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Retrospective cohort study of surgical staging for ovarian low malignant potential tumors
American Journal of Obstetrics and Gynecology (2006) 194, e20–e22
www.ajog.org
Retrospective cohort study of surgical staging for ovarian low malignant potential tumors Shana N. Wingo, MD,a Lynne M. Knowles, MD,a Kelley S. Carrick, MD,b David S. Miller, MD,a John O. Schorge, MDa,* Department of Obstetrics and Gynecology, Division of Gynecologic Oncology,a and Department of Pathology,b University of Texas Southwestern Medical Center, Dallas, TX Received for publication August 11, 2005; revised November 4, 2005; accepted November 15, 2005
KEY WORDS Borderline ovarian tumors Surgical staging Ovarian low malignant potential tumors
Objective: The purpose of this study was to determine the benefit of surgically staging ovarian low malignant potential tumors. Study design: This was a retrospective cohort study of all ovarian low malignant potential tumors that were diagnosed by frozen section or final pathologic review from 2003 to 2005. Results: Twenty-two of 32 patients (69%) were staged surgically. Sixteen low malignant potential tumors were stage I by final pathologic review, and 4 tumors were upstaged to stage II-III disease. Two other patients had early invasive ovarian carcinoma, despite a frozen section that suggested low malignant potential; 1 patient received adjuvant chemotherapy. The tumors of 10 women (31%) were unstaged. Frozen section suspicion of low malignant potential (P = .003) and surgery by a gynecologic oncologist (P ! .001) correlated with staging. Preoperative CA-125, intraoperative blood loss, and postoperative hospitalization were increased in patients with staged disease (each P ! .05). Two women who underwent fertility-sparing surgery experienced a recurrence in the contralateral ovary. Conclusion: Surgical staging of ovarian low malignant potential tumors has limited value for most patients, unless invasive carcinoma is diagnosed by final pathologic review. Ó 2006 Mosby, Inc. All rights reserved.
Ovarian low malignant potential (LMP) tumors are a subset of epithelial ovarian neoplasms that are characterized by histologic features that mimic carcinoma in the absence of stromal invasion.1 The overall long-term prognosis is excellent. More than 80% of the tumors are stage I, and complete resection is usually curative.2 The * Reprint requests: John O. Schorge, MD, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, UT Southwestern Medical Center, 5323 Harry Hines Blvd, J7.124, Dallas, TX 75390-9032. E-mail: [email protected] 0002-9378/$ - see front matter Ó 2006 Mosby, Inc. All rights reserved. doi:10.1016/j.ajog.2005.11.033
benefit of adjuvant chemotherapy is speculative, even for advanced LMP tumors.3 Surgical staging provides more accurate prognostic information but may result in additional morbidity.4 Ninety-seven percent of gynecologic oncologists advocate surgical staging of LMP tumors, but only 12% of patients undergo sampling of the peritoneum, omentum, and retroperitoneal lymph nodes in clinical practice.5,6 The inability to exclude stromal invasion reliably at frozen section prohibits the development of a consistent strategy; up to one quarter of LMP diagnoses may be reclassified as invasive ovarian carcinoma by final
Wingo et al pathologic review.5 We performed a retrospective cohort study to determine the benefit of surgically staging ovarian LMP tumors.
Material and methods Institutional review board approval was obtained to identify retrospectively a cohort of patients who had been diagnosed with ovarian LMP tumor on frozen section or final pathologic review from April 2003 to May 2005. One or more permanent histologic sections were submitted per centimeter of tumor, with emphasis on a representative sampling of any solid, papillary, or architecturally complex areas. Patients with surgically staged disease were compared with patients whose tumors were unstaged. Categoric variable comparisons were conducted by Fisher’s exact test. Continuous variables were evaluated by the Student t test. Twotailed probability values are reported. The a value for all tests was set at .05.
