread, and management.


Gynecology_Novak

Gynecology_Novak. The three most common histologic variants of uterine sarcoma are endometrial stromal sarcoma (ESS), leiomyosarcoma, and carcinosarcoma (malignant mixed m¨ullerian tumor, or MMMT) of both homologous and heterologous type (406) (Table 35.15). Variations in the relative incidences of uterine sarcomas occur in published series, probably related to the strictness of criteria used to classify smooth muscle and endometrial stromal tumors as sarcomas. Leiomyosarcoma and carcinosarcoma each constitute approximately 40% of tumors, with carcinosarcoma predominating in more recent reports, followed by ESS (15%) and other sarcomas (5%). Staging Staging of uterine sarcomas is based on the FIGO system (Table 35.16).


Gynecology_Novak

Gynecology_Novak. Stromal tumors occur primarily in perimenopausal women between ages 45 and 50 years; about one-third occurs in postmenopausal women. There is no relationship to parity, associated diseases, or prior pelvic radiotherapy. These tumors are rare in African-American women. The most frequent symptom is abnormal uterine bleeding; abdominal pain and pressure caused by an enlarging pelvic mass occur less often, and some patients do not have symptoms. Pelvic examination usually reveals regular or irregular uterine enlargement, sometimes associated with rubbery parametrial induration. The diagnosis may be determined by endometrial biopsy, but the usual preoperative diagnosis is uterine leiomyoma. At surgery, the diagnosis is suggested by the presence of an enlarged uterus filled with soft, gray-white to yellow necrotic and hemorrhagic tumors with bulging surfaces associated with wormlike elastic extensions into the pelvic veins.


Gynecology_Novak

Gynecology_Novak. Endometrial stromal tumors are composed purely of cells resembling normal endometrial stroma. They are divided into three types on the basis of mitotic activity, vascular invasion, and observed differences in prognosis: (i) endometrial stromal nodule, (ii) endometrial stromal sarcoma, and (iii) high-grade or undifferentiated sarcoma. Endometrial stromal nodule is an expansive, noninfiltrating, solitary lesion confined to the uterus with pushing margins, no lymphatic or vascular invasion, and usually less than 5 mitotic figures per 10 high-power microscopic fields (5 MF/10 HPF). These tumors should be considered benign because there are no recurrences or tumor-associated deaths reported after surgery (406,407). Table 35.15 Classifications of Uterine Sarcomas I. Pure nonepithelial tumors A. Homologous 1. Endometrial stromal tumors a. b. 2. Smooth muscle tumors a. b. 1. 2. c. Benign metastasizing tumors 1. 2. 3. B. Heterologous 1. 2. 3. 4. II. A. 1. 2.


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Gynecology_Novak. A. Homologous 1. Endometrial stromal tumors a. b. 2. Smooth muscle tumors a. b. 1. 2. c. Benign metastasizing tumors 1. 2. 3. B. Heterologous 1. 2. 3. 4. II. A. 1. 2. B. Adenosarcoma Modified from Clement P, Scully RE. Pathology of uterine sarcomas. In: Coppleson M, ed. Gynecologic oncology: principles and practice. New York: Churchill-Livingston, 1981, with permission.


Gynecology_Novak

Gynecology_Novak. Modified from Clement P, Scully RE. Pathology of uterine sarcomas. In: Coppleson M, ed. Gynecologic oncology: principles and practice. New York: Churchill-Livingston, 1981, with permission. Endometrial stromal sarcoma (formerly termed low-grade ESS or endolymphatic stromal myosis) is distinguished from high-grade ESS or undifferentiated endometrial sarcoma microscopically by a mitotic rate of less than 10 MF/10 HPF and a more protracted clinical course. Recurrences typically occur late, and local recurrence is more common than distant metastases (408–412). Although endometrial stromal sarcoma often behaves in a histologically aggressive fashion, it lacks the aneuploid DNA content and high proliferative index associated with high-grade stromal sarcoma. Flow cytometric analysis can be used to differentiate the two conditions and predict response to therapy.


