Sean C. Dowdy
Andrea Mariani
John R. Lurain
• Most risk factors for the development of endometrial carcinoma are related to prolonged, unopposed estrogen stimulation.
• Office endometrial aspiration biopsy is the accepted first step in evaluating a woman with abnormal uterine bleeding or suspected endometrial pathology.
• Serous and clear cell endometrial carcinomas make up less than 10% of endometrial cancers, yet account for more than one-half of all endometrial cancer deaths.
• Most patients with endometrial cancer should undergo surgical staging, including hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, and peritoneal cytology. Lymphadenectomy may be omitted in patients with negligible risk of lymphatic spread.
• The most important adverse prognostic variables in endometrial cancer are advancing patient age, nonendometrioid or grade 3 histology, deep myometrial invasion, lymphovascular space invasion, large tumor size, cervical extension, lymph node metastasis, and intraperitoneal spread.
• Postoperative adjuvant radiotherapy in selected patients with endometrial cancer decreases the risk of local vaginal/pelvic recurrence and improves disease-free survival.
• Overall 5-year survival rate in endometrial cancer is approximately 75%.
• Uterine sarcomas are, in general, the most malignant group of uterine tumors and differ from endometrial cancers with regard to risk factors, diagnosis, clinical behavior, pattern of spread, and management.
Endometrial carcinoma is the most common malignancy of the female genital tract, accounting for almost one-half of all gynecologic cancers in the United States. In 2011, an estimated 46,470 new cases and 8,120 cancer-related deaths are anticipated. Endometrial carcinoma is the fourth most common cancer, ranking behind breast, lung, and colorectal cancers, and the eighth leading cause of death from malignancy in women. Overall, about 2% to 3% of women develop endometrial cancer during their lifetimes (1). Certain factors are increasing awareness of and emphasis on diagnosis and treatment of endometrial cancer. These factors include the declining incidence of cervical cancer-related deaths in the United States, prolonged life expectancy, postmenopausal use of hormone therapy, and earlier diagnosis. The availability of easily applied diagnostic tools and a clearer understanding of premalignant lesions of the endometrium led to an increase in the number of women diagnosed with endometrial cancer. Although endometrial carcinoma usually presents as early-stage disease and often is managed without radical surgery or radiotherapy, deaths from endometrial carcinoma now exceed those from cervical carcinoma in the United States. Endometrial cancer is a disease that occurs primarily in postmenopausal women and is increasingly virulent with advancing age. The definite role of estrogen in the development of most endometrial cancers is established. Any factor that increases exposure to unopposed estrogen increases the risk for endometrial cancer.
The histopathology, spread patterns, and clinicopathologic factors that affect the prognosis of endometrial cancers have become better defined. Management of endometrial cancer evolved from a program of preoperative intrauterine or external pelvic radiation followed by hysterectomy based on clinical staging, to an individualized approach using hysterectomy as primary therapy and employing additional postoperative treatment depending on surgical and pathologic findings. Further analysis and investigation are needed to determine whether this initial operative approach to treatment and staging, followed by targeted postoperative therapy, will translate into improved survival rates and lower morbidity.
Table 35.1 Risk Factors for Endometrial Cancer
|
Characteristic |
Relative Risk |
|
Nulliparity |
2–3 |
|
Late menopause |
2.4 |
|
Obesity |
|
|
21–50 lb overweight |
3 |
|
>50 lb overweight |
10 |
|
Diabetes mellitus |
2.8 |
|
Unopposed estrogen therapy |
4–8 |
|
Tamoxifen therapy |
2–3 |
|
Atypical endometrial hyperplasia |
8–29 |
|
Lynch II syndrome |
20 |
Epidemiology and Risk Factors
There appear to be two pathogenetic types of endometrial cancer (2). Type I, accounting for about 75% to 85% of cases, occurs in younger, perimenopausal women with a history of exposure to unopposed estrogen, either endogenous or exogenous. In these women, tumors begin as hyperplastic endometrium and progress to carcinoma. These “estrogen-dependent” tumors tend to be better differentiated and have a more favorable prognosis than tumors that are not associated with hyperestrogenism. Type II endometrial carcinoma occurs in women without estrogenic stimulation of the endometrium. These spontaneously occurring cancers are not associated pathologically with endometrial hyperplasia, but may arise in a background of atrophic endometrium. They are less differentiated and associated with a poorer prognosis than estrogen-dependent tumors. These “estrogen-independent” tumors tend to occur in older, postmenopausal, thin women and are present disproportionately in AfricanAmerican and Asian women. Over the past decade, molecular genetic studies showed that these two tumor types evolve via distinct pathogenetic pathways (3) (see Type I and II Endometrial Carcinoma: Molecular Aberrations, below).
Several risk factors for the development of endometrial cancer are identified (4–9) (Table 35.1). Most of these risk factors are related to prolonged, unopposed estrogen stimulation of the endometrium.Nulliparous women have twoto threetimes the risk of parous women. Infertility and a history of irregular menses as a result of anovulatory cycles (prolonged exposure to estrogen without sufficient progesterone) increase risk. Natural menopause occurring after age 52 years increases the risk for endometrial cancer 2.4-fold compared with women who experienced menopause before 49 years of age, probably as a result of prolonged exposure of the uterus to progesterone-deficient menstrual cycles. The risk of endometrial cancer is increased 3 times in women who are 21 to 50 pounds overweight and 10 times in those more than 50 pounds overweight (resulting from excess estrone as a result of peripheral conversion of adrenallyderived androstenedione by aromatization in fat). The obesity epidemic in Western countries, together with growing rates of insulin resistance and “metabolic syndrome,” can be expected to increase the incidence of endometrial cancer in coming years.
Other factors leading to long-term estrogen exposure, such as polycystic ovary syndrome and functioning ovarian tumors, also are associated with an increased risk for endometrial cancer. Menopausal estrogen therapy without progestins increases the risk of endometrial cancer fourto eighttimes. This risk increases with higher doses and with more prolonged use and can be reduced to essentially baseline levels by the addition of progestin (8). The use of the antiestrogen tamoxifen for treatment of breast cancer is associated with a two- to threefold increased risk for the development of endometrial cancer, although this finding is confounded by the apparent greater risk of endometrial cancer in women who have breast cancer, with or without treatment with tamoxifen (9,10). Diabetes mellitus increases a women’s risk for endometrial cancer by 1.3 to 2.8 times. Women with Lynch II syndrome (previously referred to as hereditary nonpolyposis colorectal cancer syndrome, or HNPCC), a cancer susceptibility syndrome with germline mutations in mismatch repair genes MLH1, MSH2, and MSH6, have a 40% to 60% lifetime risk for endometrial and colon cancer (11). Other medical conditions, such as hypertension and hypothyroidism, are associated with endometrial cancer, but a causal relationship is not confirmed.
Table 35.2 Classification of Endometrial Hyperplasias
|
Type of Hyperplasia |
Progression to Cancer (%) |
|
Simple (cystic without atypia) |
1 |
|
Complex (adenomatous without atypia) |
3 |
|
Atypical |
|
|
Simple (cystic with atypia) |
8 |
|
Complex (adenomatous with atypia) |
29 |
|
From 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, with permission. |
|
Endometrial Hyperplasia
Endometrial hyperplasia represents a spectrum of morphologic and biologic alterations of the endometrial glands and stroma, ranging from an exaggerated physiologic state to carcinoma in situ. Clinically significant hyperplasias usually evolve within a background of proliferative endometrium as a result of protracted estrogen stimulation in the absence of progestin influence. Endometrial hyperplasias are important clinically because they may cause abnormal bleeding, be associated with estrogen-producing ovarian tumors, result from hormonal therapy, and precede or occur simultaneously with endometrial cancer.
The classification scheme endorsed by the International Society of Gynecological Pathologists is based on architectural and cytologic features and long-term studies that reflect the natural history of the lesions (12) (Table 35.2). Architecturally, hyperplasias are either simple or complex; the major differing features are complexity and crowding of the glandular elements. Simple hyperplasia is characterized by dilated or cystic glands with round to slightly irregular shapes, an increased glandular-to-stromal ratio without glandular crowding, and no cytologic atypia. Complex hyperplasia has architecturally complex (budding and infolding) crowded glands, with less intervening stroma without atypia. Atypical hyperplasia refers to cytologic atypia and can be categorized as simple or complex, depending on the corresponding glandular architecture. Criteria for cytologic atypia include large nuclei of variable size and shape that have lost polarity, increased nuclear-to-cytoplasmic ratios, prominent nucleoli, and irregularly clumped chromatin with parachromatin clearing (Fig. 35.1).
Figure 35.1 Atypical hyperplasia (complex hyperplasia with severe nuclear atypia) of endometrium. A: The proliferative endometrial glands reveal considerable crowding and papillary infoldings. The endometrial stroma, although markedly diminished, can still be recognized between the glands. B:Higher magnification demonstrates disorderly nuclear arrangement and nuclear enlargement and irregularity. Some contain small nucleoli. (Provided by Gordana Stevanovic, MD, and Jianyu Rao, MD, Department of Pathology, UCLA.)
The risk of endometrial hyperplasia progressing to carcinoma is related to the presence and severity of cytologic atypia. Kurman et al. retrospectively studied endometrial curettings from 170 patients with untreated endometrial hyperplasia followed a mean of 13.4 years (13). They found that progression to carcinoma occurred in 1% of patients with simple hyperplasia, 3% of patients with complex hyperplasia, 8% of patients with atypical simple hyperplasia, and 29% of patients with atypical complex hyperplasia. Most of the hyperplasias seemed to remain stable (18%) or regress (74%). The premalignant potential of hyperplasia is influenced by age, underlying ovarian disease, endocrinopathy, obesity, and exogenous hormone exposure (14,15).
As many as 25% to 43% of patients with atypical hyperplasia detected in an endometrial biopsy or curettage specimen will have an associated, usually well-differentiated, endometrial carcinoma detected during hysterectomy (16). Marked cytologic atypia, a high mitotic rate, and marked cellular stratification are features of atypical endometrial hyperplasia most often associated with the finding of an undiagnosed carcinoma at hysterectomy.
