- Email: [email protected]
Management of borderline ovarian tumours
Accepted Manuscript Management of Borderline Ovarian Tumours David M. Gershenson, MD
PII:
S1521-6934(16)30089-X
DOI:
10.1016/j.bpobgyn.2016.09.012
Reference:
YBEOG 1648
To appear in:
Best Practice & Research Clinical Obstetrics & Gynaecology
Received Date: 16 August 2016 Revised Date:
21 August 2016
Accepted Date: 7 September 2016
Please cite this article as: Gershenson DM, Management of Borderline Ovarian Tumours, Best Practice & Research Clinical Obstetrics & Gynaecology (2016), doi: 10.1016/j.bpobgyn.2016.09.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Management of Borderline Ovarian Tumours David M. Gershenson, MD
RI PT
Department of Gynecologic Oncology and Reproductive Medicine University of Texas MD Anderson Cancer Center, Unit 1362 1155 Pressler Drive
David M. Gershenson, MD
M AN U
Corresponding Author:
SC
Houston, TX 77030, USA
Department of Gynecologic Oncology and Reproductive Medicine
1155 Pressler Drive
TE D
University of Texas MD Anderson Cancer Center, Unit 1362
Houston, TX 77030, USA
EP
Phone: 1-713-745-2565 FAX: 1-713-745-3510
AC C
Email: [email protected]
ACCEPTED MANUSCRIPT
Abstract Approximately 3000 American women are diagnosed with borderline ovarian tumours annually. Borderline tumours present similar to other types of adnexal
RI PT
masses. Prognostic factors include FIGO stage, presence of peritoneal implants, micropapillary pattern (for serous histology), microinvasion, and intraepithelial
carcinoma (for mucinous histology). Approximately 65-70% of serous tumours
SC
and 90% of mucinous tumours are stage I, and 30% and 10%, respectively, are associated with extra-ovarian spread. Fertility-preservation counseling is
M AN U
recommended for young patients. Fertility-sparing surgery is feasible in a high proportion of women in the reproductive age group. Surgical staging generally includes resection of the primary borderline tumour, either by unilateral salpingooophorectomy or ovarian cystectomy, cytologic washings, omentectomy, and
TE D
peritoneal biopsies, and routine lymphadenectomy is not recommended. However, because the accuracy of frozen-section examination is less than optimal, caution is recommended. Postoperative therapy is recommended only
EP
for those women with serous borderline tumours and invasive implants.
AC C
Fortunately, relapse is uncommon.
Keywords: borderline ovarian tumours, fertility-sparing surgery, serous, mucinous
ACCEPTED MANUSCRIPT
Introduction In 1929, Taylor first described a group of patients with `semimalignant' or
RI PT
hyperplastic ovarian tumours without histological evidence of stromal invasion but with peritoneal implants [1]. He noted that these patients had a better
prognosis than those with frankly malignant tumours. However, not until the
SC
International Federation of Gynecology and Obstetrics (FIGO) recognized the
distinct clinical entity of ‘carcinoma of low malignant potential' [2] and the World
M AN U
Health Organization WHO) adopted the term ‘borderline malignancies' [3] did this group of tumours receive general acceptance. Only within the past two decades or so have we begun to understand their biological behaviour and optimal therapy.
TE D
Approximately 3000 American women are diagnosed with borderline ovarian tumours annually. Borderline ovarian tumours account for 10-15% of epithelial tumours. Histological types include serous (Fig. 1)--the most common—
EP
mucinous (Fig. 2), endometrioid, clear-cell, and transitional-cell (or Brenner)
AC C
tumours. The latter three histological types are very uncommon. Histological criteria for the diagnosis of borderline ovarian tumours include nuclear atypia, stratification of the epithelium, formation of microscopic papillary projections and the absence of stromal invasion. Principles of clinical management of borderline ovarian tumours have evolved over the past two decades as our understanding of their biological behaviour has been elucidated. However, there remain many gaps in our knowledge of these
ACCEPTED MANUSCRIPT
neoplasms that result in controversies regarding their biology and in different therapeutic approaches. Important keys to gaining additional insight into optimal clinical management include considerations for comprehensive surgical staging,
RI PT
adequate tissue sampling and adequate follow-up time. This chapter provides a
M AN U
Clinical Presentation and Diagnosis
SC
literature-based review of these contemporary management principles.
Borderline ovarian tumours present in the same manner as other adnexal masses. Patients may complain of pelvic pain or dyspareunia, although they are frequently asymptomatic. Adnexal masses may be palpated at the time of a pelvic examination. Occasionally they are detected as an incidental finding during
TE D
routine obstetrical sonography. In a study of 151 women with borderline ovarian tumours, 84% had symptoms prior to diagnosis, and the median duration of
EP
symptoms in those patients was 6 months [4] In a woman with an adnexal mass, pelvic ultrasound and serum CA 125 are
AC C
generally recommended. Ultrasound of a borderline ovarian tumour will not uncommonly reveal a complex ovarian mass. However, there is no pathognomonic sonographic appearance associated with borderline tumours. Similarly, serum CA 125 is rather non-specific. In one study, levels of serum CA 125 were within normal limits in 32% of patients with serous borderline tumours and 48% of mucinous borderline tumours [5]. In a retrospective study of 1069 patients with borderline ovarian tumours in Japan, 49% had normal serum CA
ACCEPTED MANUSCRIPT
125 levels and only 23% had serum CA 125 levels above 100 U/ml [6]. In another study from Singapore, of 198 patients with a preoperative serum CA 125, 77 (39%) had levels >35 U/ml [7]. In addition, those with CA 125 levels < 35 U/ml
RI PT
were more likely to have stage I disease. In the same report, among nine
patients who had an elevated serum CEA level, all were of mucinous cell type. Two further studies found that preoperative serum CA 125 values were more
SC
often elevated in serous compared with mucinous tumours and in advanced
stage compared with stage I [8,9]. Kolwijck et al. reported that serum CA 125
M AN U
levels > 35 U/ml were more often noted in patients with the serous type (67%) compared with the mucinous type (39%) and in patients with advanced stage
TE D
disease (83%) more frequently than in stage I disease (47%) [8].
Borderline ovarian tumours occur in women of all ages, with an average age in the mid-40s--some 15 years younger than that for invasive ovarian cancers.
EP
Therefore, a high proportion of women with borderline tumours is in the reproductive age group. Because of their relative rarity and the absence of a
AC C
reliable test or marker, borderline ovarian tumours are rather low on the differential diagnosis list. In addition, the availability of reliable frozen-section analysis in many hospitals is problematical. Nevertheless, it is important for surgeons operating on women to consider the potential diagnosis of borderline ovarian tumour and to counsel patients and their families appropriately with regard to intraoperative management.
ACCEPTED MANUSCRIPT
Prognostic Factors
RI PT
The factors most strongly associated with outcome—either relapse, survival, or both—are FIGO stage, presence of peritoneal implants, micropapillary pattern, and microinvasion [10-18]. For patients with peritoneal implants, those with
SC
invasive implants appear to have a higher relapse rate (> 50%) and worse
prognosis than those with noninvasive implants (Fig. 3) (20-50%) [19]. Additional
M AN U
factors that have emerged as predictive or prognostic in some but not all studies have been incomplete surgical staging [14,17], residual disease [11], fertilitysparing surgery [12,14,16], preoperative serum CA 125 level [12], bilateral ovarian involvement [16], and age [12.16.18]. For age, however, some studies
TE D
have found that younger patients have a worse outcome [16] while other studies indicate that older patients fare worse [12,18].
AC C
factor [20,21].
EP
On the other hand, lymph node involvement does not appear to be a prognostic
Surgical Management Operative Findings. Approximately 65-70% of all serous borderline tumours and 90% of all mucinous borderline tumours are stage I. Extraovarian spread (stages II-IV) occurs in about 30-35% of serous borderline tumours and in only 10% of mucinous borderline tumours.
ACCEPTED MANUSCRIPT
Approximately 50% of serous borderline tumours and 80-90% of mucinous borderline tumours are confined to one ovary at diagnosis. The other cell types of
stage I, and the vast majority are unilateral.
RI PT
borderline tumours--endometrioid, clear-cell and transitional--are almost always
When extraovarian spread does occur, it rarely presents as bulky metastatic
SC
disease; in most cases the so-called peritoneal implants are either microscopic or small macroscopic (< 1-2 cm). As discussed below, it is important for the surgeon
M AN U
encountering a borderline tumour to be thoroughly familiar with this information to optimize intraoperative decision-making.
Surgical Approach. Surgery is the primary treatment. One of the initial considerations in contemplating surgery for a pelvic mass is the surgical
TE D
approach—minimally invasive or open technique. Factors to be considered in the selection of minimally invasive surgical approaches (laparoscopic or robotic) include size of the ovarian mass(es), extent of tumour metastasis, number and
EP
type or previous operations, and body habitus. Several reports have documented the feasibility and safety of the minimally invasive approach when appropriately
AC C
used [22-25].
Surgical Staging for Apparent Stage I. A major question in the treatment of borderline tumours involves the role of comprehensive surgical staging. Since the presence of peritoneal implants has prognostic significance, and the most common sites of implants include the omentum and peritoneal surfaces, surgical
ACCEPTED MANUSCRIPT
staging consisting of cytologic washings, omentectomy and peritoneal biopsies is generally recommended (Table 1) [26.27].
RI PT
In a survey study of the Society of Gynecologic Oncology from 2000, Menzin et
al. reported the responses from 274 members on the topic of surgical staging for borderline tumours [28]. Of this group, 96% stated that they performed cytologic
SC
washings, 97% biopsied the omentum, and 92% performed random peritoneal biopsies. Interestingly, 97% performed pelvic lymph node biopsies, and 89%
M AN U
performed paraaortic lymph node biopsies. In a review of the MD Anderson experience, Lin et al. reviewed pathology reports of 255 cases of serous borderline tumours [29]. Approximately 12% underwent comprehensive surgical staging, including lymphadenectomy. Overall, 59% underwent omental sampling;
TE D
27% and 29% underwent abdominal or pelvic peritoneal biopsies, respectively; 18% underwent sampling of pelvic lymph nodes; and 13% underwent paraaortic lymph node biopsies. Gynecologic oncologists performed complete surgical
EP
staging in 50% of patients, compared to only 9% by obstetrician-gynecologists.
AC C
On the other hand, some reports suggest that complete surgical staging is not necessary for borderline tumours. Guvenal and colleagues reported on a Turkish experience with 539 patients with borderline tumours from 14 institutions [30]. Of all patients, 54.5% underwent surgical staging, and 77.6% of this group had comprehensive surgical staging, including lymphadenectomy. With a median follow-up time of 36 months, the 5-year survival was 100%. The authors
ACCEPTED MANUSCRIPT
concluded that comprehensive surgical staging was not beneficial in the management of borderline ovarian tumours. However, it should be pointed out that the follow-up time was relatively short, and only a small proportion of the
RI PT
patients in this study had extra-ovarian disease. Additionally, Kristensen et al., in a study of 75 patients with borderline tumours, concluded that random peritoneal
SC
biopsies are not beneficial [31].
Probably the most major question surrounding the issue of surgical staging for
M AN U
borderline tumours involves the role of routine lymphadenectomy. Winter et al. compared two cohorts of patients with borderline tumours—48 who underwent comprehensive surgical staging versus 45 without surgical staging [32]. Only 6% of the 48 patients who underwent surgical staging had lymph node involvement,
TE D
and relapse rates were not significantly different between the two groups. Because the incidence of lymph node involvement is quite low, routine pelvic and paraaortic lymphadenectomy is not recommended by most [33]. However, if
EP
lymphadenopathy is noted, resection is appropriate.
