C H A P T E R                                                        5         Adenocarcinoma of the Uterine Corpus       ...
142	                                                              5.  Adenocarcinoma of the Uterine Corpus                ...
5.  Adenocarcinoma of the Uterine Corpus	                                       143TABLE 5-1  Endometrial Cancer Risk Fact...
144	                                    5.  Adenocarcinoma of the Uterine Corpussuggest that risk factors such as multipar...
5.  Adenocarcinoma of the Uterine Corpus	                                   145and colleagues) evaluating the prophylactic...
146	                                    5.  Adenocarcinoma of the Uterine Corpusthey do not increase the risk of gynecolog...
5.  Adenocarcinoma of the Uterine Corpus	                                     147detecting endometrial cancer is approxima...
148	                                           5.  Adenocarcinoma of the Uterine Corpus                         AB        ...
5.  Adenocarcinoma of the Uterine Corpus	                                   149least expensive (£11 470/LYG). Initial inve...
150	                                            5.  Adenocarcinoma of the Uterine Corpus                                  ...
5.  Adenocarcinoma of the Uterine Corpus	                                                 151           Endometrium       ...
152	                                               5.  Adenocarcinoma of the Uterine Corpus                               ...
5.  Adenocarcinoma of the Uterine Corpus	                                              153    A                           ...
154	                                                       5.  Adenocarcinoma of the Uterine Corpusbe excluded from the cl...
5.  Adenocarcinoma of the Uterine Corpus	                                         155Stage of Disease: Depth of Invasion, ...
156	                                                        5.  Adenocarcinoma of the Uterine CorpusTABLE 5-7 Distribution...
5.  Adenocarcinoma of the Uterine Corpus	                                              157TABLE 5-10  Grade vs Positive Pe...
158	                                                     5.  Adenocarcinoma of the Uterine Corpuscancer, the extent of res...
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter
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Clinical Gynecologic Oncology, Di saia 9780323074193_ sample chapter

  1. 1. C H A P T E R 5 Adenocarcinoma of the Uterine Corpus William T. Creasman, MD, and David Scott Miller, MD O U T L I N E Incidence 141 Tumor Grade 158 Molecular Indices 159 Epidemiology 141 Correlation of Multiple Prognostic Factors 160 Diagnosis 146 Treatment 161 Pathology 149 Surgical Management of Endometrial Cancer 161 Tumor Grade 154 Radiation Therapy 166 Prognostic Factors 154 Drug Development 168 Stage of Disease: Depth of Invasion, Cervical Special Circumstances 171 Involvement, Adnexal Involvement, and Nodal Follow-Up 173 Metastasis 155 INCIDENCE of estrogen has been implicated in the apparent increased incidence during the 1970s and early 1980s; however,In the United States, cancer of the uterine corpus is the Norway and Czechoslovakia report a 50% to 60%most common malignancy unique to women. It was esti- increase in endometrial cancer, despite the fact thatmated by the American Cancer Society that uterine estrogens are rarely prescribed or are not generally avail-cancer will develop in approximately 42,160 women in able there. However, the increasing prevalence of over-2009 in the United States, making it the fourth most weight and obesity in women, especially in developedcommon cancer in women. The increased incidence of countries, may account for this apparent increase.carcinoma of the endometrium has been apparent only Regardless of the reason for the increased number ofduring the last three decades. In reviewing the predicted women with corpus cancer, this malignant neoplasm hasincidence for the 1970s, the American Cancer Society become an important factor in the care of the femalenoted a one and a half-fold increase in the number of patient.patients with endometrial cancer; however, there was adecline in incidence during the late 1980s. In the pastseveral years, the incidence has remained constant. EPIDEMIOLOGYDuring the period of increased incidence, predicteddeaths from this malignant neoplasm actually decreased Endometrial adenocarcinoma occurs during the repro-slightly. More recently, deaths from uterine cancer have ductive and menopausal years. The mean age for patientsincreased. In 1990 the American Cancer Society esti- with adenocarcinoma of the uterine corpus is 63 years;mated 4000 deaths from this cancer, increasing to 7780 most patients are between the ages of 50 and 59 yearsin 2009. An estimation of the most common new cancers (Figure 5-2). Approximately 5% of women will haveand the percentage of female deaths for 2009 in the adenocarcinoma before the age of 40 years, and 20% toUnited States is shown in Figure 5-1. The increased use 25% will be diagnosed before menopause. Bokhman 141
  2. 2. 142 5.  Adenocarcinoma of the Uterine Corpus Cervix Deaths New cases Ovary Leukemia Uterine Colorectal Lung Breast 0 20,000 40,000 60,000 80,000 100,000 120,000 140,000 160,000 180,000 200,000 220,000FIGURE 5-1  Common new cancer cases and deaths in women for 2010 in the United States. (Modified from American Cancer Society. CancerFacts and Figures 2010. Atlanta. American Cancer Society, 2010.) 3500 clearly defined. Bokhman’s data suggest that patients Surgical with the first pathogenic type mainly have well- 3000 Clinical differentiated or moderately differentiated tumor, super- ficial invasion of the myometrium, high sensitivity to 2500 progestins, and favorable prognosis (85% 5-year sur- vival in his material). The patients who fall into theNumber of patients second pathogenic group tend to have poorly differenti- 2000 ated tumors, deep myometrial invasion, high frequency of metastatic disease in the lymph nodes, decreased sen- 1500 sitivity to progestin, and poor prognosis (58% 5-year survival rate). 1000 Multiple risk factors for endometrial cancer have been identified, and MacMahon divides these into three categories: 500 • Variants of normal anatomy or physiology 0 • Frank abnormality or disease 15-29 30-39 40-49 50-59 60-69 70-79 80+ Age group • Exposure to external carcinogensFIGURE 5-2  Carcinoma of the corpus uteri; patients treated in Obesity, nulliparity, and late menopause are variants1999–2001. Age distribution by mode of staging. (Modified from Creas- of normal anatomy or physiology classically associatedman WT et al: Int J Gynecol Obstet 95(1):S105-143, 2006) with endometrial carcinoma. These three factors are evaluated in regard to the possible risk of developing endometrial cancer in Table 5-1. If a patient is nullipa- rous and obese and reaches menopause at age 52 years or older, she appears to have a fivefold increase in thesuggested that there are two pathogenic types of endo- risk of endometrial cancer above that of the patient whometrial cancer. The first type arises in women with does not satisfy these criteria (Table 5-2).obesity, hyperlipidemia, and signs of hyperestrogenism, The type of obesity in patients with endometrialsuch as anovulatory uterine bleeding, infertility, late cancer has been evaluated. In a study from the Univer-onset of menopause, and hyperplasia of the stroma of sity of South Florida, it was noted that women withthe ovaries and endometrium. The second pathogenic endometrial cancer had greater waist-to-hip circumfer-type of disease arises in women who have none of these ence ratios, abdomen-to-thigh skin ratios, and suprailiac-disease states or in whom the disease states are not to-thigh skin ratios than those of matched-control
