Obstetrics & Gynecology:
When Is a Pathology Review Indicated in Endometrial Cancer?
Kwon, Janice S. MD, MPH1; Francis, Julie A. MD2; Qiu, Feng MSc3; Weir, Michele M. MD4; Ettler, Helen C. MBChB4
From the 1Department of Gynecologic Oncology, M.D. Anderson Cancer Center, Houston, Texas; 2Division of Gynecologic Oncology, University of Western Ontario, London, Ontario, Canada; 3Department of Programming and Biostatistics, Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada; and 4Department of Pathology, London Health Sciences and University of Western Ontario, London, Ontario, Canada.
See related editorial on page 1222.
Supported by a junior scientist award from the Mitchell Family, National Ovarian Cancer Association, and Cancer Care Ontario to Dr. Kwon.
Corresponding author: Janice S. Kwon, MD, MPH, FRCSC, Department of Gynecologic Oncology, M.D. Anderson Cancer Center, PO Box 301439, Unit 1362, Houston, TX, 77230-1439; e-mail: email@example.com.
Financial Disclosure The authors have no potential conflicts of interest to disclose.
OBJECTIVE: Discrepancies may exist between an original pathology report and formal pathology review, with subsequent implications for treatment. We conducted a study of pathology review in endometrial cancer from a population-based study to identify areas of discrepancy and effect on treatment.
METHODS: This was a retrospective cohort study in Ontario, Canada from 1996 to 2000. We identified hysterectomy cases from patients with endometrial cancer that were subject to formal pathology review by a gynecologic pathologist at one of six tertiary care centers. Sarcomas and other rare histologic subtypes with fewer than five cases were excluded. We evaluated discrepancy between original pathology and review by demographics, stage, grade, and risk group. Four risk groups were defined: 1) low (stage I), 2) intermediate (stage I and II), 3) high-risk (stage I and II), and 4) advanced stage (all stage III and IV). Reclassification from one risk group to another upon pathology review represented a potential change in treatment. Factors associated with significant discrepancy were identified by a multivariable logistic regression model.
RESULTS: Formal pathology review was available on 450 cases. There were no differences by age, year, or hospital type. The overall discrepancy rate was 42.7% (95% confidence interval 38.2–47.3%). The intermediate-risk group had the highest rate of reclassification into another group (33.1%). The most significant rates of discrepancy were associated with endometrioid grades 2 and 3 tumors and stage IIA disease (39.8%, 50.9%, and 79.6%, respectively).
CONCLUSION: There was significant discrepancy between original pathology and formal review in endometrial cancer, with implications for guidelines on pathology review at a population level.
LEVEL OF EVIDENCE: III
It is well recognized that histologic type, grade, and stage are important determinants of outcome and indications for adjuvant treatment in endometrial cancer. The presence of one or more uterine factors, such as high-risk histologic subtype, high-grade, deep myometrial invasion, and cervical stromal invasion, are often indications for adjuvant therapy.1–4 Therefore it is essential that surgical pathology reports are accurate, because the information from these reports is needed to make recommendations for further treatment. Endometrial cancer is the gynecologic disease site in which the pathology report is most likely to change after expert review.5 The objectives of this study are to estimate the rate of discrepancy between original pathology report and pathology review from a previously reported population-based study, to estimate how these changes may have had an effect on treatment, and to suggest guidelines for formal pathology review within this population.