AC C
The Accuracy of Frozen Section Examination for Borderline Tumours. For every woman undergoing surgery for an adnexal mass, intraoperative frozensection examination is recommended to facilitate decision-making. Although frozen-section readings will never be perfectly accurate, they certainly can provide guidance in most cases. Of course, the expertise of the pathologist is key component in determining accuracy. For example, the difference in a frozen-
ACCEPTED MANUSCRIPT
section diagnosis of invasive ovarian cancer versus borderline tumour may well influence the decision to perform routine lymphadenectomy. Thus, caution is recommended. In the study by Winter et al., frozen-section examination was
RI PT
performed in 83 of 93 patients with a final diagnosis of borderline ovarian tumour [32]. Of these, 25% were reported as benign cystadenomas, 10% as invasive cancer, and 65% as borderline tumours. Similarly, in a study 354 cases of
SC
borderline ovarian tumours, Song et al. reported that the overall agreement between frozen-section and final pathology reports was only 64.4% [34].
M AN U
Mucinous histology was the only predictor for under-diagnosis by frozen-section analysis. The authors concluded that frozen-section examination for mucinous borderline tumours in not very accurate and is associated with a high degree of
TE D
under-diagnosis and over-diagnosis.
Surgical Restaging of Patients Who Are Incompletely Staged. For patients referred to gynecologic oncologists following a diagnosis of a borderline ovarian
EP
tumour without surgical staging, clinical management remains controversial. Although restaging surgery is associated with a significant rate of detection of
AC C
extra-ovarian peritoneal implants, it may provide only prognostic information and no therapeutic value [29,35,36]. In the study by Fauvet et al., only 15% of 54 women who underwent surgical restaging after a diagnosis of borderline tumour with incomplete staging were upstaged. In addition, there was no difference in outcome between patients who underwent complete surgical staging and those who did not. In fact, if noninvasive peritoneal implants are found on restaging,
ACCEPTED MANUSCRIPT
surveillance is still the recommended management. This information, however, will provide prognostic information to the patient and her family regarding lifetime risk of recurrence. On the other hand, if invasive peritoneal implants are
RI PT
discovered, which is extremely uncommon, current management guidelines
suggest postoperative treatment with platinum-based chemotherapy (see below). Thus, on the whole, the final decision regarding restaging surgery is an individual
SC
one, weighing the pros and cons. If restaging surgery is performed, whenever
M AN U
possible, a minimally invasive approach is recommended.
Fertility-sparing Surgery. Since a large proportion of patients with borderline tumours is young and has not completed childbearing, fertility-sparing surgery is widely practiced. For women with unilateral ovarian involvement, either ovarian
TE D
cystectomy or unilateral salpingo-oophorectomy is appropriate. For those with bilateral ovarian involvement, the most common intraoperative procedures are unilateral salpingo-oophorectomy and ovarian cystectomy or bilateral ovarian
EP
cystectomy, depending on the findings. Following ovarian cystectomy, recurrence of a borderline tumour in the ipsilateral or contralateral ovary occurs in
AC C
approximately 12-36% [37-39]. Several further reports have indicated that after fertility-sparing surgery, the most common site of recurrence is in the residual ovary(ies) [40-44]. In most cases, a repeat surgical procedure is the treatment of choice, and adjuvant therapy is unnecessary.
Cytoreductive Surgery for Advanced Stage Disease. In patients with obvious
ACCEPTED MANUSCRIPT
advanced-stage tumour, all visible disease should be surgically removed, if feasible. Aggressive cytoreductive surgery, as would be employed in patients with invasive ovarian cancer, is important because studies have shown that
RI PT
patients with gross residual disease are at greater risk for recurrence and death [11,26,45,46]. Generally, peritoneal implants are small or microscopic; thus, complicated surgical resections are rarely necessary in cases of borderline
SC
ovarian tumours. In addition, even in the face of peritoneal implants, a normal
M AN U
contralateral ovary may be preserved in young patients.
Fertility Preservation. As noted above, while fertility-sparing surgery is feasible in a high proportion of women in the reproductive age group with borderline
TE D
ovarian tumours, it is not always possible. For mucinous borderline tumours, bilateral involvement is quite rare. However, for serous borderline tumours, bilateral involvement occurs in approximately 50%. In the latter, although bilateral
EP
ovarian cystectomies or unilateral salpingo-oophorectomy plus ovarian cystectomy may be feasible in most cases, bilateral salpingo-oophorectomy may
AC C
be the only option in some patients due to the extent of ovarian involvement by tumour.
In any young patient undergoing surgery for an adnexal mass, preoperative counseling should include discussion of the possibility of bilateral salpingooophorectomy +/- hysterectomy. Preoperative referral to a reproductive
ACCEPTED MANUSCRIPT
endocrinology infertility subspecialist for fertility preservation counseling is recommended on an individual basis. In addition, for those few women found to have invasive peritoneal implants at the time of surgery and for whom
RI PT
postoperative chemotherapy is recommended, here again is an opportunity to
consider such a referral for discussion of the effects of chemotherapy on ovarian
M AN U
options for advanced reproductive technology.
SC
function—both premature ovarian failure and premature menopause--as well as
Ovarian tissue cryopreservation at the time of surgery, oocyte cryopreservation, or embryo cryopreservation for borderline ovarian tumours have been reported [47,48]. In addition, there are several reports of successful pregnancies following
TE D
conservative surgery for borderline ovarian tumours [39,42,49-51].
EP
Postoperative Treatment. As noted, the vast majority of borderline ovarian tumours, including the most common subtypes of serous and mucinous, are
AC C
stage I. Surgery alone is the standard therapy for these tumours since the relapse rate is extremely low. For serous borderline tumours, the relapse rate is < 1%. Barnhill et al. surveyed the literature and added their own Gynecologic Oncology Group GOG) study to 26 previous reports [52]. Of 988 patients with stage I serous borderline tumour, only seven (0.7%) died of tumour. In the GOG study, with a median follow-up time of 42.4 months, none of the 146 assessable patients with stage I serous borderline tumour who underwent comprehensive
ACCEPTED MANUSCRIPT
surgical staging and no adjuvant therapy had developed recurrence. However, long-term follow-up is necessary to determine the true recurrence rate associated
tumours, the relapse rate is up to 10% [53-55].
RI PT
with stage I borderline ovarian tumours. For stage I mucinous borderline
For women with serous borderline tumours and noninvasive peritoneal implants,
SC
chemotherapy was recommended historically [26,56]. However, based on the
lack of evidence of survival benefit, this recommendation was abandoned several
M AN U
years ago. Nevertheless, we now understand that these patients have a lifetime risk in the range of 20-50% of developing subsequent metastatic low-grade serous carcinoma [26,57]. Therefore, it is of utmost importance that these patients are counseled appropriately.
TE D
For women with serous borderline tumours and invasive peritoneal implants, platinum-based chemotherapy continues to be recommended postoperatively, although definitive supporting evidence of benefit is lacking [46]. Increasingly,
EP
gynecologic pathologists consider invasive peritoneal implants the equivalent of
AC C
low-grade serous carcinoma.
Surveillance Following Primary Treatment. No real standard exists in terms of how frequently patients should be followed or monitored following primary treatment of a borderline ovarian tumour. Similarly, there is no standard for methodology. In several centers, patients are followed every 3 months for the first year following treatment and gradually less frequently thereafter. In other
ACCEPTED MANUSCRIPT
centers, patients may be followed at 6 months intervals or even annual intervals. The disparate philosophies arise based on data and opinions regarding the risk of relapse related to individual patient and tumour factors. However, only a few
RI PT
studies have focused on methods for detection of relapse [58-60].
For patients who undergo fertility-sparing surgery, particularly those with stage I
SC
serous borderline tumours, the major concern is for the residual ovary. If such
patients do develop a “recurrence,” it is almost always an actual separate primary
M AN U
borderline tumour in the residual ovary. In the study by Uzan et al., sonography was the most frequent method of detection of a borderline lesion in the residual ovary [60]. On the other hand, if patients have a stage II-IV serous borderline tumour, the greatest risk is for a recurrent invasive low-grade serous carcinoma, most frequently presenting as carcinomatosis. In such cases, serum CA 125 may
TE D
be the most accurate method for this type of detection [60]. Thus, most physicians recommend surveillance following primary treatment of
EP
borderline ovarian tumours with physical examination, sonography if fertilitysparing surgery was performed, and serum tumour markers—CA 125 and/or
AC C
CEA for mucinous histology. Although serial CT or MRI imaging studies are not routinely recommended for surveillance, based on lack of evidence of efficacy, some physicians recommend these as well. Of course, if a patient develops a significant elevation of a serum tumour marker, CT imaging is the next logical step.
ACCEPTED MANUSCRIPT
Management of Relapse. Clinicopathologic risk factors for relapse are discussed above. As noted, if a “recurrence” occurs in a residual ovary following fertility-sparing surgery, it is almost always a second primary borderline tumour
RI PT
and can be adequately managed with surgery alone. Otherwise, for serous
borderline tumours, the most powerful factor associated with an invasive tumour relapse is stage, or the presence of peritoneal implants. Thus, most true
SC
recurrences involve extra-ovarian sites, and the majority of these relapses are
not serous borderline tumours but rather invasive low-grade serous carcinoma
M AN U
[20,26,46,57,61,62]. In rare cases, a serous borderline tumour may recur as a high-grade serous carcinoma [63,64].
TE D
A detailed discussion of treatment of serous borderline tumours that recur as invasive cancer is beyond the scope of this article. Briefly, initial consideration should be given to patient and tumour factors--including age, co-morbidities, and
EP
tumour distribution--in deciding whether secondary cytoreductive surgery is indicated. If it is determined that surgery is not advisable, then fine needle
AC C
aspiration/core biopsy is necessary for an accurate histologic diagnosis. Initial systemic therapy, whether the recurrence represents low-grade serous carcinoma or high-grade serous carcinoma, generally consists of platinum/taxane chemotherapy. Subsequent systemic options for recurrent low-grade serous carcinoma include hormonal therapy (aromatase inhibitors, tamoxifen, leuprolide acetate, fulvestrant, etc.), other conventional chemotherapeutic agents (pegylated liposomal doxorubicin, gemcitabine, topotecan, weekly paclitaxel,
ACCEPTED MANUSCRIPT
etc.), bevacizumab, or targeted agents (trametinib, MEK162, vemurafenib, etc.)
RI PT
[65-69].
For patients with mucinous borderline tumours who relapse following primary
surgery, the issues are somewhat different. First, because mucinous borderline
SC
tumours are most frequently unilateral, the risk of a second primary in a residual ovary is extremely low. If a recurrence of mucinous borderline tumour does
M AN U
occur, it is usually related to an incompletely resected mucinous borderline tumour and does not include an invasive component [70]. In such cases, extensive surgical resection may be required, but surgery alone is the
TE D
appropriate treatment.
Disseminated peritoneal relapses may occur in a small proportion of patients.
