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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

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 significantly interfere with fertility and sex hormone

production, are particularly problematic. It is important to notethat 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 valuesmay also increase in other diseases

such as endometriosis, uterine myomas, salpingitis and acute or

chronic pelvic inflammatory disease. The main limitation of this

marker is the low sensitivity and specificity 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 significant 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 especiallyif 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

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

A R T I C L E I N F O

Article history:

Received 30 April 2012

Received in revised form 8 September 2012Accepted 13 November 2012

Keywords:

Borderline ovarian tumor

Ovarian tumor

Controversial aspects

CA125

Laparoscopic approach

A B S T R A C T

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: :Weretrospectivelystudiedall patientstreatedat our institution from2000 to2010 takinginto account the age, the stage, the type of surgery, the tumor size, the symptoms, the pre- and post-

intervention 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 identified. The median age was 49 years (range: 1582 years). The

most frequent FIGOstage was IA(74%of the cases)with a prevalence of seroushistotype, and 49% of the

patients were asymptomatic. The CA125 level was abnormal in 55% of the patients before surgery,

returning to the normalrange inall cases after tumor removal. The PFS was 96% and 77% at five and sixty

months respectively.

Conclusion: The BOT iscloserto a benignthanto amalignant tumor inthe early stages, whenconfinedto

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 specificity, has a role in the follow-up of BOT.

2012 Published by Elsevier Ireland Ltd.

* 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).

Contents lists available at SciVerse ScienceDirect

European Journal of Obstetrics & Gynecology andReproductive Biology

journal h omepage: www.elsev ier .co m/ locate/e jogrb

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

classifications. 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, ultra-

sound 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 five 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

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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 preserva-

tion of fertility.

We recorded stage I in 93% of cases despite the lack of

symptoms and the ensuing late diagnosis. This finding 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 infiltration capacity.The small number of patients in the more advanced stages of

disease is a limitation of the study, but significant conclusions can

be drawn for stage I, representing the majority of the cases.

Although BOTs may have very variable sizes, the collected data

confirmed 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, significantly lower

compared to mucinous tumors, ranging from 40 to over 350 mm

(p 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 significant 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 theabdominal 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, ultrasono-

graphic 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 difficult, 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

thepresence 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 specificity [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

field.

When

the

cyst

is

complex,

Fig. 2. Progression-free survival KaplanMeier method.

E.M. Messalli et al./ European Journal of Obstetrics & Gynecology and Reproductive Biology 167 (2013) 868988

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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 finding 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 findings 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. Wemust 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 wholeseries 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