European Journal of Obstetrics & Gynecology and Reproductive Biology 167 (2013) 8689

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European Journal of Obstetrics & Gynecology and Reproductive Biology

journal homepage: www.elsevier.com/locate/ejogrb

Borderline ovarian tumors: features and controversial aspects

Enrico M. Messalli *, Flavio Grauso, Giancarlo Balbi, Antonella Napolitano, Elisabetta Seguino, Marco Torella
Department of Gynecologic, Obstetric and Reproduction Sciences, Second University of Naples, Naples, Italy

A R T I C L E I N F O

A B S T R A C T

Article history: Received 30 April 2012 Received in revised form 8 September 2012 Accepted 13 November 2012 Keywords: Borderline ovarian tumor Ovarian tumor Controversial aspects CA125 Laparoscopic approach

Objective: To investigate features and controversial aspects of the borderline ovarian tumor (BOT), a neoplasm with favorable prognosis representing 1015% of epithelial ovarian tumors. Study design: : We retrospectively studied all patients treated at our institution from 2000 to 2010 taking into account the age, the stage, the type of surgery, the tumor size, the symptoms, the pre- and postintervention tumor marker levels (CA125, CA19.9, CA15.3 and CEA), the presence of recurrence, the overall survival (OS), the progression-free survival (PFS). Results: A total of 43 patients were identied. The median age was 49 years (range: 1582 years). The most frequent FIGO stage was IA (74% of the cases) with a prevalence of serous histotype, and 49% of the patients were asymptomatic. The CA125 level was abnormal in 55% of the patients before surgery, returning to the normal range in all cases after tumor removal. The PFS was 96% and 77% at ve and sixty months respectively. Conclusion: The BOT is closer to a benign than to a malignant tumor in the early stages, when conned to the ovary (IA and IB). In these stages conservative surgery is safe and advisable for women seeking offspring. In the other stages the need for a careful and long-term follow-up arises. CA125, despite its modest sensitivity and specicity, has a role in the follow-up of BOT. 2012 Published by Elsevier Ireland Ltd.

1. Introduction The borderline ovarian tumor (BOT) is an intermediate form between a benign and a malignant tumor. The main histological criterion to differentiate it from malignancy is the absence of stromal invasion, but unlike benign forms, it has an increased mitotic index and the presence of nuclear atypia [1,2]. BOTs account for 1015% of epithelial ovarian tumors and have a favorable prognosis, with a 10-year survival rate higher than 95% [3]. The average age of onset is between 20 and 46 years and about 25% of the patients are younger than 35 years at the time of diagnosis. For this reason, decisions about surgical treatment, which can signicantly interfere with fertility and sex hormone production, are particularly problematic. It is important to note that conservative treatment exposes the patient to an increased relative incidence of relapse (35% of cases) compared to radical treatment (5% of cases) [4]. The main investigation method is ultrasound, where BOTs present with different echo-patterns such as a unilocular complex cyst, a septated cyst or a mass with liquid and solid components,

sometimes with endocystic vegetation [5]. Although ultrasound examination has the criteria to differentiate benign and malignant forms, it still fails to identify borderline forms [6]. CA125 is the main marker that has a close correlation with ovarian cancer, but its values may also increase in other diseases such as endometriosis, uterine myomas, salpingitis and acute or chronic pelvic inammatory disease. The main limitation of this marker is the low sensitivity and specicity in early stages, when it would be more useful. In fact, in stage I the marker is abnormal in just 50% of cases. In contrast, in advanced stages (III or IV), CA125 shows signicant elevation in more than 8085% of the patients [7]. Assays of tumor markers such as CA125 and CA19.9 are useful in follow-up, detecting disease recurrence in most cases especially if used in combination with ultrasonography. We sought to report features and controversial aspects of BOT based on our data sample. 2. Materials and methods At our institution we conducted a retrospective study of 43 patients in the period between 2000 and 2010. The parameters evaluated for each patient were age, type of surgery, tumor size, symptoms, stage, pre- and post-intervention tumor marker levels, presence of recurrence, overall survival (OS), progression-free