Results Thirty-two patients with ovarian LMP tumor were a median age of 41 years (range, 16-68 years). Fourteen women were white; 14 women were Hispanic, and 4 women were black. The median follow-up time was 7 months (range, 1-24 months). Twenty-two women (69%) underwent surgical staging (Table). Nineteen women had a frozen section that suggested LMP. One additional woman underwent partial adnexectomy at the time of cesarean delivery without frozen section and final pathologic review demonstrated LMP. She was counseled carefully and did not desire future fertility. Surgical staging that was performed 6 weeks after the delivery showed residual ipsilateral disease and contralateral ovarian LMP tumor. Two other women were staged partially without lymphadenectomy for adnexal masses O15 cm, despite a frozen section diagnosis of mucinous cystadenoma and endometriotic cyst, respectively. Clinical suspicion was high at the time of surgery that sampling error might not rule out an early malignancy, and both cases ultimately had a final diagnosis of LMP tumor. The mean number of lymph nodes was 20 (range, 8-43 nodes) among the 16 women who had nodal dissection. The tumors of 10 LMP patients (31%) were unstaged. Three had an intraoperative frozen diagnosis of LMP. One had acute abdominal pain, presumed torsion, and an infarcted adnexa that was difficult to interpret accurately by frozen section. One LMP diagnosis occurred inadvertently during abdominal aortic aneurysm repair, and staging was not advised. The third patient had focal LMP features that were not demonstrated clearly on final pathologic review. Six frozen sections were benign, and the tumors were not clinically suspicious.
e21 Table Clinical features of staged and unstaged ovarian LMP tumors Clinical feature
Staged Unstaged P (n = 22) (n = 10) value
Mean age at diagnosis (y) 43.8 Mean preoperative CA-125 m/mL 218.3 Frozen section diagnosis (n) Benign disease 2 LMP 5 ‘‘At least’’ LMP 14 Not performed 1 Primary surgeon (n) Gynecologic oncologist 20 Obstetrician/gynecologist 2 Surgical procedure (n) Hysterectomy 15 Bilateral salpingo15 oophorectomy 6 Unilateral salpingooophorectomy Ovarian cystectomy 1 Cytologic washing 20 Peritoneal biopsy 19 Omentectomy 22 16 Pelvic/para-aortic node dissection Appendectomy 9 Mean estimated blood loss (mL) 561.6 Mean days of hospitalization (n) 5.3
34.9 24.3
.11 .02 .003
6 1 2 1 !.001 1 9 N/A 1 3 6 1 8 0 0 0 0 140.5 3.2
!.001 .007
One ovarian mass was removed without intraoperative evaluation. The tumors of 16 patients were staged surgically as stage I disease. One patient had stage II tumor, and 3 patients (pelvic nodal metastasis, para-aortic nodal metastasis, microscopic noninvasive peritoneal implant) had stage III ovarian LMP tumors. Two patients who underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, complete staging, and lymphadenectomy for presumed LMP had invasive ovarian carcinoma diagnosed after the operation. One patient with stage IA grade 2 disease did not receive further treatment. The other patient had stage IC grade 3 disease and completed 6 cycles of carboplatin and paclitaxel. Ten patients with unstaged disease had clinical stage I LMP tumor. The mean preoperative CA-125 level, estimated blood loss, and length of hospital stay were increased in patients whose disease was staged surgically (all P ! .05). Age, race, gravidity, parity, and histologic type were similar between the 2 groups (each P = not significant; some data not shown). Twenty ovarian LMP tumors were serous; 7 tumors were mucinous, and 2 tumors were endometrioid. One serous adenocarcinoma, 1 mucinous adenocarcinoma, and 1 benign ovarian adenofibroma were also noted on final pathologic review. The sensitivity of the frozen
e22 section to predict ‘‘at least’’ LMP was 72% (21/29 patients), and the positive predictive value was 95% (21/22 patients). Two of the 12 patients who underwent fertility-sparing surgery experienced recurrence in the contralateral ovary and were treated by resection; neither patient had been staged initially. LMP was detected in 1 case, and the other patient had stage IA grade 1 ovarian adenocarcinoma. No patient died of disease.