Fertility Sparing Treatment of Endometrial Hyperplasia and Cancer
Younger patients with endometrial cancer tend to have disorders such as polycystic ovarian syndrome, chronic anovulation, and infertility, indicative of exposure to intrinsic estrogen excess (17). Lesions in this age group are usually welldifferentiated and of endometrioid subtype with the potential to regress with progestational therapy (18). Althoughstandard treatment for all endometrial cancer is hysterectomy and staging, nonsurgical treatment with hormonal therapy may be an option for appropriately selected women desiring to preserve fertility. Surrogate staging techniques, such as magnetic resonance imaging (MRI), may be employed to evaluate the depth of myometrial invasion or identify extrauterine disease (19,20). The sensitivity of MRI to evaluate these factors is limited and has the potential for underdiagnosis (21).
High regression rates for both endometrial cancer and atypical hyperplasia following treatment with progestin therapy are extensively documented (18,22–28). However, relatively small cohorts of patients and reports of hormone failure suggest caution when counseling patients for conservative management (27,29). In a 2004 meta-analysis, Ramirez et al. reported a comprehensive review of hormonal treatment of grade 1endometrial cancer, including 27 articles with a combined total of 81 patients. A variety of progestational agents were utilized with an overall response rate of 76% (62/81) and the median time to regression was 12 weeks (30). The recurrence rate was 24% among responders; nearly all recurrences occurred within 1year of diagnosis. Only 1month of progestational treatment was required to achieve a response in the 76% of patients without recurrence. Twenty patients achieved pregnancy following treatment. It is important to note that 24% (19/81) of the original cohort never responded to treatment, and only 68% had any documented follow-up endometrial sampling. Progestational therapy can successfully treat disease while preserving fertility for patients with atypical hyperplasia and well-differentiated presumed stage I endometrial cancer. Appropriate patient selection and exclusion criteria remain undefined. Patients must be counseled that failure to identify recurrence or extension of disease during progestational treatment may lead to a delay in definitive surgery and ultimately a compromised prognosis (27).
Continuous progestin therapy with megestrol acetate (40–160 mg per day) is probably the most reliable treatment for reversing complex or atypical hyperplasia. No clear consensus exists for an optimal follow-up interval. Therapy should be continued for at least 2 to 3 months, and endometrial biopsy should be performed 3 to 4 weeks after completion of therapy to assess response. Periodic endometrial biopsy or transvaginal ultrasonography is advisable in patients being monitored after progestin therapy for atypical hyperplasia because of the presence of undiagnosed cancer in 25% of cases, the 29% progression rate to cancer, and the high recurrence rate after treatment with progestins. In this setting the use of progesterone should be considered a temporary, rather than long-term, treatment. For women with atypical complex hyperplasia who no longer desire fertility, hysterectomy is recommended.
Endometrial Cancer Screening in the General Population
Screening for endometrial cancer should not be undertaken because of the lack of an appropriate, cost-effective, and acceptable test that reduces mortality (31–33). Routine Papanicolaou (Pap) testing is inadequate, and endometrial cytologic assessment is too insensitive and nonspecific to be useful in screening for endometrial cancer, even in a high-risk population. A progesterone challenge test reveals whether the endometrium is primed by estrogen, but it does not identify abnormal endometrial pathology. Transvaginal ultrasonographic examination of the uterus and endometrial biopsy are too expensive to be employed as screening tests.
Although many risk factors for endometrial cancer have been identified, screening of high-risk individuals using current technologies could, at best, detect only one-half of all cases of endometrial cancer. Furthermore, no controlled trials were carried out to evaluate the effectiveness of screening for endometrial cancer. Screening for endometrial cancer or its precursors may be justified for certain high-risk women, such as those receiving postmenopausal estrogen therapy without progestins and members of families with hereditary nonpolyposis colorectal cancer (34). Women taking tamoxifen receive no benefit from routine screening with transvaginal ultrasonography or endometrial biopsy (35,36).
Most patients who have endometrial cancer present with abnormal perimenopausal or postmenopausal uterine bleeding early in the development of the disease, when the tumor is still confined to the uterus. Application of an appropriate and accurate diagnostic test in this situation usually results in early diagnosis, timely treatment, and a high cure rate. It is important to recognize that the workup of abnormal uterine bleeding should include endometrial biopsy even in premenopausal patients as 5% are in women under the age of 40.
Surveillance and Prevention in Patients at High Risk
Most endometrial carcinomas are sporadic, but about 10% of cases have a hereditary basis (37–41). Two genetic models were described in the development of familial endometrial cancer: HNPCC or Lynch II syndrome and a predisposition for endometrial cancer alone; both are inherited in an autosomal dominant fashion (42). The majority of studies focused on the increased incidence of endometrial cancer associated with Lynch II syndrome, a highly penetrant disorder (80% to 85%) (43). HNPCC or Lynch II syndrome is caused by an inherited mutation in one of the following mismatch repair genes: hMSH2, hMLH1, PMS1, PMS2, or hMSH6 (44–47). The disorder is characterized by early age (average age younger than 45 years) at onset of neoplastic lesions in a variety of tissues, including the colon, uterus, stomach, ureters, ovaries, and skin (43,48,49). The lifetime risk of endometrial cancer in women with Lynch II syndrome is 32% to 60% and the lifetime risk of ovarian cancer is 10% to 12% (50,51). Interestingly, colorectal cancer is less prevalent in women with HNPCC or Lynch II syndrome than in men, whose risk approaches 100%. In a study of 1,763 patients from 50 HNPCC or Lynch II syndrome families in the Finnish Cancer Registry, the cumulative incidence of colorectal cancer in women was 54% by age 70, while the cumulative incidence of endometrial cancer was 60% (11). Although these data appear to support the use of endometrial cancer surveillance strategies for women with Lynch syndrome, a specific algorithm is not defined (50,52). No effective screening method exists for patients at increased risk for ovarian cancer.
In 2006, a European workshop of 21 experts in the treatment of hereditary gastrointestinal cancers from ninecountries (the Mallorca group) recommended the following endometrial cancer surveillance strategy for patients with HNPCC or Lynch II syndrome: annual pelvic examination, transvaginal ultrasound, and endometrial biopsy beginning at 30 to 35 years of age (53). These recommendations are by expert opinion only, and it is unknown whether these interventions are cost-effective or will impact mortality from endometrial or ovarian cancer in patients with Lynch II syndrome. An attractive alternative to early detection is prophylactic surgery after completion of childbearing (54,55). In 2006 a multi-institutional, matched case-control study found that prophylactic hysterectomy withbilateral salpingo-oophorectomy is an effective primary prevention strategy in women with Lynch II syndrome (51). No woman with hysterectomy and bilateral salpingo-oophorectomy developed endometrial, ovarian, or primary peritoneal carcinoma during the period of follow-up. In contrast, endometrial cancer developed in 33% and ovarian cancer in 5% of women who did not undergo prophylactic surgery (51).
There are rare reports of pedigrees in which family members are affected by endometrial cancer alone, and genetic studies have not found a germline mutation associated with site-specific endometrial cancer (42,56,57). A population-based study of endometrial cancer and familial risk in younger women (Cancer and Steroid Hormone, or CASH, Study Group) reported that a history of endometrial cancer in a first-degree relative increased the risk of endometrial cancer by nearly threefold (odds ratio of 2.8; 95% confidence interval [CI], 1.9–4.2) (58). A significant association was found with colorectal cancers, with an observed odds ratio of 1.9 (95% CI, 1.1–3.3). The presence of Lynch II syndrome families within the cohort may explain the latter association, but a family history of endometrial caner was an independent risk factor for endometrial cancer, after adjusting for age, obesity, and number of relatives (58).
Endometrial cancer and breast cancer share some of the same reproductive and hormonal risk factors such as nulliparity and exposure to unopposed estrogen (4,8,59–63). However, the familial association between breast and endometrial cancer is still uncertain and studies report conflicting results (63–67). For example, in the past it was thought that patients with BRCA mutations were at elevated risk for endometrial cancer, in addition to breast and ovarian cancer. A study suggests that this increase in risk is seen only in those patients with a personal history of breast cancer who are taking tamoxifen (68).
Endometrial Cancer
Clinical Features
Symptoms
Endometrial carcinoma most often occurs in women in the sixth and seventh decades of life, at an average age of 60 years; 75% of cases occur in women older than 50 years of age. About 90% of women with endometrial carcinoma have vaginal bleeding or discharge as their only presenting symptom. Most women recognize the importance of this symptom and seek medical consultation within 3 months. Some women experience pelvic pressure or discomfort indicative of uterine enlargement or extrauterine disease spread. Bleeding may not have occurred because of cervical stenosis, especially in older patients, and may be associated with hematometra or pyometra, causing a purulent vaginal discharge. This finding is often associated with a poor prognosis (69). Less than 5% of women diagnosed with endometrial cancer are asymptomatic. In the absence of symptoms, endometrial cancer usually is detected as the result of investigation of abnormal Pap test results, discovery of cancer in a uterus removed for some other reason, or evaluation of an abnormal finding on a pelvic ultrasonography examination or computed tomography (CT) scan obtained for an unrelated reason. Women who are found to have malignant cells on Pap test are more likely to have a more advanced stage of disease (70).
Abnormal perimenopausal and postmenopausal bleeding should always be taken seriously and be properly investigated, no matter how minimal or nonpersistent. Causes may be nongenital, genital extrauterine, or uterine (71). Nongenital tract sites should be considered based on the history or examination, including testing for blood in the urine and stool.
Table 35.3 Causes of Postmenopausal Uterine Bleeding
|
Cause of Bleeding |
Percentage |
|
Endometrial atrophy |
60–80 |
|
Estrogen replacement therapy |
15–25 |
|
Endometrial polyps |
2–12 |
|
Endometrial hyperplasia |
5–10 |
|
Endometrial cancer |
10 |
Invasive tumors of the cervix, vagina, and vulva are usually evident on examination, and any tumors discovered should be biopsied. Traumatic bleeding from an atrophic vagina may account for up to 15% of all causes of postmenopausal vaginal bleeding. This diagnosis can be considered if inspection reveals a thin, friable vaginal wall, but the possibility of a uterine source of bleeding must first be eliminated.