Gynecology_Novak

Gynecology_Novak. Endometrial stromal sarcoma extends beyond the uterus in 40% of cases at the time of diagnosis, but the extrauterine spread is confined to the pelvis in two-thirds of the cases. Upper-abdominal, pulmonary, and lymph node metastases are uncommon. Recurrence occurs in almost one-half of cases at an average interval of 5 years after initial therapy. Prolonged survival and cure are common even after the development of recurrent or metastatic disease. Optimum initial therapy for patients with endometrial stromal sarcoma consists of surgical excision of all grossly detectable tumor. Total abdominal hysterectomy and bilateral salpingo-oophorectomy should be performed. The adnexa should always be removed because of the propensity for tumor extension into the parametria, broad ligaments, and adnexal structures, and the possible estrogen-stimulating effect on the tumor cells if ovaries are retained. A beneficial effect of radiation therapy is reported, and pelvic radiation is recommended for


Gynecology_Novak

Gynecology_Novak. Table 35.16 Staging for Uterine Sarcomas (Leiomyosarcomas, Endometrial Stromal Sarcomas, Adenosarcomas, and Carcinosarcomas) (2008) Stage I Tumor limited to uterus IA <5cm IB >5cm Stage II Tumor extends to the pelvis IIB Tumor extends to extrauterine pelvic tissue Stage III Tumor invades abdominal tissues (not just protruding into the abdomen). IIIA One site IIIB > one site IIIC Metastasis to pelvic and/or para-aortic lymph nodes Stage I Tumor limited to uterus IA Tumor limited to endometrium/endocervix with no myometrial invasion IB Less than or equal to half myometrial invasion IC More than half myometrial invasion Stage II Tumor extends to the pelvis IIB Tumor extends to extrauterine pelvic tissue Stage III Tumor invades abdominal tissues (not just protruding into the abdomen). IIIA One site IIIB > one site IIIC Metastasis to pelvic and/or para-aortic lymph nodes Carcinosarcomas should be staged as carcinomas of the endometrium.


Gynecology_Novak

Gynecology_Novak. Carcinosarcomas should be staged as carcinomas of the endometrium. FIGO Committee on Gynecologic Oncology. FIGO staging for uterine sarcomas. Int J Gynecol Obst 2009;104:179. ∗Note: Simultaneous tumors of the uterine corpus and ovary/pelvis in association with ovarian/pelvic endometriosis should be classified as independent primary tumors. inadequately excised or locally recurrent pelvic disease (408). There is evidence that endometrial stromal sarcoma is hormone dependent or responsive. Objective responses to progestin therapy were reported in 48% of patients in one series (410). Recurrent or metastatic lesions may be amenable to surgical excision. Long-term survival and apparent cures were noted in patients with pulmonary metastases (413).


Gynecology_Novak

Gynecology_Novak. High-grade ESS or undifferentiated endometrial sarcoma is a highly malignant neoplasm. Histologically, it exhibits greater than 10 MF/10 HPF and often completely lacks recognizable stromal differentiation. This tumor has a much more aggressive clinical course and poorer prognosis than endometrial stromal sarcoma (406,408,413–416). The 5-year disease-free survival is about 25%. Treatment of undifferentiated endometrial sarcoma should consist of total abdominal hysterectomy and bilateral salpingo-oophorectomy. The poor therapeutic results suggest that radiation therapy, chemotherapy, or both should be used in combination with surgery. These tumors, unlike endometrial stromal sarcoma, are not responsive to progestin therapy.


Gynecology_Novak

Gynecology_Novak. Uterine tumor resembling ovarian sex-cord tumor (UTROSCT) is a rare variant of endometrial stromal sarcoma in which benign glands and epithelial cells are found. Immunohistochemically, these tumors express cytokeratin, epithelial membrane antigen, vimentin, and smooth muscle actin. Although some of these tumors have infiltrative margins, almost all of them behave benignly. The so-called mixed UTROSCT have a significant endometrial stromal sarcoma component and tend to behave more aggressively (417,418).


Gynecology_Novak

Gynecology_Novak. Leiomyosarcoma The median age for women with leiomyosarcoma (43 to 53 years) is somewhat lower than for other uterine sarcomas, and premenopausal patients have a better chance of survival. This malignancy has no relationship with parity, and the incidence of associated diseases is not as high as in carcinosarcoma or endometrial adenocarcinoma. AfricanAmerican women have a higher incidence and a poorer prognosis than women of other races. A history of prior pelvic radiation therapy can be elicited in about 4% of patients with leiomyosarcoma. The incidence of sarcomatous change in benign uterine leiomyomas is reported to be between 0.13% and 0.81% (419–429).