  3. 3. 5.  Adenocarcinoma of the Uterine Corpus 143TABLE 5-1  Endometrial Cancer Risk Factors of consumption of most types of meats, eggs, beans, added fats, and sugar. Conversely, significant protectionRisk Factors Risk was noted with an elevated intake of most vegetables,Obesity 2.5-4.5× fresh fruits, whole grain bread, and pasta. This reflectedNulliparity a low risk with increased intake of ascorbic acid and  Compared with 1 child 2×  Compared with 5 or more children beta-carotene. Of dietary interest is that the intake of 3×Late menopause 2.4× olive oil seemed beneficial in Switzerland but resembled other added fats in the Italian women. It has been previ- ously noted that the amount and type of dietary fat influence estrogen metabolism because estrogen reab-TABLE 5-2 Multiple Risk Factors sorption from the bowel seems to be increased by diets Risk rich in beef or fats. Diabetes mellitus and hypertension are frequentlyNulliparous Parous associated with endometrial cancer. Elwood and col-Top 15% in weightMenopause at 52 years  5× more than  Lower two thirds in weight Menopause at <49 years leagues reported a RR of 2.8 associated with a history of diabetes after controlling for age, body weight, and socioeconomic status. High levels of insulin-like growth factor I, coupled with elevated estrogen levels, are thought to have neoplastic potential that accounts forwomen. As these ratios increased, the relative risk (RR) the observed increased risk of endometrial cancer. Highof endometrial cancer increased. The researchers con- blood pressure is prevalent in elderly obese patients butcluded that upper-body fat localization is a significant does not appear to be a significant factor by itself, evenrisk factor for endometrial cancer. In a large multicenter though 25% of patients with endometrial cancer havecase-control study of 403 endometrial cancer cases and hypertension or arteriosclerotic heart disease.297 control cases, Swanson and associates confirmed As extensively detailed in Chapter 4, the relationshipand amplified these findings. Women whose weight of unopposed estrogen and endometrial cancer is wellexceeded 78 kg had a risk 2.3 times that of women documented. Fortunately, the addition of a progestinweighing less than 58 kg. For women weighing more appears to be protective. Adequacy of progesterone isthan 96 kg, the RR increased to 4.3. Upper-body obesity important in prevention of endometrial cancer. In a(waist-to-height ratio) was a risk factor independent of study from Sweden, at the end of 5 years excess risk ofbody weight. Patients in the highest quartile of both endometrial cancer was 6.6 but with combined estrogenweight and waist-to-thigh circumference had a risk of progestin (E + P), RR was 1.6 for 11 to 15 days of proges-5.8 times. The amount of body fat has been associated tin, 2.9 for 10 days of use, and 0.2 if continuous E + Pwith decreased circulating levels of both progesterone was given. The Million Women study from the Unitedand sex hormone-binding proteins. There was a strong Kingdom has recently reported their findings of endo-inverse association between sitting height and risk of metrial cancer and hormone replacement therapy (HRT).endometrial cancer. This may be related to sex hormone- This study, which first reported on HRT and breastbound globulin (SHBG), which appears to be depressed cancer, has been severely criticized mainly on methodol-in women with endometrial cancer. The level of SHBG ogy factors. They had an average follow-up of 3.4 years,is progressively depressed with increasing upper-body during which 1320 incident endometrial cancers werefat localization. With lower SHBG, there is a higher diagnosed. At time of recruitment 22% of HRT usersendogenous production of non–protein-bound estradiol. (total number was 320,953 women) last used continuousBecause endometrial cancer is related to obesity, dietary combined therapy, 45% last used cyclic combinedhabits appear to be important. Data suggest that the therapy with progestogen usually added for 10 to 14levels of estriol, total estrogens, and prolactin were lower days per month, 19% last used tibolone, and 4% usedand those of SHBG were higher in postmenopausal estrogen alone. Compared with nonusers, RR of endo-women who were vegetarians. In a case-control study, metrial cancer was 0.71%, CI 0.56 to 0.90, P = 0.005; 1.05,Levi and colleagues evaluated dietary factors in 274 CI 0.91 to 1.22; 1.79, CI 1.43 to 2.25, P <0.001; and 1.45,patients with endometrial cancer and 572 control sub- CI 1.02 to 2.06, P = 0.04, respectively. Of note, the adversejects from two areas in Switzerland and northern Italy. effects of tibolone and estrogen only were greatest in theExtensive dietary history was obtained. Their data con- nonobese woman and the beneficial effects of combinedfirmed the relationship between obesity and endome- HRT were greatest in obese women. Although the risktrial cancer. In relation to diet, they noted an increased of unopposed estrogen is present, women taking estro-association with total energy intake. After correction for gen who develop endometrial cancer appear to havetotal energy intake, a risk was present with the frequency favorable prognostic factors. Several but not all studies
  4. 4. 144 5.  Adenocarcinoma of the Uterine Corpussuggest that risk factors such as multiparity and obesity differences are unexplained. An analysis of the Gyneco-are lower in the estrogen users. Stage of disease and logic Oncology Group (GOG) database evaluated thishistologic grade appear to be lower in estrogen users. factor in 600 white and 91 black women with clinicalWith correction for stage and grade, estrogen users still stage I or stage II endometrial cancer. A larger numberhave less myometrial invasion than nonestrogen users of the African American women were diagnosed afterdo. The poor prognostic subtypes, such as clear cell car- age 70 years, and they had a higher proportion of papil-cinoma and adenosquamous cancer, appear less fre- lary serous (PS) and clear cell histologic types; the blackquently in estrogen users. As a result, survival rates with women also had more advanced disease, grade, vascularestrogen-related endometrial cancer are much better space involvement, depth of invasion, and lymph nodethan those of nonestrogen cancers. In fact, some studies metastases than the white women did. Survival (5-year)note just as good if not better survival in estrogen users was 77% for white women and 60% for black women.than in women with nonestrogen, nonendometrial Survival difference remained even in high-risk groupscancers. such as grade III tumors (59% vs 37%, respectively). The Data indicate that the use of combination oral contra- unadjusted hazard rate was 2.0, which was statisticallyceptives decreases the risk for development of endome- significant. With adjustment for age, cell type, and extenttrial cancer. The Centers for Disease Control and of disease, the RR dropped to 1.2. The adjusted risk ratePrevention evaluated endometrial cancer cases of all suggests that race is not a significant factor; nevertheless,women aged 20 to 54 years from eight population-based race does denote an increased risk for poor prognosticcancer registries and compared them with control factors, which clinically may be important.patients selected at random from the same centers. A Tamoxifen is used to prevent or treat breast cancer.comparison of the first 187 cases with 1320 control cases Tamoxifen was first introduced in clinical trials in theshowed that women who used oral contraceptives at early 1970s and was approved in 1978 by the U.S. Foodsome time had a 0.5 RR of developing endometrial and Drug Administration (FDA) for treatment ofcancer compared with women who had never used oral advanced breast carcinoma in postmenopausal woman.contraceptives. This protection occurred in women who Tamoxifen, although labeled an antiestrogen, is knownused oral contraceptives for at least 12 months, and pro- to have estrogenic properties and truly is a weak estro-tection continued for at least 10 years after oral contra- gen. Women receiving tamoxifen also appear to haveceptive use. Protection was most notable for nulliparous some protection from osteoporosis and heart diseasewomen. These investigators estimated that about 2000 (decreased lactate dehydrogenase and cholesterol),cases of endometrial cancer are prevented each year in much like women receiving estrogen replacementthe United States by past or current use of oral contra- therapy. Extensive experience with this drug has beenceptives. Of interest, cigarette smoking appears to reported. It is estimated that more than 4 million womendecrease the risk for developing endometrial cancer. In in the United States have taken tamoxifen for almost 8a population-based case-control study of women aged million women-years of use. One of its major benefits is40 to 60 years, Lawrence and associates found a signifi- that in women taking tamoxifen, there has been a sub-cant decline in RR of endometrial carcinoma with stantial decrease in the incidence of a second cancer inincreased smoking (P >0.05). The RR decreased by about the opposite breast compared with similar women who30% when one pack of cigarettes was smoked per day were taking a placebo.and by another 30% when more than one pack was The Early Breast Cancer Trialists Collaborative Groupsmoked per day. The effects of smoking did not appear (EBCTCG) has produced an important meta-analysis ofto vary with menstrual status or exogenous estrogen. 194 randomized trials of adjuvant chemotherapy orThere was a fourfold increase in smoking-related odds endocrine therapy with at least 15 years of follow-up.ratio with body weight; the greatest reduction in risk by The analysis evaluated the effects of adjuvant tamoxifensmoking was in the heaviest women. However, the esti- on breast cancer recurrence and survival. It was shownmated risk increased twelvefold in overweight women that 5 years of tamoxifen therapy, compared to no adju-who were nonsmokers and whose primary source of vant therapy, reduced the 15-year probability of breastestrogen was peripheral conversion of androgen to cancer recurrence (from 45% to 33%) and breast cancerestrogen. Although smoking apparently reduces the risk mortality (from 35% to 26%). In addition, tamoxifen hasfor development of early-stage endometrial cancer, this been shown to provide a preventive benefit in womenadvantage is strongly outweighed by the increased risk at risk for developing breast cancer.of lung cancer and other major health hazards associated There has been a considerable amount of discussionwith cigarette smoking. in the literature in regard to the association of tamoxifen Incidence and survival are higher in white women with endometrial cancer. At least three studies (Fishercompared with black women. Reasons for these and colleagues, Powels and colleagues, and Veronesi