EP
Khunamornpong et al., in a study of 171 mucinous borderline tumours, found that risk factors for relapse included age > 45 years, microinvasion, intraepithelial
AC C
carcinoma, or stage > stage IC [53]. For patients who do develop recurrence, other than those with incompletely resected primary mucinous borderline tumour discussed above, the relapses are peritoneal or retroperitoneal, are invasive carcinoma or intraepithelial carcinoma, and are associated with a very poor prognosis [17,53,55]. There is no standard treatment of recurrent invasive mucinous carcinoma following a diagnosis of mucinous borderline tumour. As with invasive relapses of serous borderline tumours, secondary surgery is a
ACCEPTED MANUSCRIPT
consideration and should be individualized. For systemic therapy, some would initially recommend platinum/taxane chemotherapy while others would recommend a regimen used for a gastrointestinal cancer, such as oxaliplatin, 5-
RI PT
fluoro-urail or capecitabine, and bevacizumab. Since some mucinous carcinomas have molecular aberrations, such as a RAS mutation or HER-2/neu amplification,
SC
targeted therapy may be an option.
M AN U
Summary
Borderline ovarian tumours present similarly to other types of adnexal masses. Surgery is the primary treatment. Fertility-sparing surgery is feasible in a high proportion of women in the reproductive age group. If frozen-section examination
TE D
reveals a borderline tumour, surgical staging should be performed, including cytologic washings, omentectomy, and peritoneal biopsies. Routine lymphadenectomy is not recommended. Prognostic factors include FIGO stage,
EP
presence of micropapillary pattern (for serous tumours), intraepithelial carcinoma
AC C
(for mucinous tumours), microinvasion, and the presence of peritoneal implants. Postoperative therapy is recommended only for those patients with serous borderline tumours with invasive peritoneal implants. In those few patients who experience relapse, most commonly it represents invasive carcinoma.
ACCEPTED MANUSCRIPT
Conflict of Interest Statement I have no conflict of interest that could influence the content of this article.
RI PT
David M. Gershenson, MD
Borderline ovarian tumours present similarly to other types of adnexal
M AN U
•
SC
Practice Points
masses. •
Surgery is the primary treatment, and the surgical approach—open versus minimally invasive—should be individualized.
•
For women in the reproductive age group, preoperative fertility
•
TE D
preservation counseling is recommended. Since most borderline tumours are confined to the ovary(ies) and may involve one ovary, fertility-sparing surgery is feasible in a high proportion
Even if bilateral ovarian involvement is noted, fertility-sparing surgery may
AC C
•
EP
of women in the reproductive age group.
still be feasible with bilateral ovarian cystectomies or ovarian cystectomy plus unilateral salpingo-oophorectomy.
•
If borderline ovarian tumour is diagnosed on frozen section examination, surgical staging should include cytologic washings, omentectomy, and peritoneal biopsies.
•
Routine lymphadenectomy is not recommended as part of surgical
ACCEPTED MANUSCRIPT
staging. •
If extra-ovarian spread is noted at surgery, maximum cytoreductive surgery with no gross residual should be the objective. Postoperative treatment is recommended only for those patients with
RI PT
•
serous borderline tumours and invasive peritoneal implants.
If relapse with borderline tumour occurs, standard treatment consists of surgery alone.
•
If relapse with invasive carcinoma occurs, treatment may include
M AN U
secondary surgery and chemotherapy.
Research Agenda •
SC
•
Prevention of relapse in women with serous borderline tumours and
•
TE D
peritoneal implants, e.g., hormonal therapy Studies of alternative therapies for women with serous borderline tumours
•
EP
and invasive peritoneal implants
Prevention of relapse in women with mucinous borderline tumours the
AC C
contain areas of microinvasion or intraepithelial carcinoma •
Optimal therapy for women with invasive carcinoma following a diagnosis
of borderline ovarian tumour—either serous or mucinous
ACCEPTED MANUSCRIPT
References 1. Taylor HC. Malignant and semimalignant tumours of the ovary. Surg
RI PT
Gynecol Obstet 1929; 48: 204-230. 2. International Federation of Gynecology and Obstetrics: classification and staging of malignant tumours in the female pelvis. Acta Obstet Gynecol
SC
Scand 1971; 50: 1-7.
3. Serov SF, Scully RE & Solvin LH. International histologic classification of
M AN U
tumours. No. 9: Histologic typing of ovarian tumours, pp 37-41. Geneva: World Health Organization, 1973.
4. Vine MF, Ness RB, Calingaert B, Schildkraut JM, Berchuck A. Types and Duration of Symptoms Prior to Diagnosis of Invasive or Borderline Ovarian Tumour. Gynecol Oncol. 2001;83(3):466–71.
TE D
5. Tamakoshi K, Kikkawa F, Shibata K et al. Clinical value of CA125, CA199, CEA, CA72-4 and TPA in borderline ovarian tumour. Gynecol Oncol 1996; 62: 67-72.
EP
6. Ochiai K, Shinozaki H, Takada A et al. A retrospective study of 1069
AC C
epithelial borderline malignancies of the ovary treated in Japan. Proceedings of the Annual Meeting of the American Society of Clinical Oncology 1998; 17: A1429.
7. Wong HF, Low JJH, Chua Y, Busmanis I, Tay EH, Ho TH. Ovarian tumours of borderline malignancy: a review of 247 patients from 1991 to 2004. Int J Gynecol Cancer. 2007;17(2):342–9. 8. Kolwijck E, Thomas CMG, Bulten J, Massuger LFAG. Preoperative CA-
ACCEPTED MANUSCRIPT
125 levels in 123 patients with borderline ovarian tumours. Int J Gynecol Cancer. 2009;19(8):1335–8. 9. *Tang A, Chennakesavan SK, Ngan H, Zusterzeel P, Quinn M, Carter J, et
RI PT
al. Prognostic value of elevated preoperative serum CA125 in ovarian
tumours of low malignant potential: A multinational collaborative study (ANZGOG0801). Gynecol Oncol. 2012;126(1):36–40.
SC
10. Ayhan A, Guvendag Guven ES, Guven S, Kucukali T. Recurrence and
Sep;98(3):439–45.
M AN U
prognostic factors in borderline ovarian tumours. Gynecol Oncol. 2005
11. Shih KK, Zhou Q, Huh J, Morgan JC, Iasonos A, Aghajanian C, et al. Risk factors for recurrence of ovarian borderline tumours. Gynecol Oncol. 2011 Mar 1;120(3):480–4.
TE D
12. Obermair A, Tang A, Kondalsamy-Chennakesavan S, Ngan H, Zusterzeel P, Quinn M, et al. Nomogram to Predict the Probability of Relapse in Patients Diagnosed With Borderline Ovarian Tumours. Int J Gynecol
EP
Cancer. 2013 Jan;23(2):264–7.
13. *Morice P, MD CU, MD RF, MD SG, MD PD, MD PED. Borderline ovarian
AC C
tumour: pathological diagnostic dilemma and risk factors for invasive or lethal recurrence. Lancet Oncol. 2012;13(3):e103–15.
14. *Bois du A, Ewald-Riegler N, de Gregorio N, Reuss A, Mahner S, Fotopoulou C, et al. Borderline tumours of the ovary: A cohort study of the Arbeitsgmeinschaft Gyna ̈kologische Onkologie (AGO) Study Group. Eur J Cancer. 2013;49(8):1905–14.
ACCEPTED MANUSCRIPT
15. Hannibal CG, Vang R, Junge J, Frederiksen K, Kjaerbye-Thygesen A, Andersen KK, et al. A nationwide study of serous “borderline” ovarian tumours in Denmark 1978–2002: Centralized pathology review and overall
RI PT
survival compared with the general population. Gynecol Oncol. 2014;134(2):267–73.
16. Karlsen NMS, Karlsen MA, Hogdall E, Nedergaard L, Christensen IJ,
SC
Høgdall C. Relapse and disease specific survival in 1143 Danish women
2016;142(1):50–3.
M AN U
diagnosed with borderline ovarian tumours (BOT). Gynecol Oncol.
17. *Sobiczewski P, Kupryjanczyk J, Michalski W, Spiewankiewicz B. The Evaluation of Risk Factors Associated With Relapse and Recurrence of Borderline Ovarian Tumours With Long-Term Follow-up. Int J Gynecol
TE D
Cancer. 2016;26(6):1053–61.
18. Song T, Lee Y-Y, Choi CH, Kim T-J, Lee J-W, Bae D-S, et al. Risk Factors for Progression to Invasive Carcinoma in Patients With Borderline Ovarian
EP
Tumours. Int J Gynecol Cancer. 2014 Sep;24(7):1206–14. 19. Gershenson DM. Clinical management potential tumours of low
AC C
malignancy. Best Pract Res Clin Obstet Gynaecol. 2002;16(4):513–27.
20. Longacre TA, McKenney JK, Tazelaar HD, Kempson RL, Hendrickson MR. Ovarian serous tumours of low malignant potential (borderline tumours): outcome-based study of 276 patients with long-term (> or =5year) follow-up. Am J Surg Pathol. 2005 Jun;29(6):707–23. 21. Lesieur B, Kane A, Duvillard P, Gouy S, Pautier P, Lhommé C, et al.
ACCEPTED MANUSCRIPT
Prognostic value of lymph node involvement in ovarian serous borderline tumours. Am J Obstet Gynecol. 2011;204(5):438.e1–438.e7. 22. Maneo A, Vignali M, Chiari S, Colombo A, Mangioni C, Landoni F. Are
RI PT
borderline tumours of the ovary safely treated by laparoscopy? Gynecol Oncol. 2004;94(2):387-392.
23. Deffieux X, Morice P, Camatte S, Fourchotte V, Duvillard P, Castaigne D.
SC
Results after laparoscopic management of serous borderline tumour of the ovary with peritoneal implants. Gynecol Oncol. 2005;97(1):84-89.
M AN U
24. Desfeux P, Camatte S, Chatellier G, Blanc B, Querleu D, Lécuru F. Impact of surgical approach on the management of macroscopic early ovarian borderline tumours. Gynecol Oncol. 2005;98(3):390-395. 25. Romagnolo C, Gadducci A, Sartori E, Zola P, Maggino T. Management of
TE D
borderline ovarian tumours: Results of an Italian multicenter study. Gynecol Oncol. 2006;101(2):255-260. 26. *Gershenson DM, Silva EG, Tortolero-Luna G, Levenback C, Morris M,
EP
Tornos C. Serous borderline tumours of the ovary with noninvasive peritoneal implants. Cancer. 1998;83(10):2157–63.
AC C
27. Fotopoulou C, Schumacher G, Schefold JC, Denkert C, Lichtenegger W, Sehouli J. Systematic Evaluation of the Intraoperative Tumour Pattern in Patients With Borderline Tumour of the Ovary. Int J Gynecol Cancer. 2009;19(9):1550-1555.
28. Menzin AW, Gal D, Lovecchio JL. Contemporary Surgical Management of Borderline Ovarian Tumours: A Survey of the Society of Gynecologic
ACCEPTED MANUSCRIPT
Oncologists. Gynecol Oncol. 2000;78(1):7–9. 29. Lin PS, Gershenson DM, Bevers MW, Lucas KR, Burke TW, Silva EG. The current status of surgical staging of ovarian serous borderline
RI PT
tumours. Cancer. 1999;85(4):905–11.
30. Guvenal T, Dursun P, Hasdemir PS, Hanhan M, Guven S, Yetimalar H, et al. Effect of surgical staging on 539 patients with borderline ovarian
SC
tumours: a Turkish Gynecologic Oncology Group study. Gynecol Oncol. 2013;131(3):546–50.
M AN U
31. Kristensen GS, Schledermann D, Mogensen O, Jochumsen KM. The value of random biopsies, omentectomy, and hysterectomy in operations for borderline ovarian tumours. Int J of Gynecol Cancer. 2014;24(5):874– 9.
TE D
32. Winter WE, Kucera PR, Rodgers W, McBroom JW, Olsen C, Maxwell GL. Surgical staging in patients with ovarian tumours of low malignant potential. Obstet Gynecol. 2002;100(4):671–6.