MATERIALS AND METHODS
Approval for this study was obtained from the Health Services Research Ethics Board at the Institute for Clinical Evaluative Sciences, Toronto Sunnybrook Hospital, Canada. All electronic records of endometrial cancer (International Classification of Diseases codes 179 or 182) were identified from the Ontario Cancer Registry from 1996 to 2000. Details of histopathology, grade, lymphovascular space invasion, and determinants of stage (depth of myometrial invasion, cervical involvement, adnexal disease, and nodal involvement) were abstracted from pathology records. To be included in this analysis, all patients must have had definitive surgery (hysterectomy, bilateral salpingo-oophorectomy, with or without pelvic, and/or para-aortic lymphadenectomy or sampling) with an initial pathology report, and histopathologic slides from these surgical cases had to be subsequently reviewed by a gynecologic pathologist at one of the six tertiary care centers in the province, who then provided a formal report of the pathology review. Initial pathology reports of endometrioid, uterine papillary serous, and clear cell carcinomas were included, and sarcomas and other rare histologic subtypes for which there were fewer than five cases were excluded. We compared the initial report and pathology review and reported discrepancy rates between these two reports as a percentage with 95% confidence intervals (CIs). Statistical analysis was performed using SAS 8.2 (SAS Institute Inc., Cary, NC). We used a χ2 test to evaluate rates of discrepancy according to patient age, year of diagnosis, and hospital type where surgery took place (ie, community or teaching hospital). The original pathology report and pathology review were compared by stage, grade, and risk group and expressed as reliability coefficients by Stuart-Maxwell χ2 tests for homogeneity. Four risk groups were established from stage and grade combinations to estimate how adjuvant therapy may have changed, including three early stage (stage I and II) risk groups and one advanced-stage risk group. Low risk was defined as Stages IA and IB with endometrioid histology grades 1 and 2. Intermediate risk was defined as Stages IA and 1B grade 3, stage IC and IIA grades 1 and 2, and stage IIA grade 3 with less than 50% myometrial invasion. This definition was adopted from criteria for PORTEC-2 (Postoperative Radiation Therapy in Endometrial Cancer), a multicenter randomized phase III trial comparing adjuvant pelvic radiotherapy to vault brachytherapy for intermediate risk endometrial cancer.6 High risk was defined as stage IC grade 3, stage IIA grade 3 with greater than 50% myometrial invasion, stage IIB, and all stage I and II uterine papillary serous carcinoma and clear cell carcinoma. We defined the advanced-stage risk group as those who had stage III or IV carcinoma with any grade. Based on practice patterns in Ontario and Clinical Practice Guidelines for Uterine Neoplasms from the National Cancer Comprehensive Network, women with low-risk disease were unlikely to receive adjuvant therapy, whereas patients in the intermediate risk group may have received some type of adjuvant therapy (eg, vault brachytherapy with or without external beam pelvic radiotherapy), and the majority of women in the high-risk group were expected to receive at least adjuvant pelvic radiotherapy.7,8 Patients in the advanced-stage disease group were expected to receive adjuvant chemotherapy with or without radiotherapy.8 A multivariable logistic regression model identified factors associated with significant rates of discrepancy.
A total of 3,875 women had surgery for endometrial cancer in Ontario, Canada during the study period, for whom practice patterns and outcomes have been previously reported.7 A pathology review was obtained on 484 patients (12.5%). After excluding all sarcomas and rare histologic subtypes, such as squamous cell, small cell, and mucinous carcinomas, there were 450 cases available for review (11.6%). There were 76 hospitals from which surgical cases were submitted for formal pathology review. Histopathologic slides (hysterectomy, bilateral salpingo-oophorectomy, with or without other specimens obtained at the time of surgery) were sent to one of 12 gynecologic pathologists at one of six tertiary care centers where a formal pathology report was issued after review of these slides. Discrepancy between the original pathology report and pathology review occurred in 192 cases, for an overall discrepancy rate of 42.7% (95% CI 38.2–47.3%). Table 1 summarizes the discrepancy rates between these pathology reports by year of diagnosis, patient age, and hospital type where surgery took place. We did not find significant differences in these rates according to these demographic variables.
The Stuart-Maxwell χ2 test for homogeneity reveals that the distributions of stage, grade, and risk group differ significantly between original pathology report and formal pathology review. Table 2 summarizes the changes in stage from the original pathology report. The original stage was changed in 104 cases (23.1%, 95% CI 19.5–27.2%). The highest rate of discrepancy was observed among stage II patients (43 of 64, 67.2%). Among the 44 patients who were initially diagnosed as having stage IIA disease, the diagnosis was changed in almost 80% of cases after pathology review. The majority of these patients (24 of 44, 54.5%) in fact had cervical stromal invasion instead of endocervical intraepithelial involvement only. Similarly, of the 20 patients who were originally diagnosed as having stage IIB disease, the stage was changed in 40%, with more than one half of these patients being downstaged to stage IIA. However, if the original pathologist had identified intraabdominal disease (stage IVB), this was confirmed on pathology review in 100% of cases.
Table 3 summarizes the changes in histology and grade from the original pathology report. The original grade was changed in of 281 of 391 (71.9%, 95% CI 67.2–76.1%) of all endometrioid tumors. The highest rate of discrepancy was found among grade 3 endometrioid tumors (49.1%), which were “down-graded” to grade 2 in 22.8% of cases, or changed to a high-risk histologic subtype (uterine papillary serous carcinoma or clear cell carcinoma) in 28.1% of cases. None of the grade 3 tumors were “down-graded” to grade 1, and none of the grade 1 tumors were “up-graded” to grade 3. Grade 2 endometrioid tumors were more often “down-graded” to grade 1 (31.3%) than “up-graded” to grade 3 (8.5%). The original diagnosis of uterine papillary serous carcinoma or clear cell carcinoma did not change; if the original pathologist made the diagnosis of uterine papillary serous carcinoma or clear cell carcinoma, this was confirmed on review in 100% of cases.