Comment Surgical staging of ovarian LMP tumors has limited value for most patients, unless invasive carcinoma is diagnosed by final pathologic review. Four LMP tumors were upstaged to more advanced disease, which included 2 tumors that had lymph node metastases. More accurate prognostic information was obtained for these 4 women, but the survival impact is speculative. Sixteen patients with staged disease with a final diagnosis of LMP appeared to derive no benefit from staging procedures. Two of the 22 patients with staged disease directly benefited from intraoperative surgical evaluation and lymphadenectomy by a gynecologic oncologist. Adjuvant chemotherapy was administered to 1 patient and was avoided in the other patient because of negative staging. Our study emphasizes the difficulty in the prediction of which tumors will ultimately have an invasive component. We advocate cytologic washings, exploratory procedures, random peritoneal biopsies, and partial omentectomy when LMP is suspected intraoperatively because of the potential for a final diagnosis of invasive ovarian cancer. These procedures can be performed easily by laparoscopy or laparotomy without extending the incision or appreciably prolonging the operation. Hysterectomy and bilateral salpingo-oophorectomy are appropriate in postmenopausal women and those women who do no not desire future fertility. Pelvic and paraaortic lymphadenectomy has a low yield in LMP tumors and presumably was one of the main factors that contributed to additional blood loss and a longer hospital stay in this study.4,7 Nodal sampling may be warranted in some circumstances and was performed fortuitously in both our patients with early invasive disease. None of the patients in this study had grossly evident invasive implants or unresectable disease that
Wingo et al would have suggested the need for postoperative chemotherapy.8 Most of the patients with unstaged LMP tumors were thought to have a benign adnexal mass by frozen section. Underdiagnosis of LMP tumors occurs commonly because of sampling error in large tumors with relatively focal malignant features.9 Only 1 case did not have any intraoperative evaluation. Surgical restaging is hard to justify in most patients with an unexpected final pathologic diagnosis of ovarian LMP tumor that is confined to a single ovary.10 The 2 contralateral ovarian recurrences in this study were more a result of fertilitysparing surgery than a lack of staging.11
References 1. Ozols R, Ruben S, Thomas G, Robboy S. Epithelial ovarian cancer. In: Hoskins WJ, Perez CA, Young RC, Barakat R, Markman M, Randall M, editors. Principles and practice of gynecologic oncology. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2005. p. 895-987. 2. Trimble CL, Kosary C, Trimble EL. Long-term survival and patterns of care in women with ovarian tumors of low malignant potential. Gynecol Oncol 2002;86:34-7. 3. Sutton GP, Bundy BN, Omura GA, Yordan EL, Beecham JB, Bonfiglio T. Stage III ovarian tumors of low malignant potential treated with cisplatin combination therapy. Gynecol Oncol 1991;41:230-3. 4. Rao GG, Skinner E, Gehrig PA, Duska LR, Coleman RL, Schorge JO. Surgical staging of ovarian low malignant potential tumors. Obstet Gynecol 2004;104:261-6. 5. Menzin AW, Gal D, Lovecchio JL. Contemporary surgical management of borderline ovarian tumors: a survey of the society of gynecologic oncologists. Gynecol Oncol 2000;78:7-9. 6. Lin PS, Gershenson DM, Bevers MW, Lucas KR, Burke TW, Silva EG. The current status of surgical staging of ovarian serous borderline tumors. Cancer 1999;85:905-11. 7. Winter WE, Kucera PR, Rodgers W, McBroom JW, Olsen C, Maxwell GL. Surgical staging in patients with ovarian tumors of low malignant potential. Obstet Gynecol 2002;100:671-6. 8. Longacre TA, McKenney JK, Tazelaar HD, Kempson RL, Hendrickson MR. Ovarian serous tumors of low malignant potential (borderline tumors): outcome-based study of 276 patients with long-term (R5-year) follow-up. Am J Surg Pathol 2005;29:707-23. 9. Houck K, Nikrui N, Duska L, Chang Y, Fuller AF, Bell D. Borderline tumors of the ovary: correlation of frozen and permanent histopathologic diagnosis. Obstet Gynecol 2000;95:839-43. 10. Land R, Perrin L, Nicklin J. Evaluation of restaging in clinical stage IA low malignant potential ovarian tumours. Aust N Z J Obstet Gynecol 2002;42:379-82. 11. Rao GG, Skinner EN, Gehrig PA, Duska LR, Miller DS, Schorge JO. Fertility-sparing surgery for ovarian low malignant potential tumors. Gynecol Oncol 2005;98:263-6.