  5. 5. 5.  Adenocarcinoma of the Uterine Corpus 145and colleagues) evaluating the prophylactic use of the prevention of recurrences and new breast cancer intamoxifen in women without breast cancer have reported comparison to new endometrial cancers were evaluatedan association between tamoxifen use and endometrial in the NSABP study. The benefits suggest that 121 fewercancer. In addition, several cases of endometrial cancer breast-related events per 1000 women treated withhave been described in women receiving tamoxifen. In tamoxifen were seen compared with 6.3 endometriala prospective, randomized study of the National Surgi- cancers per 1000 women. Therefore the benefit fromcal Adjuvant Breast and Bowel Project (NSABP), 2843 tamoxifen is apparent.patients with node-negative estrogen receptor–positive It was initially suggested that the rate of endometrialinvasive breast cancer were randomly assigned to receive cancers associated with tamoxifen might be equal toa placebo or 20 mg/day of tamoxifen. An additional that associated with unopposed estrogen replacement1220 tamoxifen-treated patients were registered and therapy. Because tamoxifen is a weak estrogen, similargiven the drug. The average time in the study was 8 characteristics of endometrial cancer were also impliedyears for the randomly assigned patients and 5 years for (i.e., well-differentiated superficially invasive cancers).the registered patients. Of the 1419 patients randomly Barakat and associates reviewed five studies, includingassigned to tamoxifen, 15 developed uterine cancer, of the study by Magriples, the NSABP, their own data fromwhich two were sarcomas. One patient randomly Memorial Sloan-Kettering Hospital, and two studiesassigned to receive tamoxifen did not take the drug and from overseas. A total of 103 patients were evaluated indeveloped endometrial cancer 78 months after random- regard to histologic features, grade of tumor, Interna-ization. In the placebo group, two developed endome- tional Federation of Gynecology and Obstetrics (FIGO)trial cancer; however, both were receiving tamoxifen at staging, and deaths from uterine cancer; an increase wasthe time of their uterine malignant disease. One patient not found in poor prognostic histologic findings, tumorhad a breast recurrence and was prescribed tamoxifen, differentiation, or stage compared with what would beand the other was given tamoxifen after colon cancer. expected in a similar group of non–tamoxifen-treatedTwo of the patients with endometrial cancer had been patients with uterine cancer. Jordan, in an evaluation oftaking tamoxifen for only 5 and 8 months before their the SEER data and of tamoxifen-associated endometrialdiagnosis of uterine disease was made. Five patients cancer in the literature, reported similar findings.in the tamoxifen group developed endometrial cancer It is suggested that all women, irrespective of whetherafter the drug had been discontinued for 7 to 73 months. they are taking tamoxifen, should have yearly gyneco-In the registered patients who received tamoxifen, eight logic examinations. The endometrium should be evalu-uterine tumors (seven endometrial) were subsequently ated if the patient is symptomatic. We do not currentlydiagnosed. Three of these patients had been taking recommend endometrial sampling or ultrasound evalu-tamoxifen for less than a year (2 months, 2 months, and ation of the endometrium just because an individual is9 months). The authors determined the average annual taking tamoxifen. This possible concern of tamoxifenhazard rate of endometrial cancer per 1000 women in and endometrial cancer may lessen in the near futuretheir population of patients. This was 0.2 per 1000 in the because the aromatase inhibitors (AIs) may appear to beplacebo group and 1.6 per 1000 for the randomized better than tamoxifen in the prevention of recurrent ortamoxifen-treated patients. In the registered patients contralateral breast cancer. Several clinical trials havereceiving tamoxifen, the average annual hazard rate was demonstrated the comparable if not greater efficacy1.4 per 1000, similar to that of the randomized tamoxifen- of AIs compared to tamoxifen. Although tamoxifentreated group. The hazard rate of endometrial cancer in remains an option for adjuvant therapy for postmeno-the placebo group was low compared with the Surveil- pausal women, AIs are thought to be more effectivelance, Epidemiology, and End Results (SEER) data and in preventing breast cancer recurrence in the first 2with previous NSABP randomized tamoxifen–placebo years after surgery. AIs reduce estrogen levels instudies; these data suggest that the average annual postmenopausal women by inhibiting or inactivatinghazard rate is 0.7 per 1000. aromatase, the enzyme that synthesize estrogens These data, based on a limited number of patients from circulating androgens. AIs should be avoided inwith endometrial cancer while receiving tamoxifen, premenopausal women, including those who have expe-suggest that there may be a RR of 2.3 for development rienced chemotherapy-induced amenorrhea. Whereasof endometrial cancer while receiving tamoxifen. This tamoxifen is a partial agonist, AIs are not agonists anddoes not take into account the well-known fact that are not associated with estrogenic-related thromboem-women who develop breast cancer are at an increased bolic events and uterine cancers. The activity of third-risk for development of endometrial cancer irrespective generation agents anastrozole, letrozole, and exemestaneof subsequent treatment. The RR of 1.72 to more than is generally considered comparable. Although AIs3 has been reported. The risks and benefits of are associated with a significant risk of osteoporosis,
  6. 6. 146 5.  Adenocarcinoma of the Uterine Corpusthey do not increase the risk of gynecologic problems. In ovaries has been shown to decrease the risk of uterineone large adjuvant therapy trial (the Anastrozole, and ovarian cancer in these high-risk patients.Tamoxifen Alone or in Combination Trial [ATAC]), anas-trozole was associated with fewer cerebrovascular events(2.0% vs 2.8%), endometrial cancers (0.2% vs 0.8%) DIAGNOSISthromboembolism (2.8% vs 4.5%), hot flashes (41% vs36%), and vaginal bleeding (5.4% vs 10.2%) compared Routine screening for uterine adenocarcinoma and itswith tamoxifen. The role of AIs as prophylaxis is precursors is not recommended. Women receiving HRTbeing investigated, but data are lacking at the present (estrogen and progesterone) do not need endometrialtime. biopsy before institution of therapy or during replace- Although most cases of endometrial cancer are spo- ment therapy unless abnormal bleeding occurs. Monthlyradic, hereditary endometrial cancer has been identified withdrawal bleeding after progestin is not consideredin association with hereditary nonpolyposis colon abnormal bleeding. However, breakthrough bleedingcancer (HNPCC), also known as Lynch II syndrome. should be evaluated. The use of continuous estrogenThis is an autosomal-dominant inherited cancer that alone increases the risk of adenocarcinoma. Estrogeninvolves a germline mutation in one of the genes in the plus progesterone appears to decrease the risk of adeno-DNA mismatch repair gene family, which includes carcinoma and therefore is the preferred treatment. InMSH2, MLM1, and MSH6. Fortunately, HNPCC asymptomatic high-risk patients, periodic screeningaccounts for only 1% to 5% of all colorectal cancers, but may be advisable. All postmenopausal women withit is associated with a 39% to 54% lifetime risk of devel- uterine bleeding must be evaluated for endometrialoping colon cancer. There is a lifetime risk of 30% to cancer, although only 20% of these patients will have a61% of developing endometrial cancer. There is also an malignant genital neoplasm. As the patient’s ageincreased risk of ovarian cancers and other nongyneco- increases after menopause, there is a progressivelylogic cancers. In a study by Lu and associates, they increasing probability that her uterine bleeding is causednoted that about half the time, the endometrial or by endometrial cancer. Feldman and associates foundovarian cancer appeared before the colon cancer. In both that age was the greatest independent risk factor associ-instances, the age at diagnosis was in the early 40s. ated with endometrial cancer or complex hyperplasia. InThere was a median of 11 years between the gynecologic women aged 70 years or older, the odds ratio was 9.1. Ifcancer and the colon cancer. About 14% of the time the complex hyperplasia was present, the odds ratiogynecologic and colon cancers were diagnosed simulta- increased to 16. When a woman was older than 70 years,neously. Several “red flags” should prompt an evalua- her chance of having cancer when vaginal bleeding wastion for HNPCC. These include any individual with a present was about 50%. If she was also nulliparouspersonal or family history of colon cancer at an early and had diabetes, the risk was 87%. A perimenopausalage of onset (usually before age 50) or endometrial patient who may have abnormal uterine bleeding indic-cancer at an early age of onset (premenopausal or before ative of endometrial cancer is frequently not evaluatedage 50) and two or more HNPCC-related cancers in an because the patient or her physician interprets her newindividual or family. Assessing a patient’s risk for bleeding pattern as resulting from menopause. Duringhereditary cancer is an important process, beginning this time in a woman’s life, the menstrual periods shouldwith screening for the “red flags” of hereditary colon become lighter and lighter and farther and farther apart.