Possible uterine causes of perimenopausal or postmenopausal bleeding include endometrial atrophy, endometrial polyps, estrogen therapy, hyperplasia, and cancer or sarcoma (72–75) (Table 35.3). Uterine leiomyomas should never be accepted as a cause of postmenopausal bleeding. Endometrial atrophy is the most common endometrial finding in women with postmenopausal bleeding, accounting for 60% to 80% of such bleeding. Women with endometrial atrophy usually were menopausal for about 10 years. Endometrial biopsy often yields insufficient tissue or only blood and mucus, and usually bleeding ceases after biopsy. Endometrial polyps account for 2% to 12% of postmenopausal bleeding. Polyps are often difficult to identify with office endometrial biopsy or curettage. Hysteroscopy, transvaginal ultrasonography, or both may be useful adjuncts in identifying endometrial polyps. Unrecognized and untreated polyps may be a source of continued or recurrent bleeding, leading eventually to unnecessary hysterectomy.
Estrogen therapy is an established risk factor for endometrial hyperplasia and cancer. The risk for endometrial cancer is fourto eighttimes greater in postmenopausal women receiving unopposed estrogen therapy, and the risk increases with time and higher estrogen doses. This risk can be decreased by the addition of a progestin to the estrogen, either cyclically or continuously. Endometrial biopsy should be performed as indicated to assess unscheduled bleeding or annually in women not taking a progestin. Endometrial hyperplasia occurs in 5% to 10% of patients with postmenopausal uterine bleeding. The sources of excess estrogen should be considered, including obesity, exogenous estrogen, or an estrogen-secreting ovarian tumor. Only about 10% of patients with postmenopausal bleeding have endometrial cancer.
Premenopausal women with endometrial cancer invariably have abnormal uterine bleeding, which is often characterized as menometrorrhagia or oligomenorrhea, or cyclical bleeding that continues past the usual age of menopause. The diagnosis of endometrial cancer must be considered in premenopausal women if abnormal bleeding is persistent or recurrent or if obesity or chronic anovulation is present.
Signs
Physical examination seldom reveals any evidence of endometrial carcinoma, although obesity and hypertension are commonly associated constitutional factors. Special attention should be given to the more common sites of metastasis. Peripheral lymph nodes and breasts should be assessed carefully. Abdominal examination is usually unremarkable, except in advanced cases in which ascites or hepatic or omental metastases may be palpable. On gynecologic examination, the vaginal introitus and suburethral area, and the entire vagina and cervix, should be carefully inspected and palpated. Bimanual rectovaginal examination should be performed specifically to evaluate the uterus for size and mobility, the adnexa for masses, the parametria for induration, and the cul-de-sac for nodularity.
Diagnosis
Office endometrial aspiration biopsy is the accepted first step in evaluating a patient with abnormal uterine bleeding or suspected endometrial pathology (76). The diagnostic accuracy of office-based endometrial biopsy is 90% to 98% when compared with subsequent findings at dilation and curettage (D&C) or hysterectomy (77–79).
The narrow plastic cannulas are relatively inexpensive, often can be used without a tenaculum, cause less uterine cramping (resulting in increased patient acceptance), and are successful in obtaining adequate tissue samples in more than 95% of cases. If cervical stenosis is encountered, a paracervical block can be performed, and the cervix can be dilated. Premedication with an antiprostaglandin agent can reduce uterine cramping. Complications following endometrial biopsy are exceedingly rare; uterine perforation occurs in only 1 to 2 cases per 1,000. Endocervical curettage may be performed at the time of endometrial biopsy if cervical pathology is suspected. A Pap test is an unreliable diagnostic test because only 30% to 50% of patients with endometrial cancer have abnormal Pap test results (80).
Hysteroscopy and D&C should be reserved for situations in which cervical stenosis or patient tolerance does not permit adequate evaluation by aspiration biopsy, bleeding recurs after a negative endometrial biopsy, or the specimen obtained is inadequate to explain the abnormal bleeding. Hysteroscopy is more accurate in identifying polyps and submucous myomas than endometrial biopsy or D&C alone (81–83).
Transvaginal ultrasonography may be a useful adjunct to endometrial biopsy for evaluating abnormal uterine bleeding and selecting patients for additional testing (84–87). Transvaginal ultrasonography, with or without endometrial fluid instillation (sonohysterography), may be helpful in distinguishing between patients with minimal endometrial tissue whose bleeding is related to perimenopausal anovulation or postmenopausal atrophy and patients with significant amounts of endometrial tissue or polyps who are in need of further evaluation. The finding of an endometrial thickness greater than 4 mm, a polypoid endometrial mass, or a collection of fluid within the uterus requires further evaluation. Although most studies agree that an endometrial thickness of 5 mm or less in a postmenopausal woman is consistent with atrophy, more data are needed before ultrasonography findings can be considered to eliminate the need for endometrial biopsy in a patient with symptoms (88).
Pathology
The histologic classification of carcinoma arising in the endometrium is shown in Table 35.4 (12,89).
Table 35.4 Classification of Endometrial Carcinomas
|
Endometrioid adenocarcinoma |
|
Variants |
|
Villoglandular or papillary |
|
Secretory |
|
With squamous differentiation |
|
Mucinous carcinoma |
|
Papillary serous carcinoma |
|
Clear cell carcinoma |
|
Squamous carcinoma |
|
Undifferentiated carcinoma |
|
Mixed carcinoma |
Endometrioid Adenocarcinoma
The endometrioid type of adenocarcinoma accounts for about 80% of endometrial carcinomas. These tumors are composed of glands that resemble normal endometrial glands; they have columnar cells with basally oriented nuclei, little or no intracytoplasmic mucin, and smooth intraluminal surfaces (Fig. 35.2). As tumors become less differentiated, they contain more solid areas, less glandular formation, and more cytologic atypia. The well-differentiated lesions may be difficult to separate from atypical hyperplasia.
Criteria that indicate the presence of invasion and are used to diagnose carcinoma are desmoplastic stroma, back-to-back glands without intervening stoma, extensive papillary pattern, and squamous epithelial differentiation. These changes, with the exception of the infiltrating pattern with desmoplastic reaction, require an area of involvement equal to or exceeding one-half of a low-power microscopic field (LPF) (>1 LPF; 4.2 mm in diameter) (90,91).
The differentiation of a carcinoma, expressed as its grade, is determined by architectural growth pattern and nuclear features (Table 35.5). In the International Federation of Gynecology and Obstetrics (FIGO) grading system proposed in 1989, tumors are grouped into three grades: grade 1, 5% or less of the tumor shows a solid growth pattern; grade 2, 6% to 50% of the tumor shows a solid growth pattern; and grade 3, more than 50% of the tumor shows a solid growth pattern. The presence of notable nuclear atypia that is inappropriate for the architectural grade increases the tumor grade by one.
Adenocarcinomas with squamous differentiation are graded according to the nuclear grade of the glandular component. This FIGO system is applicable to all endometrioid carcinomas, including its variants, and to mucinous carcinomas. In serous and clear cell carcinomas, nuclear grading takes precedence; however, most investigators believe that these two carcinomas should always be considered high-grade lesions, making grading unnecessary.
About 15% to 25% of endometrioid carcinomas have areas of squamous differentiation (Fig. 35.3). In the past, tumors with benign-appearing squamous areas were called adenoacanthomas, and tumors with malignant-looking squamous elements were called adenosquamous carcinomas. It is recommended that the term endometrial carcinoma with squamous differentiation be used to replace these two designations because the degree of differentiation of the squamous component parallels that of the glandular component, and the behavior of the tumor is largely dependent on the grade of the glandular component (92,93).
Figure 35.2 Well-differentiated adenocarcinoma of endometrium. The glands and complex papillae are in direct contact with no intervening endometrial stroma, the so-called back-to-back pattern. (Provided by Gordana Stevanovic, MD, and Jianyu Rao, MD, Department of Pathology, UCLA.)
Table 35.5 FIGO Definition for Grading of Endometrial Carcinoma
|
Histopathologic degree of differentiation: |
|
G1 <5% nonsquamous or nonmorular growth pattern |
|
G2 6%–50% nonsquamous or nonmorular growth pattern |
|
G3 >50% nonsquamous or nonmorular growth pattern |
|
Notes on pathologic grading: |
|
Notable nuclear atypia, inappropriate for the architectural grade, raises a grade 1 (G1) |
|
or grade 2 (G2) tumor by one grade. |
|
In serous adenocarcinoma, clear cell adenocarcinoma, and squamous cell carcinoma, |
|
nuclear grading takes precedence. |
|
Adenocarcinomas with squamous differentiation are graded according to the nuclear grade |
|
of the glandular component. |
|
FIGO Committee on Gynecologic Oncology. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynecol Obst 2009;105:103–104. |
Figure 35.3 Adenocarcinoma with squamous differentiation of endometrium. This lesion is also classified as adenoacanthoma. Squamous cells with eosinophilic cytoplasm and distinct cell borders form solid clusters in the lumina of neoplastic glands. (Provided by Gordana Stevanovic, MD, and Jianyu Rao, MD, Department of Pathology, UCLA.)
Avilloglandular configuration is present in about 2% of endometrioid carcinomas (94,95). In these tumors, the cells are arranged along fibrovascular stalks, giving a papillary appearance but maintaining the characteristics of endometrioid cells. The villoglandular variants of endometrioid carcinomas are always well-differentiated lesions that behave like the regular endometrioid carcinomas, and they should be distinguished from serous carcinomas. Secretory carcinoma is a rare variant of endometrioid carcinoma that accounts for about 1% of cases (96,97). It occurs mostly in women in their early postmenopausal years. The tumors are composed of well-differentiated glands with intracytoplasmic vacuoles similar to early secretory endometrium. These tumors behave as regular well-differentiated endometrioid carcinomas and have an excellent prognosis. Secretory carcinoma may be an endometrioid carcinoma that exhibits progestational changes, but a history of progestational therapy is rarely elicited. Secretory carcinoma must be differentiated from clear cell carcinoma because both tumors have predominately clear cells. These two tumors can be distinguished by their structure: secretory carcinomas have uniform glandular architecture, uniform cytology, and low nuclear grade, whereas clear cell carcinomas have more than one architectural pattern and a high nuclear grade.