Gynecology_Novak

Gynecology_Novak. Presenting symptoms, which are of short duration (mean, 6 months) and not specific to the disease, include vaginal bleeding, pelvic pain or pressure, and awareness of an abdominopelvic mass. The principal physical finding is the presence of a pelvic mass. The diagnosis should be suspected if severe pelvic pain accompanies a pelvic tumor, especially in a postmenopausal woman. Endometrial biopsy, although not as useful as in other sarcomas, may establish the diagnosis in as many as one-third of cases when the lesion is submucosal. Survival rates for patients with uterine leiomyosarcoma range from 20% to 63% (mean, 47%). The pattern of tumor spread is to the myometrium, pelvic blood vessels and lymphatics, contiguous pelvic structures, abdomen, and then distantly, most often to the lungs. The number of mitoses in the tumor traditionally was the most reliable microscopic indicator of malignant behavior (Fig. 35.8).


Gynecology_Novak

Gynecology_Novak. Tumors with less than 5 MF/10 HPF behave in a benign fashion, and tumors with more than 10 MF/10 HPF are frankly malignant with a poor prognosis. Tumors with 5 to 10 MF/10 HPF, termed cellular leiomyomas or smooth muscle tumors of uncertain malignant potential, are less predictable. In addition to mitotic index greater than 10, other histologic indicators used to classify uterine smooth muscle tumors as malignant are severe cytologic atypia and coagulative tumor cell necrosis (430). Uterine smooth muscle tumors with any two of these three features are associated with a poor prognosis. Gross presentation of the tumor at the time of surgery is an important prognostic indicator. Tumors with infiltrating tumor margins or extension beyond the uterus are associated with poor prognosis, whereas tumors less than 5 cm, originating within myomas, or with pushing margins are associated with prolonged survival.


Gynecology_Novak

Gynecology_Novak. Five other clinical pathologic variants of uterine smooth muscle tumors deserve special comment: (i) myxoid leiomyosarcoma, (ii) leiomyoblastoma, (iii) intravenous leiomyomatosis, (iv) benign metastasizing uterine leiomyoma, and (v) disseminated peritoneal leiomyomatosis. Myxoid leiomyosarcoma is characterized grossly by a gelatinous appearance and apparent circumscribed border. Microscopically, the tumors have a myxomatous stroma and extensively invade adjacent tissue and blood vessels (431). The mitotic rate is low (0 to 2 MF/10 HPF), which belies their aggressive behavior and poor prognosis. Surgical excision by hysterectomy is the mainstay of treatment. The low mitotic rate and abundance of intracellular myxomatous tissue suggest that these tumors would not be responsive to radiation therapy or chemotherapy.


Gynecology_Novak

Gynecology_Novak. Leiomyoblastoma includes smooth muscle tumors designated as epithelioid leiomyomas, clear cell leiomyomas, and plexiform tumorlets (432,433). This group of atypical smooth muscle tumors is distinguished by the predominance of rounded rather than spindle-shaped cells and by a clustered or cordlike pattern. These lesions should be regarded as specialized low-grade leiomyosarcomas with fewer than 5 MF/10 HPF. Leiomyoblastoma is treated with hysterectomy, and the prognosis is excellent. Intravenous leiomyomatosis is characterized by the growth of histologically benign smooth muscle into venous channels within the broad ligament and then into uterine and iliac veins (434-437). The intravascular growth takes the form of visible, wormlike projections that extend Figure 35.8 Leiomyosarcoma of the uterus. Interlacing bundles of spindle cells have fibrillar cytoplasm, irregular and hyperchromatic nuclei, and multiple mitotic figures. (Provided by


Gynecology_Novak

Gynecology_Novak. Figure 35.8 Leiomyosarcoma of the uterus. Interlacing bundles of spindle cells have fibrillar cytoplasm, irregular and hyperchromatic nuclei, and multiple mitotic figures. (Provided by Gordana Stevanovic, MD, and Jianyu Rao, MD, Department of Pathology, UCLA.) out from a myomatous uterus into the parametria toward the pelvic sidewalls. It may be confused with low-grade stromal sarcoma. Symptoms are related to the associated uterine myomas. Most patients are in the late fifth and early sixth decades of life. The prognosis is excellent, even when tumor is left in pelvic vessels. Late local recurrences can occur, and deaths from extension into the inferior vena cava or metastases to the heart were reported. Estrogen may stimulate the proliferation of these intravascular tumors. Treatment should be total abdominal hysterectomy and bilateral salpingo-oophorectomy with removal of as much of the tumor as possible.