* Corresponding author at: Largo Madonna delle Grazie, 1, 80138 Napoli (Italy). Tel.: +390815665601; fax: +390815665610. E-mail address: enricom.messalli@unina2.it (E.M. Messalli). 0301-2115/$ see front matter 2012 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.ejogrb.2012.11.002

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survival (PFS) and time of follow-up. Histopathology grading and staging were performed according to the WHO and FIGO classications. The histologic types were serous, mucinous, endometrioid, clear cell and Brenner. Serum tumor marker levels were examined to evaluate the trend after surgery. Follow-up was a combination of clinical examination, ultrasound scan and measurement of markers. During the initial two years, follow-up evaluation was performed every three months. Patients were then evaluated biannually from three to ve years after surgery and then annually thereafter. A progression-free survival (PFS) curve was derived using the KaplanMeier Method. Statistical analysis was performed using Students t test and the Fisher exact test when appropriate. P < 0.05 was considered signicant. 3. Results BOT accounted for 8.23% of all ovarian tumors diagnosed and treated in our hospital. Among the 43 patients enrolled, 33 had complete data sampling and regular follow-up. Patients were between 15 and 82 years old, with an average age of 49 and a median age of 49. It is important to emphasize that 25% were younger than 35 years old. The most frequent stage was IA (74%) followed by stage IC (12%) and IB (7%). Only three patients were in stage II (2% IIA and 5% IIC). In our study the most frequent histological type were serous (52%) and mucinous (46%), with all other types accounting for less than 2%. We distinguished three mucinous subgroups: unspecied mucinous (65%), intestinal mucinous (30%) and endocervical mucinous (5%). We found serous tumors (20230 mm) to be smaller than mucinous tumors (40354 mm) with an average and median size of 77 mm and 72 mm, versus 149 mm and 130 mm, for serous and mucinous tumors respectively (p < 0.01). Patients were asymptomatic in 49% of the cases (21 cases). In the premenopausal age group, the most common sign was menstrual irregularities (44%, i.e. 7/16). Bleeding occurred in 7% of cases in the post-menopausal period (two women out of 27). Pelvic pain occurred fairly frequently (23%), while we rarely observed abdominal tenderness (5%) or dysuria (2%).

We found noninvasive implants in 7% of the examined cases (3/ 43) but no patient was affected by invasive implants; among the noninvasive implants, the epithelial type accounted for 75% (3 cases), while the desmoplastic type accounted for one case. Although these results are not different from other studies, the small number of cases severely restricts their validity. All our patients underwent primary surgery. Complete pelvic clearance was performed in 44% of cases (19/43) and conservative surgery (dened as cystectomy or unilateral oophorectomy) in 56% (24/43). No patient had bowel/appendix involvement. The laparotomic approach was used in 91% of the cases, while the laparoscopic approach was reserved for few selected cases amounting to 9% (4 cases). Only two patients underwent a second operation for recurrence. In our series only four patients were selected for laparoscopic surgery. Their median age was 33 years. The size of the cysts ranged from 33 to 107 mm with a median of 57 mm. The ultrasonographic ndings pointed to a benign form without presence of thick septa, irregular margins or vegetations. The cysts did not show any signal to echo colour Doppler. Serum levels of CA125 pre- and post-intervention were determined in 33 patients. For each patient the average before and after primary surgery was calculated. The mean pre-surgery value of CA125 was 67.3 U/ml (median = 53.4 U/ml) with 55% of the patients being above the upper limit of the normal range. Conversely its post-surgery mean value was 11.1 U/ml (median = 9.7 U/ml), consistent with a return to the normal range in 100% of cases (Fig. 1). In addition to CA125 we evaluated other markers such as CA19.9, CA15.3 and CEA. The last two did not show any association with tumor presence. CA19.9 was abnormal in 21% of all patients (7/33) and in 45% (5/11) of patients with the mucinous histotype. The mean pre-surgery value of CA19.9 was 28.7 U/ml (median = 13.9 U/ml). The mean post-surgery value was 7.51 U/ml (median = 7.8 U/ml). Levels returned to the normal range in 100% of cases after primary surgery. OS was excellent, in 100% of cases, and no patient died either of borderline tumor or of any other cause. A curve showing the PFS was plotted according to the KaplanMeier method. Through this

