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Gynecologic Oncology 111 (2008) 244 – 248 www.elsevier.com/locate/ygyno
Accuracy of preoperative endometrial sampling diagnosis of FIGO grade 1 endometrial adenocarcinoma Mario M. Leitao Jr. a,⁎, Siobhan Kehoe a , Richard R. Barakat a , Kaled Alektiar b , Leda P. Gattoc d , Catherine Rabbitt a , Dennis S. Chi a , Robert A. Soslow c , Nadeem R. Abu-Rustum a a
Department of Surgery, Division of Gynecology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA b Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA c Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA d Department of Obstetrics and Gynecology, Long Island Jewish Medical Center, New York, NY, USA Received 18 June 2008 Available online 27 August 2008
Abstract Objective. To evaluate the ability of a preoperative diagnosis of FIGO grade 1 endometrial adenocarcinoma and intraoperative depth of myoinvasion (DOI) to predict low-risk (LR) and high-risk (HR) final uterine pathology. Methods. We reviewed 1423 consecutive cases of endometrial cancer treated at our institution between 1/1/93 and 5/31/06 to identify cases with a preoperative endometrial biopsy demonstrating FIGO grade 1 endometrial adenocarcinoma. All cases were pathologically reviewed at our institution and underwent surgical therapy at our institution. We excluded equivocal preoperative biopsies as well as those with serous or clear cell histology. Final uterine pathologic findings were grouped into low- and high-risk. Chi-square and Fisher-exact tests were used as appropriate. Results. We identified 490 cases with a median age of 60 years (range 29–90 years). In 482 cases in which final pathologic grade was assessable, FIGO grade was greater in 71 (14.7%) cases; (66 [13.7%] were grade 2, and 5 [1%] were grades 2–3/3). Serous or clear cell histology was diagnosed in 6 (1.2%) additional cases. HR final uterine pathology was seen in 86 (18.5%) cases. Frozen section assessment of DOI, when performed, was associated with HR pathology (p b 0.001). HR pathology was present in 3 (3.6%) of 84 cases with either no tumor or myoinvasion identified on frozen section. Lymph node metastasis was identified in 9 (4.4%) of 205 patients that underwent nodal evaluation. Conclusions. Preoperative FIGO grade 1 diagnosis correlates with final post-hysterectomy grade in 85% of cases. The rate of HR uterine pathology based on preoperative grade 1 alone is 18.5%. Frozen section may help further stratify for the risk of final HR uterine pathology but is not entirely accurate. The rate of HR uterine pathology is 4% if no cancer or myoinvasion is identified on frozen section and 18% if myoinvasion up to 50% is identified. © 2008 Elsevier Inc. All rights reserved. Keywords: Preoperative; FIGO grade 1; Encometrial; Adenocarcinoma; Hysterectomy
Introduction Endometrial cancer is the most common gynecologic malignancy and the fourth most common malignancy in women overall in the United States, with an estimated 40,100 new cases diagnosed annually [1]. This high incidence rate is also evident in many other countries, with an estimated 136,000 new cases diagnosed worldwide in 2002 [2]. The International Federation of Gynecology and Obstetrics (FIGO) replaced an ⁎ Corresponding author. Fax: +1 212 717 3214. E-mail address:
[email protected] (M.M. Leitao). 0090-8258/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2008.07.033
inaccurate clinical staging system with a surgically staged system in 1988 [3,4]. The importance of surgical staging was supported by the findings from a large prospective surgicalpathologic study in patients with clinical stage I and II endometrial carcinoma conducted by the Gynecologic Oncology Group (GOG) [5,6]. Extra-uterine disease, including pelvic and para-aortic lymph node metastasis, was found relatively frequently in this study. The risk of nodal metastasis was associated with both final pathologic FIGO tumor grade and depth of myometrial invasion [5]. Multiple extra-uterine findings were also associated with outcome [6]. These findings led to the change in the FIGO staging system. FIGO stage I was
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subdivided based on depth of myometrial invasion, and nodal involvement was designated as FIGO stage IIIC. Many surgeons have not embraced complete surgical staging with lymph node removal despite the noted risk of nodal involvement in clinically apparent stage I disease, especially if the preoperative endometrial sampling revealed a FIGO grade 1 adenocarcinoma. This may be due to a variety of factors such as surgeon's familiarity with lymph node dissection techniques, the perceived low incidence of nodal metastasis, and concern over complications, including prolonged operative times. It has been estimated that lymph node dissections are performed in only 30% of patients with endometrial carcinoma [7]. Preoperative tumor grading with intraoperative assessment of depth of myometrial invasion, as well as histologic subtype, is frequently used to decide if lymph node dissection is necessary at the time of hysterectomy. Surgeons base this approach on extrapolation of data from various reports that