The distinction of inner-half invasion from outer-half invasion is usually straightforward, and both the probability of recurrence and likelihood of death from tumor are markedly increased for women with deeply invasive tumors. However, there are 3 situations in which the determination of maximal invasion may be difficult. In the first situation, lymphatic invasion may be most easily recognized and prominent in the myometrium deep to the invasive front of the carcinoma. The lymphatic channels containing masses of neoplastic cells may be found in the outer-half of the myometrium whereas the rest of the neoplasm is confined to the inner-half of the uterus. In such cases, I believe it is most appropriate to classify the tumor as a stage IB (inner-half myoinvasive) tumor and simply note the presence of lymphatic invasion, which represents a separate poor prognostic factor. In the second case, for a highly exophytic tumor, the location of the endometrial myometrial interface may be obscured by the presence of smooth muscle fibers that extend upward into the endometrium. No rules have been proposed for determination of the depth of invasion in this situation, but Ali et al (6) have offered a few useful suggestions. In such cases, I have arbitrarily estimated the depth of invasion based on the thickness of the myometrium in a portion of the fundus not affected by the neoplasm. In the third situation, carcinoma is found confined to foci of adenomyosis in the deep myometrium. Several studies have demonstrated that this should not be considered a form of deep myoinvasion, as the outcome for these women is no worse than for those in whom tumor is absent from the adenomyosis (8,9).
HISTOLOGIC GRADE (GRADES 1, 2, AND 3)
Stage I endometrial carcinomas are further subdivided by histologic grade, reflecting the prognostic importance of tumor differentiation, particularly in early stage disease. Although assignment of histologic grade is not particularly problematic currently, this largely reflects the significant clarification regarding histologic grading provided by pathologists during the past 2 decades. In the early 1980s, the pathology committee of the GOG arbitrarily defined an architecturally based grading system for endometrial adenocarcinomas, using the percentage of the surface area in which there is glandular arrangement of the neoplasm (10). Grade I tumors are those in which less than 5% of the neoplasm is arranged as solid growth; grade 2 tumors are those in which 5% to 50% of the neoplasm is arranged in solid sheets; and grade 3 tumors are those in which greater than 50% of the neoplasm form solid masses. Foci of squamous differentiation are not included in the assessment. This system was later found to effectively discriminate survival probability for women with clinically stage I and II endometrioid endometrial adenocarcinomas, with 5-year survivals of 93% for women with grade 1 tumors, 85% for grade 2 tumors, and 69% for grade 3 tumors (11). Interestingly, it was later found useful not only in stratifying the overall survival for women with surgical stage I disease, with 5-year survival rates of 92%, 88%, and 75%, respectively, but also for those with metastatic (stage III) disease, with rates of 70%, 63%, and 40%.
FIGO adopted this general schema for the 1988 system, but added the 3 provisos that follows: 1) notable nuclear atypia, inappropriate for the architectural grade, raises the grade of a grade 1 or grade 2 tumor by 1; 2) in serous, clear cell and squamous cell carcinoma, nuclear grading takes precedence; and 3) adenocarcinomas with squamous differentiation are graded according to the nuclear grade of the glandular component (1). Notable nuclear atypia was not precisely defined. The first and third of these provisos were subsequently addressed in studies by the GOG. Of 715 women with endometrioid adenocarcinomas, with or without squamous differentiation, Zaino et al. (12) found that upgrading was prognostically justified only for those tumors in which the majority of the neoplasm was composed of cells with large, pleomorphic nuclei, coarse chromatin, and large irregular nucleoli (Fig. 3). A lesser degree of nuclear atypia or severe but only focal nuclear atypia was not associated with a significantly diminished probability of survival. With respect to endometrioid adenocarcinomas with squamous differentiation, the architectural differentiation of the gland-forming portion of the tumors provided better prognostic information than the nuclear grade of the glandular or squamous component (12). Although grading is prognostically important for endometrioid adenocarcinoma and its subtypes, it has not been found to be useful for serous, clear cell, or pure squamous carcinomas. Tumors of these cell types are associated with an aggressive behavior that does not seem to be influenced by architectural or nuclear features that have been studied to date. Consequently, by convention, serous and clear cell carcinomas of the endometrium are considered to be grade 3.