Fig. 1. Average level of CA125 for each patient before and after surgery.

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Fig. 2. Progression-free survival KaplanMeier method.

method we were able to calculate the time between diagnosis and relapse (PFS) and to relate it to recurrence risk. The PFS at 5 and 60 months was respectively 96% and 77% (Fig. 2). 4. Comment The median age of our patients was slightly higher than other global studies (49 years vs 4243 years) [4,8,9]. Similar to other studies [10], 25% of the patients were below 35 years old, which strengthens the need for conservative surgery allowing preservation of fertility. We recorded stage I in 93% of cases despite the lack of symptoms and the ensuing late diagnosis. This nding is in line with other studies [4,810], with 90% of BOTs diagnosed at stage I. Such a high frequency supports the conclusion that borderline tumors are more similar to benign tumors, differentiating themselves from malignant ones by their low inltration capacity. The small number of patients in the more advanced stages of disease is a limitation of the study, but signicant conclusions can be drawn for stage I, representing the majority of the cases. Although BOTs may have very variable sizes, the collected data conrmed the tendency of tumors with a mucinous histotype to be larger than those with a serous histotype. For serous tumors we found a size range varying from 20 to 230 mm, signicantly lower compared to mucinous tumors, ranging from 40 to over 350 mm (p < 0.01). Our study conrmed the absence of symptoms in BOTs. In fact, in 49% of cases the patients did not report any symptoms and the diagnosis was fortuitous: usually ultrasound investigation performed for other reasons showed a suspect cyst. In the case of mucinous tumors, larger than serous, the symptomatology was characterized by the presence of abdominal tenderness (5%) or pelvic pain (23%) due to the tumor behaving as a space-occupying lesion. Irregularities of menstrual ow were detected in 44% of affected women in the premenopausal period. Other symptoms were present in less than 18.5% of cases. In contrast, in the postmenopausal period bleeding was not very common, occurring in about 7% of cases. The absence of symptoms in half of the patients was the main obstacle to an early diagnosis and the main reason for performing a careful and long post-surgery follow-up in order to diagnose a potential relapse within a reasonable time frame. In fact, except for the menstrual irregularities, all other symptoms (tension, discomfort, soreness, dysuria) were nonspecic and not readily attributable to the gynecological area.