describe the rates of nodal metastasis as well as therapeutic benefits of lymphadenectomy. This is not an accurate method of nodal risk stratification as almost all of those reports are based on final pathologic assessments of grade and depth of myometrial invasion. A higher FIGO grade on final hysterectomy pathologic assessment will be diagnosed in 24% of patients with preoperative FIGO grade 1, combining results from published series [8,9–14]. Intraoperative assessment of myometrial invasion is also an inaccurate predictor of the actual depth of myometrial invasion [11]. The combination of both preoperative grade and intraoperative assessments of myometrial invasion has a low predictive value for final pathologic findings in the hysterectomy specimen [11]. The published series to date have mostly combined all preoperative grades with relatively small numbers. Most surgeons will routinely perform a lymphadenectomy for FIGO grades 2 and 3 and non-endometrioid endometrial adenocarcinomas. However, many still question the need for a full lymphadenectomy if the preoperative endometrial sampling revealed a FIGO grade 1 adenocarcinoma. We sought to review our endometrial cancer database of patients who underwent hysterectomy at our institution to identify all cases diagnosed with FIGO grade 1 endometrial adenocarcinomas on preoperative sampling. Our primary objective was to correlate preoperative grading with final pathologic assessment of the hysterectomy specimen. Our secondary objective was to determine if frozen section assessment of depth of myometrial invasion would provide additional information in the prediction of final pathologic assessment of the hysterectomy specimen.
lymphadenectomy at our institution as primary treatment of their endometrial cancer. It is our institutional policy to confirm all outside diagnosis of cancer prior to operating on patients for uterine or other malignancies. Cases were included if the pathologic review at our institution of a preoperative endometrial biopsy, by either dilatation and curettage or office endometrial biopsy, demonstrated an unequivocal diagnosis of FIGO grade 1 (welldifferentiated) endometrial adenocarcinoma. Pathologic diagnoses from the referring institutions were not abstracted. All preoperative nuclear grades, if described, were included. All histologies were included except for those with obvious serous or clear cell adenocarcinoma whether alone or mixed with other subtype. Non-epithelial histologies were also not included. Cases with FIGO grade 1 adenocarcinoma in the background of complex atypical hyperplasia (CAH) were included. However, cases were excluded if the primary diagnosis was CAH alone or with any of the following qualifications: “bordering on adenocarcinoma” or “focal area suspicious for adenocarcinoma”. Cases were also excluded if the preoperative diagnosis was inconclusive or graded as FIGO grades 1–2. Cases with either obvious extra-uterine disease preoperatively or who received hormonal, cytotoxic, or radiation therapy prior to hysterectomy were also excluded. Data were abstracted from the electronic medical record for the identified cases. Operative reports were reviewed to determine intraoperative findings and exact nature of procedure. Pathologic reports of the specimens removed from these procedures were reviewed and the following data were abstracted: frozen section determinations of depth of myometrial invasion (if performed), FIGO grade, histologic subtypes, actual depth of myoinvasion (DOI), presence of extra-uterine metastases, peritoneal cytologic results, and presence of lymphvascular space invasion (LVSI). Nodal counts were abstracted and nodal metastases were noted. Dates of last follow-up and disease status at last follow-up were also abstracted. Final pathologic findings of the hysterectomy specimens were then analyzed and dichotomized into low-risk (LR) or high-risk (HR) based on final FIGO grade and DOI (Table 1). This was done using both FIGO (LR- or HR-FIGO) and GOG 33 (LR-GOG or HR-GOG) groupings of DOI [5]. LR-FIGO was defined as tumor limited to endometrium of any grade Table 1 Risk groupings using final FIGO grade and depth of invasion (DOI) in hysterectomy specimen and based on the risk of nodal metastasis reported in other series (LR = low-risk; HR = high-risk) DOI
Materials and methods Following approval from our Institutional Review Board, we reviewed 1423 consecutive cases of endometrial malignancies treated at our institution between 1/1/93 and 5/31/06. These cases were identified from a prospectively maintained database. All pathology reports were reviewed to identify cases which had their preoperative endometrial biopsies reviewed at our institution. All patients had a hysterectomy with or without
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FIGO-based [15] Limited to endometrium b50% DOI ≥50% DOI GOG-based [5] Limited to endometrium ≤33% DOI N33% to b67% DOI ≥67% DOI a
Grade 1
Grade 2
Grade 3 a
LR-FIGO LR-FIGO HR-FIGO
LR-FIGO HR-FIGO HR-FIGO
LR-FIGO HR-FIGO HR-FIGO
LR-GOG LR-GOG LR-GOG HR-GOG
LR-GOG HR-GOG HR-GOG HR-GOG
LR-GOG HR-GOG HR-GOG HR-GOG
Serous/clear cell (pure or mixed) considered as grade 3.