Multiple prognostically useful alternative grading systems have been proposed during the past decade, based on either a 2-tiered or a 3-tiered division according to architectural grade, nuclear grade, or a combination of both (13–16). All of the systems display moderate to good reproducibility in limited investigations. It is not clear whether any of the alternative systems would significantly improve the reproducibility, ease, or prognostic utility of the current method.
STAGE II (CARCINOMAS THAT EXTEND INTO THE UTERINE CERVIX)
Women with endometrial adenocarcinoma that spread to the cervix have a diminished probability of survival compared with women whose tumors are confined to the uterine corpus, with FIGO results from 2003 indicating a 75% 5-year overall survival compared with about 88% for stage I tumors (7). However, tumors that spread to the cervix more often display other poor prognostic features, such as high grade, invasion of the outer-half of the myometrium, and lymphatic invasion, than do tumors confined to the corpus (17). In one study of 170 women with stage II carcinoma, 58% had outer-half myoinvasion (versus 44% for stage I), 42% had capillary/lymphatic space involvement, and 72% were grade 2 or 3 (versus 60% for stage I ). It is unclear whether involvement of the cervix is prognostically significant after adjustment for other poor-risk factors, but the effect of cervical spread in isolation seems to be a weak factor, if present.
Stage II carcinomas are further divided into stage IIA (Fig. 4A), which are those tumors in which carcinoma is confined to the endocervical glands, and stage IIB, which are those tumors in which carcinoma involves the cervical stroma (Fig. 4B). FIGO has not provided any guidelines regarding the histologic definition or identification of carcinoma confined to glands, and different authors have considered it to represent surface epithelial involvement only, surface and underlying gland involvement, or mucosal spread (although no mucosa exists in the cervix) (8,19–22). Some of these definitions imply either a Pagetoid spread of neoplastic cells within the basement membrane of the epithelium from a contiguous primary tumor, or implantation and replacement of denuded epithelium after curettage. In practice, for grade 1 endometrial tumors, it is often difficult to determine whether the neoplastic glands in the cervix represent preexisting or newly formed glands, particularly as a desmoplastic host response often is absent in low-grade tumors. In contrast, higher-grade tumors have solid masses of neoplasm that infiltrate the stroma and often provoke a desmoplastic response. Most tumors classified as stage IIA are grade 1. Consequently, it is not surprising that various studies have yielded conflicting data with survival and recurrence rates for women with stage IIB disease either worse or no different from those for women with stage IIA disease (5,8,19–25). In most studies, stage IIA disease is associated with the same prognosis as stage I tumors. In summary, neither the prognostic importance nor the reproducibility of the diagnosis of stage II (and substages IIA and IIB) tumors has been rigorously evaluated, but reproducibility seems to be poor and prognostic importance weak.
STAGE IIIA (TUMOR INVADES UTERINE SEROSA, ADNEXA, OR POSITIVE PERITONEAL CYTOLOGY)
Stage IIIA is extraordinarily heterogenous, as it includes those tumors that have not demonstrated spread beyond the uterus, those tumors which are present as isolated cells in peritoneal fluid but may not be capable of implantation, and those tumors with definite metastasis to other pelvic organs.
Between 3% and 30% of women with clinical stage I or II endometrial carcinoma are found to have tumor cells in either ascitic fluid or in pelvic washing cytology, but only about 5% to 10% of women with no extrauterine metastases identified pathologically have positive peritoneal cytology (26–35). Numerous studies have produced conflicting results regarding the significance of positive peritoneal fluid cytology as a risk factor for tumor recurrence or survival in women with clinical stage I or II carcinoma. In about half of the reports, it is associated with increased recurrence rates and decreased survival (28,32–34,36–40), but in the other half, no difference was detected (28–32,34,35,39,41–43). Positive peritoneal fluid cytology is frequently associated with other high-risk factors such as high histologic grade, deep myometrial invasion, and extrauterine disease. The reported 5-year survival for those women with positive cytology but with no extrauterine metastases varies from about 80% to 90%, whereas the recurrence rate is about 30%. In a somewhat dated but excellent review of 17 studies and over 3,800 patients by Milosevic and colleagues in 1992 (33), they identified 5 studies in which multivariate analyses had been conducted that included grade and depth of invasion in the models. In the 3 larger studies, a malignant cytology was associated with a significant, independent decrease in survival or increase in the rate of recurrence, but its effect was less important than histologic grade. In the 2 smaller studies, no such effect was found. Recurrence in this group of patients is typically as disseminated intraperitoneal carcinomatosis. In about 5% of peritoneal fluid cytology specimens, atypical cells are present that may represent either reactive mesothelial cells or low-grade adenocarcinoma. In the absence of immunohistochemical stains that are absolutely specific and sensitive, it is likely that this group that is indefinite for stage IIIA cancer cannot be reduced further.