EP
33. Rao GG, Skinner E, Gehrig PA, Duska LR, Coleman RL, Schorge JO. Surgical Staging of Ovarian Low Malignant Potential Tumours. Obstet
AC C
Gynecol. 2004;104(2):261-266.
34. *Song T, Choi CH, Kim H-J, Kim MK, Kim T-J, Lee J-W, et al. Accuracy of frozen section diagnosis of borderline ovarian tumours. Gynecol Oncol. 2011;122(1):127–31.
35. Fauvet R, Boccara J, Dufournet C, David-Montefiore E, Poncelet C, Daraï E. Restaging surgery for women with borderline ovarian tumours. Cancer.
ACCEPTED MANUSCRIPT
2004;100(6):1145–51. 36. Zapardiel I, Rosenberg P, Peiretti M, Zanagnolo V, Sanguineti F, Aletti G, et al. The role of restaging borderline ovarian tumours: Single institution
RI PT
experience and review of the literature. Gynecol Oncol. 2010;119(2):274– 7.
37. Tazelaar HD, Bostwick DG, Ballon SC, et al. Conservative treatment of
SC
borderline ovarian tumours. Obstet Gynecol. 1985;66:417-422.
38. Lim-Tan SK, Cajigas HE, Scully RE. Ovarian cystectomy for serous
1988;72:775-781.
M AN U
borderline tumours: A follow-up study of 35 cases. Obstet Gynecol.
39. Morice P, Camatte S, Hassan El J, Pautier P, Duvillard P, Castaigne D. Clinical outcomes and fertility after conservative treatment of ovarian
TE D
borderline tumours. Fertil Steril. 2001;75(1):92-96.
40. Park J-Y, Kim D-Y, Kim J-H, Kim Y-M, Kim Y-T, Nam J-H. Surgical management of borderline ovarian tumours: The role of fertility-sparing
EP
surgery. Gynecol Oncol. 2009;113(1):75-82. 41. Rao GG, Skinner EN, Gehrig PA, Duska LR, Miller DS, Schorge JO.
AC C
Fertility-sparing surgery for ovarian low malignant potential tumours. Gynecol Oncol. 2005;98(2):263-266.
42. Song T, Choi CH, Park HS, et al. Fertility-Sparing Surgery for Borderline Ovarian Tumours. Int J Gynecol Cancer. 2011;21(4):640-646.
43. Uzan C, Kane A, REY A, Gouy S, Duvillard P, Morice P. Outcomes after conservative treatment of advanced-stage serous borderline tumours of
ACCEPTED MANUSCRIPT
the ovary. Ann Oncol. 2009;21(1):55-60. 44. Suh-Burgmann E. Long-term outcomes following conservative surgery for borderline tumour of the ovary: a large population-based study. Gynecol
RI PT
Oncol. 2006;103(3):841–7.
45. Leake JF, Currie JL, Rosenshein NB & Woodru JD. Long-term follow-up of serous ovarian tumours of low malignant potential. Gynecol Oncol.
SC
1992;47: 150-158.
46. Gershenson DM, Silva EG, Levy L, Burke TW, Wolf JK, Tornos C. Ovarian
1998;82(6):1096–103.
M AN U
serous borderline tumours with invasive peritoneal implants. Cancer.
47. Fain-Kahn V, Poirot C, Uzan C, Prades M, Gouy S, Genestie C, et al. Feasibility of ovarian cryopreservation in borderline ovarian tumours. Hum
TE D
Reprod. 2009 Apr;24(4):850–5.
48. Huang JYJ, Buckett WM, Gilbert L, Tan SL, Chian R-C. Retrieval of immature oocytes followed by in vitro maturation and vitrification: A case
EP
report on a new strategy of fertility preservation in women with borderline ovarian malignancy. Gynecol Oncol. 2007;105(2):542–4.
AC C
49. Boran N, Cil AP, Tulunay G, Ozturkoglu E, Koc S, Bulbul D, et al. Fertility and recurrence results of conservative surgery for borderline ovarian tumours. Gynecol Oncol. 2005;97(3):845–51.
50. Kane A, Uzan C, Gouy S, Pautier P, Duvillard P, Morice P. Fertility results and outcomes after pure laparoscopic management of advanced-stage serous borderline tumours of the ovary. Fertil Steril. 2010;94(7):2891–4.
ACCEPTED MANUSCRIPT
51. Morris RT, Gershenson DM, Silva EG, Follen M, Morris M, Wharton JT. Outcome and reproductive function after conservative surgery for borderline ovarian tumours. Obstet Gynecol. 2000;95(4):541–7.
RI PT
52. Barnhill DR, Kurman RJ, Brady MF et al. Preliminary analysis of the
behavior of stage I ovarian serous tumours of low malignant potential: a Gynecologic Oncology Group study. J Clin Oncol 1995; 13: 2752-2756.
SC
53. *Khunamornpong S, Settakorn J, Sukpan K, Suprasert P, Siriaunkgul S. Mucinous Tumour of Low Malignant Potential (“Borderline” or ‘Atypical
M AN U
Proliferative’ Tumour) of the Ovary. Int J Gynecol Pathol. 2011;33(3):218– 30.
54. Kleppe M, Bruls J, Van Gorp T, Massuger L, Slangen BFM, Van de Vijver KK, et al. Mucinous borderline tumours of the ovary and the appendix: A
TE D
retrospective study and overview of the literature. Gynecol Oncol. 2014;133(2):155–8.
55. *Lee KR, Scully RE. Mucinous tumours of the ovary: a clinicopathologic
EP
study of 196 borderline tumours (of intestinal type) and carcinomas, including an evaluation of 11 cases with 'pseudomyxoma peritonei'. Am J
AC C
Surg Pathol. 2000;24(11):1447–64.
56. *Shih KK, Zhou QC, Aghajanian C, Huh J, Soslow RA, Morgan JC, et al. Patterns of recurrence and role of adjuvant chemotherapy in stage II–IV serous ovarian borderline tumours. Gynecol Oncol. 2010 Nov 1;119(2):270–3.
57. Silva EG, Gershenson DM, Malpica A, Deavers M. The recurrence and
ACCEPTED MANUSCRIPT
the overall survival rates of ovarian serous borderline neoplasms with noninvasive implants is time dependent. Am J Surg Pathol. 2006;30(11):1367–71.
RI PT
58. Poncelet C, Fauvet R, Boccara J, Darai E. Recurrence after cystectomy
for borderline ovarian tumours: results of a French multicenter study. Ann Surg Oncol 2006;13:565-71.
SC
59. Zanetta G, Rota S, Lissoni A, Meni A, Brancatelli G, Buda A. Ultrasound, physician examination, and CA 125 measurement for the detection of
M AN U
recurrence after conservative surgery for early borderline ovarian tumours. Gynecol Oncol 2001;81:63-66.
60. Uzan C, Kane A, Rey A, eta l. How to follow up advanced-stage borderline tumours? Mode of diagnosis of recurrence in a large series stage II-III
TE D
serous borderline tumours of the ovary. Ann Oncol 2011;22:631-35. 61. *Crispens MA, Bodurka D, Deavers M, Lu K, Silva EG, Gershenson DM. Response and survival in patients with progressive or recurrent serous
10.
EP
ovarian tumours of low malignant potential. Obstet Gynecol. 2002;99(1):3–
AC C
62. Shvartsman HS, Sun CC, Bodurka DC, Mahajan V, Crispens M, Lu KH, et al. Comparison of the clinical behavior of newly diagnosed stages II-IV low-grade serous carcinoma of the ovary with that of serous ovarian tumours of low malignant potential that recur as low-grade serous carcinoma. Gynecol Oncol. 2007;105(3):625–9.
63. Dehari R, Kurman RJ, Logani S, Shih I-M. The development of high-grade
ACCEPTED MANUSCRIPT
serous carcinoma from atypical proliferative (borderline) serous tumours and low-grade micropapillary serous carcinoma: a morphologic and molecular genetic analysis. Am J Surg Pathol. 2007;31(7):1007-1012.
RI PT
64. Boyd C, McCluggage WG. Low-grade ovarian serous neoplasms (low-
grade serous carcinoma and serous borderline tumour) associated with high-grade serous carcinoma or undifferentiated carcinoma: report of a
SC
series of cases of an unusual phenomenon. Am J Surg Pathol. 2012;36(3):368-375.
M AN U
65. Gershenson DM, Sun CC, Bodurka D, Coleman RL, Lu KH, Sood AK, et al. Recurrent low-grade serous ovarian carcinoma is relatively chemoresistant. Gynecol Oncol. 2009;114(1):48–52. 66. Gershenson DM, Sun CC, Iyer RB, Malpica AL, Kavanagh JJ, Bodurka
TE D
DC, et al. Hormonal therapy for recurrent low-grade serous carcinoma of the ovary or peritoneum. Gynecol Oncol. 2012;125(3):661–6. 67. Grisham RN, Iyer G, Sala E, Zhou Q, Iasonos A, DeLair D, et al.
EP
Bevacizumab Shows Activity in Patients With Low-Grade Serous Ovarian and Primary Peritoneal Cancer. Int J Gynecol Cancer. 2014;24(6):1010–4.
AC C
68. Farley J, Brady WE, Vathipadiekal V, Lankes HA, Coleman R, Morgan MA, et al. Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. Lancet Oncol. 2013;14(2):134–40.
69. Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay J-Y, et al. Vemurafenib in Multiple Nonmelanoma Cancers with BRAFV600
ACCEPTED MANUSCRIPT
Mutations. N Engl J Med. 2015;373(8):726–36. 70. Irving JA, Clement PB. Recurrent Intestinal Mucinous Borderline Tumours
AC C
EP
TE D
M AN U
SC
RI PT
of the Ovary. Int J Gynecol Pathol. 2014;33(2):156–65.
Table 1. Recommended surgical principles for borderline ovarian tumors
ACCEPTED MANUSCRIPT •
Determine optimal surgical approach—open versus minimally invasive
•
Consideration of fertility-sparing surgery in patients of reproductive age based on preoperative counseling, including fertility preservation
RI PT
counseling o Options for unilateral ovarian involvement: Ovarian cystectomy versus unilateral salpingo-oophorectomy
SC
o Options for bilateral ovarian involvement: Bilateral ovarian
cystectomies or unilateral salpingo-oophorectomy + ovarian
•
M AN U
cystectomy
Frozen section examination of ovarian mass(es) o Caveats
Frozen section diagnosis of mucinous ovarian tumors is not very accurate, leading to both under-diagnosis and
TE D
over-diagnosis
In at least 10% of cases in which the frozen section diagnosis is borderline tumor, final diagnosis will indicate
Recommended surgical staging:
AC C
•
EP
invasive carcinoma
o Evacuation of ascites or cytologic washings o Omentectomy o Multiple peritoneal biopsies o Careful palpation and inspection of entire peritoneal cavity and retroperitoneum with resection of any abnormal areas or lymphadenopathy
•
For obvious metastatic disease, maximum cytoreduction to achieve no gross residual tumor
ACCEPTED MANUSCRIPT
Figure Legends Fig. 1: Photomicrograph of serous borderline tumor with typical histologic pattern.
RI PT
Fig. 2: Photomicrograph of mucinous borderline tumor—intestinal type.