Gynecology_Novak

Gynecology_Novak. Benign metastasizing uterine leiomyoma is a rare condition in which a histologically benign uterine smooth muscle tumor acts in a somewhat malignant fashion and produces benign metastases, usually to the lungs or lymph nodes (438). In most instances, intravenous leiomyomatosis is not apparent. The metastasizing myomas are capable of growth at distant sites, whereas the intravenous tumors spread only by direct extension within blood vessels. Both experimental and clinical evidence suggests that these tumors are stimulated by estrogen. Removing the source of estrogen, by castration or withdrawal of exogenous estrogen, or by treatment with progestins, tamoxifen, or a gonadotropin agonist, has an ameliorating effect (439). Surgical treatment should consist of total abdominal hysterectomy and bilateral salpingo-oophorectomy and resection of pulmonary metastases, if possible.


Gynecology_Novak

Gynecology_Novak. Disseminated peritoneal leiomyomatosis is a rare clinical entity characterized by benign smooth muscle nodules scattered throughout the peritoneal cavity (440). This condition probably arises as a result of metaplasia of subperitoneal mesenchymal stem cells to smooth muscle, fibroblasts, myofibroblasts, and decidual cells under the inﬂuence of estrogen and progesterone. Most reported cases occurred in 30-to 40-year-old women who are or who recently were pregnant or who have a long history of oral contraceptive use. Intriguing features of this disease are its grossly malignant appearance, benign histology, and favorable clinical outcome. Intraoperative diagnosis requires frozen-section examination. Extirpative surgery, including total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and excision of as much gross disease as possible, may be indicated in menopausal women. Removal of the source of excess estrogen, treatment with progestins, or both resulted in


Gynecology_Novak

Gynecology_Novak. omentectomy, and excision of as much gross disease as possible, may be indicated in menopausal women. Removal of the source of excess estrogen, treatment with progestins, or both resulted in regression of unresected tumor masses. Almost all patients have a good prognosis.


Gynecology_Novak

Gynecology_Novak. Carcinosarcoma Carcinosarcoma is composed histologically of a mixture of sarcoma and carcinoma. The carcinomatous element is usually glandular, whereas the sarcomatous element may resemble the normal endometrial stroma (homologous or the so-called carcinosarcoma), or it may be composed of tissues foreign to the uterus, such as cartilage, bone, or striated muscle (heterologous). These tumors are most likely derived from totipotential endometrial stromal cells (441–444). Almost all of these tumors occur after menopause, at a median age of 62 years. The incidence is higher in AfricanAmerican women. These tumors are often found in association with other medical conditions, such as obesity, diabetes mellitus, and hypertension. A history of previous pelvic radiation can be obtained in 7% to 37% of patients.


Gynecology_Novak

Gynecology_Novak. The most frequent presenting symptom is postmenopausal bleeding, which occurs in 80% to 90% of cases. Other less common symptoms are vaginal discharge, abdominal or pelvic pain, weight loss, and passage of tissue from the vagina. The duration of symptoms usually is only a few months. On physical examination, uterine enlargement is present in 50% to 95% of patients, and a polypoid mass may be seen within or protruding from the endocervical canal in up to 50% of patients. Diagnosis can usually be determined by biopsy of an endocervical mass or endometrial curettage.


Gynecology_Novak

Gynecology_Novak. The tumor grows as a large, soft, polypoid mass, filling and distending the uterine cavity; necrosis and hemorrhage are prominent features. The myometrium is invaded to various degrees in almost all cases. The most frequent areas of spread are the pelvis, lymph nodes, peritoneal cavity, lungs, and liver. This metastatic pattern suggests that these neoplasms spread by local extension and regional lymph node metastasis in a manner similar to that of endometrial adenocarcinoma, although they behave more aggressively.


Gynecology_Novak

Gynecology_Novak. The most important single factor affecting prognosis in patients with carcinosarcoma is the extent of tumor at the time of treatment. One study noted that in patients with tumor apparently confined to the uterine corpus (stage I), the 2-year survival rate was 53%, whereas the survival rate dropped to 8.5% when disease had extended to the cervix, vagina, or parametria (stage II and III); no patients with disease outside the pelvis (stage IV) survived (445). In another study, 5-year survival for patients with disease confined to the corpus (74%) was significantly greater than for those with more advanced disease (24%) (446).