(and endometrial) cancer. Individuals with any of the Any other bleeding pattern should be evaluated with“red flags” should enter into a discussion about genetic carcinoma of the endometrium in mind. A high index oftesting to determine if this is appropriate for them. suspicion must be maintained if the diagnosis of endo-Medical management strategies can be tailored depend- metrial cancer is to be made in the young patient. Pro-ing on the genetic testing results and may include longed and heavy menstrual periods and intermenstrualincreased surveillance, chemoprevention, and prophy- spotting may indicate cancer, and endometrial samplinglactic surgery. The Cancer Study Consortium suggests is advised. Most young patients who develop endome-colonoscopy every 1 to 3 years beginning at age 25 in trial cancer are obese, in many instances massively over-individuals with this hereditary disorder. The data weight, often with anovulatory menstrual cycles.suggest that if surveillance is done, survival is improved. Historically, fractional dilation and curettage (D&C)Women should be offered surveillance with ultrasound has been the definitive diagnostic procedure used inand endometrial sampling from age 25 to 35, although ruling out endometrial cancer. Today, most advocate thethere are no data to suggest this will improve survival routine use of the endometrial biopsy as an office proce-if endometrial cancer is diagnosed by these means. As dure to make a definitive diagnosis and spare the patientreported by Schmeler and colleagues, risk-reducing hospitalization and an anesthetic. Several studies havesurgery consisting of removal of the uterus and bilateral indicated that the accuracy of the endometrial biopsy in
  7. 7. 5.  Adenocarcinoma of the Uterine Corpus 147detecting endometrial cancer is approximately 90%. 65 primary studies on the use of hysteroscopy to diag-Cytologic detection of endometrial cancer by routine nose endometrial cancer and endometrial disease (can­cervical Papanicolaou (Pap) smear has generally been cer, hyperplasia, or both), including more than 26,000poor in comparison with the efficacy of the Pap smear women. All of the patients had abnormal premeno-in diagnosing early cervical disease. Several studies in pausal or postmenopausal uterine bleeding. Using endo-the literature indicate that only one third to half of the metrial histologic findings as a reference, a positivepatients with adenocarcinoma of the endometrium have hysteroscopy result was associated with a 72% probabil-abnormal Pap smears on routine cervical screening. The ity of endometrial cancer, whereas a negative resultmain reason for the poor detection with the cervical Pap reduced this probability to 0.6%. The correspondingsmear is that cells are not removed directly from the probabilities for endometrial disease were 55% with alesion as they are on the cervix. When a cytologic prepa- positive result and 3% with a negative result. The accu-ration is obtained directly from the endometrial cavity, racy of hysteroscopy tended to be higher among post-malignant cells are present in higher numbers than those menopausal women and in an outpatient setting. Theyfound if routine cervical or vaginal smears are obtained. concluded that hysteroscopy is highly accurate andTechniques that obtain only a cytologic preparation are thereby clinically useful in diagnosing endometrialgenerally inadequate if they are used alone. cancer in women with abnormal uterine bleeding and is Several commercial apparatuses are available for moderately useful in diagnosing endometrial disease.sampling the endometrial cavity on an outpatient basis. Because many patients with endometrial cancer can beIf diagnosis of endometrial cancer can be made on an diagnosed with office biopsy, that is our preferred firstoutpatient basis, the patient can avoid hospitalization diagnostic step. If the biopsy result is negative andand a minor surgical procedure. Devices that remove further evaluation is needed, we proceed to hysteros-tissue for histologic evaluation have generally been good copy. With its use, surgeons can direct biopsies of focalif tissue is obtained from the endometrial cavity. Stovall lesions that might be missed by D&C. Hysteroscopy canand colleagues evaluated 40 patients known to have also be used to evaluate the endocervical canal.endometrial cancer with the Pipelle instrument. Ninety Ultrasonography (US) has been suggested as a diag-percent of the women were postmenopausal. Only in nostic tool in evaluating women with irregular bleeding,one patient was cancer not identified with the Pipelle. particularly the postmenopausal patient (Figure 5-3).This patient had a prior D&C that revealed a grade I The endometrial stripe as seen with transvaginal USlesion. The Pipelle diagnosis was atypical adenomatous appears to be indicative of endometrial thickness. Severalhyperplasia, and the hysterectomy specimen revealed a studies suggest that if a thin endometrial stripe is present,focus of adenocarcinoma in situ. The pathologist noted a histologic diagnosis is not necessary because atrophicthat the obtainable tissue was acceptable for analysis in endometrium would be present. Granberg and associ-100% of patients. Discomfort was recorded as mild in ates evaluated 205 women with postmenopausal bleed-80%, and only two patients (5%) reported severe pain. ing, 30 postmenopausal asymptomatic women, and 30Goldchmit and coworkers reported similar accuracy postmenopausal patients with known endometrialwith the Pipelle in 176 consecutive patients undergoing cancer. In the two groups of 60 patients, the endometrialD&C. Whereas endometrial biopsy and D&C appear to thickness was 3.2 (mean) versus 17.7, respectively. In thebe equivalent in terms of diagnosing cancer, the accuracy group of 205 women, 18 were found to have endometrialof endometrial biopsy appears to be inferior to D&C in cancer. No cancers were present in the endometrium thatpredicting final posthysterectomy tumor grade. In a had an endometrial thickness of 8 mm or less. There wasrecent study by Leitao and colleagues, 18% of endome- considerable overlap of endometrial thickness by alltrial biopsy specimens were upgraded on final hysterec- histologic groups. The authors noted that if a cutoff oftomy specimen, whereas only 9% of D&C specimens 5 mm was used, no false-negative findings were present.were upgraded. In the symptomatic patient in whom With this measurement, the positive predictive valueinadequate tissue (or no tissue at all) is obtained for was 87%, with specificity of 96% and sensitivity of 100%pathologic evaluation, a D&C must be considered. for identifying endometrial abnormalities. It has been Hysteroscopy has been suggested as adjuvant in suggested that if US could save a large number of endo-making the diagnosis of endometrial cancer and in metrial biopsies, there would be a large cost savingsestablishing the extent of disease. Hysteroscopy has with less discomfort to the patient. As previously noted,been used frequently in the evaluation of patients with significant pain with the newer disposable endometrialabnormal uterine bleeding and has the advantages of biopsy techniques affects only a small number of patients;allowing the physician to see the pathologic lesion and and a certain number of patients, because of consider-direct biopsy, identify other competing diagnoses able endometrial thickness, will require endometrial(fibroids, polyps), and perform the procedure on an out- sampling anyway. Clark and colleagues investigatedpatient basis. Clark and colleagues analyzed data from the cost-effectiveness of initial diagnostic strategies for
  8. 8. 148 5.  Adenocarcinoma of the Uterine Corpus AB CFIGURE 5-3  A, Ultrasound of the uterus showing the “triple line” indicating the thickness of the endometrium. B, Ultrasound of the uterusshowing a “thickened endometrium” of more than 10 mm. C, Saline instillation of the endometrial cavity notes a well-defined submucous fibroidand not thickened endometrium.postmenopausal bleeding. A decision analytic model reviews, clinical outcomes from published literature andwas constructed to reflect current service provision, cost estimates from local and National Health Servicewhich evaluated 12 diagnostic strategies using endome- sources. The main outcome measure was the cost pertrial biopsy, ultrasonography (4- and 5-mm endometrial additional life year gained (£/LYG). Compared with car-thickness cutoff), and hysteroscopy. Diagnostic probabil- rying out no initial investigation, a strategy based onity estimates were derived from systematic quantitative initial diagnosis with US using a 5-mm cutoff was the