AC C
EP
TE D
M AN U
SC
Fig. 3: Photomicrograph of noninvasive peritoneal implant.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
Highlights Surgical approach—open or minimally invasive—should be individualized Fertility-sparing surgery is feasible in a high proportion of young patients Surgical staging is recommended for borderline ovarian tumours
AC C
EP
TE D
M AN U
SC
RI PT
• • •
PII:
S1521-6934(16)30089-X
DOI:
10.1016/j.bpobgyn.2016.09.012
Reference:
YBEOG 1648
To appear in:
Best Practice & Research Clinical Obstetrics & Gynaecology
Received Date: 16 August 2016 Revised Date:
21 August 2016
Accepted Date: 7 September 2016
Please cite this article as: Gershenson DM, Management of Borderline Ovarian Tumours, Best Practice & Research Clinical Obstetrics & Gynaecology (2016), doi: 10.1016/j.bpobgyn.2016.09.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Management of Borderline Ovarian Tumours David M. Gershenson, MD
RI PT
Department of Gynecologic Oncology and Reproductive Medicine University of Texas MD Anderson Cancer Center, Unit 1362 1155 Pressler Drive
David M. Gershenson, MD
M AN U
Corresponding Author:
SC
Houston, TX 77030, USA
Department of Gynecologic Oncology and Reproductive Medicine
1155 Pressler Drive
TE D
University of Texas MD Anderson Cancer Center, Unit 1362
Houston, TX 77030, USA
EP
Phone: 1-713-745-2565 FAX: 1-713-745-3510
AC C
Email: [email protected]
ACCEPTED MANUSCRIPT
Abstract Approximately 3000 American women are diagnosed with borderline ovarian tumours annually. Borderline tumours present similar to other types of adnexal
RI PT
masses. Prognostic factors include FIGO stage, presence of peritoneal implants, micropapillary pattern (for serous histology), microinvasion, and intraepithelial
carcinoma (for mucinous histology). Approximately 65-70% of serous tumours
SC
and 90% of mucinous tumours are stage I, and 30% and 10%, respectively, are associated with extra-ovarian spread. Fertility-preservation counseling is
M AN U
recommended for young patients. Fertility-sparing surgery is feasible in a high proportion of women in the reproductive age group. Surgical staging generally includes resection of the primary borderline tumour, either by unilateral salpingooophorectomy or ovarian cystectomy, cytologic washings, omentectomy, and
TE D
peritoneal biopsies, and routine lymphadenectomy is not recommended. However, because the accuracy of frozen-section examination is less than optimal, caution is recommended. Postoperative therapy is recommended only
EP
for those women with serous borderline tumours and invasive implants.
AC C
Fortunately, relapse is uncommon.
Keywords: borderline ovarian tumours, fertility-sparing surgery, serous, mucinous
ACCEPTED MANUSCRIPT
Introduction In 1929, Taylor first described a group of patients with `semimalignant' or
RI PT
hyperplastic ovarian tumours without histological evidence of stromal invasion but with peritoneal implants [1]. He noted that these patients had a better
prognosis than those with frankly malignant tumours. However, not until the
SC
International Federation of Gynecology and Obstetrics (FIGO) recognized the
distinct clinical entity of ‘carcinoma of low malignant potential' [2] and the World
M AN U
Health Organization WHO) adopted the term ‘borderline malignancies' [3] did this group of tumours receive general acceptance. Only within the past two decades or so have we begun to understand their biological behaviour and optimal therapy.
TE D
Approximately 3000 American women are diagnosed with borderline ovarian tumours annually. Borderline ovarian tumours account for 10-15% of epithelial tumours. Histological types include serous (Fig. 1)--the most common—
EP
mucinous (Fig. 2), endometrioid, clear-cell, and transitional-cell (or Brenner)
AC C
tumours. The latter three histological types are very uncommon. Histological criteria for the diagnosis of borderline ovarian tumours include nuclear atypia, stratification of the epithelium, formation of microscopic papillary projections and the absence of stromal invasion. Principles of clinical management of borderline ovarian tumours have evolved over the past two decades as our understanding of their biological behaviour has been elucidated. However, there remain many gaps in our knowledge of these
ACCEPTED MANUSCRIPT
neoplasms that result in controversies regarding their biology and in different therapeutic approaches. Important keys to gaining additional insight into optimal clinical management include considerations for comprehensive surgical staging,
RI PT
adequate tissue sampling and adequate follow-up time. This chapter provides a
M AN U
Clinical Presentation and Diagnosis
SC
literature-based review of these contemporary management principles.
Borderline ovarian tumours present in the same manner as other adnexal masses. Patients may complain of pelvic pain or dyspareunia, although they are frequently asymptomatic. Adnexal masses may be palpated at the time of a pelvic examination. Occasionally they are detected as an incidental finding during
TE D
routine obstetrical sonography. In a study of 151 women with borderline ovarian tumours, 84% had symptoms prior to diagnosis, and the median duration of
EP
symptoms in those patients was 6 months [4] In a woman with an adnexal mass, pelvic ultrasound and serum CA 125 are
AC C
generally recommended. Ultrasound of a borderline ovarian tumour will not uncommonly reveal a complex ovarian mass. However, there is no pathognomonic sonographic appearance associated with borderline tumours. Similarly, serum CA 125 is rather non-specific. In one study, levels of serum CA 125 were within normal limits in 32% of patients with serous borderline tumours and 48% of mucinous borderline tumours [5]. In a retrospective study of 1069 patients with borderline ovarian tumours in Japan, 49% had normal serum CA
ACCEPTED MANUSCRIPT
125 levels and only 23% had serum CA 125 levels above 100 U/ml [6]. In another study from Singapore, of 198 patients with a preoperative serum CA 125, 77 (39%) had levels >35 U/ml [7]. In addition, those with CA 125 levels < 35 U/ml
RI PT
were more likely to have stage I disease. In the same report, among nine
patients who had an elevated serum CEA level, all were of mucinous cell type. Two further studies found that preoperative serum CA 125 values were more
SC
often elevated in serous compared with mucinous tumours and in advanced
stage compared with stage I [8,9]. Kolwijck et al. reported that serum CA 125
M AN U
levels > 35 U/ml were more often noted in patients with the serous type (67%) compared with the mucinous type (39%) and in patients with advanced stage
TE D
disease (83%) more frequently than in stage I disease (47%) [8].
Borderline ovarian tumours occur in women of all ages, with an average age in the mid-40s--some 15 years younger than that for invasive ovarian cancers.
EP
Therefore, a high proportion of women with borderline tumours is in the reproductive age group. Because of their relative rarity and the absence of a
AC C
reliable test or marker, borderline ovarian tumours are rather low on the differential diagnosis list. In addition, the availability of reliable frozen-section analysis in many hospitals is problematical. Nevertheless, it is important for surgeons operating on women to consider the potential diagnosis of borderline ovarian tumour and to counsel patients and their families appropriately with regard to intraoperative management.
ACCEPTED MANUSCRIPT
Prognostic Factors
RI PT
The factors most strongly associated with outcome—either relapse, survival, or both—are FIGO stage, presence of peritoneal implants, micropapillary pattern, and microinvasion [10-18]. For patients with peritoneal implants, those with
SC
invasive implants appear to have a higher relapse rate (> 50%) and worse
prognosis than those with noninvasive implants (Fig. 3) (20-50%) [19]. Additional
M AN U
factors that have emerged as predictive or prognostic in some but not all studies have been incomplete surgical staging [14,17], residual disease [11], fertilitysparing surgery [12,14,16], preoperative serum CA 125 level [12], bilateral ovarian involvement [16], and age [12.16.18]. For age, however, some studies
TE D
have found that younger patients have a worse outcome [16] while other studies indicate that older patients fare worse [12,18].
AC C
factor [20,21].
EP
On the other hand, lymph node involvement does not appear to be a prognostic
Surgical Management Operative Findings. Approximately 65-70% of all serous borderline tumours and 90% of all mucinous borderline tumours are stage I. Extraovarian spread (stages II-IV) occurs in about 30-35% of serous borderline tumours and in only 10% of mucinous borderline tumours.
ACCEPTED MANUSCRIPT
Approximately 50% of serous borderline tumours and 80-90% of mucinous borderline tumours are confined to one ovary at diagnosis. The other cell types of
stage I, and the vast majority are unilateral.
RI PT
borderline tumours--endometrioid, clear-cell and transitional--are almost always
When extraovarian spread does occur, it rarely presents as bulky metastatic
SC
disease; in most cases the so-called peritoneal implants are either microscopic or small macroscopic (< 1-2 cm). As discussed below, it is important for the surgeon
M AN U
encountering a borderline tumour to be thoroughly familiar with this information to optimize intraoperative decision-making.
Surgical Approach. Surgery is the primary treatment. One of the initial considerations in contemplating surgery for a pelvic mass is the surgical
TE D
approach—minimally invasive or open technique. Factors to be considered in the selection of minimally invasive surgical approaches (laparoscopic or robotic) include size of the ovarian mass(es), extent of tumour metastasis, number and
EP
type or previous operations, and body habitus. Several reports have documented the feasibility and safety of the minimally invasive approach when appropriately
AC C
used [22-25].
Surgical Staging for Apparent Stage I. A major question in the treatment of borderline tumours involves the role of comprehensive surgical staging. Since the presence of peritoneal implants has prognostic significance, and the most common sites of implants include the omentum and peritoneal surfaces, surgical
ACCEPTED MANUSCRIPT
staging consisting of cytologic washings, omentectomy and peritoneal biopsies is generally recommended (Table 1) [26.27].
RI PT
In a survey study of the Society of Gynecologic Oncology from 2000, Menzin et
al. reported the responses from 274 members on the topic of surgical staging for borderline tumours [28]. Of this group, 96% stated that they performed cytologic
SC
washings, 97% biopsied the omentum, and 92% performed random peritoneal biopsies. Interestingly, 97% performed pelvic lymph node biopsies, and 89%
M AN U
performed paraaortic lymph node biopsies. In a review of the MD Anderson experience, Lin et al. reviewed pathology reports of 255 cases of serous borderline tumours [29]. Approximately 12% underwent comprehensive surgical staging, including lymphadenectomy. Overall, 59% underwent omental sampling;
TE D
27% and 29% underwent abdominal or pelvic peritoneal biopsies, respectively; 18% underwent sampling of pelvic lymph nodes; and 13% underwent paraaortic lymph node biopsies. Gynecologic oncologists performed complete surgical
EP
staging in 50% of patients, compared to only 9% by obstetrician-gynecologists.
AC C
On the other hand, some reports suggest that complete surgical staging is not necessary for borderline tumours. Guvenal and colleagues reported on a Turkish experience with 539 patients with borderline tumours from 14 institutions [30]. Of all patients, 54.5% underwent surgical staging, and 77.6% of this group had comprehensive surgical staging, including lymphadenectomy. With a median follow-up time of 36 months, the 5-year survival was 100%. The authors
ACCEPTED MANUSCRIPT
concluded that comprehensive surgical staging was not beneficial in the management of borderline ovarian tumours. However, it should be pointed out that the follow-up time was relatively short, and only a small proportion of the
RI PT
patients in this study had extra-ovarian disease. Additionally, Kristensen et al., in a study of 75 patients with borderline tumours, concluded that random peritoneal
SC
biopsies are not beneficial [31].
Probably the most major question surrounding the issue of surgical staging for
M AN U
borderline tumours involves the role of routine lymphadenectomy. Winter et al. compared two cohorts of patients with borderline tumours—48 who underwent comprehensive surgical staging versus 45 without surgical staging [32]. Only 6% of the 48 patients who underwent surgical staging had lymph node involvement,
TE D
and relapse rates were not significantly different between the two groups. Because the incidence of lymph node involvement is quite low, routine pelvic and paraaortic lymphadenectomy is not recommended by most [33]. However, if
EP
lymphadenopathy is noted, resection is appropriate.