Mucinous Carcinoma
About 5% of endometrial carcinomas have a predominant mucinous pattern in which more than one-half of the tumor is composed of cells with intracytoplasmic mucin (98,99). Most of these tumors have a well-differentiated glandular architecture; their behavior is similar to that of common endometrioid carcinomas, and the prognosis is good. It is important to recognize mucinous carcinoma of the endometrium as an entity and to differentiate it from endocervical adenocarcinoma. Features that favor a primary endometrial carcinoma are the merging of the tumor with areas of normal endometrial tissue, presence of foamy endometrial stromal cells, presence of squamous metaplasia, or presence of areas of typical endometrioid carcinoma. Positive perinuclear immunohistochemical staining with vimentin suggests an endometrial origin (100).
Serous Carcinoma
About 3% to 4% of endometrial carcinomas resemble serous carcinoma of the ovary and fallopian tube (101–104). Most often, these tumors are composed of fibrovascular stalks lined by highly atypical cells with tufted stratification (Fig. 35.4). Psammoma bodies frequently are observed.
Figure 35.4 Serous carcinoma of endometrium. Branching papillae are supported by delicate fibrovascular cores and lined with columnar cells with moderate nuclear atypism, multiple nucleoli, and mitotic figures. (Provided by Gordana Stevanovic, MD, and Jianyu Rao, MD, Department of Pathology, UCLA.)
Serous carcinomas, also referred to as uterine papillary serous carcinomas, are considered high-risk lesions. The first description in 1982, noted that this entity usually occurred in elderly, hypoestrogenic women who presented with advanced-stage disease and accounted for up to one-half of deaths from endometrial carcinoma (101). Since then, several reports documented the aggressive nature and poor prognosis of serous carcinomas.
They are commonly admixed with other histologic patterns, but mixed tumors behave as aggressively as pure serous carcinomas. Even patients with a very small proportion of serous features (5%) remain at high risk of recurrence (105). Serous carcinomas are often associated with lymph–vascular space and deep myometrial invasion. The presence of lymph node metastases, positive peritoneal cytology, and intraperitoneal tumor does not necessarily correlate with increasing myometrial invasion (104). Even when these tumors appear to be confined to the endometrium or endometrial polyps without myometrial or vascular invasion, they behave more aggressively than endometrioid carcinomas and have a propensity to spread intra-abdominally, simulating the behavior of ovarian carcinoma.In one series, 37% of patients with serous carcinomas of the endometrium confined to a polyp demonstrated extrauterine disease when subjected to exploration and surgical staging (106).
A multi-institutional review of 206 patients with surgical stage I and II serous carcinomas demonstrated recurrence in 21% (105). Substage and treatment with platinum-based chemotherapy were associated with improved overall survival. Survival of surgically staged patients without myometrial invasion or extrauterine disease is between 89% and 100%, suggesting that observation may be appropriate in select patients, particularly in elderly patients with comorbidities (107). However, stage I patients, particularly those with myometrial invasion, remain at high risk of both peritoneal and vaginal recurrence. Therefore, platinum-based chemotherapy and vaginal brachytherapy should be considered in these patients (107–109).
Surgical treatment of advanced disease is no different fromthe endometrioid subtype, consisting of complete extirpation of visible disease (108). In one investigation from the Mayo Clinic, cytoreduction to microscopic residual was associated with a median overall survival of 51 versus 12 months for those patients with any residual (110). Postoperative treatment of advanced disease in the United States consists of chemotherapy and pelvicradiation, with or withoutpara-aortic radiation. The Gynecologic Oncology Group study GOG184 included serous carcinomas and randomized patients to carboplatin and paclitaxelversus cisplatin, doxorubicin (Adriamycin), and paclitaxel together with tumor volume–directed radiation (111). The former regimen demonstrated similar outcomes with less toxicity. Limited data suggest that delivering radiation “sandwiched” with chemotherapy improves progression-free and overall 3-year survival rates (112). Ongoing studies are evaluating the role of chemotherapy alone for these tumors, especially because of the high rate of peritoneal dissemination and recurrences. It remains unknown whether radiation improves survival in addition to chemotherapy alone. For elderly patients with multiple comorbidities who cannot tolerate multimodal therapy, chemotherapy alone.
Clear Cell Carcinoma
Clear cell carcinoma accounts for less than 5% of all endometrial carcinomas (96,113,114). Clear cell carcinoma usually has a mixed histologic pattern, including papillary, tubulocystic, glandular, and solid types. The cells have highly atypical nuclei and abundant clear or eosinophilic cytoplasm. Often, the cells have a hobnail configuration arranged in papillae with hyalinized stalks (Fig. 35.5).
Figure 35.5 Clear cell adenocarcinoma of the endometrium. Back-to-back glands lined by polygonal to columnar cells with distinct cell membrane, abundant granular to clear cytoplasm, and variably sized nuclei (including binucleated and multinucleated forms) with prominent nucleoli (magnification X400). (Provided by Gordana Stevanovic, MD, and Jianyu Rao, MD, Department of Pathology, UCLA.)
Clear cell carcinoma characteristically occurs in older women and like serous carcinoma is considered a poor prognosticator. Traditionally clear cell carcinoma was associated with very poor outcomes with overall survival rates varying from 33% to 64%. A multi-institutional review of 99 patients with uterine clear cell carcinoma documented only 1 recurrence (vaginal) in the 22 patients without extrauterine disease subjected to thorough surgical staging (115). Considering all 49 patients with stage I or II disease (regardless of the extent of staging), only 1 hematologic failure was noted. These data argue against the use of systemic therapy in patients with clear cell carcinoma limited to the pelvis, while the 10% vaginal cuff failure suggests that vaginal brachytherapy alone may be sufficient treatment. In contrast, others argued for systemic treatment of patients with stage I disease (116).
Complete surgical staging is important because 52% of patients with clinical stage I clear cell carcinoma have metastatic disease. Patients who undergo a complete cytoreduction appear to have improved progression-free and overall survivals compared to women left with residual disease following surgery (115). Postoperative therapy for patients with advanced disease is platinum-based (116).
Squamous Carcinoma
Squamous carcinoma of the endometrium is rare. Some tumors are pure, but most have a few glands. To establish primary origin within the endometrium, there must be no connection with or spread from cervical squamous epithelium. Squamous carcinoma often is associated with cervical stenosis, chronic inflammation, and pyometra at the time of diagnosis. This tumor has a poor prognosis, with an estimated 36% survival rate in patients with clinical stage I disease (117).
Simultaneous Tumors of the Endometrium and Ovary
Synchronous endometrial and ovarian cancers are the most frequent simultaneously occurring genital malignancies, with a reported incidence of 1.4% to 3.8% (118–122). Most commonly, both the ovarian and endometrial tumor are well-differentiated endometrioid adenocarcinomas of low stage, resulting in an excellent prognosis. Patients often are premenopausal and present with abnormal uterine bleeding. The ovarian cancer usually is discovered as an incidental finding and is diagnosed at an earlier stage because of the symptomatic endometrial tumor, leading to a more favorable outcome. Up to 29% of patients with endometrioid ovarian adenocarcinomas have associated endometrial cancer. If more poorly differentiated, nonendometrioid histologic subtypes are present or if the uterine and ovarian tumors are histologically dissimilar, the prognosis is less favorable. Immunohistochemical studies, flow cytometry, and assessment of molecular DNA patterns to detect loss of heterozygosity may be helpful in distinguishing between metastatic and independent tumors, but the differential diagnosis can usually be determined by conventional clinical and pathologic criteria.
Pretreatment Evaluation
After establishing the diagnosis of endometrial carcinoma, the next step is to evaluate the patient thoroughly to determine the best and safest approach to management of the disease. A complete history and physical examination areof utmost importance. Patients with endometrial carcinoma are often elderly and obese with a variety of medical problems, such as diabetes mellitus and hypertension, which complicate surgical management. Any abnormal symptoms, such as bladder or intestinal symptoms, should be evaluated.
On physical examination, attention should be directed to enlarged or suspicious lymph nodes, including the inguinal area, abdominal masses, and possible areas of cancer spread within the pelvis.Evidence of distant metastasis or locally advanced disease in the pelvis, such as gross cervical involvement or parametrial spread, may alter the treatment approach.
Chest radiography should be performed to exclude pulmonary metastasis and to evaluate the cardiorespiratory status of the patient. Other routine preoperative studies should include electrocardiography, complete blood and platelet counts, serum chemistries (including renal and liver function tests), and blood type and screen. Other preoperative or staging studies are neither required nor necessary for most patients with endometrial cancer. Studies such as cystoscopy, colonoscopy, intravenous pyelography, and barium enema are not indicated unless dictated by patient symptoms, physical findings, or other laboratory tests (123). CT scanning of the abdomen and pelvis may be considered in patients with type II uterine cancer to determine if minimally invasive surgery is appropriate. Stage IV disease is usually clinically evident based on patient symptomatology and clinical examination. Ultrasonography and MRI can be used to assess myometrial invasion preoperatively with a fairly high degree of accuracy (124). This information may be of use in planning the surgical procedure with regard to whether lymph node sampling should be undertaken.
Serum CA125, an antigenic determinant that is elevated in 80% of patients with advanced epithelial ovarian cancers, is elevated in most patients with advanced or metastatic endometrial cancer(125). In one study, 23 of 81 patients with apparently localized disease preoperatively had elevated CA125 levels. At surgery, 20 (87%) of these 23 patients with an elevated CA125 were found to have extrauterine disease, whereas only 1 of 58 patients with a normal CA125 had disease spread outside the uterus (126). Another study found that 78% of endometrial cancer patients with lymph node metastases had an elevated preoperative CA125 level (127). Preoperative measurement of serum CA125 may help determine the extent of surgical staging and, if elevated, may be useful as a tumor marker in assessing response to subsequent therapy (128,129).
Clinical Staging
Clinical staging, according to the 1971 FIGO system, should be performed only in patients who are deemed not to be surgical candidates because of their poor medical condition or the degree of disease spread (130). The current FIGO staging is surgical, as discussed below, which has supplanted the old clinical system. With improvements in preoperative and postoperative care, anesthesia administration, and surgical techniques, almost all patients are medically suitable for operative therapy. One study reported an operability rate of 87% in a series of 595 consecutive patients with clinical early-stage endometrial cancer (131). A small percentage of patients will not be candidates for surgical staging because of gross cervical involvement, parametrial spread, invasion of the bladder or rectum, or distant metastasis.