  9. 9. 5.  Adenocarcinoma of the Uterine Corpus 149least expensive (£11 470/LYG). Initial investigation with endometrial thickness on US of 5 mm or more versusendometrial biopsy or US using a 4-mm cutoff was com- 19% in the non-tamoxifen group (51% vs 8% more thanparably cost-effective (<£30 000/LYG vs US with a 5-mm 10 mm, respectively). Hysteroscopy findings noted thatcutoff). The strategies involving initial evaluation with 28% of uterine mucosa was atrophic versus 87% in thetest combinations or hysteroscopy alone were not cost- non-tamoxifen control group. Histopathologic examina-effective. They concluded that women presenting for the tion noted atrophic endometrium in 60% of tamoxifen-first time with postmenopausal bleeding should undergo treated patients versus 79% of control subjects. Theinitial evaluation with US or endometrial biopsy. biggest difference between the two groups was the Unfortunately, endometrial cancer has been identified finding of polyps in 18% of the tamoxifen group versuswhen the endometrial thickness is less than 5 mm. 0% of the control group; this appears to be a frequentAlthough studies may evaluate several hundred patients, finding in the tamoxifen-treated patient. So-called mega-most do not have many cancer patients included. Wang polyps measuring up to 12 cm have been described.and associates reviewed the ultrasound of 52 women Other uterine disease has been attributed to tamoxifen,who were diagnosed with papillary serous clear cell and including increased uterine volume, lower impedance toother high-grade carcinomas. Of the 52, 34 (65%) had blood flow in uterine arteries, endometriosis, focal peri-thickened endometrium measuring 5 mm or more; in 9 glandular condensation of stromal cells, and epithelial(17%) the endometrium was less tham 5 mm, and in an metaplasia. Data now suggest that the markedly thick-additional 9 women (17%) the endometrium was indis- ened endometrium (up to 40 mm) in patients receivingtinct. In the women with nonthickened endometrium, tamoxifen is not thickened endometrium but proximalother ultrasound abnormalities were noted: intracavi- myometrium.tary fluid or lesion, myometrial mass, enlarged uterus, US has also been evaluated as a means for determin-or adnexal mass. Multiple factors can affect endometrial ing depth of myometrial invasion. Gordon and associ-thickness. These include estrogen, estrogen plus proges- ates studied 15 known patients with endometrial cancertin, body mass index (BMI), diabetes, poor histotype, by US and magnetic resonance imaging (MRI). By use ofrace, and postmenopausal status. The Committee on criteria of greater than 50% myometrial wall involve-Gynecologic Practice of the American College of Obste- ment as deep invasion and less than 50% as superficialtricians and Gynecologists issued an opinion on the role invasion, US was judged to be more accurate than MRIof transvaginal ultrasonography in the evaluation of in five studies; MRI was better in three, both were equallypostmenopausal bleeding. They concluded that women accurate in four, and neither was accurate in three. It haswith postmenopausal bleeding may be assessed initially been suggested by some that US can accurately predictwith either endometrial biopsy or transvaginal ultraso- myometrial invasion in about 75% of cases. Althoughnography. This initial evaluation does not require per- knowing the depth of invasion preoperatively would beformance of both tests. Transvaginal ultrasonography important information to the clinician, the data fromcan be useful in the triage of patients in whom endome- studies as noted before would currently appear to be tootrial sampling was performed but tissue was insufficient premature or too costly to use routinely. We prefer tofor diagnosis. When transvaginal ultrasonography is evaluate depth of myometrial invasion intraoperativelyperformed for patients with postmenopausal bleeding with gross examination or frozen section.and an endometrial thickness of less than or equal to4 mm is found, endometrial sampling is not required. PathologyMeaningful assessment of the endometrium by ultraso-nography is not possible in all patients. In such cases, Careful evaluation of the uterus by the pathologist isalternative assessment should be completed. When essential for proper diagnosis and treatment of corpusbleeding persists despite negative initial evaluations, cancer (Figure 5-4). Gross inspection of a bivalved uterusadditional assessment is indicated. at the time of hysterectomy can offer an impression of The reliability determining endometrial thickness in the size of the lesion, its location (involvement of fundus,the postmenopausal patient does not appear to be appli- lower uterine segment, or cervix), and depth of tumorcable to women taking tamoxifen. In all studies, the penetration into the myometrium (depth of invasion). Aendometrium in the tamoxifen-treated patient is consid- clinically enlarged uterus may be caused by increasingerably thicker than in the non–tamoxifen-treated patient. tumor volume, but this should not be the only gauge forHistologic evaluation revealed atrophic endometrium significant local disease. Obviously, many patients canin a large number of these tamoxifen-treated patients. have enlarged uteri because of factors other than adeno-Lahti and colleagues evaluated 103 asymptomatic post- carcinoma. Carcinoma of the endometrium may start asmenopausal patients (51 receiving tamoxifen and 52 a focal discrete lesion, as in an endometrial polyp. It maycontrol subjects) with US, hysteroscopy, and endometrial also be diffuse in several different areas, in some situa-histologic examination. In the tamoxifen group, 84% had tions involving the entire endometrial surface. As the
  10. 10. 150 5.  Adenocarcinoma of the Uterine Corpus TABLE 5-3  Endometrial Carcinoma Subtypes Type Number (%) 11 12 Endometrioid 6231 (84) 13 Adenosquamous 317 (4.2) 5 14 Mucinous 74 (0.9) 4 Papillary serous 335 (4.5) Clear cell 185 (2.5) 3 Squamous cell 28 (0.04) Other 285 (3.8) 2 10 From Pecorelli S (ed): Int J Gynecol Obstet 83:79, 2003. 1 9 8 7 6 of patients. Historically, patients with a squamous com- ponent were further stratified according to whether the squamous component appeared benign (designated adenoacanthoma, AA) or malignant (designated adeno- squamous carcinoma, AS). It was suggested that AA indicated a good prognosis, and those with AS had a poor survival. Today, this distinction has been ques-FIGURE 5-4  Pathologic evaluation of endometrial cancer. (Courtesy tioned in regard to its prognostic importance. Zaino andPaul Underwood, MD.) co-workers, in reporting data from the GOG, suggest that the notation of squamous component irrespective of differentiation does not affect survival. Patients withtumor grows, it can become larger and/or spread within clinical stage I and stage II cancers were evaluated, andthe endometrium or myometrium. Endometrial cancer 456 with typical adenocarcinoma (AC) and 175 withmay disseminate to regional lymph nodes, by emboliza- squamous differentiation (AC + SQ) were identified. Thetion or direct extension into the pelvis or vagina, or latter were subdivided into 99 with AA and 69 with AS.hematogenously to distant organs (Figure 5-5). The risk Multiple known prognostic factors were compared withof spread is related to several factors, including depth of differentiation of glandular and squamous componentinvasion into the myometrium, tumor grade, and histo- of the tumor. Age, depth of myometrial invasion, archi-logic type. tecture, nuclear grade, and combined grade were similar Adenocarcinoma, the most common histologic type, for AC and AC + SQ, although patients with AA wereis usually preceded by a predisposing lesion, atypical better differentiated than those with AS and had lessendometrial hyperplasia (Table 5-3). Only those hyper- myometrial invasion. Both glandular and squamous dif-plasias with cellular atypia are considered to be precur- ferentiation correlated with frequency of pelvic andsors of adenocarcinoma of the endometrium. For most para-aortic node metastasis. Nodal metastasis, when itpatients with endometrioid-type tumors, particularly was stratified for grade and depth of invasion, wasgrade I-II lesions, and hyperplasia, hyperestrogenism is similar in AC and AC + SQ patients. The differentiationthe etiologic basis. Pathologically, endometrial cancer is of squamous component is closely correlated with thecharacterized by the presence of glands in an abnormal differentiation of the glandular element, and the glandu-relationship to each other, with the hallmark of little if lar element is a better predictor of outcome. It wouldany intervening stroma between the glands. There can therefore appear that the previous designation of AAbe variations in the size of the glands, and infolding is and AS has no added predictive property than differen-common. The cells are usually enlarged, as are the nuclei, tiation of glandular component and probably shouldalong with nuclear chromatin clumping and nucleolar be dropped as a diagnostic term. The authors suggestenlargement. Mitosis may be frequent. Differentiation of the term squamous differentiation instead, with differ-adenocarcinoma (mild, moderate, and severe, or grades entiation of the glandular component noted as theI-III) is important prognostically and is incorporated into important prognostic factor. Subsequently, Abeler andFIGO surgical staging (Figure 5-6). Most studies suggest Kjorstad reviewed 255 cases and made the samethat 60% to 65% of all endometrial cancers are of this recommendations.subtype. Secretory adenocarcinoma (Figure 5-7) is an uncom- For almost a century, it has been recognized that a mon type of endometrial cancer. It usually representssquamous component may be associated with an adeno- well-differentiated carcinoma with progestationalcarcinoma of the endometrium. This occurs in about 25% changes. It is difficult to differentiate it from secretory