Gynecology_Novak

Gynecology_Novak. Disease extends outside the uterus in 40% to 60% of cases at the time of diagnosis, indicating the highly malignant nature of this lesion. Even when disease is believed to be confined to the uterus preoperatively, surgical and pathologic staging identifies extrauterine spread of disease in a significant number of cases. In one study, 55% of women with clinical stage I carcinosarcoma had a higher surgical–pathologic stage. Only 28% of tumors were actually confined to the uterine corpus, 16% had extension to the cervix, and 56% showed extrauterine spread (447). In a significant number of patients, lymph node metastases and positive peritoneal cytology werefound with early-stage carcinosarcoma (446,448,449). Deep myometrial invasion, which is present in about one-half of stage I cases, is associated with poor prognosis. Almost all patients in whom tumor involves the outer one-half of the myometrium die from the disease. Patients who die from carcinosarcoma tend to have larger tumors and


Gynecology_Novak

Gynecology_Novak. with poor prognosis. Almost all patients in whom tumor involves the outer one-half of the myometrium die from the disease. Patients who die from carcinosarcoma tend to have larger tumors and a higher incidence of LVSI. Patients with a history of prior pelvic radiation have a poorer prognosis. Overall, the 5-year survival rate for patients with carcinosarcoma is about 20% to 30%.


Gynecology_Novak

Gynecology_Novak. Adenosarcoma is an uncommon variant of carcinosarcoma (450,451). It consists of an admixture of benign-appearing neoplastic glands and a sarcomatous stroma. Most patients present with postmenopausal vaginal bleeding, and the disease is diagnosed or suspected based on endometrial curettage. Most adenosarcomas are well circumscribed and limited to the endometrium or superficial myometrium. The treatment is hysterectomy and bilateral salpingo-oophorectomy, with or without adjuvant radiotherapy. Because recurrences, mostly in the form of local pelvic or vaginal disease, are reported in 40% to 50% of cases, adjuvant postoperative intravaginal or pelvic radiation is recommended.


Gynecology_Novak

Gynecology_Novak. Treatment Recurrences develop in more than one-half of cases of uterine sarcoma, even when disease is apparently localized at the time of treatment (452–454). At least one-half of recurrences occur outside the pelvis, with isolated pelvic failures accounting for less than 10% of recurrences. The most common sites of recurrence are the abdomen and lungs. These data emphasize that the major limitation to cure of uterine sarcomas is distant spread. Based on this evidence, treatment of most stage I and II uterine sarcomas should include hysterectomy, bilateral salpingo-oophorectomy, and treatment of the pelvic lymphatics by radiation or surgery. Strong consideration should be given to the use of adjuvant chemotherapy to decrease the incidence of distant metastases. Stage III uterine sarcomas are probably best treated by an aggressive combined approach of surgery, radiation therapy, and chemotherapy, while patients with stage IV disease are candidates for combination chemotherapy.


Gynecology_Novak

Gynecology_Novak. Surgery The first step in the treatment of early uterine sarcoma should be exploration. Because extirpative survey is the most important aspect of treatment, and knowledge of the extent and spread of the disease is important for further management, one should not forgo or delay surgery by using radiation therapy or chemotherapy first. At the time of surgery, the peritoneal cavity should be carefully explored and peritoneal washings obtained. Special attention should be given to the pelvic and para-aortic lymph nodes; lymphadenectomy should be performed with ESS and carcinosarcoma, but may be omitted in leiomyosarcoma, in which the risk of lymph node metastases is low and the therapeutic and diagnostic value is questionable (428). Total abdominal hysterectomy is the standard procedure, and bilateral salpingo-oophorectomy should be performed in all patients except premenopausal women with leiomyosarcoma. Based on the surgical and pathologic findings, additional therapy with radiation


Gynecology_Novak

Gynecology_Novak. bilateral salpingo-oophorectomy should be performed in all patients except premenopausal women with leiomyosarcoma. Based on the surgical and pathologic findings, additional therapy with radiation therapy or chemotherapy can be planned. Rarely, a patient may be cured by excision of an isolated pulmonary metastasis (455,456).


Gynecology_Novak

Gynecology_Novak. Radiation Therapy Several studies showed that adjuvant preoperative or postoperative radiation therapy is beneficial in decreasing pelvic recurrences and increasing quality of life in patients with localized ESS and carcinosarcoma, but not with leiomyosarcoma (457–465). Radiation was not demonstrated to improve survival. One trial randomized patients with uterine sarcomas to pelvic radiotherapy versus observation. Althoughthe risk of local relapse significantly decreased from 24% to 14%, there was no difference in survival between groups (466). The GOG randomized patients to whole abdomen radiation versus three cycles of cisplatin, ifosfamide, and mesna in patients with less than 1 cm of residual disease (467). Whole-abdomen radiation was associated with significant toxicity and the chemotherapy regimen appeared to confer a nonsignificant survival advantage.