In our series, the nding of only noninvasive implants was a further element that conrmed the borderline tumors inability to inltrate. We also recorded the prevalence of epithelial (75%) rather than desmoplastic (25%) implants. The results obtained in terms of OS and relapse (PFS > 77% at 5 years) show that conservative surgery may be considered appropriate for this type of tumor: in our experience more than half of the patients (56%) were treated with this type of surgery and only 8.3% (2/24) were affected by relapse. In relation to stages there are no signicant differences in PFS because we observed only two recurrences, both in patients at stage I. Regarding treatment, the type of surgery deserves the same level of attention. According to the theory of Maneo et al. [11], borderline tumors are best treated with laparotomic surgery from stage IC. This theoretical assumption is based on the fact that the more frequent rupture of the cyst in laparoscopic surgery is a negative event because it disseminates neoplastic cells in the abdominal cavity. Knowledge of the exact stage is in most cases possible only after surgery and histological examination [12], representing a major practical limit in identifying stage IC or higher. In our hospital patients would qualify as candidates for the laparoscopic approach based on three criteria: age, ultrasonographic features and negativity of tumor markers. Regarding age, the basic principle is that benign lesions are more frequently found in the younger age group, as opposed to malignant being more typical of old age. One fundamental characteristic of the cyst is its size; too large cysts make the execution of the laparoscopic technique difcult, especially with regard to the phase of extraction, and reduce the accuracy of frozen section diagnosis that we use selectively in more suspicious cysts. In addition to size we considered additional features such as the presence of solid areas within the cyst, and the presence of irregular margins, vegetations (> 3 mm), thick septa (>3 mm) and ascites. Their absence certainly argues for a markedly benign cyst and leads us to prefer a laparoscopic approach. Finally we considered the values of tumor markers, whose negativity generally points to a benign cyst taking into account the relative sensitivity and specicity [13], especially if associated with color doppler ultrasound evaluation [14]. These factors suggest that the removal of a benign simple cyst is best achieved through a laparoscopy, which yields the same result as a laparotomy but requires smaller incisions, is less invasive, and allows a rapid recovery and better aesthetic results. Last but not least, it has the undeniable advantage of allowing a close examination of the operative eld. When the cyst is complex,

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with malignant ultrasonographic features or even after positive intraoperative frozen section, the laparoscopic approach should be abandoned and replaced by a type of open surgery. The nding of an elevation of serum CA125 values in more than half the cases (54.5%) shows a good correlation between this marker and borderline tumors. In fact, given the low rate of systemic involvement of this type of tumor (more than 90% were in stage I), the frequency of CA125 elevation is not surprising. It may be considered normal or even optimal, in line with the ndings of a recent study on tumor markers [13] reporting that a CA125 elevation occurs in only 50% of cases in the early stages in contrast to the advanced stages (III-IV stages), when it occurs in 8085% of cases. An important aspect to highlight is the ability of CA125 to be in the normal range after surgical excision of the tumor; this condition, occurring in all patients examined, assigns to CA125 the role of preferred marker for follow-up of borderline tumors and more generally of ovarian tumors. We must admit, however, that we also recorded a case in which the CA125 value remained normal, despite the presence of both pelvic recurrence and noninvasive implants, diagnosed through histologic examination after secondary open surgery. Regarding CEA and CA15.3 we did not observe any correlation with BOTs. CA19.9 deserves instead some explanation. If the whole series is considered, the value of CA19.9 was abnormal in 21% of cases. Taking into account only the mucinous type, this value was abnormal in 45% of cases (p < 0.05). As for CA125, the value tended to normalize after surgical tumor excision. These ndings conrm the role of CA19.9 in the follow-up of patients with a borderline mucinous histotype. Our study conrms that BOTs are closer to a benign than to a malignant tumor, provided that the diagnosis and treatment are carried out within a short period of time. A borderline tumor conned to the ovary (stage IA and IB) does not give problems after surgical removal in almost all patients if there are no invasive peritoneal implants or residual disease after surgery, as stated by Morice et al. [12]. Although our study is limited to a decade, we believe, as do Silva et al., that for other stages with implants the need for careful and long-term follow up arises because tumor recurrence has been identied even several decades after primary surgery [15]. The improvement and evolution of surgical techniques allows conservative surgery for this type of tumor with increasing safety and preservation of fertility in women seeking offspring, but more attention should be paid to the type of surgical approach. Considering the increasing development of laparoscopic techniques and the difculty in diagnosing BOT, we can reasonably assume that in the near future laparoscopy will be the validated technique of

choice for the therapeutic approach to this type of ovarian tumor. Despite its modest sensitivity and specicity in the initial stages, CA125 conrms its role, together with the pelvic examination and ultrasound, in the follow-up of BOTs. Condensation Borderline tumors conned to the ovary (stage IA and IB) do not pose any threats after surgical removal in almost all patients. References
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