  11. 11. 5.  Adenocarcinoma of the Uterine Corpus 151 Endometrium Stage Ia Endocervical Stage Ib Stage Ic glands Myometrium Stage IIb Stage IIa Stage IIb Stage IIa Endocervical stroma Endocervical canal Stage Ia: Tumor limited to endometrium Stage IIa: Endocervical glandular involvement only Stage Ib: Invasion to less than half the myometrium Stage IIb: Cervical stroma invasion Stage Ic: Invasion to more than half the myometrium Stage I Stage II Pelvic Periaortic nodes nodes Positive cytology Stage IIIA Stage IIIB Stage IIIC Omentum Inguinal nodes Stage IVa Stage IVb
  12. 12. 152 5.  Adenocarcinoma of the Uterine Corpus Pelvic Organs Lymph Nodes Aortics Common iliacs Loose cancer cells Hypogastrics in peritoneal cavity External iliacs Small bowel implants Involved ovary Extension to broad ligament Obturator Vaginal Inguinals ParacervicalFIGURE 5-5  Spread pattern of endometrial cancer with particular emphasis on potential lymph node spread. Pelvic and periaortic nodes areat risk, even in stage I disease.endometrium. Survival is good and comparable to that that has a propensity for vascular or lymphatic vascularassociated with the pure adenocarcinoma. Although it is space involvement (LVSI). Well-formed papillae arean interesting histologic variant, the separation of the lined by neoplastic cells with grade III cytologic featuresentity as it relates to treatment and survival is probably (Figure 5-8). Differentiation between papillary architec-not warranted. ture and syncytial metaplasia with benign endometrial Increasing emphasis has been placed on the impor- alterations must be made because the papillary architec-tance of the histologic subtype serous adenocarcinoma ture alone does not designate PS. The uterus may appear(SC) of the uterus (also called uterine papillary serous grossly normal but can have extensive myometrial inva-carcinoma, UPSC). This subtype represents less than sion. Most UPSC tumors are aneuploid and have a10% of all adenocarcinomas but is a highly aggressive high S-phase. Serous cancers can be pure or admixedcarcinoma of the uterus. Unlike the more common vari- with other histologic types (endometrioid, clear cell,ants, PS is not associated with hyperestrogenism and carcinosarcoma).frequently develops in the setting of atrophic endome- Clear cell carcinomas (Figure 5-9) are also infrequenttrium. It is more commonly seen in older and nonwhite in number but have distinct histologic criteria. Clear cellpatients. Hendrickson, in the early 1980s, noted that in tumors are characterized by large polyhedral epithelialmore than 250 endometrial cancers, only 10% had histo- cells that may be admixed with typical non–clearlogic features of SC, but these accounted for 50% of cell adenocarcinomas. Some authorities accept theall treatment failures. The histopathologic appearance mesonephritic-type hobnail cells as part of this pattern,resembles a high-grade serous carcinoma of the ovary whereas others believe that this histologic type should
  13. 13. 5.  Adenocarcinoma of the Uterine Corpus 153 A FIGURE 5-7  High-power view of well-differentiated secretory car- cinoma invading inner one-third of the myometrium. (Courtesy William M. Christopherson, MD, Louisville, Kentucky.) B FIGURE 5-8  Serous adenocarcinoma. Similarity to ovarian carci- noma is apparent. (Courtesy Gregory Spiegel, MD.) CFIGURE 5-6  Histologic patterns of differentiation in endometrialcarcinoma. A, Well-differentiated (G1). B, Moderately differentiated(G2). C, Poorly differentiated (G3). (Courtesy Gregory Spiegel, MD.) FIGURE 5-9  Clear cell carcinoma of the endometrium. Clear cell component is quite evident. (Courtesy Gregory Spiegel, MD.)
  14. 14. 154 5.  Adenocarcinoma of the Uterine Corpusbe excluded from the clear cell category. Silverberg and grade, raises the grade of a grade I or grade II tumor byDeGiorgi and Kurman and Scully suggested a worse one. By convention, serous and clear tumors are consid-prognosis for clear cell adenocarcinoma than for pure ered grade III/high-grade tumors.adenocarcinoma. This was confirmed in studies byChristopherson and co-workers. Even in stage I disease,only 44% of patients with clear cell carcinomas survive PROGNOSTIC FACTORS5 years. Neither the FIGO classification nor nucleargrade correlates with survival. Photopulos and associ- Following hysterectomy and lymph node dissection,ates, in a review of their material, noted that their patients clinical-pathologic characteristics are commonly used towith this entity were older and tended to have a worse predict risk of recurrence and to optimize therapy. Mul-prognosis. They did note that patients with stage I clear tiple factors have been identified for endometrial carci-cell carcinomas had a 5-year survival similar to that of noma that have prognostic value (Table 5-4). Essentiallypatients with stage I pure adenocarcinoma of the all reports in the literature agree stage (extent of diseaseendometrium. spread), grade of tumor, and depth of invasion are important prognostic considerations. Before 1988 endo- metrial cancer was clinically staged with stage assign-Tumor Grade ments based on uterine size and clinical extent of disease.In addition to histologic type, pathologists assign a Because of the considerable discrepancy between themeasure of tumor differentiation, known as grade, to clinical extent of disease spread and pathologic spreadendometrial cancers. Grade I lesions are well differenti- noted after surgical staging, FIGO adopted a surgical-ated, are frequently associated with estrogen excess, pathologic staging classification in 1988. In 2009 FIGOclosely resemble hyperplastic endometrium, and are updated the staging system (Table 5-5). FIGO staginggenerally associated with a favorable prognosis. Grade classification attempts to categorize patients into prog-III lesions are poorly differentiated, do not resemble nostic groups based on extent of disease and tumornormal endometrium, and frequently have a poorer grade.prognosis. Grade II tumors are moderately well differ-entiated and have an intermediate prognosis. Both archi-tectural criteria and nuclear grade are used to classify.Architectural grade is related to the proportion of solidtumor growth, with grade I having an adenocarcinoma TABLE 5-4  Prognostic Factors in Endometrial Adenocarcinomain which less than 5% of the tumor growth is in solid Histologic type (pathology)sheets, grade II has 6% to 50% of the neoplasm arranged Histologic differentiationin solid sheets of neoplastic cells, and grade III has Stage of diseasegreater than 50% of the neoplastic cells in solid masses. Myometrial invasionRegions of squamous differentiation are excluded from Peritoneal cytology Lymph node metastasisthis assessment. The FIGO rules for grading state that Adnexal metastasisnotable nuclear atypia, inappropriate for architecturalTABLE 5-5  2009 FlGO Staging System for Carcinoma of the EndometriumStage I* Tumor contained to the corpus uteri IA No or less than half myometrial invasion IB Invasion equal to or more than half of the myometriumStage II Tumor invades the cervical stroma but does not extend beyond the uterus†Stage III* Local and/or regional spread of tumor‡ IIIA Tumor invades the serosa of the corpus uteri and/or adnexas IIIB Vaginal and/or parametrial involvement IIIC Metastases to pelvis and/or para-aortic lymph nodes IIICl Positive pelvic nodes IIIC2 Positive para-aortic lymph nodes with or without positive pelvic lymph nodesStage IV* Tumor invades bladder and/or bowel mucosa and/or distant metastases IVA Tumor invasion of bladder and/or bowel mucosa IVB Disant metastases, including intra-abdominal metastases and/or inguinal lymph nodes*Includes grades 1, 2, or 3.† Endocervical glandular involvement only should be considered as stage I and no longer as stage II.‡ Positive cytology has to be reported separately without changing the stage.