AC C
The Accuracy of Frozen Section Examination for Borderline Tumours. For every woman undergoing surgery for an adnexal mass, intraoperative frozensection examination is recommended to facilitate decision-making. Although frozen-section readings will never be perfectly accurate, they certainly can provide guidance in most cases. Of course, the expertise of the pathologist is key component in determining accuracy. For example, the difference in a frozen-
ACCEPTED MANUSCRIPT
section diagnosis of invasive ovarian cancer versus borderline tumour may well influence the decision to perform routine lymphadenectomy. Thus, caution is recommended. In the study by Winter et al., frozen-section examination was
RI PT
performed in 83 of 93 patients with a final diagnosis of borderline ovarian tumour [32]. Of these, 25% were reported as benign cystadenomas, 10% as invasive cancer, and 65% as borderline tumours. Similarly, in a study 354 cases of
SC
borderline ovarian tumours, Song et al. reported that the overall agreement between frozen-section and final pathology reports was only 64.4% [34].
M AN U
Mucinous histology was the only predictor for under-diagnosis by frozen-section analysis. The authors concluded that frozen-section examination for mucinous borderline tumours in not very accurate and is associated with a high degree of
TE D
under-diagnosis and over-diagnosis.
Surgical Restaging of Patients Who Are Incompletely Staged. For patients referred to gynecologic oncologists following a diagnosis of a borderline ovarian
EP
tumour without surgical staging, clinical management remains controversial. Although restaging surgery is associated with a significant rate of detection of
AC C
extra-ovarian peritoneal implants, it may provide only prognostic information and no therapeutic value [29,35,36]. In the study by Fauvet et al., only 15% of 54 women who underwent surgical restaging after a diagnosis of borderline tumour with incomplete staging were upstaged. In addition, there was no difference in outcome between patients who underwent complete surgical staging and those who did not. In fact, if noninvasive peritoneal implants are found on restaging,
ACCEPTED MANUSCRIPT
surveillance is still the recommended management. This information, however, will provide prognostic information to the patient and her family regarding lifetime risk of recurrence. On the other hand, if invasive peritoneal implants are
RI PT
discovered, which is extremely uncommon, current management guidelines
suggest postoperative treatment with platinum-based chemotherapy (see below). Thus, on the whole, the final decision regarding restaging surgery is an individual
SC
one, weighing the pros and cons. If restaging surgery is performed, whenever
M AN U
possible, a minimally invasive approach is recommended.
Fertility-sparing Surgery. Since a large proportion of patients with borderline tumours is young and has not completed childbearing, fertility-sparing surgery is widely practiced. For women with unilateral ovarian involvement, either ovarian
TE D
cystectomy or unilateral salpingo-oophorectomy is appropriate. For those with bilateral ovarian involvement, the most common intraoperative procedures are unilateral salpingo-oophorectomy and ovarian cystectomy or bilateral ovarian
EP
cystectomy, depending on the findings. Following ovarian cystectomy, recurrence of a borderline tumour in the ipsilateral or contralateral ovary occurs in
AC C
approximately 12-36% [37-39]. Several further reports have indicated that after fertility-sparing surgery, the most common site of recurrence is in the residual ovary(ies) [40-44]. In most cases, a repeat surgical procedure is the treatment of choice, and adjuvant therapy is unnecessary.
Cytoreductive Surgery for Advanced Stage Disease. In patients with obvious
ACCEPTED MANUSCRIPT
advanced-stage tumour, all visible disease should be surgically removed, if feasible. Aggressive cytoreductive surgery, as would be employed in patients with invasive ovarian cancer, is important because studies have shown that
RI PT
patients with gross residual disease are at greater risk for recurrence and death [11,26,45,46]. Generally, peritoneal implants are small or microscopic; thus, complicated surgical resections are rarely necessary in cases of borderline
SC
ovarian tumours. In addition, even in the face of peritoneal implants, a normal
M AN U
contralateral ovary may be preserved in young patients.
Fertility Preservation. As noted above, while fertility-sparing surgery is feasible in a high proportion of women in the reproductive age group with borderline
TE D
ovarian tumours, it is not always possible. For mucinous borderline tumours, bilateral involvement is quite rare. However, for serous borderline tumours, bilateral involvement occurs in approximately 50%. In the latter, although bilateral
EP
ovarian cystectomies or unilateral salpingo-oophorectomy plus ovarian cystectomy may be feasible in most cases, bilateral salpingo-oophorectomy may
AC C
be the only option in some patients due to the extent of ovarian involvement by tumour.
In any young patient undergoing surgery for an adnexal mass, preoperative counseling should include discussion of the possibility of bilateral salpingooophorectomy +/- hysterectomy. Preoperative referral to a reproductive
ACCEPTED MANUSCRIPT
endocrinology infertility subspecialist for fertility preservation counseling is recommended on an individual basis. In addition, for those few women found to have invasive peritoneal implants at the time of surgery and for whom
RI PT
postoperative chemotherapy is recommended, here again is an opportunity to
consider such a referral for discussion of the effects of chemotherapy on ovarian
M AN U
options for advanced reproductive technology.
SC
function—both premature ovarian failure and premature menopause--as well as
Ovarian tissue cryopreservation at the time of surgery, oocyte cryopreservation, or embryo cryopreservation for borderline ovarian tumours have been reported [47,48]. In addition, there are several reports of successful pregnancies following
TE D
conservative surgery for borderline ovarian tumours [39,42,49-51].
EP
Postoperative Treatment. As noted, the vast majority of borderline ovarian tumours, including the most common subtypes of serous and mucinous, are
AC C
stage I. Surgery alone is the standard therapy for these tumours since the relapse rate is extremely low. For serous borderline tumours, the relapse rate is < 1%. Barnhill et al. surveyed the literature and added their own Gynecologic Oncology Group GOG) study to 26 previous reports [52]. Of 988 patients with stage I serous borderline tumour, only seven (0.7%) died of tumour. In the GOG study, with a median follow-up time of 42.4 months, none of the 146 assessable patients with stage I serous borderline tumour who underwent comprehensive
ACCEPTED MANUSCRIPT
surgical staging and no adjuvant therapy had developed recurrence. However, long-term follow-up is necessary to determine the true recurrence rate associated
tumours, the relapse rate is up to 10% [53-55].
RI PT
with stage I borderline ovarian tumours. For stage I mucinous borderline
For women with serous borderline tumours and noninvasive peritoneal implants,
SC
chemotherapy was recommended historically [26,56]. However, based on the
lack of evidence of survival benefit, this recommendation was abandoned several
M AN U
years ago. Nevertheless, we now understand that these patients have a lifetime risk in the range of 20-50% of developing subsequent metastatic low-grade serous carcinoma [26,57]. Therefore, it is of utmost importance that these patients are counseled appropriately.
TE D
For women with serous borderline tumours and invasive peritoneal implants, platinum-based chemotherapy continues to be recommended postoperatively, although definitive supporting evidence of benefit is lacking [46]. Increasingly,
EP
gynecologic pathologists consider invasive peritoneal implants the equivalent of
AC C
low-grade serous carcinoma.
Surveillance Following Primary Treatment. No real standard exists in terms of how frequently patients should be followed or monitored following primary treatment of a borderline ovarian tumour. Similarly, there is no standard for methodology. In several centers, patients are followed every 3 months for the first year following treatment and gradually less frequently thereafter. In other
ACCEPTED MANUSCRIPT
centers, patients may be followed at 6 months intervals or even annual intervals. The disparate philosophies arise based on data and opinions regarding the risk of relapse related to individual patient and tumour factors. However, only a few
RI PT
studies have focused on methods for detection of relapse [58-60].
For patients who undergo fertility-sparing surgery, particularly those with stage I
SC
serous borderline tumours, the major concern is for the residual ovary. If such
patients do develop a “recurrence,” it is almost always an actual separate primary
M AN U
borderline tumour in the residual ovary. In the study by Uzan et al., sonography was the most frequent method of detection of a borderline lesion in the residual ovary [60]. On the other hand, if patients have a stage II-IV serous borderline tumour, the greatest risk is for a recurrent invasive low-grade serous carcinoma, most frequently presenting as carcinomatosis. In such cases, serum CA 125 may
TE D
be the most accurate method for this type of detection [60]. Thus, most physicians recommend surveillance following primary treatment of
EP
borderline ovarian tumours with physical examination, sonography if fertilitysparing surgery was performed, and serum tumour markers—CA 125 and/or
AC C
CEA for mucinous histology. Although serial CT or MRI imaging studies are not routinely recommended for surveillance, based on lack of evidence of efficacy, some physicians recommend these as well. Of course, if a patient develops a significant elevation of a serum tumour marker, CT imaging is the next logical step.
ACCEPTED MANUSCRIPT
Management of Relapse. Clinicopathologic risk factors for relapse are discussed above. As noted, if a “recurrence” occurs in a residual ovary following fertility-sparing surgery, it is almost always a second primary borderline tumour
RI PT
and can be adequately managed with surgery alone. Otherwise, for serous
borderline tumours, the most powerful factor associated with an invasive tumour relapse is stage, or the presence of peritoneal implants. Thus, most true
SC
recurrences involve extra-ovarian sites, and the majority of these relapses are
not serous borderline tumours but rather invasive low-grade serous carcinoma
M AN U
[20,26,46,57,61,62]. In rare cases, a serous borderline tumour may recur as a high-grade serous carcinoma [63,64].
TE D
A detailed discussion of treatment of serous borderline tumours that recur as invasive cancer is beyond the scope of this article. Briefly, initial consideration should be given to patient and tumour factors--including age, co-morbidities, and
EP
tumour distribution--in deciding whether secondary cytoreductive surgery is indicated. If it is determined that surgery is not advisable, then fine needle
AC C
aspiration/core biopsy is necessary for an accurate histologic diagnosis. Initial systemic therapy, whether the recurrence represents low-grade serous carcinoma or high-grade serous carcinoma, generally consists of platinum/taxane chemotherapy. Subsequent systemic options for recurrent low-grade serous carcinoma include hormonal therapy (aromatase inhibitors, tamoxifen, leuprolide acetate, fulvestrant, etc.), other conventional chemotherapeutic agents (pegylated liposomal doxorubicin, gemcitabine, topotecan, weekly paclitaxel,
ACCEPTED MANUSCRIPT
etc.), bevacizumab, or targeted agents (trametinib, MEK162, vemurafenib, etc.)
RI PT
[65-69].
For patients with mucinous borderline tumours who relapse following primary
surgery, the issues are somewhat different. First, because mucinous borderline
SC
tumours are most frequently unilateral, the risk of a second primary in a residual ovary is extremely low. If a recurrence of mucinous borderline tumour does
M AN U
occur, it is usually related to an incompletely resected mucinous borderline tumour and does not include an invasive component [70]. In such cases, extensive surgical resection may be required, but surgery alone is the
TE D
appropriate treatment.
Disseminated peritoneal relapses may occur in a small proportion of patients.
EP
Khunamornpong et al., in a study of 171 mucinous borderline tumours, found that risk factors for relapse included age > 45 years, microinvasion, intraepithelial
AC C
carcinoma, or stage > stage IC [53]. For patients who do develop recurrence, other than those with incompletely resected primary mucinous borderline tumour discussed above, the relapses are peritoneal or retroperitoneal, are invasive carcinoma or intraepithelial carcinoma, and are associated with a very poor prognosis [17,53,55]. There is no standard treatment of recurrent invasive mucinous carcinoma following a diagnosis of mucinous borderline tumour. As with invasive relapses of serous borderline tumours, secondary surgery is a
ACCEPTED MANUSCRIPT
consideration and should be individualized. For systemic therapy, some would initially recommend platinum/taxane chemotherapy while others would recommend a regimen used for a gastrointestinal cancer, such as oxaliplatin, 5-
RI PT
fluoro-urail or capecitabine, and bevacizumab. Since some mucinous carcinomas have molecular aberrations, such as a RAS mutation or HER-2/neu amplification,
SC
targeted therapy may be an option.