www.ajog.org
Retrospective cohort study of surgical staging for ovarian low malignant potential tumors Shana N. Wingo, MD,a Lynne M. Knowles, MD,a Kelley S. Carrick, MD,b David S. Miller, MD,a John O. Schorge, MDa,* Department of Obstetrics and Gynecology, Division of Gynecologic Oncology,a and Department of Pathology,b University of Texas Southwestern Medical Center, Dallas, TX Received for publication August 11, 2005; revised November 4, 2005; accepted November 15, 2005
KEY WORDS Borderline ovarian tumors Surgical staging Ovarian low malignant potential tumors
Objective: The purpose of this study was to determine the benefit of surgically staging ovarian low malignant potential tumors. Study design: This was a retrospective cohort study of all ovarian low malignant potential tumors that were diagnosed by frozen section or final pathologic review from 2003 to 2005. Results: Twenty-two of 32 patients (69%) were staged surgically. Sixteen low malignant potential tumors were stage I by final pathologic review, and 4 tumors were upstaged to stage II-III disease. Two other patients had early invasive ovarian carcinoma, despite a frozen section that suggested low malignant potential; 1 patient received adjuvant chemotherapy. The tumors of 10 women (31%) were unstaged. Frozen section suspicion of low malignant potential (P = .003) and surgery by a gynecologic oncologist (P ! .001) correlated with staging. Preoperative CA-125, intraoperative blood loss, and postoperative hospitalization were increased in patients with staged disease (each P ! .05). Two women who underwent fertility-sparing surgery experienced a recurrence in the contralateral ovary. Conclusion: Surgical staging of ovarian low malignant potential tumors has limited value for most patients, unless invasive carcinoma is diagnosed by final pathologic review. Ó 2006 Mosby, Inc. All rights reserved.
Ovarian low malignant potential (LMP) tumors are a subset of epithelial ovarian neoplasms that are characterized by histologic features that mimic carcinoma in the absence of stromal invasion.1 The overall long-term prognosis is excellent. More than 80% of the tumors are stage I, and complete resection is usually curative.2 The * Reprint requests: John O. Schorge, MD, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, UT Southwestern Medical Center, 5323 Harry Hines Blvd, J7.124, Dallas, TX 75390-9032. E-mail: [email protected] 0002-9378/$ - see front matter Ó 2006 Mosby, Inc. All rights reserved. doi:10.1016/j.ajog.2005.11.033
benefit of adjuvant chemotherapy is speculative, even for advanced LMP tumors.3 Surgical staging provides more accurate prognostic information but may result in additional morbidity.4 Ninety-seven percent of gynecologic oncologists advocate surgical staging of LMP tumors, but only 12% of patients undergo sampling of the peritoneum, omentum, and retroperitoneal lymph nodes in clinical practice.5,6 The inability to exclude stromal invasion reliably at frozen section prohibits the development of a consistent strategy; up to one quarter of LMP diagnoses may be reclassified as invasive ovarian carcinoma by final
Wingo et al pathologic review.5 We performed a retrospective cohort study to determine the benefit of surgically staging ovarian LMP tumors.
Material and methods Institutional review board approval was obtained to identify retrospectively a cohort of patients who had been diagnosed with ovarian LMP tumor on frozen section or final pathologic review from April 2003 to May 2005. One or more permanent histologic sections were submitted per centimeter of tumor, with emphasis on a representative sampling of any solid, papillary, or architecturally complex areas. Patients with surgically staged disease were compared with patients whose tumors were unstaged. Categoric variable comparisons were conducted by Fisher’s exact test. Continuous variables were evaluated by the Student t test. Twotailed probability values are reported. The a value for all tests was set at .05.