Table 4 summarizes the changes in risk group after pathology review. Forty percent of cases subject to pathology review (180 of 450) were initially classified as low-risk. More than 90% (90.6%, 95% CI 85.3–94.1%) of the original low-risk group remained in this group after review. Only 66.9% (95% CI 58.9–74.1%) of the intermediate risk group remained in this group, whereas 13.1% and 20% were reclassified into the low- and high-risk groups, respectively. Of the high-risk group, 87.5% (95% CI 77.7–93.5%) remained in this group, whereas the rest were reclassified as low or intermediate risk or advanced-stage disease. Less than 10% of the 52 patients in the advanced-stage group (stage III and IV) were downstaged.
Table 5 outlines the multivariable logistic regression model of factors associated with discrepancy between original pathology report and formal pathology review. Original pathology reports of endometrioid grades 2 and 3 tumors and stage IIA disease were associated with significantly higher rates of discrepancy (39.8%, 50.9%, 79.6%, respectively) compared with the reference category for each variable (grade 1 and stage IA).
This is a large study evaluating pathology review in endometrial cancer within a specific population. The high rate of discrepancy in this study is similar to that described in other smaller single institution studies9,10 and in PORTEC.11 There may be limited reproducibility for histologic features that determine grade and stage. Several authors have proposed a binary grading system that accounts for this difficulty in reproducibility, by essentially combining grades 1 and 2 tumors as “low-grade”, and keeping grade 3 separate as “high-grade”, resulting in higher agreement rates between pathology reports.12–15 By adopting a binary system, the discrepancy rate in this study (ie, change from low grade to high grade) was only 4.3%. On the other hand, the diagnosis of uterine papillary serous carcinoma or clear cell carcinoma on hysterectomy specimens in this study was confirmed in 100% of cases upon pathology review. Our study suggests that the histologic characteristics of these two aggressive subtypes can be readily identified,16–18 although only 59 cases were subject to pathology review.
Many tertiary care centers have a policy of mandating formal pathology review for all cases before consultation.19–21 However, not all cases of endometrial cancer are referred to a tertiary care center, and our results reflect practice patterns within a specific population of approximately 11 million during the study period.22 Of 3,875 primary surgical cases for endometrial cancer, only 12.5% were subject to formal pathology review. We did not have information from administrative databases about the reasons for pathology review, and there may have been a selection bias toward “diagnostically challenging” cases. We do not know whether the gynecologic pathologist responsible for the review was blinded to the results of the original pathology report, and in the event of a discrepancy between the original report and pathology review, whether any additional gynecologic pathologists were involved in reviewing the original slides, and if there was consensus. Zaino et al23 reported a complete diagnostic agreement rate of only 40% among a panel of three experienced gynecologic pathologists in a prospective Gynecologic Oncology Group study of atypical endometrial hyperplasia. However, with consensus defined as agreement among at least two of the three pathologists, Trimble et al24 reported a rate of nonconsensus of only 6%. Without subjecting all surgical cases for formal review, the accuracy and reliability of original pathology reports for adjuvant therapy recommendations in this population is unknown. The ideal population-based study would be prospective, with consistent application of surgical specimen processing techniques and evaluation of slides, and agreement between at least two gynecologic pathologists.
Discrepancies in pathology report are not always clinically significant, and therefore the focus of this study was potential change in management by classifying the study cohort into risk groups, based on PORTEC-2 and National Cancer Comprehensive Network clinical practice guidelines.6,8 Change from one risk group to another represented a potential change in adjuvant therapy recommendations. Although almost one third of the original intermediate risk group was reclassified as low or high risk, we cannot confirm that treatment recommendations changed consistently as a result of reclassification without a detailed chart review. Furthermore, practice patterns vary considerably with respect to surgery and adjuvant radiotherapy,7 therefore a revision in pathology report may not have consistently changed management across the province.