M AN U
Summary
Borderline ovarian tumours present similarly to other types of adnexal masses. Surgery is the primary treatment. Fertility-sparing surgery is feasible in a high proportion of women in the reproductive age group. If frozen-section examination
TE D
reveals a borderline tumour, surgical staging should be performed, including cytologic washings, omentectomy, and peritoneal biopsies. Routine lymphadenectomy is not recommended. Prognostic factors include FIGO stage,
EP
presence of micropapillary pattern (for serous tumours), intraepithelial carcinoma
AC C
(for mucinous tumours), microinvasion, and the presence of peritoneal implants. Postoperative therapy is recommended only for those patients with serous borderline tumours with invasive peritoneal implants. In those few patients who experience relapse, most commonly it represents invasive carcinoma.
ACCEPTED MANUSCRIPT
Conflict of Interest Statement I have no conflict of interest that could influence the content of this article.
RI PT
David M. Gershenson, MD
Borderline ovarian tumours present similarly to other types of adnexal
M AN U
•
SC
Practice Points
masses. •
Surgery is the primary treatment, and the surgical approach—open versus minimally invasive—should be individualized.
•
For women in the reproductive age group, preoperative fertility
•
TE D
preservation counseling is recommended. Since most borderline tumours are confined to the ovary(ies) and may involve one ovary, fertility-sparing surgery is feasible in a high proportion
Even if bilateral ovarian involvement is noted, fertility-sparing surgery may
AC C
•
EP
of women in the reproductive age group.
still be feasible with bilateral ovarian cystectomies or ovarian cystectomy plus unilateral salpingo-oophorectomy.
•
If borderline ovarian tumour is diagnosed on frozen section examination, surgical staging should include cytologic washings, omentectomy, and peritoneal biopsies.
•
Routine lymphadenectomy is not recommended as part of surgical
ACCEPTED MANUSCRIPT
staging. •
If extra-ovarian spread is noted at surgery, maximum cytoreductive surgery with no gross residual should be the objective. Postoperative treatment is recommended only for those patients with
RI PT
•
serous borderline tumours and invasive peritoneal implants.
If relapse with borderline tumour occurs, standard treatment consists of surgery alone.
•
If relapse with invasive carcinoma occurs, treatment may include
M AN U
secondary surgery and chemotherapy.
Research Agenda •
SC
•
Prevention of relapse in women with serous borderline tumours and
•
TE D
peritoneal implants, e.g., hormonal therapy Studies of alternative therapies for women with serous borderline tumours
•
EP
and invasive peritoneal implants
Prevention of relapse in women with mucinous borderline tumours the
AC C
contain areas of microinvasion or intraepithelial carcinoma •
Optimal therapy for women with invasive carcinoma following a diagnosis
of borderline ovarian tumour—either serous or mucinous
ACCEPTED MANUSCRIPT
References 1. Taylor HC. Malignant and semimalignant tumours of the ovary. Surg
RI PT
Gynecol Obstet 1929; 48: 204-230. 2. International Federation of Gynecology and Obstetrics: classification and staging of malignant tumours in the female pelvis. Acta Obstet Gynecol
SC
Scand 1971; 50: 1-7.
3. Serov SF, Scully RE & Solvin LH. International histologic classification of
M AN U
tumours. No. 9: Histologic typing of ovarian tumours, pp 37-41. Geneva: World Health Organization, 1973.
4. Vine MF, Ness RB, Calingaert B, Schildkraut JM, Berchuck A. Types and Duration of Symptoms Prior to Diagnosis of Invasive or Borderline Ovarian Tumour. Gynecol Oncol. 2001;83(3):466–71.
TE D
5. Tamakoshi K, Kikkawa F, Shibata K et al. Clinical value of CA125, CA199, CEA, CA72-4 and TPA in borderline ovarian tumour. Gynecol Oncol 1996; 62: 67-72.
EP
6. Ochiai K, Shinozaki H, Takada A et al. A retrospective study of 1069
AC C
epithelial borderline malignancies of the ovary treated in Japan. Proceedings of the Annual Meeting of the American Society of Clinical Oncology 1998; 17: A1429.
7. Wong HF, Low JJH, Chua Y, Busmanis I, Tay EH, Ho TH. Ovarian tumours of borderline malignancy: a review of 247 patients from 1991 to 2004. Int J Gynecol Cancer. 2007;17(2):342–9. 8. Kolwijck E, Thomas CMG, Bulten J, Massuger LFAG. Preoperative CA-
ACCEPTED MANUSCRIPT
125 levels in 123 patients with borderline ovarian tumours. Int J Gynecol Cancer. 2009;19(8):1335–8. 9. *Tang A, Chennakesavan SK, Ngan H, Zusterzeel P, Quinn M, Carter J, et
RI PT
al. Prognostic value of elevated preoperative serum CA125 in ovarian
tumours of low malignant potential: A multinational collaborative study (ANZGOG0801). Gynecol Oncol. 2012;126(1):36–40.
SC
10. Ayhan A, Guvendag Guven ES, Guven S, Kucukali T. Recurrence and
Sep;98(3):439–45.
M AN U
prognostic factors in borderline ovarian tumours. Gynecol Oncol. 2005
11. Shih KK, Zhou Q, Huh J, Morgan JC, Iasonos A, Aghajanian C, et al. Risk factors for recurrence of ovarian borderline tumours. Gynecol Oncol. 2011 Mar 1;120(3):480–4.
TE D
12. Obermair A, Tang A, Kondalsamy-Chennakesavan S, Ngan H, Zusterzeel P, Quinn M, et al. Nomogram to Predict the Probability of Relapse in Patients Diagnosed With Borderline Ovarian Tumours. Int J Gynecol
EP
Cancer. 2013 Jan;23(2):264–7.
13. *Morice P, MD CU, MD RF, MD SG, MD PD, MD PED. Borderline ovarian
AC C
tumour: pathological diagnostic dilemma and risk factors for invasive or lethal recurrence. Lancet Oncol. 2012;13(3):e103–15.
14. *Bois du A, Ewald-Riegler N, de Gregorio N, Reuss A, Mahner S, Fotopoulou C, et al. Borderline tumours of the ovary: A cohort study of the Arbeitsgmeinschaft Gyna ̈kologische Onkologie (AGO) Study Group. Eur J Cancer. 2013;49(8):1905–14.
ACCEPTED MANUSCRIPT
15. Hannibal CG, Vang R, Junge J, Frederiksen K, Kjaerbye-Thygesen A, Andersen KK, et al. A nationwide study of serous “borderline” ovarian tumours in Denmark 1978–2002: Centralized pathology review and overall
RI PT
survival compared with the general population. Gynecol Oncol. 2014;134(2):267–73.
16. Karlsen NMS, Karlsen MA, Hogdall E, Nedergaard L, Christensen IJ,
SC
Høgdall C. Relapse and disease specific survival in 1143 Danish women
2016;142(1):50–3.
M AN U
diagnosed with borderline ovarian tumours (BOT). Gynecol Oncol.
17. *Sobiczewski P, Kupryjanczyk J, Michalski W, Spiewankiewicz B. The Evaluation of Risk Factors Associated With Relapse and Recurrence of Borderline Ovarian Tumours With Long-Term Follow-up. Int J Gynecol
TE D
Cancer. 2016;26(6):1053–61.
18. Song T, Lee Y-Y, Choi CH, Kim T-J, Lee J-W, Bae D-S, et al. Risk Factors for Progression to Invasive Carcinoma in Patients With Borderline Ovarian
EP
Tumours. Int J Gynecol Cancer. 2014 Sep;24(7):1206–14. 19. Gershenson DM. Clinical management potential tumours of low
AC C
malignancy. Best Pract Res Clin Obstet Gynaecol. 2002;16(4):513–27.
20. Longacre TA, McKenney JK, Tazelaar HD, Kempson RL, Hendrickson MR. Ovarian serous tumours of low malignant potential (borderline tumours): outcome-based study of 276 patients with long-term (> or =5year) follow-up. Am J Surg Pathol. 2005 Jun;29(6):707–23. 21. Lesieur B, Kane A, Duvillard P, Gouy S, Pautier P, Lhommé C, et al.
ACCEPTED MANUSCRIPT
Prognostic value of lymph node involvement in ovarian serous borderline tumours. Am J Obstet Gynecol. 2011;204(5):438.e1–438.e7. 22. Maneo A, Vignali M, Chiari S, Colombo A, Mangioni C, Landoni F. Are
RI PT
borderline tumours of the ovary safely treated by laparoscopy? Gynecol Oncol. 2004;94(2):387-392.
23. Deffieux X, Morice P, Camatte S, Fourchotte V, Duvillard P, Castaigne D.
SC
Results after laparoscopic management of serous borderline tumour of the ovary with peritoneal implants. Gynecol Oncol. 2005;97(1):84-89.
M AN U
24. Desfeux P, Camatte S, Chatellier G, Blanc B, Querleu D, Lécuru F. Impact of surgical approach on the management of macroscopic early ovarian borderline tumours. Gynecol Oncol. 2005;98(3):390-395. 25. Romagnolo C, Gadducci A, Sartori E, Zola P, Maggino T. Management of
TE D
borderline ovarian tumours: Results of an Italian multicenter study. Gynecol Oncol. 2006;101(2):255-260. 26. *Gershenson DM, Silva EG, Tortolero-Luna G, Levenback C, Morris M,
EP
Tornos C. Serous borderline tumours of the ovary with noninvasive peritoneal implants. Cancer. 1998;83(10):2157–63.
AC C
27. Fotopoulou C, Schumacher G, Schefold JC, Denkert C, Lichtenegger W, Sehouli J. Systematic Evaluation of the Intraoperative Tumour Pattern in Patients With Borderline Tumour of the Ovary. Int J Gynecol Cancer. 2009;19(9):1550-1555.
28. Menzin AW, Gal D, Lovecchio JL. Contemporary Surgical Management of Borderline Ovarian Tumours: A Survey of the Society of Gynecologic
ACCEPTED MANUSCRIPT
Oncologists. Gynecol Oncol. 2000;78(1):7–9. 29. Lin PS, Gershenson DM, Bevers MW, Lucas KR, Burke TW, Silva EG. The current status of surgical staging of ovarian serous borderline
RI PT
tumours. Cancer. 1999;85(4):905–11.
30. Guvenal T, Dursun P, Hasdemir PS, Hanhan M, Guven S, Yetimalar H, et al. Effect of surgical staging on 539 patients with borderline ovarian
SC
tumours: a Turkish Gynecologic Oncology Group study. Gynecol Oncol. 2013;131(3):546–50.
M AN U
31. Kristensen GS, Schledermann D, Mogensen O, Jochumsen KM. The value of random biopsies, omentectomy, and hysterectomy in operations for borderline ovarian tumours. Int J of Gynecol Cancer. 2014;24(5):874– 9.
TE D
32. Winter WE, Kucera PR, Rodgers W, McBroom JW, Olsen C, Maxwell GL. Surgical staging in patients with ovarian tumours of low malignant potential. Obstet Gynecol. 2002;100(4):671–6.