Gynecology_Novak

Gynecology_Novak. Chemotherapy Several chemotherapeutic agents have activity in sarcomas, including vincristine, actinomycin D, cyclophosphamide, doxorubicin, dimethyl triazeno imidazole carboxamide (dacarbazine, DTIC), cisplatin, ifosfamide paclitaxel, gemcitabine, and liposomal doxorubicin (468). Doxorubicin appears to be the most active single agent in the treatment of leiomyosarcoma, producing a 25% response rate (469). Ifosfamide has a lesser degree of activity (470). Cisplatin and ifosfamide demonstrated clear activity in carcinosarcoma, with response rates of 18% to 42% and 32%, respectively (471–473). Doxorubicin demonstrated less than a 10% response rate in carcinosarcoma (469). Paclitaxel yielded an 18% response rate with carcinosarcoma, but had limited activity in leiomyosarcomas (474,475). Gemcitabine and liposomaldoxorubicin showed activity in leiomyosarcomas (476,477).


Gynecology_Novak

Gynecology_Novak. Combination chemotherapy with doxorubicin and DTIC, or these two drugs plus vincristine and cyclophosphamide, was yielded somewhat higher response rates (478–480). Similarly, ifosfamide was combined with mesnauroprotection, doxorubicin, and DTIC to treat metastatic pure sarcomas (481). Gemcitabine combined with docetaxel for treatment of metastatic leiomyosarcoma yielded an overall response rate of 53%, including patients previously treated with doxorubicin (482). Median time to progression was 5.6 months. Several retrospective investigations concluded that neither chemotherapy nor radiation impacts survival for patients with ESS or leiomyosarcoma (428,483,484).


Gynecology_Novak

Gynecology_Novak. Combined ifosfamide and cisplatin chemotherapy resulted in a higher response rate (54% versus 36%) and a longer progression-free survival than ifosfamide chemotherapy alone for treatment of advanced carcinosarcoma (485). Overall survival was unchanged (8 versus 9 months), and the combined regimen was significantly more toxic. A 3-day regimen of ifosfamide with or without paclitaxel in patients with advanced and recurrent carcinosarcoma demonstrated improved response rates (29% versus 45%) and median overall survival (8 versus 13 months) in the combination chemotherapy arm (486). This regimen appears to be the most efficacious for patients with advanced or recurrent carcinosarcoma. A combination of paclitaxel and carboplatin for treatment of advanced uterine carcinosarcoma resulted in a complete response rate of 80% and a median progression-free interval of 18 months (487). The GOG completed a phase II evaluation of paclitaxel and carboplatin with the results awaiting maturation. A


Gynecology_Novak

Gynecology_Novak. complete response rate of 80% and a median progression-free interval of 18 months (487). The GOG completed a phase II evaluation of paclitaxel and carboplatin with the results awaiting maturation. A randomized phase III evaluation of paclitaxel plus carboplatin versus ifosfamide plus paclitaxel in chemotherapy naive patients with carcinosarcoma is accruing.


Gynecology_Novak

Gynecology_Novak. Adjuvant Treatment Because of the relatively low survival rate in localized uterine sarcomas and the high incidence of failure resulting from subsequent distant metastasis, adjuvant treatment programs employing chemotherapy were tested (487–490). Most reports were unable to show a clear improvement in survival by the addition of postoperative adjuvant chemotherapy in early uterine sarcoma. The GOG conducted a trial of postoperative adjuvant doxorubicin in stage I and II uterine sarcoma patients. Of the 75 patients randomized to receive doxorubicin, 41% developed a recurrence, compared with 53% of 81 patients receiving no adjuvant chemotherapy, but these differences were not significant (487). Other smaller, nonrandomized adjuvant chemotherapy studies employing cyclophosphamide, cisplatin plus doxorubicin, and ifosfamide plus cisplatin reported recurrence rates of 33%, 24%, and 31%, respectively (488–490). 1.


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Gynecology_Novak. 1. Siegel R, Ward E, Brawley O, et al. Cancer statistics, 2011. CA Cancer J Clin 2011;61:212–236. http://cacancerjournal.org 2. Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol 1983;15:10–17. 3. Lax SF. Molecular genetic pathways in various types of endometrial carcinoma: from a phenotypical to a molecular-based classification. Virchows Arch 2004;444:213–223. 4. MacMahon B. Risk factors for endometrial cancer. Gynecol Oncol 1974;2:122–129. 5. Parazzini F, LaVecchia C, Bocciolone L, et al. The epidemiology of endometrial cancer. Gynecol Oncol 1991;41:1–16. 6. Parazzini F, LaVecchia C, Negri E, et al. Reproductive factors and risk of endometrial cancer. Am J Obstet Gynecol 1991;64:522–527. 7. Brinton LA, Berman ML, Mortel R, et al.Reproductive, menstrual and medical risk factors for endometrial cancer: results from a case control study. Am J Obstet Gynecol 1993;81:265–271. 8.