Surgical Staging
Widely accepted management of endometrial cancer consists of hysterectomy, removal of remaining adnexal structures, and appropriate surgical staging in patients considered at risk for extrauterine disease (132–134). Surgical staging was recommended for patients with endometrial cancer since 1988 (134). In spite of this general recommendation, the incorporation of a systematic pelvic and para-aortic lymphadenectomy in all patients is not universally accepted (135–137). This recommendation became more controversial after the publication of two large prospective randomized trials that failed to demonstrate improved outcomes for patients who underwent pelvic lymphadenectomy (138,139). These two studies show differences in their design: in the ASTEC trial all women with clinical stage I were included without exclusion criteria, whereas the Italian study excluded women with stage IA and IB grade 1 tumors, and nonendometrioid malignancies. In the Italian study, systematic nodal dissection was performed, as opposed to pelvic node sampling in the ASTEC trial (median number of lymph nodes harvested 30 vs. 12, respectively). The studies share characteristics that could lead to misinterpretation of their results. The percentage of nodal positivity is low in both studies (13% and 9%), suggesting that regardless of differences in exclusion criteria, low-risk cases were included in both studies, thus diluting possible (if any) therapeutic benefit of lymphadenectomy. Another important limitation is that nodal dissection was limited to the pelvis without any recommendation for para-aortic lymphadenectomy. It was demonstrated previously that radiotherapy limited to the pelvis does not improve survival (136). It is not surprising that pelvic lymphadenectomy alone has no therapeutic impact, considering that 67% of patients with nodal involvement have para-aortic lymph node metastases and 16% of patients with documented lymphatic dissemination have isolated para-aortic metastases (140). Neither study used the information derived from lymphadenectomy to target postoperative treatment (i.e., to spare patients with negative nodes from radiotherapy or to target postoperative treatment to the metastatic areas), thus eliminating one of the potential benefits of this surgical procedure.
Table 35.6 Carcinoma of the Endometrium (2008)
|
Stage I∗ |
Tumor confined to the corpus uteri |
|
IA∗ |
No or less than half myometrial invasion |
|
IB∗ |
Invasion equal to or more than half of the myometrium |
|
Stage II∗ |
Tumor invades cervical stroma, but does not extend beyond the uterus∗∗ |
|
Stage III∗ |
Local and/or regional spread of the tumor |
|
IIIA∗ |
Tumor invades the serosa of the corpus uteri and/or adnexae# |
|
IIIB∗ |
Vaginal and/or parametrial involvement# |
|
IIIC∗ |
Metastases to pelvic and/or para-aortic lymph nodes# |
|
IIIC1∗ |
Positive pelvic nodes |
|
IIIC2∗ |
Positive para-aortic lymph nodes with or without positive pelvic lymph nodes |
|
Stage IV∗ |
Tumor invades bladder and/or bowel mucosa, and/or distant metastases |
|
IVA∗ |
Tumor invasion of bladder and/or bowel mucosa |
|
IVB∗ |
Distant metastases, including intra-abdominal metastases and/or inguinal lymph nodes |
|
FIGO Committee on Gynecologic Oncology. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynecol Obst 2009;105:103--104. |
|
Systematic pelvic and para-aortic lymphadenectomy remains one of the most important steps to assess the presence of extrauterine disease and to guide targeted postoperative treatment. GOG33 demonstrated that patients with absent or superficial myometrial invasion have a low probability of lymphatic metastases (141). Furthermore, Mariani et al. demonstrated that no patient with en-dometrioid grade 1 or 2 disease and superficial myometrial invasion harbored a lymphatic metastasis when the tumor diameter was 2 cm or less (137). The importance of tumor size as a predictor for lymphatic spread was reported by Schink et al. (142). It is possible to identify a group of pa-tients in whom lymphadenectomy is likely to increase the risk of surgical complications without producing any concrete benefits. Tumor diameter, along with myometrial invasion and histologic grade and subtype, can be utilized to determine whether or not lymphadenectomy is appropriate.
An observational study reported a significant survival benefit of para-aortic lymphadenectomy in patients at intermediate or high risk of recurrence (based on presence of histologic grade 3 or deep myometrial invasion, or lymphovascular invasion, or evidence of spread outside of the uterine corpus), compared to patients who had hysterectomy with pelvic lymphadenectomy but without para-aortic dissection. This benefit was not observed in patients with low-risk endometrial cancer (143). In addition, the Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC) studies identified patients with stage IC, grade 3 endometrial carcinoma as being at high risk of early distant spread and death when treated with hysterectomy only (no staging), followed by pelvic external-beam radiation therapy. These patients had a 31% risk of distant recurrence (136). From the literature, it seems that the patients who have the potential to benefit from surgical staging are those with risk factors such as histologic grade 3, deep myometrial invasion, or lymphovascular invasion.
In summary, surgical staging should (i) identify patients with disseminated disease who are at high risk of recurrence; (ii) target postoperative treatment; (iii) reduce the number of patients potentially requiring postoperative treatment when the provided information is used appropriately (avoiding the risk of morbidity without reasonable benefit); and (iv) possibly eradicate lymphatic disease. In spite of these potential benefits in high-risk patients, prospective randomized data demonstrating a survival advantage or reduction in overall morbidity resulting from a potential reduction of adjuvant treatment still are not available.
The FIGO published the updated surgical staging system for endometrial cancer (Table 35.6) (144). In comparison with recommendations from 1988, the new system introduces the following changes: (i) former stages IA and IB are combined; (ii) former stage IIA was eliminated so that only the presence of cervical stroma involvement is considered stage II disease; (iii) alone, peritoneal cytologic findings positive for endometrial cancer are no longer a criterion for disease upstaging (although FIGO still recommends the collection of peritoneal washing, recognizing the predictive value of positive cytologic findings when combined with other poor-prognosis factors); and (iv) stage IIIC was divided into IIIC1 and IIIC2 in accordance with the absence or presence of positive para-aortic nodes. The presence of parametrial disease is now formally recognized as stage IIIB disease.
Prognostic Variables
Although disease stage is the most significant variable affecting survival, a number of other individual prognostic factors for disease recurrence or survival are known, includingtumor grade, histopathology, depth of myometrial invasion, patient age, and surgical–pathologic evidence of extrauterine disease spread (Tables 35.7 and 35.8). Other factors, such as tumor size, peritoneal cytology, hormone receptor status, flow cytometric analysis, and oncogene perturbations, are implicated as having prognostic importance.
Table 35.7 Surgical-Pathologic Findings in Clinical Stage I Endometrial Cancer
|
Surgical-Pathologic Finding |
Percentage of Patients |
|
Histology |
|
|
Adenocarcinoma |
80 |
|
Adenosquamous |
16 |
|
Other (papillary serous, clear cell) |
4 |
|
Grade |
|
|
1 |
29 |
|
2 |
46 |
|
3 |
25 |
|
Myometrial invasion |
|
|
None |
14 |
|
Inner third |
45 |
|
Middle third |
19 |
|
Outer third |
22 |
|
Lymph–vascular space invasion |
15 |
|
Isthmic tumor |
16 |
|
Adnexal involvement |
5 |
|
Positive peritoneal cytology |
12 |
|
Pelvic lymph node metastasis |
9 |
|
Aortic lymph node metastasis |
6 |
|
Other extrauterine metastasis |
6 |
|
Modified from Creasman WT, Morrow CP, Bundy BN, et al. Surgical pathologic spread patterns of endometrial cancer. Cancer 1987;60:2035–2041, with permission. |
|
Table 35.8 Prognostic Variables in Endometrial Carcinoma
|
Age |
|
Histologic type |
|
Histologic grade |
|
Myometrial invasion |
|
Lymph–vascular space invasion |
|
Isthmus–cervix extension |
|
Adnexal involvement |
|
Lymph node metastasis |
|
Intraperitoneal tumor |
|
Tumor size |
|
Peritoneal cytology |
|
Hormone receptor status |
|
DNA ploidy/proliferative index |
|
Genetic/molecular tumor markers |
Age
In general, younger women with endometrial cancer have a better prognosis than older women. Two reports observed no deaths related to disease in patients with endometrial cancer diagnosed before 50 years of age (145,146). Another series demonstrated a 60.9% 5-year survival rate for patients older than 70 years of age, compared with 92.1% survival rate for patients younger than 50 years of age (147). Decreased survival was associated with an increased risk for extrauterine spread (38% vs. 21%) and deep myometrial invasion (57% vs. 24%) for these two groups. The GOG reported 5-year survival rates of 96.3% for patients 50 years of age or younger, 87.3% for patients 51 to 60 years, 78% for patients 61 to 70 years, 70.7% for patients 71 to 80 years, and 53.6% for patients older than 80 years (148).
Increased risk for recurrence in older patients was related to a higher incidence of grade 3 tumors or unfavorable histologic subtypes; however, age appears to be an independent prognostic variable. Increasing patient age appears to be independently associated with disease recurrence in endometrial cancer. In one study, the mean age at diagnosis of patients who had recurrence or died of disease was 68.6 years, compared with 60.3 years for patients without recurrence. For every 1year increase in age, the estimated rate of recurrence increased 7%. None of the patients younger than 50 years of age developed recurrent cancer, compared with 12% of patients aged 50 to 75 years and 33% of patients older than 75 years (149).
Histologic Type
Nonendometrioid histologic subtypes account for about 10% of endometrial cancers and carry an increased risk for recurrence and distant spread (150,151). In a retrospective review of 388 patients treated at the Mayo Clinic for endometrial cancer, 52 (13%) had an uncommon histologic subtype, including 20 adenosquamous, 14 serous, 11 clear cell, and 7 undifferentiated carcinomas. In contrast to the 92% survival rate among patients with endometrioid tumors, the overall survival for patients with one of these more aggressive subtypes was only 33%. At the time of surgical staging, 62% of the patients with an unfavorable histologic subtype had extrauterine spread of disease (150).