Women whose tumors have spread to the adnexa have a diminished survival compared with those women without adnexal involvement. Once again, most of these women also have other adverse features such as high grade, lymphatic invasion, deep myometrial invasion, and other sites of extrauterine disease. Connell et al. (44) reported a 5-year disease-free survival of 37% for those with adnexal spread, but it was 71% for those without other extrauterine involvement. The latter figure is close to the mean disease-free survival of 79% taken from a literature review for solitary adnexal involvement (44). This data should be viewed with caution as almost 5% of women with endometrial adenocarcinoma are found to have carcinoma in the ovary, and many of these patients are believed to have separate primary tumors, for whom the prognosis is excellent (45). Until better ways are routinely employed to distinguish synchronous primary tumors from metastases, the impact of isolated ovarian or tubal metastases will remain obscure.
The third subgroup of stage IIIA consists of women whose tumors have extended through the myometrium to the uterine serosa. It was found in about 7% of women treated by primary surgery, of whom half had extrauterine spread, and overall carries a poor prognosis, with a 5-year disease-free survival of about 30% in one study (46). As an isolated finding in the absence of known metastasis (a relatively uncommon event), the survival increased, but was still poor at 41% at 5 years (46). Mariani and colleagues (47) found a better 5-year survival rate, but 83% of the tumors recurred in extra-abdominal sites in that period of time.
STAGE IIIB (TUMOR SPREAD TO THE VAGINA)
Although vaginal recurrences of endometrial adenocarcinomas are relatively common, less than 1% of patients present with vaginal metastasis in the absence of spread to lymph nodes or distant sites (48). More specifically, only about 2% to 3% of women with stage III tumors are stage IIIB. Such tumors are biologically aggressive, with a reported 5-year survival of about 25% and a median survival of only 1 to 2 years. As the patients typically do not have contiguous spread from uterine corpus to cervix to vagina, it is likely that the tumor reflects a lymphatic metastasis. The sites of recurrent disease in this group of patients are quite variable, and include pelvis, lymph nodes, abdomen, and distant sites.
STAGE IIIC (TUMOR METASTASIS TO PELVIC OR PARA-AORTIC LYMPH NODES)
About 10% of women with clinical stage I and II endometrial carcinoma are found at the time of surgico-pathologic staging to have metastasis to pelvic and/or para-aortic lymph nodes (49–51). After lymphadenectomy, radiation therapy is often directed to the pelvis and nodal regions. The probability of nodal spread is strongly related to risk factors, including cell type, histologic grade, depth of myometrial invasion, and lymphatic invasion (17). There is a relatively predictable pattern of spread of endometrial carcinoma to regional nodes, with the pelvic nodes involved first, followed by ascent to the para-aortic chain. About one-third to one-half of women who have disease in the pelvic nodes also have spread to the para-aortic lymph nodes (17,49,50). Even this substage is quite heterogeneous. Mariani and colleagues (52) reviewed 51 patients with stage IIIC disease. Although the 5 years recurrence-free survival was 68% for women who had lymph nodes as the only site of extrauterine disease, it dropped to 25% for those whose tumors also involved uterine serosa, adnexa, vagina, or peritoneal cytology (52). Relapses in the former group were largely confined to the node-bearing areas; whereas, the majority of the latter group had recurrences in other areas. Similar but even more dramatic differences in survival between the 2 groups (93% versus 39%) were found by McMeekin et al. (53), who also noted that the depth of invasion in the uterus remained significant in a multivariate analysis of survival. Women with metastatic disease in the para-aortic lymph nodes have a much worse prognosis than those with spread only to the pelvic lymph nodes, with 5-year survivals of about 30% to 40% versus 70% to 80% (50,51,54). Further risk stratification is found according to the presence of residual nodal disease, divided as occult, macroscopic resected, and macroscopic residual (49).