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Gynecology_Novak. 7. Brinton LA, Berman ML, Mortel R, et al.Reproductive, menstrual and medical risk factors for endometrial cancer: results from a case control study. Am J Obstet Gynecol 1993;81:265–271. 8. Grady D, Gebretsadik T, Kerlikowske K, et al. Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol 1995;85:304–313. 9. Fisher B, Constantino JP, Redmond CK, et al. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project B-14. J Natl Cancer Inst 1994;86:527–537. 10. Assikis VJ, Jordan VC. Gynecologic effects of tamoxifen and the association with endometrial carcinoma. Int J Gynaecol Obstet 1995;49:241–257. 11. Aarnio M, Sankila R, Pukkala E, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 1999;81:214– 218. 12. Gordon MD, Ireland K. Pathology of hyperplasia and carcinoma of the endometrium. Semin Oncol 1994;21:64–70. 13.


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Gynecology_Novak. 12. Gordon MD, Ireland K. Pathology of hyperplasia and carcinoma of the endometrium. Semin Oncol 1994;21:64–70. 13. Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia: a long term study of “untreated” hyperplasia in 170 patients. Cancer 1985;56:403–412. 14. Tavassoli F, Kraus FT. Endometrial lesions in uteri resected for atypical endometrial hyperplasia. Am J Clin Pathol 1978;70:770– 779. 15. Hunter JE, Tritz DE, Howell MG, et al. The prognostic and therapeutic implications of cytologic atypia in patients with endometrial hyperplasia. Gynecol Oncol 1994;55:66–71. 16. Trimble C, Kauderer J, Silverberg S, et al. Concurrent endometrial carcinoma in women with biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Gynecol Oncol 2004;92:393(abst). 17. Ota T, Yoshida M, Kimura M, et al. Clinicopathologic study of uterine endometrial carcinoma in young women aged 40 years and younger. Int J Gynecol Cancer 2005;15:657–662.


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Gynecology_Novak. 17. Ota T, Yoshida M, Kimura M, et al. Clinicopathologic study of uterine endometrial carcinoma in young women aged 40 years and younger. Int J Gynecol Cancer 2005;15:657–662. 18. Randall TC, Kurman RJ. Progestin treatment of atypical hyperplasia and well-differentiated carcinoma of the endometrium in women under age 40. Obstet Gynecol 1997;90:434–440. 19. Ben-Shachar I, Vitellas KM, Cohn DE. The role of MRI in the conservative management of endometrial cancer. Gynecol Oncol 2004;93:233–237. 20. Minderhoud-Bassie W, Treurniet FE, Koops W, et al. Magnetic resonance imaging (MRI) in endometrial carcinoma; preoperative estimation of depth of myometrial invasion. Acta Obstet Gynecol Scand 1995;74:827–831. 21. Nakao Y, Yokoyama M, Hara K, et al. MR imaging in endometrial carcinoma as a diagnostic tool for the absence of myometrial invasion. Gynecol Oncol 2006;102:343–347. 22.


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Gynecology_Novak. 21. Nakao Y, Yokoyama M, Hara K, et al. MR imaging in endometrial carcinoma as a diagnostic tool for the absence of myometrial invasion. Gynecol Oncol 2006;102:343–347. 22. Lai CH, Huang HJ. The role of hormones for the treatment of endometrial hyperplasia and endometrial cancer. Curr Opin Obstet Gynecol 2006;18:29–34. 23. Shamshirsaz AA, Withiam-Leitch M, Odunsi K, et al. Young patients with endometrial carcinoma selected for conservative treatment: a need for vigilance for synchronous ovarian carcinomas, case report and literature review. Gynecol Oncol 2007;104:757–760. 24. Wildemeersch D, Dhont M. Treatment of nonatypical and atypical endometrial hyperplasia with a levonorgestrel-releasing intrauterine system. Am J Obstet Gynecol 2003;188:1297–1298. 25. Montz FJ, Bristow RE, Bovicelli A, et al. Intrauterine progesterone treatment of early endometrial cancer. Am J Obstet Gynecol 2002;186:651–657. 26.