Histologic Grade
Histologic grade of the endometrial tumor is strongly associated with prognosis (132,141,149,152–156). In one study, recurrences developed in 7.7% of grade 1 tumors, 10.5% of grade 2 tumors, and 36.1% of grade 3 tumors. Patients with grade 3 tumors were in excess of fivetimes more likely to have a recurrence than were patients with grades 1 and 2 tumors. The 5-year disease-free survival rates for patients with grades 1 and 2 tumors were 92% and 86%, respectively, compared with 64% for patients with grade 3 tumors (149). Another study reported similar results, noting recurrences in 9% of patients with grades 1 and 2 tumors compared with 39% of patients with grade 3 lesions (153). Increasing tumor anaplasia is associated with deep myometrial invasion, cervical extension, lymph node metastasis, and both local recurrence and distant metastasis.
Tumor Size
Tumor size is a significant prognostic factor for lymph node metastasis and survival in patients with endometrial cancer (142,157). One report determined tumor size in 142 patients with clinical stage I endometrial cancer and found lymph node metastasis in 4% of patients with tumors 2 cm or smaller, in 15% of patients with tumors larger than 2 cm, and in 35% of patients with tumors involving the entire uterine cavity (156). Tumor size better defined an intermediate-risk group for lymph nodes metastasis (i.e., patients with grade 2 tumors with less than 50% myometrial invasion). Overall, these patients had a 10% risk for lymph node metastasis, but there was no nodal metastasis associated with tumors 2 cm or smaller, compared with 18% when tumors were larger than 2 cm. Five-year survival rates were 98% for patients with tumors 2 cm or smaller, 84% for patients with tumors larger than 2 cm, and 64% for patients with tumors involving the whole uterine cavity (137,157).
Hormone Receptor Status
Estrogen receptor and progesterone receptor levels are prognostic indicators for endometrial cancer independent of grade in several studies (158–164). Patients whose tumors are positive for one or both receptors have longer survival times than patients whose carcinomas lack the corresponding receptors. Even patients with metastasis have an improved prognosis with receptor-positive tumors (161). Progesterone receptor levels appear to be stronger predictors of survival than estrogen receptor levels, and the higher the absolute level of the receptors, the better the prognosis.
DNA Ploidy and Proliferative Index
About two-thirds of endometrial adenocarcinomas have a diploid DNA content as determined by flow cytometric analysis (162,165–174). The proportion of nondiploid tumors increases with stage, lack of tumor differentiation, and depth of myometrial invasion. In several studies, DNA content was related to clinical course of the disease, with death rates reported to be higher in women whose tumors contained aneuploid populations of cells. The proliferative index is related to prognosis.
Myometrial Invasion
Because access to the lymphatic system increases as cancer invades into the outer one-half of the myometrium, increasing depth of invasion is associated with increasing likelihood of extrauterine spread and recurrence(153,155,175). The association of depth of myometrial invasion with extrauterine disease and lymph node metastases was reported (175). Of patients without demonstrable myometrial invasion, only 1% had pelvic lymph node metastasis, compared with patients with outer one-third myometrial invasion who had 25% pelvic and 17% aortic lymph node metastases. Deep myometrial invasion (>50% for all stages; ≥66% for stage I) is the strongest predictor of hematogenous recurrence (176). Survival decreases with increasing depth of myometrial invasion. In general, patients with noninvasive or superficially invasive tumors have an 80% to 90% 5-year survival rate, whereas those with deeply invasive tumors have a 60% survival rate. The most sensitive indicator of the effect of myometrial invasion on survival is distance from the tumor–myometrial junction to the uterine serosa. Patients with tumors that are less than 5 mm from the serosal surface are at much higher risk for recurrence and death than those with tumors greater than 5 mm from the serosal surface (177,178).
Lymph–Vascular Space Invasion
Lymph–vascular space invasion (LVSI) appears to be an independent risk factor for recurrence and death from all types of endometrial cancer (178–181). The overall incidence of LVSI in early endometrial cancer is about 15%, although it increases with increasing tumor grade and depth of myometrial invasion. One study reported LVSI in 2% of grade 1 tumors and 5% of superficially invasive tumors, compared with 42% of grade 3 tumors and 70% of deeply invasive tumors (180). LVSI was demonstrated to be a strong predictor of lymphatic dissemination and lymphatic recurrence (182). Another study reported deaths in 26.7% of patients with clinical stage I disease who had LVSI, compared with 9.1% of those without LVSI (183). Likewise, an 83% 5-year survival rate was reported for patients without demonstrable LVSI, compared with a 64.5% survival rate for those in whom LVSI was present (181). Using multivariate analysis, only depth of myometrial invasion, DNA ploidy, and vascular invasion–associated changes correlated significantly with survival of patients with stage I endometrial adenocarcinomas in another report (165).
Isthmus and Cervix Extension
The location of the tumor within the uterus is important. Involvement of the uterine isthmus, cervix, or both is associated with an increased risk for extrauterine disease, lymph node metastasis, and recurrence. Cervical stromal invasion was a strong predictor of lymphatic dissemination and lymphatic recurrence, especially for pelvic lymph nodes (182). One study reported that if the fundus of the uterus alone was involved with tumor, there was a 13% recurrence rate, whereas if the lower uterine segment or cervix was involved with occult tumor, there was a 44% recurrence rate (151). A subsequent GOG study found that tumor involvement of the isthmus or cervix without evidence of extrauterine disease was associated with a 16% recurrence rate and a relative risk of 1.6 (132). Patients with cervical involvement tended to have higher-grade, larger, and more deeply invasive tumors, undoubtedly contributing to the increased risk for recurrence.
Peritoneal Cytology
Several reports noted increased recurrence rates and decreased survival rates and, on this basis, recommended treatment for positive cytology (184–186). Most of the studies included patients with other evidence of extrauterine disease spread and were performed without appropriate multivariate analysis and with patients who were incompletely staged. The GOG studycritically analyzed 1,180 clinical stagesI and II endometrial cancer patients in whom appropriate surgical and pathologic staging was performed (132). Considering only the 697 patients for whom peritoneal cytology status and adequate follow-up were available, 25 (29%) of 86 patients with positive cytology developed recurrence, compared with 64 (10.5%) of 611 patients with negative cytology. They noted that 17 of the 25 recurrences in the positive cytology group were outside the peritoneal cavity.
In contrast to these reports, an equal number of studies found no significant relationship between malignant peritoneal cytology and an increased incidence of disease recurrence in the absence of other risk factors such as extrauterine disease (186–189). Patients with positive peritoneal cytology as the only site of extrauterine disease (i.e., no adnexal or uterine serosal invasion) and without poor prognosticators (i.e., myometrial invasion more than50%, nonendometrioid histologic subtype, grade 3, lymphovascular space invasion, cervical invasion) have a very favorable outcome with an absence of extra-abdominal recurrences (190). These patients have an associated 5-year survival of 98% to 100% even when not treated with adjuvant therapy (148,191,192). On the other hand, patients with positive cytology in addition to poor prognostic factors demonstrate a high rate (47%) of distant extra-abdominal failure and may potentially benefit from systemic chemotherapy. Positive peritoneal cytology seems to have an adverse effect on survival only if the endometrial cancer has spread to the adnexa, peritoneum, or lymph nodes, not if the disease is otherwise confined to the uterus (188,189,191). These considerations led to the omission of cytology as a factor impacting stage in the FIGO 2009 staging criteria.
The following conclusions may be reached regarding the prognostic implications of positive peritoneal cytology:
1. Positive peritoneal cytology is associated with other known poor prognostic factors.
2. Positive peritoneal cytology in the absence of other evidence of extrauterine disease or poor prognostic factors has no significant effect on recurrence and survival.
3. Positive peritoneal cytology, when associated with other poor prognostic factors or extrauterine disease, increases the likelihood for distant as well as intra-abdominal disease recurrence and has a significant adverse effect on survival.
4. Use of several different therapeutic modalities has not resulted in any proven benefit to patients with endometrial cancer and positive peritoneal cytology.
Stage IIIA: Adnexal or Uterine Serosal Involvement
Most patients with stage IIIA disease have other poor prognostic factors that place them at high risk for recurrence. One series described treatment of all patients with serosal or adnexal invasion (or both) with whole-abdomen radiotherapy. Failures were observed outside the abdomen in 100% of patients with full thickness myometrial invasion or uterine serosal invasion, and in 20% to 25% of cases in the presence of isolated adnexal invasion (132,193). These patients may benefit from postoperative systemic chemotherapy.
Lymph Node Metastasis
Lymph node metastasis is the most important prognostic factor in clinical early-stage endometrial cancer. Of patients with clinical stage I disease, about 10% will have pelvic and 6% will have para-aortic lymph node metastases. Patients with lymph node metastases have almost a sixfold higher likelihood of developing recurrent cancer than patients without lymph node metastases. One study reported a recurrence rate of 48% with positive lymph nodes, including 45% with positive pelvic nodes and 64% with positive aortic nodes, compared with 8% with negative nodes. The 5-year disease-free survival rate for patients with lymph node metastases was 54%, compared with 90% for patients without lymph node metastases (148). The GOG found that the presence or absence of para-aortic lymph node metastases was of paramount importance in determining prognosis. Of 48 para-aortic node–positive patients, 28 (58%) developed progressive or recurrent cancer, and only 36% of these patients were alive at 5 years, compared with 85% of patients without para-aortic node involvement (194). One series examined patients with lymph nodes metastases in addition to other extrauterine sites of disease (vagina, uterine serosa, positive peritoneal cytology, adnexal invasion). The recurrence rateswere67% (41% extranodal) for those with lymphatic dissemination versus. 32% (5% extranodal) for those with other sites of extrauterine disease spread (190).
Intraperitoneal Metastases
Extrauterine metastasis, excluding peritoneal cytology and lymph node metastasis, occurs in about 4% to 6% of patients with clinical stage I endometrial cancer. Gross intraperitoneal spread is highly correlated with lymph node metastases; one study noted that 51% of patients with intraperitoneal tumor had positive lymph nodes, whereas only 7% of patients without gross peritoneal spread had positive nodes (141). Extrauterine spread other than lymph node metastasis issignificantly associated with tumor recurrence. Another study found that 50% of patients with extrauterine disease developed recurrence, compared with 11% of patients without extrauterine disease, making recurrence almost fivetimes more likely in patients with extrauterine disease spread. The 5-year disease-free survival rate for patients with nonlymphatic extrauterine disease was 50%, compared with 88% in other patients (148). Predictors of peritoneal relapse include stage IV disease or stage II or III disease with two or more of the following risk factors: cervical invasion, positive peritoneal cytology, positive lymph nodes, and nonendometrioid histology (195).