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(FIGO stage IA, grades 1–3) or FIGO grade 1 with DOI b50% (FIGO stage IB, grade 1). LR-GOG was defined as tumor limited to endometrium of any grade or FIGO grade 1 with inner or middle third invasion. These risk groupings were based on the risk of nodal metastasis reported in prior series [5,15]. Cases without any residual carcinoma in the hysterectomy specimen were considered to have tumor limited to the endometrium. Serous and clear cell histologies were considered as final FIGO grade 3. Chi-square and Fisher's exact tests were used, as appropriate, to compare nominal variables. All statistical analyses were performed using SPSS for Windows version 15.0.1 (Chicago, IL). Results We identified 490 cases that met our inclusion criteria. Table 2 summarizes the findings of the pathologic review of the preoperative endometrial sampling. All were diagnosed as FIGO grade 1 preoperatively. The majority (61%) of endometrial samples were obtained via an office endometrial biopsy. There were only 7 cases with a high nuclear grade (2–3 or 3). Frozen section assessment of DOI was performed in 270 (55%) of cases. The FIGO grade and histology subtype seen in the hysterectomy specimens are summarized in Table 3. FIGO grade 2 or higher was seen in 71 (14.7%) of the hysterectomy specimens. Pure or mixed serous or clear cell adenocarcinomas were identified in 6 (1.2%) cases. The hysterectomy specimen revealed a higher FIGO grade or high-risk histology in 77 (15.8%) of the 488 assessable cases for which FIGO grade was reported or histology was documented. The reason Table 2 Pathologic findings of the preoperative endometrial biopsies (all FIGO grade 1) and frozen section assessment of DOI Variable Age (years) Median (range) Endometrial sampling method D&C Office EMB N/A CAH present Yes Not mentioned Mucinous histology Yes No Nuclear grade Low (1,1–2,2) High (2–3,3) N/A Frozen section DOI No cancer identified No myoinvasion b50% myoinvasion ≥ 50% myoinvasion Not done
N (%) 60 (29–90) 187 (38.6) 298 (61.4) 5 123 (25) 367 (75) 13 (2.7) 477 (97.3) 122 (94.6) 7 (5.4) 361 44 (16.3) 48 (17.8) 153 (56.7) 25 (9.3) 220
EMB = office endometrial biopsy; N/A = data not available; CAH = complex atypical hyperplasia; DOI = depth of myoinvasion.
Table 3 Final pathologic assessment of FIGO grade and histology in hysterectomy specimens Variable
N (%)
Final FIGO grade 1 or no residual 2 2–3 3 N/A Final histology Endometrioid Adenocarcinoma, NOS Adenosquamous Mucinous Mixed endometrioid/mucinous Mixed endometrioid/clear cell Mixed endometrioid/serous Clear cell Serous Final upgraded a No Yes (≥grade 2 or high-risk histo b)
411 (85.3) 66 (13.7) 1 (0.2) 4 (0.8) 8 455 (92.9) 15 (3.1) 2 (0.4) 5 (1) 7 (1.4) 1 (0.2) 2 (0.4) 1 (0.2) 2 (0.4) 411 (84.2) 77 (15.8)
N/A = not assessed; NOS = not otherwise specified. a Assessable in 488 cases. b High-risk histology defined as pure serous or clear cell, or mixed with either serous or clear cell histology.