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Gynecology_Novak. 25. Montz FJ, Bristow RE, Bovicelli A, et al. Intrauterine progesterone treatment of early endometrial cancer. Am J Obstet Gynecol 2002;186:651–657. 26. Giannopoulos T, Butler-Manuel S, Tailor A. Levonorgestrelreleasing intrauterine system (LNG-IUS) as a therapy for endometrial carcinoma. Gynecol Oncol 2004;95:762–764. 27. Huang S-Y, Jung S-M, Ng K-K, et al. Ovarian metastasis in a nulliparous woman with endometrial adenocarcinoma failing conservative hormonal treatment. Gynecol Oncol 2005;97:652– 655. 28. Kaku T, Yoshikawa H, Tsuda H, et al. Conservative therapy for adenocarcinoma and atypical endometrial hyperplasia of the endometrium in young women: central pathologic review and treatment outcome. Cancer Lett 2001;167:39–48. 29. Dhar KK, Needhi-Rajan T, Koslowski M, et al. Is levonorgestrel intrauterine system effective for treatment of early endometrial cancer? Report of four cases and review of the literature. Gynecol Oncol 2005;97:924–927. 30.


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Gynecology_Novak. 34. Smith RA, Cokkinides V, von Eschenbach AC, et al. American Cancer Society guidelines for the early detection of cancer. CA Cancer J Clin 2002;52:8–22. 35. Gerber B, Krause A, Heiner M, et al. Effects of adjuvant tamoxifen in postmenopausal women with breast cancer: a prospective long-term study using transvaginal ultrasound. J Clin Oncol 2000;18: 3464–3470. 36. Barakat RR, Gilewski TA, Almadrones L, et al. Effect of adjuvant tamoxifen on the endometrium in women with breast cancer: a prospective study using office endometrial biopsy. J Clin Oncol 2000;18:3459–3463. 37. Ollikainen M, Abdel-Rahman WM, Moisio A-L, et al. Molecular analysis of familial endometrial carcinoma: a manifestation of hereditary nonpolyposis colorectal cancer or a separate syndrome? J Clin Oncol 2005;23:4609–4616. 38.


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Gynecology_Novak. 38. Parc YR, Halling KC, Burgart LJ, et al. Microsatellite instability and hMLH1/hMSH2 expression in young endometrial carcinoma patients: associations with family history and histopathology. Int J Cancer 2000;86:60–66. 39. Dunlop M, Farrington S, Carothers A, et al. Cancer risk associated with germline DNA mismatch repair gene mutations. Hum Mol Genet 1997;6:105–110. 40. Kunkel TA, Erie DA. DNA mismatch repair. Annu Rev Biochem 2005;74:681–710. 41. Marti TM, Kunz C, Fleck O. DNA mismatch repair and mutation avoidance pathways. J Cell Physiol 2002;191:28–41. 42. Boltenberg A, Furgyik S, Kullander S. Familial cancer aggregation in cases of adenocarcinoma corporis uteri. Acta Obstet Gynecol Scand 1990;69:249–258. 43. Vasen HFA, Watson P, Mecklin J-P, et al. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology 1999;116:1453–1456. 44.


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Gynecology_Novak. 44. Peltomaki P, Vasen HF. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer. Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. Gastroenterology 1997;113:1146–1158. 45. Miyaki M, Konishi M, Tanaka K, et al. Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet 1997;17:271–272. 46. Akiyama Y, Sato H, Yamada T, et al. Germ-line mutation of the hmSH6/GTPB gene in an atypical hereditary nonpolyposis colorectal cancer kindred. Cancer Res 1997;57:3920–3923. 47. Hendriks YMC, Jagmohan-Changur S, van der Klift HM, et al. Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome). Gastroenterology 2006;130:312–322. 48.


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Gynecology_Novak. Hendriks YMC, Jagmohan-Changur S, van der Klift HM, et al. Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome). Gastroenterology 2006;130:312–322. 48. Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch Syndrome) and microsatellite instability. J Natl Cancer Inst 2004;96:261–268. 49. Lynch HT, Lynch JF. The Lynch syndrome: melding natural history and molecular genetics to genetic counseling and cancer control. Cancer Control 1996;3:13–19. 50. Renkonen-Sinisalo L, B¨utzow R, Leminen A, et al. Surveillance for endometrial cancer in hereditary nonpolyposis colorectal cancer syndrome. Int J Cancer 2007;120:821–824. 51. Schmeler KM, Lynch HT, Chen LM, et al. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med 2006;354:261–269. 52.


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