Types I and II Endometrial Carcinoma: Molecular Aberrations
Based on their etiological and pathological features, sporadic endometrial cancer is classified into two subtypes (2,134). Type I (endometrioid histology) represents the majority of lesions (approximately 80%), whichare mostly low grade, estrogen receptor positive, associated with hyperestrogenism, and arise from atypical complex hyperplasia (196,197). Hyperestrogenism may be attributed to obesity with peripheral conversion of androgens to estrogens, anovulation, or exposure to excessive exogenous estrogen (134,198–202). Obesity, polycystic ovarian syndrome, tamoxifen use, and unopposed estrogen use are all associated with increased risk of endometrial cancer. Other associated findings include late onset of menopause, nulliparity, diabetes mellitus, and hypertension. The molecular basis for the progression from hyperplasia to invasive endometrial carcinoma as a result of hyperestrogenism remains unknown because the involvement of only a minority of factors is reproducible (203). In contrast, type II endometrial cancer (serous, clear cell carcinoma) appears to be unrelated to high estrogen levels and often develops in nonobese women. Type II cancers arise from its precursor, endometrial intraepithelial carcinoma (EIC) adjacent to an atrophic endometrium background in relatively older women (204). Distinct molecular changes are associated with these two subtypes. Common genetic changes in endometrioid endometrial cancer include mutations in PTEN (205–212), or β-catenin genes (213–215). In contrast, type II cancers frequently demonstrate alterations in HER2/neu, p53, p16, e-cadherin, and loss of heterozygosity (LOH) (216–218). These distinct molecular alterations underscore prognostic differences. Type I endometrial cancer is limited to the uterus in 70% of cases with a 5-year survival greater than 85%. Type II endometrial cancer displays a more aggressive clinical course and a poor prognosis; even in tumors with little or no myometrial invasion, more than one in three patients will have extensive extrauterine spread with complete surgical staging, resulting in an overall survival of 20% (106,110,114,219).
Inactivation of the PTEN tumor-suppressor gene is one of the earliest aberrations observed in endometrial cancer precursors and is the most common genetic defect in type I cancers, observed in up to 83% of tumors (206). Tumors with PTEN mutations tend to be well differentiated and minimally invasive (220–222). Approximately 20% of sporadic endometrioid cancers demonstrate a molecular phenotype referred to as microsatellite instability (MSI) (223–225). Microsatellites are short segments of repetitive DNA bases scattered throughout the genome. MSI describes the accumulation of sequence changes in these DNA segments that occur because of the inactivation of intranuclear proteins that comprise the mismatch repair system (226). Inactivation of MLH1, a component of the mismatch repair system, is a common event in type I endometrial cancer. This alteration occurs through hypermethylation of CpG islands in the gene promoter, a process known as epigenetic silencing (227). This is in contrast to colon cancer, in which MSI and inactivation of the mismatch repair genes occurs through mutations in mismatch repair genes, including hMSH2, hMLH1, PMS1, PMS2, or hMSH6 (44–46). MSI and abnormal methylation of MLH1 are early events in endometrial carcinogenesis and are described in precancerous lesions (196,224). Mutations in codons 12 or 13 of the K-ras oncogene are reported in 10% to 20% of endometrial adenocarcinomas (228). The presence of mutations of K-ras appears to be an independent unfavorable prognostic factor (229,230).
Chromosomal instability with extensive genomic derangements is commonly found in type II endometrial cancers (231). The most frequent genetic alteration is TP53 mutation, present in about 90% of serous carcinomas (205,227,232,233). In contrast to endometrioid carcinoma, MSI is rare (<5%), as are K-ras and PTEN mutations (210,234,235). Other genetic alterations that occur more frequently in serous compared to endometrioid carcinomas are inactivation of p16 (45%) and overexpression and gene amplification of HER2/neu oncogene (45% and 70%, respectively) (232,236,237). HER-2/neuoverexpression is related to diminished, progression-free survival (238–240). E-cadherin, an oncogene responsible for cell-to-cell adhesion that seems to play a critical role in initiation and progression of endometrial neoplasia, is absent or reduced in 62% to 87% of cases. Loss of E-cadherin is often associated with advanced stage and LOH in both serous and clear cell carcinomas (214,241,242).
Surgical Treatment
An algorithm for the management of patients with clinical stage I and II endometrial cancer is presented in Figure 35.6. The most common current protocol for surgical management of endometrial cancer includes peritoneal cytology, hysterectomy and bilateral salpingo-oophorectomy, and surgical staging.In patients with nonendometrioid cancer, omentectomy along with appendectomy and peritoneal biopsies may be performed. The need to perform lymphadenectomy is based on the type of endometrial cancer, the grade of the tumor, the tumor size and extent of myometrial invasion determined during the surgery, and the presence of extrauterine disease. Bilateral pelvic and para-aortic lymphadenectomy is performed if the patient has any of the following factors:evidence of extrauterine disease, tumor that is FIGO grade 3, nonendometrioid-type endometrial cancer, or evidence of tumor invasion more than 50% of the thickness of the myometrium.In the absence of these risk factors only bilateral pelvic lymphadenectomy is performed, if the tumor size is greater than 2cm; para-aortic lymphadenectomy would be performed only if pelvic lymph nodes were positive (Fig. 35.7). Lymphadenectomy is omitted altogether for patients without the above risk factors, absence of cervical involvement, and tumor size less than2cm. The decision to administer postoperative radiation, chemotherapy, or both is predicated on the final results of pathological examination of the surgical specimen and cytology, according to previously described criteria (243).
Figure 35.6 Surgical management of patients with stage I–II endometrial carcinoma.
Figure 35.7 Radical pelvic sidewall resection. Photo taken of a patient with a left pelvic sidewall recurrence following resection of psoas muscle and bony ilium. Structures from lower to upper aspect of the photo (medial to lateral) include ureter, internal and external iliac artery, common iliac vein, lumbosacral trunk, obturator nerve (sacrificed), and femoral nerve. The cut edge of the psoas muscle is seen at left. (Provided by Sean C. Dowdy, MD, Mayo Clinic.)
Hysterectomy with bilateral salpingo-oophorectomy represents the first step in the treatment of endometrial cancer. The most debated issue in endometrial cancer management concerns the utility of lymph node dissection. This topic is extensively discussed in the “Surgical Staging” section of this chapter.
Vaginal Hysterectomy
Vaginal hysterectomy may be considered for selected patients who are extremely obese and have a poor medical status or for patients with extensive uterovaginal prolapse. Vaginal hysterectomy with bilateral salpingo-oophorectomy may be considered adequate treatment for patients with low risk tumors (endometrioid, grade 1 or 2, <50% myometrial invasion, and tumor diameter <2 cm; Fig. 35.7. Vaginal hysterectomy is particularly suitable for patients who are at lowrisk for extrauterine spread of disease (i.e., those with clinical stage I, well-differentiated tumors). In one report, a 94% survival rate was found in 56 patients with clinical stage I endometrial carcinoma treated by vaginal hysterectomy, with or without postoperative radiotherapy (mostly brachytherapy). Three-fourths of these patients had grade 1 lesions (244). Others reported similar good results (245–247). Vaginal hysterectomy is preferable to radiation therapy alone, but should be reserved for specific patients.
Laparoscopic Management
Advances in endoscopic technologies and power sources allowed application of a laparoscopic approach to the management of endometrial cancer. Since 1992, there were multiple reports documenting the feasibility of laparoscopicallyassisted vaginal hysterectomy with bilateral salpingo-oophorectomy and laparoscopic lymphadenectomy for staging and treatment of patients with endometrial cancer(248–256). These early studies demonstrated no differences in lymph node counts, estimated blood loss, and recurrence or survival rates with laparoscopy versus laparotomy, whereas decreased perioperative morbidity, longer operating times, shorter hospital stays, and earlier return to work were associated with laparoscopy.
Although the literature has isolated case reports of port site metastases, there are few data documenting the incidence. Martinez et al. analyzed 1,216 patients with endometrial and cervical cancer and showed that the port site metastasis rate was less than 0.5%; no port site metastases occurred after excluding patients with peritoneal disease (257).
A large prospective study by GOG randomized patients to laparoscopy versus laparotomy for the primary treatment of patients with endometrial cancer (258). Over 2,500 patients were enrolled, 1,696 to laparoscopy and 920 to laparotomy. Consistent with early reports, patients randomized to laparoscopy had shorter hospital stay (52% more than 2 days vs. 94% in the laparotomy group), less blood loss, and fewer postoperative complications (14% vs. 21%). The rate of intra-operative complications was similar, and the operative time was longer in the laparoscopy cohort. There was no difference in lymph node counts, and stage distribution was identical between groups. A follow-up quality-of-life investigation of the same cohorts revealed improved Functional Assessment of Cancer Therapy–General (FACT-G) scores, better physical functioning, better body image, less pain and its interference with quality of life, and an earlier resumption of normal activities and return to work over the 6-week recovery period in the laparoscopic group (259). Although the differences were modest and negligible by 6 months, the analysis was performed as per intention to treat. Of concern is the 24% rate of conversions in the laparoscopic cohort; only 4% were converted because of advanced disease. Furthermore, the conversion rate increased dramatically with body mass index (BMI). This is problematic recognizing that the vast majority of patients with endometrial cancer are obese. The conversion rate for patients with a BMI of 40 was 57%. This implies a limitation of the surgical technique in obese patients.
The use of extraperitoneal laparoscopic staging for para-aortic lymphadenectomy was reported in a prospective investigation of 293 patients with endometrial cancer (260). The extraperitoneal approach greatly improved exposure by circumventing handling of the small bowel and was successful in over 90% of unselected patients up to a BMI of 51. There was no difference in lymph node counts, all dissections were performed to the level of the renal veins, and significant improvements in blood loss, postoperative complications, and length of stay were noted compared to the laparotomy group. The ability to gain access to the renal veins is important, given that 60% of patients with nodal involvement above the inferior mesenteric artery have negative ipsilateral inframesenteric para-aortic nodes (140). Thus, 38% to 46% of patients with para-aortic metastases will be missed if the dissection is limited to the region below the inframesenteric artery. Althoughinfrarenal lymphadenectomy has yet to be proven necessary, the extraperitoneal approach offers the most reliable method to consistently perform a thorough dissection.