for this not being assessed in 2 cases was suboptimal specimen preservation. Table 4 summarizes the overall pathologic assessment of the hysterectomy specimens combining both FIGO grade and DOI. Myoinvasion into the outer half of the uterus was seen in 64 (13%) of 489 for which this was assessable. Myoinvasion into the outer third was seen in 40 (8.6%) of 465 for which myoinvasion by thirds was assessable. HR-FIGO and HR-GOG uterine pathology was seen in 109 (22.4%) and 86 (18.5%) cases, respectively (Table 5). These overall findings did not change after excluding the 7 cases with preoperative nuclear grades of 2–3 or 3 (data not shown). However, HR-FIGO and HR-GOG uterine pathology were identified in 3 (43%) and 4 (57%) of these 7 cases, respectively. Frozen section assessment of DOI was performed in 270 (45%) cases. The exact correlation of frozen section assessments with final pathologic assessment occurred in 204 (75.6%) of these cases. Overall, more myoinvasion in the final uterine specimen was identified in 40 (16.3%) of the 245 cases that were felt to have b50% myoinvasion at the time of frozen section. The other 25 cases were felt to already have ≥ 50% Table 4 Final pathologic assessments of both FIGO grade and FIGO DOI in the hysterectomy specimens of patients with a preoperative biopsy revealing FIGO grade 1 adenocarcinoma Myoinvasion (FIGO stage)
Grade 1
Grade 2
Grade 3 a
Limited to endometrium (IA) b50% myoinvasion (IB) ≥50% myoinvasion (IC)
164 (33.7%) 208 (42.7%) 40 (8.2%)
6 (1.2%) 39 (8%) 19 (3.9%)
0 (0) 6 (1.2%) 5 (1%)
Data not assessable in 3 cases. a Serous/clear cell adenocarcinoma (pure or mixed) considered as grade 3.
M.M. Leitao Jr. et al. / Gynecologic Oncology 111 (2008) 244–248 Table 5 Risk groupings based on final pathologic assessments of hysterectomy specimens Risk groups a
N (%)
FIGO-based LR-FIGO HR-FIGO N/A GOG-based LR-GOG HR-GOG N/A
378 (77.6) 109 (22.4) 3 378 (81.5) 86 (18.5) 26
N/A = not assessable. a See Table 1 for definitions (pure or mixed serous/clear cell considered as grade 3).
myoinvasion at the time of frozen section. The rate of HR-FIGO and HR-GOG uterine pathology based on frozen section assessment of DOI is summarized in Table 6. HR-FIGO and HR-GOG uterine findings were identified in 4% and 3.6% of the cases, respectively, if no carcinoma was seen or if carcinoma was identified but limited to the endometrium on frozen section. Oophorectomy was performed in 477 (97.3%) cases. Ovarian malignancy was identified in 15 (3.2%) of these 477 cases. These malignancies were metastatic from the endometrium in 8 (1.7%) and synchronous ovarian carcinomas in 7 (1.5%). Malignant peritoneal cytology was identified in 22 (5.1%) of 429 cases. Lymph node removal was performed in 205 (41.8%) cases (143 pelvic and para-aortic; 45 pelvic only; 17 para-aortic only). The median lymph counts were: pelvic = 14 (range, 1–44); para-aortic = 5 (range, 1–24); and total = 18 (range, 1–56). There was nodal metastasis in 9 (4.4%) of the 205 cases with 5 being microscopic-only metastases. Gross extra-uterine disease at the time of surgery was present in 7 (1.4%) cases, of which 4 were gross nodal disease and 3 gross intraperitoneal disease. The distribution of final FIGO stage, although not all were comprehensively staged, is summarized in Table 7. FIGO stages II, III, and IV were diagnosed in 69 (16.1%) cases. This likely represents an underestimation of true FIGO stage. There were nine cases with nodal metastasis as noted above. Gross nodal involvement was seen in 4 (44%) of these 9 cases. The final post-hysterectomy FIGO grades were grade 1 (n = 3), Table 6 Risk groupings a of uterine pathologic findings in cases with a preoperative diagnosis of FIGO grade 1 endometrial adenocarcinoma based on frozen section assessments of DOI Final pathologic assessments
FIGO-based LR-FIGO HR-FIGO GOG-based LR-GOG HR-GOG a
Frozen section assessment of myoinvasion
p-value
No cancer or no invasion
b50% myoinvasion
≥50% myoinvasion
87 (96%) 4 (4%)
120 (78%) 33 (22%)
2 (8%) 23 (92%)
b0.001
81 (96.4%) 3 (3.6%)
120 (81.6%) 27 (18.4%)
8 (34.8%) 15 (65.2%)
b0.001
See Table 1 for definitions of risk groupings.
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Table 7 Final FIGO stage Stage
N (%)
IA IB IC IIA IIB IIIA IIIB IIIC IVA IVB
160 (32.7) 224 (45.7) 37 (7.6) 13 (2.7) 20 (4.1) 26 (5.3) 0 (0) 9 (1.8) 0 (0) 1 (0.2)
Lymph node removal performed in 205 cases.