Results Thirty-two patients with ovarian LMP tumor were a median age of 41 years (range, 16-68 years). Fourteen women were white; 14 women were Hispanic, and 4 women were black. The median follow-up time was 7 months (range, 1-24 months). Twenty-two women (69%) underwent surgical staging (Table). Nineteen women had a frozen section that suggested LMP. One additional woman underwent partial adnexectomy at the time of cesarean delivery without frozen section and final pathologic review demonstrated LMP. She was counseled carefully and did not desire future fertility. Surgical staging that was performed 6 weeks after the delivery showed residual ipsilateral disease and contralateral ovarian LMP tumor. Two other women were staged partially without lymphadenectomy for adnexal masses O15 cm, despite a frozen section diagnosis of mucinous cystadenoma and endometriotic cyst, respectively. Clinical suspicion was high at the time of surgery that sampling error might not rule out an early malignancy, and both cases ultimately had a final diagnosis of LMP tumor. The mean number of lymph nodes was 20 (range, 8-43 nodes) among the 16 women who had nodal dissection. The tumors of 10 LMP patients (31%) were unstaged. Three had an intraoperative frozen diagnosis of LMP. One had acute abdominal pain, presumed torsion, and an infarcted adnexa that was difficult to interpret accurately by frozen section. One LMP diagnosis occurred inadvertently during abdominal aortic aneurysm repair, and staging was not advised. The third patient had focal LMP features that were not demonstrated clearly on final pathologic review. Six frozen sections were benign, and the tumors were not clinically suspicious.
e21 Table Clinical features of staged and unstaged ovarian LMP tumors Clinical feature
Staged Unstaged P (n = 22) (n = 10) value
Mean age at diagnosis (y) 43.8 Mean preoperative CA-125 m/mL 218.3 Frozen section diagnosis (n) Benign disease 2 LMP 5 ‘‘At least’’ LMP 14 Not performed 1 Primary surgeon (n) Gynecologic oncologist 20 Obstetrician/gynecologist 2 Surgical procedure (n) Hysterectomy 15 Bilateral salpingo15 oophorectomy 6 Unilateral salpingooophorectomy Ovarian cystectomy 1 Cytologic washing 20 Peritoneal biopsy 19 Omentectomy 22 16 Pelvic/para-aortic node dissection Appendectomy 9 Mean estimated blood loss (mL) 561.6 Mean days of hospitalization (n) 5.3
34.9 24.3
.11 .02 .003
6 1 2 1 !.001 1 9 N/A 1 3 6 1 8 0 0 0 0 140.5 3.2
!.001 .007
One ovarian mass was removed without intraoperative evaluation. The tumors of 16 patients were staged surgically as stage I disease. One patient had stage II tumor, and 3 patients (pelvic nodal metastasis, para-aortic nodal metastasis, microscopic noninvasive peritoneal implant) had stage III ovarian LMP tumors. Two patients who underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, complete staging, and lymphadenectomy for presumed LMP had invasive ovarian carcinoma diagnosed after the operation. One patient with stage IA grade 2 disease did not receive further treatment. The other patient had stage IC grade 3 disease and completed 6 cycles of carboplatin and paclitaxel. Ten patients with unstaged disease had clinical stage I LMP tumor. The mean preoperative CA-125 level, estimated blood loss, and length of hospital stay were increased in patients whose disease was staged surgically (all P ! .05). Age, race, gravidity, parity, and histologic type were similar between the 2 groups (each P = not significant; some data not shown). Twenty ovarian LMP tumors were serous; 7 tumors were mucinous, and 2 tumors were endometrioid. One serous adenocarcinoma, 1 mucinous adenocarcinoma, and 1 benign ovarian adenofibroma were also noted on final pathologic review. The sensitivity of the frozen
e22 section to predict ‘‘at least’’ LMP was 72% (21/29 patients), and the positive predictive value was 95% (21/22 patients). Two of the 12 patients who underwent fertility-sparing surgery experienced recurrence in the contralateral ovary and were treated by resection; neither patient had been staged initially. LMP was detected in 1 case, and the other patient had stage IA grade 1 ovarian adenocarcinoma. No patient died of disease.