Robotic-assisted surgery gained popularity for endometrial cancer treatment (see Chapter 25). Improved instrumentation and visualization allow minimally invasive surgery to be performed by surgeons with less laparoscopic experience, and in patients, particularly obese patients, who otherwise might not be candidates for minimally invasive surgery. In one report limited to obese patients with endometrial carcinoma, the robotic approach offered reduced operating times, less blood loss, higher lymph node yields, and shorter hospital stays compared to laparoscopy (261). The extent of para-aortic dissection was not described in this report, and infrarenal para-aortic lymphadenectomy remains challenging, even with robotic assistance.
When not limited to obese patients, robotic-assisted surgery appears to offer the same benefits as laparoscopy in regards to postoperative morbidity and convalescence compared to laparotomy, but with shorter operative times (262). Althoughoncologic outcomes have yet to be proven in patients with endometrial cancer, robotic surgery is simply an advanced laparoscopic tool, and it can be expected to find equal outcomes. Given the great costs associated with robotic instruments and the absence of differential reimbursement, it is still undetermined which group of patients will benefit most from this approach from a clinical and financial perspective.
Radical Hysterectomy
Radical hysterectomy, with removal of the parametria and upper vagina, and bilateral pelvic lymphadenectomy, does not improve survival of patients with clinical stage I disease compared with extrafascial hysterectomy and bilateral salpingo-oophorectomy alone (263–266). Radical hysterectomy increases both intraoperative and postoperative morbidity and should not be performed for treatment of apparent early endometrial cancer. In the presence of demonstrable invasion of the cervix, a modified extrafascial hysterectomy may be performed. This may improve outcomes and decrease the risk of local recurrences, especially if postoperative local radiation is not planned in younger patients (267).
Radiation Therapy as Primary Treatment
Primary surgery followed by individualized radiation therapy is the most widely accepted treatment for early-stage endometrial cancers. However, about 5% to 15% of endometrial cancer patients have severe medical conditions that render them unsuitable for surgery (131). These patients tend to be elderly and obese with multiple chronic or acute medical illnesses, such as hypertension, cardiac disease, diabetes mellitus, and pulmonary, renal, and neurologic diseases.
Several series show that radiotherapy is effective treatment for patients with inoperable endometrial cancer (268–277) (Table 35.9). One reported on the treatment of 120 patients with clinical stage I and 17 patients with clinical stage II endometrial cancer with radiation alone, 85% of whom received only intracavitary radiation. Because of the high incidence of death caused by intercurrent illness in this group of patients, the 5- and 10-year overall survival rates were only 55% and 28%, respectively, compared with disease-specific survival rates of 87% and 85%, respectively. There was no difference in disease-specific survival rates between patients with stage I and II disease. Intrauterine cancer recurred in 14% of patients, and extrauterine pelvic disease recurred in 3%. The authors treated 15 patients with stage III and IV disease, usually with a combination of external-beam and intracavitary radiation therapy, yielding a 5-year disease-specific survival rate of 49%. Five patients (3%) had serious late complications of radiation therapy (277).
Table 35.9 Review of Recent Series of Endometrial Carcinoma Treated with Radiation Alone
Although it is generally agreed that intracavitary radiation is necessary to achieve adequate local control, the indications for external-beam radiation therapy in the primary treatment of endometrial cancer are less well defined. Patients with cervical involvement and known or suspected extrauterine pelvic spread undoubtedly would benefit from external-beam radiation therapy. Theoretically, external-beam radiation could sterilize microscopic nodal disease and possibly increase the radiation dose to deep myometrial or subserosal uterine disease, which may receive an insufficient dose from intracavitary radiation alone. A correlation between tumor grade and recurrence was noted in several reports. One found that the 5-year progression-free survival rate for medically inoperable patients with clinical stage I disease treated with radiotherapy alone 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.
Patterns of Metastatic Dissemination: Implications for Postoperative and Disease-Based Adjuvant Treatment
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).
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. 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).
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.
Table 35.10 Rates of Recurrence at 5 Years According to the Different Risk Categories for 915 Patients
|
Risk Category |
Recurrence at 5 Years (%) |
|
Hematogenous |
|
|
All stages |
|
|
Myometrial invasion ≤50% |
4 |
|
Myometrial invasion >50% |
28 |
|
Stage I (negative lymph nodes) |
|
|
Myometrial invasion <66% |
2 |
|
Myometrial invasion ≥66% |
34 |
|
Lymphatic |
|
|
No risk factors |
2 |
|
CSI and/or positive lymph nodes |
31 |
|
Peritoneal |
|
|
Stage IV disease |
63 |
|
Stage II–III disease and ≥2 risk factorsa |
21 |
|
Stage I–III disease and ≤1 risk factora |
1 |
|
Overallb |
|
|
Not at riskc |
2 |
|
At riskc |
46 |
|
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. |
|
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. 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).
Table 35.11 Recurrence in High-Risk, Comprehensively Staged, Early-Stage Endometrial Cancer after Adjuvant Vaginal Brachytherapy Alone (No Pelvic ERT)
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 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).
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).
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.
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% 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 effect on overall survival(294).
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%.
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 para-aortic lymph nodes (132,295–298).
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).
Whole-Abdomen Radiation
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%).
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 5-year, 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). 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).
Progestins
Because most endometrial cancers have both estrogen and progesterone receptors and progestins were used successfully to treat metastatic endometrial cancer, postoperative adjuvant progestin 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 progestintherapy (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).
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 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).
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.
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).
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.
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. 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 para-aortic lymphadenectomy
2. Combined radiation and surgery (external pelvic radiation and intracavitary radium or cesium followed in 6 weeks by total abdominal hysterectomy and bilateral salpingo-oophorectomy)
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. 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).
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).
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 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.
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).
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 is limited to the bladder, rectum, or both (345,346).
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, 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.
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 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 treated with combined radiotherapy and progestins, and two patients with local recurrence and lung metastases treated with radiotherapy, surgery, and progestins survived.
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.
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 blocwith 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 carcinoma. Seventy-five percent died of their cancer within 1 year of operation, and 14% were alive after 5 years (349).
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 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.
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 within 1 month.The mean survival time for the entire group was 10.4 months. In a follow-up study comparing 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.
Table 35.12 Response to Progestin Therapy in Advanced or Recurrent Endometrial Cancer
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 tumor burden, and advanced primary versus recurrent disease (360, 363).
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).
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 tamoxifenwere 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 single-agent progestintherapy.
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 long-term 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 (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.
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 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.
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.
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)
Table 35.14 Surgically Staged Endometrial Cancer: Actuarial 5-Year Survival Rate (%) by Histologic Grade and Stage (1988 staging criteria)
Follow-Up after Treatment
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.
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.
Ovarian Preservation and Estrogen Replacement
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).
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 patients in the study was insufficient, given the exceptionally low recurrence rate is this low-risk group (399). Although the safety of estrogentherapy 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).
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 Sarcoma
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.
Classification and Staging
The three most common histologic variants of uterine sarcoma are endometrial stromal sarcoma (ESS), leiomyosarcoma, and carcinosarcoma (malignant mixed müllerian 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%).
Table 35.15 Classifications of Uterine Sarcomas
|
I. Pure nonepithelial tumors |
|
A. Homologous |
|
1. Endometrial stromal tumors |
|
a. Low-grade stromal sarcoma |
|
b. High-grade or undifferentiated stromal sarcoma |
|
2. Smooth muscle tumors |
|
a. Leiomyosarcoma |
|
b. Leiomyoma variants |
|
1. Cellular leiomyoma |
|
2. Leiomyoblastoma (epithelioid leiomyoma) |
|
c. Benign metastasizing tumors |
|
1. Intravenous leiomyomatosis |
|
2. Benign metastasizing leiomyoma |
|
3. Disseminated peritoneal leiomyomatosis |
|
B. Heterologous |
|
1. Rhabdomyosarcoma |
|
2. Chondrosarcoma |
|
3. Osteosarcoma |
|
4. Liposarcoma |
|
II. Mixed epithelial–nonepithelial tumors |
|
A. Malignant mixed müllerian tumor |
|
1. Homologous (carcinosarcoma) |
|
2. Heterologous |
|
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. |
Staging
Staging of uterine sarcomas is based on the FIGO system (Table 35.16).
Table 35.16 Staging for Uterine Sarcomas (Leiomyosarcomas, Endometrial Stromal Sarcomas, Adenosarcomas, and Carcinosarcomas) (2008)
|
(1) Leiomyosarcomas |
|
|
Stage |
Definition |
|
Stage I |
Tumor limited to uterus |
|
IA |
<5 cm |
|
IB |
>5 cm |
|
Stage II |
Tumor extends to the pelvis |
|
IIA |
Adnexal involvement |
|
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 IV |
|
|
IVA |
Tumor invades bladder and/or rectum |
|
IVB |
Distant metastasis |
|
(2) Endometrial stromal sarcomas (ESS) and adenosarcomas* |
|
|
Stage |
Definition |
|
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 |
|
IIA |
Adnexal involvement |
|
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 IV |
|
|
IVA |
Tumor invades bladder and/or rectum |
|
IVB |
Distant metastasis |
|
(3) Carcinosarcomas |
|
|
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. |
|
Endometrial Stromal Tumors
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.
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).
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.
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 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).
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.
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).
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).
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).
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.)
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.
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.
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 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.
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.
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 regression of unresected tumor masses. Almost all patients have a good prognosis.
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.
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.
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.
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).
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 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%.
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.
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.
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 therapy or chemotherapy can be planned. Rarely, a patient may be cured by excision of an isolated pulmonary metastasis (455,456).
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.
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). Doxorubicindemonstrated 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).
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).
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 randomized phase III evaluation of paclitaxel plus carboplatin versus ifosfamide plus paclitaxel in chemotherapy naive patients with carcinosarcoma is accruing.
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).
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