In the absence of Level 1 or 2 evidence, how do we decide on when a pathology review is really indicated in endometrial cancer in this population? At the present time there are no provincial guidelines for pathology review, and the decision to obtain pathology review may depend on many factors, including the primary physician (gynecologist or gynecologic oncologist), the original pathologist, consulting subspecialist (radiation or medical oncologist), and preexisting, institution-specific policies. Without question, pathology review should be mandatory if it may lead to adjuvant therapy that improves survival. At present, the only adjuvant therapy known to improve survival in endometrial cancer in a phase III clinical trial is platinum-based chemotherapy for advanced (stage III and IV) disease, as reported by Randall et al25 of the Gynecologic Oncology Group, and therefore the identification of all patients with stage III or IV disease is imperative. Based on the results of our study, only high-risk stage I and II patients had the possibility of being reclassified as advanced stage upon pathology review, and therefore we would recommend pathology review for these patients. Because of the implications for treatment, we would recommend review for all stage III and IV cases to confirm advanced-stage disease.
Another important endpoint of pathology review is the identification of patients who would be spared adjuvant therapy (ie, low risk). Only intermediate risk patients had a significant rate of reclassification to the low-risk group, which would have obviated the need for adjuvant radiotherapy, and therefore we would recommend pathology review for these patients.
Formal systematic review of all endometrial cancer cases in the population would identify any case with potential for change in management, including adjuvant pelvic radiotherapy and vault brachytherapy. However, while these therapies reduce the risk of local–regional recurrence, they have not yet been proven in a phase III clinical trial to improve survival in endometrial cancer.1,3,4,26 Furthermore, a policy of universal pathology review may be impractical and unfeasible. The cost of formal pathology review is not necessarily prohibitive, as it would include regional courier costs for histopathologic slides ($15.00),27 the pathologist's consultative fee ($64.70),28 and administrative costs for medical report transcription ($15.73 per hour of secretarial support),29 for a total of less than $100 per pathology review. If two pathologists are involved, the cost is approximately $160 per review. For an estimated 1,600 annual endometrial cancer cases in Ontario, this translates into a cost of approximately $160,000 to $256,000 for the entire population.30 However, the majority of endometrial cancer cases in this population and others are known to be low-risk,31,32 and the discrepancy rate upon pathology review for this risk group based on our study seems to be less than 10%. Most of these discrepant cases are reclassified as intermediate risk, for which vault brachytherapy with or without pelvic radiotherapy may be recommended. Even in the absence of adjuvant therapy, the majority of these patients can be salvaged with radiotherapy at the time of recurrence, and their survival outcomes are similar to those who receive adjuvant vault or pelvic radiotherapy immediately after surgery. 1,3,4,26,33 The Ministry of Health, responsible for allocation of health care funding and resources in the province, is unlikely to support a policy of universal pathology review when there are other competing priorities for health care providers in our single-payer, publicly-funded health care system. A discrepancy rate of less than 10% for the low-risk group might be considered acceptable, because the effect of reclassification of this group seems to be clinically insignificant.
A policy of universal pathology review would enable us to establish the true discrepancy rate between original report and formal review in endometrial cancer within our population. Recognizing that this process may not be feasible within our current health care system, we can only make recommendations based on available empiric data. We would currently recommend pathology review for all non–low-risk endometrial cancers, with ongoing appraisal of provincial data to refine our recommendations for pathology review in the future.
1. Aalders J, Abeler V, Kolstad P, Onsrud M. Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical and histopathologic study of 540 patients. Obstet Gynecol 1980;56:419–27.
2. Carey MS, O'Connell GJ, Johanson CR, Goodyear MD, Murphy KJ, Daya DM, et al. Good outcome associated with a standardized treatment protocol using selective postoperative radiation in patients with clinical stage I adenocarcinoma of the endometrium. Gynecol Oncol 1995;57:138–44.
3. Creutzberg CL, van Putten WL, Koper PC, Lybeert ML, Jobsen JJ, Warlam-Rodenhuis CC, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet 2000;355:1404–11.
4. Keys HM, Roberts JA, Brunetto VL, Zaino RJ, Spirtos NM, Bloss JD, et al. A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2004;92:744–51.
5. Chafe S, Honore L, Pearcey R, Capstick V. An analysis of the impact of pathology review in gynecologic cancer. Int J Radiat Oncol Biol Phys 2000;48:1433–8.
7. Kwon JS, Carey MS, Cook EF, Qiu F, Paszat L. Patterns of practice and outcomes in intermediate- and high-risk stage I and II endometrial cancer: a population-based study. Int J Gynecol Cancer 2007;17:433–40.