  15. 15. 5.  Adenocarcinoma of the Uterine Corpus 155Stage of Disease: Depth of Invasion, care for patients with endometrial cancer. GOG protocolCervical Involvement, Adnexal Involvement, 33 was a surgical-pathologic study of 621 patients with clinical stage I endometrial cancer who were uniformlyand Nodal Metastasis treated with total abdominal hysterectomy, bilateralStaging of patients with malignancies is designed to salpingo-oophorectomy, peritoneal cytologic evaluation,have prognostic value by classifying the size and extent and selective pelvic and para-aortic selected lymphad-of tumor. The survival rate in regard to stage of disease enectomy. Before this study, it was presumed mosthas been consistent, and Table 5-6 and Figure 5-10 show patients with endometrial cancer were at risk for nodalthe 5-year survival rate reported by FIGO (FIGO 1988 metastases and nearly all patients required some formstaging). The patterns of disease spread in endometrial of pelvic radiation therapy (either preoperatively orcancer was evaluated in a prospective study performed postoperatively). The study demonstrated importantby the GOG (GOG protocol 33) and reported by Creas- relationships between pathologic factors and risk ofman. This study is required reading for physicians who nodal disease. For example, factors associated with nodal disease included higher tumor grade, deeper myometrial invasion, cervical involvement, (+) cytology,TABLE 5-6 Five-Year Survival in Endometrial Cancer: Surgical and LVSI. As a result of this study FIGO accepted aStage surgical-based staging system of endometrial cancer in 1988.Stage No. of Patients Five-Year Survival (%) For endometrial cancer, FIGO staging reflects the pro- Ia 1063 91 gression of disease within the uterus and at extrauterine Ib 2735 90 sites. Approximately 75% of patients with endometrial Ic 1219 81 cancer present with disease limited to the uterus (Table IIa 364 79 IIb 426 71 5-7). For stage I disease, depth of tumor invasion into the IIIa 484 60 myometrium is an important prognostic factor. The IIIb 73 30 degree of myometrial invasion is a consistent indicator IIIc 293 52 of tumor virulence (Figure 5-11). DiSaia and associates IVa 47 15 noted that recurrences were directly related to depth of IVb 160 17 myometrial invasion in patients with stage I cancerFrom Pecorelli S (ed): Int J Gynecol Obstet 83:95, 2003. treated primarily with surgery (Table 5-8). The Annual 100 Stage Ia (n ϭ 1063) Stage Ib (n ϭ 2735) Stage Ic (n ϭ 1219) 80 Stage IIa (n ϭ 364) Stage IIb (n ϭ 426) Proportion surviving Stage IIIa (n ϭ 484) 60 Stage IIIc (n ϭ 293) 40 Stage IIIb (n ϭ 73) 20 Stage IVb (n ϭ 150) Stage IVc (n ϭ 47) 0 0 1 2 3 4 5 Years after diagnosisFIGURE 5-10  Carcinoma of the corpus uteri; patients treated in 1990–1992 (FIGO). Survival by surgical stage (n = 5694). [From Pecorelli S (ed):Int J Gynecol Obstet 83:95, 2003. © International Federation of Gynecology and Obstetrics.]
  16. 16. 156 5.  Adenocarcinoma of the Uterine CorpusTABLE 5-7 Distribution of Endometrial Carcinoma by Stage TABLE 5-8  Relationship between Depth of Myometrial(Surgical) Invasion and Recurrence in Patients with Stage I Endometrial CarcinomaStage Patients (%) Endometrial only 7/92 (8%) I 3839 (73) Superficial myometrium 10/80 (13%) II 574 (11) Medium myometrium 2/17 (12%) III 694 (13) Deep myometrium 15/33 (46%) IV 166 (3) Modified from DiSaia PJ et al: Am J Obstet Gynecol 151:1009, 1985.From Pecorelli S (ed): J Epidemiol Biostat 3:41, 1998. Myometrial invasion TABLE 5-9  Relationship between Depth of Myometrial Invasion and Five-Year Survival Rate (Stage I) Endometrium Inner Outer Cervical or only half half extrauterine Stage Patients 5-Year Survival (%) involvement IaG1 698 93 Grade 1 IbG1 1030 88 IcG1 442 87 Grade 2 IaG2 229 91 IbG2 1307 93 Grade 3 IcG2 485 84 IaG3 66 75 Low risk Intermediate risk High risk IbG3 280 82 IcG3 247 66FIGURE 5-11  Risk assignment based on surgical staging/extent ofdisease in patients with endometrial cancer. From Pecorelli S (ed): Int J Gynecol Obstet 83:95, 2003.Report of FIGO demonstrated a decrease in the survival than do those with only fundal disease (8%). There is arate as myometrial penetration increased (Table 5-9). similar frequency of para-aortic nodal metastases: a 16%Lutz and co-workers determined that the depth of myo- incidence from disease of the lower uterine segment andmetrial penetration was not as important as the proxim- a 4% incidence when only fundal disease is present.ity of the invading tumor to the uterine serosa. Patients Previously, endocervical curettage (ECC) was commonlywhose tumors invaded to within 5 mm of the serosa had used to determine whether the patient had cervicala 65% 5-year survival rate, whereas patients whose involvement. Many false-positive results occur throughtumors were more than 10 mm from the serosa had a the use of this technique, however. In addition, the prog-97% survival rate. The depth of myometrial invasion is nostic significance of endocervical glandular spread (for-associated with the other prognostic factors, such as the merly stage IIa) has been challenged. The new surgicalgrade of the tumor. As noted by DiSaia and associates, staging adopted by FIGO in 2009 includes only thosethe survival rate of patients with poorly differentiated patients with cervical stromal invasion in the stage IIlesions and deep myometrial invasion is poor in contrast category. In some cases, cervical biopsy and/or ECC isto that of patients who have well-differentiated lesions required in the pretreatment planning of a patient withbut no myometrial invasion. This suggests that virulence suspected cervical involvement.of the tumor may vary considerably, and as a result, Patients with stage III-IV disease may have a hetero-therapy should depend on the combination of prognos- geneous mix of disease characteristics. It is well recog-tic factors. nized that endometrial cancer can and frequently does Location of the tumor within the endometrial cavity metastasize to the adnexa. Patients with adnexal and/is important because tumors low in the cavity may or serosal involvement are categorized as stage IIIA andinvolve the cervix earlier than fundal lesions. Prognosis are considered to have a higher risk of peritoneal recur-for women with cervical involvement (stage II) is worse rence. In GOG 33, 5% of patients had adnexal involve-than with stage I disease. Cervical involvement is often ment. Adnexal metastasis was significantly associateda surrogate marker for extrauterine disease spread or for with involved pelvic (32%) and para-aortic (20%) lymphrisk of local recurrence. Data from GOG 33 showed that nodes. In a large surgical trial comparing laparoscopythose with disease of the lower uterine segment had a to open staging (GOG Lap 2 trial), 5% of 2616 patientshigher incidence of pelvic lymph node metastases (16%) enrolled were found to have stage IIIA disease (FIGO
  17. 17. 5.  Adenocarcinoma of the Uterine Corpus 157TABLE 5-10  Grade vs Positive Pelvic and Aortic Nodes TABLE 5-12 Frequency of Pelvic and Para-Aortic Nodal DiseaseGrade (n) Pelvic Nodes (%) Aortic Nodes (%) GradeG1 (180) 5 (3) 3 (2) Grade I Grade II Grade IIIG2 (288) 25 (9) 14 (5) Depth of Invasion (n = 180) (n = 288) (n = 153)G3 (153) 28 (18) 17 (11) Endometrial only 0%/0% 3%/3% 0%/0%Modified from Creasman WT et al: Cancer 60:2035, 1987. (n = 86) Inner one-third 3%/1% 5%/4% 9%/4% (n = 281) Middle one-third 0%/5% 9%/0% 4%/0% (n = 115)TABLE 5-11 Maximal Invasion and Node Metastasis Outer one-third 11%/6% 19%/14% 34%/23% (n = 139)Maximal invasion (n) Pelvic Nodes (%) Aortic Nodes (%) (Pelvic Nodal Positivity/Para-aortic Nodal Positivity)Endometrium only (87) 1 (1) 1 (1) Modified from Creasman WT et al: Cancer 60:2035, 1987.Superficial muscle (279) 15 (5) 8 (3)Intermediate muscle (116) 7 (6) 1 (1)Deep muscle (139) 35 (25) 24 (17)Modified from Creasman WT et al: Cancer 60:2035, 1987. tumors had pelvic nodal metastases of 3%, 9%, and 18% respectively. Similarly, patients with no myometrial invasion, inner one third, middle one third, and outer1988 staging). In an analysis of 222 patients with clinical one third invasion had 1%, 5%, 6%, and 25% pelvic