EP
33. Rao GG, Skinner E, Gehrig PA, Duska LR, Coleman RL, Schorge JO. Surgical Staging of Ovarian Low Malignant Potential Tumours. Obstet
AC C
Gynecol. 2004;104(2):261-266.
34. *Song T, Choi CH, Kim H-J, Kim MK, Kim T-J, Lee J-W, et al. Accuracy of frozen section diagnosis of borderline ovarian tumours. Gynecol Oncol. 2011;122(1):127–31.
35. Fauvet R, Boccara J, Dufournet C, David-Montefiore E, Poncelet C, Daraï E. Restaging surgery for women with borderline ovarian tumours. Cancer.
ACCEPTED MANUSCRIPT
2004;100(6):1145–51. 36. Zapardiel I, Rosenberg P, Peiretti M, Zanagnolo V, Sanguineti F, Aletti G, et al. The role of restaging borderline ovarian tumours: Single institution
RI PT
experience and review of the literature. Gynecol Oncol. 2010;119(2):274– 7.
37. Tazelaar HD, Bostwick DG, Ballon SC, et al. Conservative treatment of
SC
borderline ovarian tumours. Obstet Gynecol. 1985;66:417-422.
38. Lim-Tan SK, Cajigas HE, Scully RE. Ovarian cystectomy for serous
1988;72:775-781.
M AN U
borderline tumours: A follow-up study of 35 cases. Obstet Gynecol.
39. Morice P, Camatte S, Hassan El J, Pautier P, Duvillard P, Castaigne D. Clinical outcomes and fertility after conservative treatment of ovarian
TE D
borderline tumours. Fertil Steril. 2001;75(1):92-96.
40. Park J-Y, Kim D-Y, Kim J-H, Kim Y-M, Kim Y-T, Nam J-H. Surgical management of borderline ovarian tumours: The role of fertility-sparing
EP
surgery. Gynecol Oncol. 2009;113(1):75-82. 41. Rao GG, Skinner EN, Gehrig PA, Duska LR, Miller DS, Schorge JO.
AC C
Fertility-sparing surgery for ovarian low malignant potential tumours. Gynecol Oncol. 2005;98(2):263-266.
42. Song T, Choi CH, Park HS, et al. Fertility-Sparing Surgery for Borderline Ovarian Tumours. Int J Gynecol Cancer. 2011;21(4):640-646.
43. Uzan C, Kane A, REY A, Gouy S, Duvillard P, Morice P. Outcomes after conservative treatment of advanced-stage serous borderline tumours of
ACCEPTED MANUSCRIPT
the ovary. Ann Oncol. 2009;21(1):55-60. 44. Suh-Burgmann E. Long-term outcomes following conservative surgery for borderline tumour of the ovary: a large population-based study. Gynecol
RI PT
Oncol. 2006;103(3):841–7.
45. Leake JF, Currie JL, Rosenshein NB & Woodru JD. Long-term follow-up of serous ovarian tumours of low malignant potential. Gynecol Oncol.
SC
1992;47: 150-158.
46. Gershenson DM, Silva EG, Levy L, Burke TW, Wolf JK, Tornos C. Ovarian
1998;82(6):1096–103.
M AN U
serous borderline tumours with invasive peritoneal implants. Cancer.
47. Fain-Kahn V, Poirot C, Uzan C, Prades M, Gouy S, Genestie C, et al. Feasibility of ovarian cryopreservation in borderline ovarian tumours. Hum
TE D
Reprod. 2009 Apr;24(4):850–5.
48. Huang JYJ, Buckett WM, Gilbert L, Tan SL, Chian R-C. Retrieval of immature oocytes followed by in vitro maturation and vitrification: A case
EP
report on a new strategy of fertility preservation in women with borderline ovarian malignancy. Gynecol Oncol. 2007;105(2):542–4.
AC C
49. Boran N, Cil AP, Tulunay G, Ozturkoglu E, Koc S, Bulbul D, et al. Fertility and recurrence results of conservative surgery for borderline ovarian tumours. Gynecol Oncol. 2005;97(3):845–51.
50. Kane A, Uzan C, Gouy S, Pautier P, Duvillard P, Morice P. Fertility results and outcomes after pure laparoscopic management of advanced-stage serous borderline tumours of the ovary. Fertil Steril. 2010;94(7):2891–4.
ACCEPTED MANUSCRIPT
51. Morris RT, Gershenson DM, Silva EG, Follen M, Morris M, Wharton JT. Outcome and reproductive function after conservative surgery for borderline ovarian tumours. Obstet Gynecol. 2000;95(4):541–7.
RI PT
52. Barnhill DR, Kurman RJ, Brady MF et al. Preliminary analysis of the
behavior of stage I ovarian serous tumours of low malignant potential: a Gynecologic Oncology Group study. J Clin Oncol 1995; 13: 2752-2756.
SC
53. *Khunamornpong S, Settakorn J, Sukpan K, Suprasert P, Siriaunkgul S. Mucinous Tumour of Low Malignant Potential (“Borderline” or ‘Atypical
M AN U
Proliferative’ Tumour) of the Ovary. Int J Gynecol Pathol. 2011;33(3):218– 30.
54. Kleppe M, Bruls J, Van Gorp T, Massuger L, Slangen BFM, Van de Vijver KK, et al. Mucinous borderline tumours of the ovary and the appendix: A
TE D
retrospective study and overview of the literature. Gynecol Oncol. 2014;133(2):155–8.
55. *Lee KR, Scully RE. Mucinous tumours of the ovary: a clinicopathologic
EP
study of 196 borderline tumours (of intestinal type) and carcinomas, including an evaluation of 11 cases with 'pseudomyxoma peritonei'. Am J
AC C
Surg Pathol. 2000;24(11):1447–64.
56. *Shih KK, Zhou QC, Aghajanian C, Huh J, Soslow RA, Morgan JC, et al. Patterns of recurrence and role of adjuvant chemotherapy in stage II–IV serous ovarian borderline tumours. Gynecol Oncol. 2010 Nov 1;119(2):270–3.
57. Silva EG, Gershenson DM, Malpica A, Deavers M. The recurrence and
ACCEPTED MANUSCRIPT
the overall survival rates of ovarian serous borderline neoplasms with noninvasive implants is time dependent. Am J Surg Pathol. 2006;30(11):1367–71.
RI PT
58. Poncelet C, Fauvet R, Boccara J, Darai E. Recurrence after cystectomy
for borderline ovarian tumours: results of a French multicenter study. Ann Surg Oncol 2006;13:565-71.
SC
59. Zanetta G, Rota S, Lissoni A, Meni A, Brancatelli G, Buda A. Ultrasound, physician examination, and CA 125 measurement for the detection of
M AN U
recurrence after conservative surgery for early borderline ovarian tumours. Gynecol Oncol 2001;81:63-66.
60. Uzan C, Kane A, Rey A, eta l. How to follow up advanced-stage borderline tumours? Mode of diagnosis of recurrence in a large series stage II-III
TE D
serous borderline tumours of the ovary. Ann Oncol 2011;22:631-35. 61. *Crispens MA, Bodurka D, Deavers M, Lu K, Silva EG, Gershenson DM. Response and survival in patients with progressive or recurrent serous
10.
EP
ovarian tumours of low malignant potential. Obstet Gynecol. 2002;99(1):3–
AC C
62. Shvartsman HS, Sun CC, Bodurka DC, Mahajan V, Crispens M, Lu KH, et al. Comparison of the clinical behavior of newly diagnosed stages II-IV low-grade serous carcinoma of the ovary with that of serous ovarian tumours of low malignant potential that recur as low-grade serous carcinoma. Gynecol Oncol. 2007;105(3):625–9.
63. Dehari R, Kurman RJ, Logani S, Shih I-M. The development of high-grade
ACCEPTED MANUSCRIPT
serous carcinoma from atypical proliferative (borderline) serous tumours and low-grade micropapillary serous carcinoma: a morphologic and molecular genetic analysis. Am J Surg Pathol. 2007;31(7):1007-1012.
RI PT
64. Boyd C, McCluggage WG. Low-grade ovarian serous neoplasms (low-
grade serous carcinoma and serous borderline tumour) associated with high-grade serous carcinoma or undifferentiated carcinoma: report of a
SC
series of cases of an unusual phenomenon. Am J Surg Pathol. 2012;36(3):368-375.
M AN U
65. Gershenson DM, Sun CC, Bodurka D, Coleman RL, Lu KH, Sood AK, et al. Recurrent low-grade serous ovarian carcinoma is relatively chemoresistant. Gynecol Oncol. 2009;114(1):48–52. 66. Gershenson DM, Sun CC, Iyer RB, Malpica AL, Kavanagh JJ, Bodurka
TE D
DC, et al. Hormonal therapy for recurrent low-grade serous carcinoma of the ovary or peritoneum. Gynecol Oncol. 2012;125(3):661–6. 67. Grisham RN, Iyer G, Sala E, Zhou Q, Iasonos A, DeLair D, et al.
EP
Bevacizumab Shows Activity in Patients With Low-Grade Serous Ovarian and Primary Peritoneal Cancer. Int J Gynecol Cancer. 2014;24(6):1010–4.
AC C
68. Farley J, Brady WE, Vathipadiekal V, Lankes HA, Coleman R, Morgan MA, et al. Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. Lancet Oncol. 2013;14(2):134–40.
69. Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay J-Y, et al. Vemurafenib in Multiple Nonmelanoma Cancers with BRAFV600
ACCEPTED MANUSCRIPT
Mutations. N Engl J Med. 2015;373(8):726–36. 70. Irving JA, Clement PB. Recurrent Intestinal Mucinous Borderline Tumours
AC C
EP
TE D
M AN U
SC
RI PT
of the Ovary. Int J Gynecol Pathol. 2014;33(2):156–65.
Table 1. Recommended surgical principles for borderline ovarian tumors
ACCEPTED MANUSCRIPT •
Determine optimal surgical approach—open versus minimally invasive
•
Consideration of fertility-sparing surgery in patients of reproductive age based on preoperative counseling, including fertility preservation
RI PT
counseling o Options for unilateral ovarian involvement: Ovarian cystectomy versus unilateral salpingo-oophorectomy
SC
o Options for bilateral ovarian involvement: Bilateral ovarian
cystectomies or unilateral salpingo-oophorectomy + ovarian
•
M AN U
cystectomy
Frozen section examination of ovarian mass(es) o Caveats
Frozen section diagnosis of mucinous ovarian tumors is not very accurate, leading to both under-diagnosis and
TE D
over-diagnosis
In at least 10% of cases in which the frozen section diagnosis is borderline tumor, final diagnosis will indicate
Recommended surgical staging:
AC C
•
EP
invasive carcinoma
o Evacuation of ascites or cytologic washings o Omentectomy o Multiple peritoneal biopsies o Careful palpation and inspection of entire peritoneal cavity and retroperitoneum with resection of any abnormal areas or lymphadenopathy
•
For obvious metastatic disease, maximum cytoreduction to achieve no gross residual tumor
ACCEPTED MANUSCRIPT
Figure Legends Fig. 1: Photomicrograph of serous borderline tumor with typical histologic pattern.
RI PT
Fig. 2: Photomicrograph of mucinous borderline tumor—intestinal type.
AC C
EP
TE D
M AN U
SC
Fig. 3: Photomicrograph of noninvasive peritoneal implant.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
Highlights Surgical approach—open or minimally invasive—should be individualized Fertility-sparing surgery is feasible in a high proportion of young patients Surgical staging is recommended for borderline ovarian tumours
AC C
EP
TE D
M AN U
SC
RI PT
• • •