grade 2 (n = 5), and grade 3 (n = 1). HR-FIGO or HR-GOG uterine pathology was present in 8 (89%) of these cases. Frozen section assessment of DOI was performed in 4 cases, of which, 3 (75%) had more than 50% DOI noted on frozen section assessment. Discussion The importance of surgical staging was supported by the findings from a large prospective surgical-pathologic study in patients with clinical stage I and II endometrial carcinoma conducted by the Gynecologic Oncology Group (GOG) [5,6]. However, the surgical approach to endometrial carcinoma has been and continues to be inconsistent among various practitioners due to a variety of reasons. The surgical approach ranges from total hysterectomy alone for all patients, hysterectomy with lymphadenectomy relying on the surgeon's criteria for risk of nodal metastasis based on preoperative grading and/or intraoperative assessments, hysterectomy with limited lymphadenectomy; to hysterectomy with full pelvic and para-aortic lymphadenectomy for all patients. This inconsistency is most apparent in patients who have a preoperative endometrial sampling diagnosis of grade 1 adenocarcinoma. Preoperative tumor grading with intraoperative assessment of depth of myometrial invasion, as well as histologic subtype, is frequently used to decide if lymph node dissection is necessary at the time of hysterectomy. Surgeons commonly base this approach on personal experience and on extrapolation of data from various reports that describe the rates on nodal metastasis, principally the above mentioned GOG trials [5,6]. However, this is not an accurate method of nodal risk stratification as all of these reports are based on final, posthysterectomy, pathologic assessments of grade and depth of myometrial invasion and not preoperative grade or intraoperative DOI. Preoperative tumor grade based on endometrial sampling by various methods has uniformly been reported to not accurately correlate with final pathologic grade [9–14,16–19]. A higher FIGO grade on final hysterectomy pathologic assessment will be diagnosed in 24% of patients with preoperative FIGO grade 1 combining published series [9–14,16]. The majority of cases will be upgraded to FIGO grade 2, but approximately 3% will be upgraded to FIGO grade 3 or be diagnosed as a serous or
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clear cell carcinoma on final pathologic assessment of the hysterectomy specimen. Our series is a large single institution experience with expert pathologic assessments of preoperative endometrial biopsies confirming FIGO grade 1 adenocarcinoma. We noted a higher FIGO grade in the hysterectomy specimen in 14.7% of the cases and an additional 1.2% had serous or clear cell adenocarcinoma. This is lower than the combined results of previously published series but clearly remains as an important clinical observation. These findings may be explained by the fact that FIGO grading is based on the percentage of solid growth within a specimen and therefore will vary once the final specimen is obtained and more tissue volume is examined. Intraoperative assessment of myometrial invasion is also an inaccurate predictor of the actual depth of myometrial invasion. In a series of 112 patients, Frumovitz et al. reported that a frozen section diagnosis of no myometrial invasion is not accurate in 72% of cases, and 26% of cases with a frozen section of myometrial invasion b50% will actually have deeper invasion, cervical invasion, and/or extra-uterine disease [11]. The combination of both preoperative grade and intraoperative assessments of myometrial invasion does not always predict for final pathologic findings on the hysterectomy specimen [11]. Our data confirm these findings in a group of 490 patients with a preoperative diagnosis of FIGO grade 1 endometrial adenocarcinoma. The modeled risk of pelvic and para-aortic lymph node metastasis reported by Frumovitz et al. had a risk of missing nodal metastases in up to 6% of cases if lymphadenectomy is not performed based on these preoperative and intraoperative assessments [20]. Our data again confirm this in that 18–22% of the final uterine pathologic findings will be associated with a high-risk of nodal metastasis. Disease beyond the uterine body at the time of hysterectomy was also identified in a significant number of our cases. Cervical involvement was seen in nearly 7% of cases and FIGO stage III or IV disease was diagnosed in 7.3% of cases. Additionally, ovarian malignancy was identified in 3.2% of our cases. This is a single institution series with comprehensive pathologic review confirming the need for comprehensive surgical staging in patients with preoperative endometrial sampling diagnosis of FIGO grade 1 endometrial adenocarcinoma. Preoperative FIGO grade 1 correlates with final uterine grade in 85% of cases. The rate of HR uterine pathology based on preoperative grade 1 alone is over 18% with a significant risk of nodal metastasis. Preoperative and intraoperative assessments are inaccurate in risk stratification for nodal and other extra-uterine metastasis and should not be routinely used as a determinant for comprehensive staging, including lymphadenectomy. Frozen section may help further stratify for the risk of HR uterine pathology but is also not entirely accurate. Additionally, the accuracy of frozen section analysis may vary tremendously among institutions. All patients with an endometrial sampling diagnosis of endometrial carcinoma, including FIGO grade 1, who can medically and technically undergo surgery should be routinely offered comprehensive surgical staging as part of their initial therapy.
Conflict of interest statement The authors have no conflicts of interest to declare.
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