nodalstage I carcinoma of the endometrium reported by disease, respectively. The highest risk group includedDiSaia and colleagues, 16 (7%) were found to have patients with grade III tumors and outer one third inva-metastasis in the adnexa. This finding correlated with sion who had pelvic nodal involvement in 34% of casesmany but not all of the other prognostic factors. Spread (Table 5-12). Without a lymphadenectomy, one mayto the adnexa did not seem to be related to the size of grossly estimate the probability of nodal involvementthe uterus. The grade of the disease did not appear based on these data to select for or against the use ofprognostically important in regard to this in that 6% of adjuvant therapy. This strategy potentially results inpatients with grade I tumors had adnexal disease com- undertreatment or overtreatment of patients, however.pared with only 10% if poorly differentiated carcinoma In two large prospective randomized trials, routinewas present. The depth of invasion did appear to be lymphadenectomy resulted in the identification of moresignificant, however, in that only 4% of patients with patients with nodal disease (9% to 13%), compared toonly the endometrium involved had adnexal spread, when only clinically suspicious nodes were removedcompared with 24% who had adnexal metastases if (1% to 3%). It is clear that patients with nodal diseasedeep muscle was involved. If tumor was limited to the have poorer prognosis (3- to 5-year survival of 50% tofundus of the uterus, only 5% of patients had disease 75%) and different patterns of failure (nodal, distant)in the adnexa; however, if the lower uterine segment or than patients with negative nodes (3- to 5-year survivalthe endocervix was involved, one-third had spread to of 80% to 95%, vaginal cuff failures predominate).the adnexa. When metastasis was present in the adnexa, Patients with nodal involvement include those with60% of patients had malignant cells in the peritoneal pelvic nodal disease (IIIC1) or any para-aortic involve-cytologic fluid, compared with only 11% if the adnexa ment (IIIC2). The substaging was created in 2009 givenwere not involved. Recurrences appeared in only 14% the belief of different outcomes associated with differentof these individuals who did not have metastasis to the levels of nodal involvement. The number of involvedadnexa, compared with recurrences in 38% of patients nodes and the extent of resection of grossly involvedwith adnexal metastasis. nodes also affect outcome. In addition Mariani and Metastatic spread to lymph nodes (stage IIIC) has McMeekin have suggested that patients with (+) nodalprognostic and therapeutic implications. It is clear that disease plus other stage III defining features (positivelymphadenectomy is the most sensitive way to identify cytology, adnexal or serosal involvement) have a muchnodal disease. The GOG 33 study demonstrated that as poorer prognosis than those with nodal disease only.the depth of tumor invasion or tumor grade increased, Patients with stage IV/distant disease spread (intraperi-the frequency of pelvic and para-aortic nodal metastases toneal, lung, liver) have a particularly poor prognosis,also increased (Tables 5-10 and 5-11). For all 621 patients, with 5-year survival of less than 20%. The extent of sur-58 (9%) had positive pelvic nodes and 34 (6%) had posi- gical resection has been suggested to alter prognosis intive para-aortic nodes. Patients with grade 1, 2, and 3 patients with advanced-stage disease. As with ovarian
  18. 18. 158 5.  Adenocarcinoma of the Uterine Corpuscancer, the extent of resection of disease reflects biology invasion, whereas patients with a poorly differentiatedof the tumor, aggressiveness of the surgery, and response malignant neoplasm might have only endometrial orto postoperative therapies. superficial myometrial involvement. Lymphovascular Space InvolvementTumor Grade Hanson and colleagues described 111 patients with stageThe degree of histologic differentiation (tumor grade) of I endometrial cancer and found capillary-like spaceendometrial cancer is a sensitive indicator of prognosis (CLS) involvement in 16. This was most frequentlyand is included in FIGO stage assignment. The Annual found in patients with poorly differentiated tumors withReport on the Results of Treatment in Gynecological deep invasion. These patients had a 44% recurrence rate,Cancer has evaluated survival in regard to grade in compared with 2% if the CLS was not involved. This waspatients with clinical stage I adenocarcinoma of the an independently significant prognostic factor. In theendometrium (Table 5-13). Tumor grade is inversely GOG study of 621 patients, it was shown that 93 (15%)related to survival decreases; as grade increases, survival had CLS involvement. The incidences of pelvic andis poorer. In their review of 244 patients with stage I para-aortic node metastases were 27% and 19%, respec-disease, Genest and colleagues noted that patients with tively. This compares with a 7% occurrence of pelvicgrade I disease had a 5-year survival rate of 96%. This node metastasis and a 3% occurrence of para-aortic nodedropped to 79% and 70% for grade II and grade III, metastasis when there is no CLS involvement. In riskrespectively. Data presented by Morrow for outcomes in models predicting risk of recurrence in node-negative/patients enrolled on GOG 33 show that recurrence-free early-stage endometrial cancer, the GOG has suggestedsurvival markedly diminishes with increasing grade, that LVSI is an important risk factor. In the Post Opera-with progression-free survival (PFS) at 48 months being tive Radiation Therapy in Endometrial Cancer (PORTEC)approximately 95%, 85%, and 68% for grade I, II, and III trial, LVSI was considered to be a factor associated withtumors, respectively. Grade of tumor also correlates with distant site of failure.other factors of prognosis. Table 5-14 shows the relation-ship between differentiation of the tumor and depth of Tumor Sizemyometrial invasion as reported by Creasman from the Schink and co-workers evaluated tumor size in 91GOG 33 study. As the tumor becomes less differentiated, patients with stage I disease. The incidence of lymphthe chances of deep myometrial involvement increase. node metastases in patients with tumor size less thanHowever, exceptions can occur: Patients with a well- 2 cm was only 6%. If tumor was greater than 2 cm indifferentiated lesion can have deep myometrial diameter, there were nodal metastases of 21% and up to 40% if the entire endometrium was involved. Patients with lesions greater than 2 cm in size and less than half myometrial invasion had no nodal metastasis. UsingTABLE 5-13  Relationship between Tumor Differentiation multivariate analysis, the authors showed that tumorand Five-Year Survival Rate, Stage I (Surgical) size was an independently significant prognostic factor.Grade Survival (n = 5017) (%) Watanabe and associates did not find cancer size was predictive of lymph node metastasis. Gynecologic oncol- 1 91 2 90 ogists from the Mayo Clinic have developed a risk model 3 81 predicting nodal metastases and have suggested that grade I-II tumors that are less than 2 cm are particularlyFrom Pecorelli S (ed): FIGO Annual Report, years 1996–98, Int J Gynecol Obstet83:95, 2003. low risk for nodal disease. Peritoneal Cytology The importance of peritoneal cytology in endometrialTABLE 5-14  Correlation of Differentiation and Myometrial cancer is controversial. In GOG 33, 76 (12%) had malig-Invasion in Stage I Cancer nant cells identified by cytologic examination of perito- Grade neal washings. Of these patients, 25% had positive pelvic nodes, compared with 7% of patients in whom no malig-Myometrial Invasion 1 (%) 2 (%) 3 (%) nant cells were found in peritoneal cytologic specimensNone 24 11 11 (P > 0.0001). It is true that peritoneal cytology, to a certainSuperficial 53 45 35 degree, mimics other known prognostic factors—that is,Mid 12 24 16 if peritoneal cytologic specimens are positive, otherDeep 10 20 42 known poor prognostic factors may also be identified.Modified from Creasman WT et al: Cancer 60:2035, 1987. In addition, data from GOG 33 also suggested that the