GENERAL COMMENTS AND A FEW NOTES ON THERAPY
As one reviews the voluminous literature, it is evident that the prognosis of endometrial adenocarcinoma is related to a wide variety of features including those intrinsic to the tumor (such as cell type and grade), those related to its growth in the uterus (including the depth of myometrial invasion and lymphatic invasion), and those related to extrauterine spread. As noted previously, some of the features of the tumor in the uterus still affect the prognosis for women with metastatic tumor, and no single characteristic seems to represent an overwhelmingly dominant prognostic factor. Thus, the prognosis, and sometimes therapeutic decisions, for an individual patient often is based on a constellation of features, rather than simply the identification of the most advanced site of spread. This set of observations complicates the creation of an optimal staging system.
In the prior discussion, I have focused on prognostic issues. I will follow with a series of brief and provocative generalizations about the current limitations or controversies regarding therapy. Although 70% to 80% of women with endometrial adenocarcinoma are cured by surgery alone, disease beyond the uterus remains a source of tremendous frustration, and staging systems should address the differences between nodal disease, localized pelvic spread, peritoneal carcinomatosis, and extra-abdominal metastasis. Patients with high-risk, localized cancers treated with adjuvant radiation to the pelvis or abdomen have lower rates of pelvic recurrence, but are at equal risk for later distant failure and seem to have no survival benefit. Whole abdominal radiation therapy is inferior to chemotherapy for the treatment of women with maximally debulked advanced endometrial adenocarcinoma. Several studies have suggested that lymphadenectomy, in itself, may result in improved survival for women with metastasis to pelvic and para-aortic lymph nodes. Targeted radiation therapy may be effective for the treatment of localized vaginal recurrences, but neither hormonal nor chemotherapy provides more than short term and incomplete responses in most of the women with distant or disseminated disease. In summary, therapy for advanced or recurrent endometrial adenocarcinoma remains suboptimal, with mean survival measured in months to a few years, for most situations. Further advances in treatment outcomes are unlikely to result from conventional forms of hormonal, radiation, or chemotherapy.
A SUMMARY OF PROBLEMS AND SUGGESTIONS FOR REFINEMENT IN THE FIGO STAGING SYSTEM
- 1) Stage IA (tumors confined to the endometrium) cannot reliably be distinguished from stage IB (tumors invading the superficial myometrium) microscopically in many cases;
- 2) Stage IIA and IIB are poorly defined pathologically and may not differ prognostically;
- 3) Stage II is probably not a statistically significant independent prognosticator of survival;
- 4) Stage III disease is very heterogeneous;
- 5) Stage IIIA alone is heterogeneous; isolated positive peritoneal cytology alone is rare and probably significant but with small survival effect (85% 5-year survival); isolated adnexal spread is more significant (70% 5-year survival); uterine serosal involvement carries a poor prognosis (30% 5-year survival);
- 6) Stage IIIB (vaginal metastasis) is very rare and has a prognosis similar to stage IV tumors (25% 5-year survival);
- 7) Stage IIIC is heterogeneous, and patients who have nodal spread without other extrauterine spread have a significantly better prognosis (70%–90% 5-year survival) than those with both nodal and other extranodal disease (25%–40% 5-year survival);
- 8) Among women with stage IIIC disease, the prognosis for those with pelvic node metastasis is significantly better (70%–80% 5-year survival) than for those with positive para-aortic nodes (30%–40% 5-year survival);
- 9) Among women with stage IIIC disease, the survival rates vary according to whether the nodes are grossly or microscopically positive (as assessed by the operating surgeon), and whether the disease can be completely resected.
Given the described problems in reproducibility, accuracy, and predictive value noted previously, and to provoke further discussion, I would suggest that consideration be given to a staging system as shown in Table 3. If we are to make further improvements in treatment and prognostication, it is time for pathologists, gynecologic oncologists, radiation oncologists, and medical oncologists to engage in this conversation together. I look forward to the discussion that may follow.
The author thanks Drs Catherine Abendroth and Timothy Leonard for their critical review and Amanda Smith for her excellent assistance in the preparation of this manuscript.
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Keywords:©2009International Society of Gynecological Pathologists
Endometrium; Carcinoma; FIGO; Stage