Comment Surgical staging of ovarian LMP tumors has limited value for most patients, unless invasive carcinoma is diagnosed by final pathologic review. Four LMP tumors were upstaged to more advanced disease, which included 2 tumors that had lymph node metastases. More accurate prognostic information was obtained for these 4 women, but the survival impact is speculative. Sixteen patients with staged disease with a final diagnosis of LMP appeared to derive no benefit from staging procedures. Two of the 22 patients with staged disease directly benefited from intraoperative surgical evaluation and lymphadenectomy by a gynecologic oncologist. Adjuvant chemotherapy was administered to 1 patient and was avoided in the other patient because of negative staging. Our study emphasizes the difficulty in the prediction of which tumors will ultimately have an invasive component. We advocate cytologic washings, exploratory procedures, random peritoneal biopsies, and partial omentectomy when LMP is suspected intraoperatively because of the potential for a final diagnosis of invasive ovarian cancer. These procedures can be performed easily by laparoscopy or laparotomy without extending the incision or appreciably prolonging the operation. Hysterectomy and bilateral salpingo-oophorectomy are appropriate in postmenopausal women and those women who do no not desire future fertility. Pelvic and paraaortic lymphadenectomy has a low yield in LMP tumors and presumably was one of the main factors that contributed to additional blood loss and a longer hospital stay in this study.4,7 Nodal sampling may be warranted in some circumstances and was performed fortuitously in both our patients with early invasive disease. None of the patients in this study had grossly evident invasive implants or unresectable disease that
Wingo et al would have suggested the need for postoperative chemotherapy.8 Most of the patients with unstaged LMP tumors were thought to have a benign adnexal mass by frozen section. Underdiagnosis of LMP tumors occurs commonly because of sampling error in large tumors with relatively focal malignant features.9 Only 1 case did not have any intraoperative evaluation. Surgical restaging is hard to justify in most patients with an unexpected final pathologic diagnosis of ovarian LMP tumor that is confined to a single ovary.10 The 2 contralateral ovarian recurrences in this study were more a result of fertilitysparing surgery than a lack of staging.11
References 1. Ozols R, Ruben S, Thomas G, Robboy S. Epithelial ovarian cancer. In: Hoskins WJ, Perez CA, Young RC, Barakat R, Markman M, Randall M, editors. Principles and practice of gynecologic oncology. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2005. p. 895-987. 2. Trimble CL, Kosary C, Trimble EL. Long-term survival and patterns of care in women with ovarian tumors of low malignant potential. Gynecol Oncol 2002;86:34-7. 3. Sutton GP, Bundy BN, Omura GA, Yordan EL, Beecham JB, Bonfiglio T. Stage III ovarian tumors of low malignant potential treated with cisplatin combination therapy. Gynecol Oncol 1991;41:230-3. 4. Rao GG, Skinner E, Gehrig PA, Duska LR, Coleman RL, Schorge JO. Surgical staging of ovarian low malignant potential tumors. Obstet Gynecol 2004;104:261-6. 5. Menzin AW, Gal D, Lovecchio JL. Contemporary surgical management of borderline ovarian tumors: a survey of the society of gynecologic oncologists. Gynecol Oncol 2000;78:7-9. 6. Lin PS, Gershenson DM, Bevers MW, Lucas KR, Burke TW, Silva EG. The current status of surgical staging of ovarian serous borderline tumors. Cancer 1999;85:905-11. 7. Winter WE, Kucera PR, Rodgers W, McBroom JW, Olsen C, Maxwell GL. Surgical staging in patients with ovarian tumors of low malignant potential. Obstet Gynecol 2002;100:671-6. 8. Longacre TA, McKenney JK, Tazelaar HD, Kempson RL, Hendrickson MR. Ovarian serous tumors of low malignant potential (borderline tumors): outcome-based study of 276 patients with long-term (R5-year) follow-up. Am J Surg Pathol 2005;29:707-23. 9. Houck K, Nikrui N, Duska L, Chang Y, Fuller AF, Bell D. Borderline tumors of the ovary: correlation of frozen and permanent histopathologic diagnosis. Obstet Gynecol 2000;95:839-43. 10. Land R, Perrin L, Nicklin J. Evaluation of restaging in clinical stage IA low malignant potential ovarian tumours. Aust N Z J Obstet Gynecol 2002;42:379-82. 11. Rao GG, Skinner EN, Gehrig PA, Duska LR, Miller DS, Schorge JO. Fertility-sparing surgery for ovarian low malignant potential tumors. Gynecol Oncol 2005;98:263-6.