9. Ali A, Black D, Soslow RA. Difficulties in assessing the depth of myometrial invasion in endometrial carcinoma. Int J Gynecol Pathol 2007;26:115–23.
10. Jacques SM, Qureshi F, Munkarah A, Lawrence WD. Interinstitutional surgical pathology review in gynecologic oncology: II. Endometrial cancer in hysterectomy specimens. Int J Gynecol Pathol 1998;17:42–5.
11. Scholten AN, van Putten WL, Beerman H, Smit VT, Koper PC, Lybeert ML, et al. Postoperative radiotherapy for Stage 1 endometrial carcinoma: long-term outcome of the randomized PORTEC trial with central pathology review. Int J Radiat Oncol Biol Phys 2005;63:834–8.
12. Alkushi A, Abdul-Rahman ZH, Lim P, Schulzer M, Coldman A, Kalloger SE, et al. Description of a novel system for grading of endometrial carcinoma and comparison with existing grading systems. Am J Surg Pathol 2005;29:295–304.
13. Lax SF, Kurman RJ, Pizer ES, Wu L, Ronnett BM. A binary architectural grading system for uterine endometrial endometrioid carcinoma has superior reproducibility compared with FIGO grading and identifies subsets of advance-stage tumors with favorable and unfavorable prognosis. Am J Surg Pathol 2000;24:1201–8.
14. Scholten AN, Smit VT, Beerman H, van Putten WL, Creutzberg CL. Prognostic significance and interobserver variability of histologic grading systems for endometrial carcinoma. Cancer 2004;100:764–72.
15. Taylor RR, Lieberman RW, O'Connor DM. An analysis of two versus three grades for endometrial carcinoma. Gynecol Oncol 1999;74:3–6.
16. Abeler VM, Kjorstad KE. Serous papillary carcinoma of the endometrium: a histopathological study of 22 cases. Gynecol Oncol 1990;39:266–71.
17. Abeler VM, Kjorstad KE. Clear cell carcinoma of the endometrium: a histopathological and clinical study of 97 cases. Gynecol Oncol 1991;40:207–17.
18. Hendrickson M, Ross J, Eifel P, Martinez A, Kempson R. Uterine papillary serous carcinoma: a highly malignant form of endometrial adenocarcinoma. Am J Surg Pathol 1982;6:93–108.
19. Khalifa MA, Dodge J, Covens A, Osborne R, Ackerman I. Slide review in gynecologic oncology ensures completeness of reporting and diagnostic accuracy. Gynecol Oncol 2003;90:425–30.
20. Santoso JT, Coleman RL, Voet RL, Bernstein SG, Lifshitz S, Miller D. Pathology slide review in gynecologic oncology. Obstet Gynecol 1998;91:730–4.
21. Selman AE, Niemann TH, Fowler JM, Copeland LJ. Quality assurance of second opinion pathology in gynecologic oncology. Obstetrics and gynecology 1999;94:302–6.
23. Zaino RJ, Kauderer J, Trimble CL, Silverberg SG, Curtin JP, Lim PC, et al. Reproducibility of the diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer 2006;106:804–11.
24. Trimble CL, Kauderer J, Zaino R, Silverberg S, Lim PC, Burke JJ 2nd, et al. Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer 2006;106:812–9.
25. Randall ME, Filiaci VL, Muss H, Spirtos NM, Mannel RS, Fowler J, et al. Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol 2006;24:36–44.
26. Orton J. Adjuvant external beam radiotherapy (EBRT) in the treatment of endometrial cancer: Results of the randomised MRC-ASTEC and NCIC CTG EN.5 trial. J Clin Oncol 2007;25:18S.
31. Aalders JG, Thomas G. Endometrial cancer—revisiting the importance of pelvic and para aortic lymph nodes. Gynecol Oncol 2007;104:222–31.
32. Hogberg T, Fredstorp-Lidebring M, Alm P, Baldetorp B, Larsson G, Ottosen C, et al. A prospective population-based management program including primary surgery and postoperative risk assessment by means of DNA ploidy and histopathology. Adjuvant radiotherapy is not necessary for the majority of patients with FIGO stage I-II endometrial cancer. Int J Gynecol Cancer 2004;14:437–50.
33. Ackerman I, Malone S, Thomas G, Franssen E, Balogh J, Dembo A. Endometrial carcinoma—relative effectiveness of adjuvant irradiation vs therapy reserved for relapse. Gynecol Oncol 1996;60:177–83.
Figure. No caption available.
© 2007 The American College of Obstetricians and Gynecologists