REVIEW

Peri- and post-menopausal incidental adnexal masses and the risk ofsporadic ovarian malignancy: new insights and clinical management

FAUSTINO R. PEREZ-LOPEZ1, PETER CHEDRAUI2, & JUAN M. TROYANO-LUQUE3

1Department of Obstetrics and Gynaecology, Facultad de Medicina, Universidad de Zaragoza, Hospital Clınico de Zaragoza,

Zaragoza 50009, Spain, 2Academic and Research Department, Hospital Gineco-Obstetrico Enrique C. Sotomayor, Guayaquil,

Ecuador, and 3Department of Obstetrics and Gynaecology, Facultad de Medicina, Universidad de La Laguna,

Hospital Universitario de Canarias, Tenerife 38071, Spain

(Received 11 January 2010; accepted 15 April 2010)

AbstractAdnexal masses are common among peri- and post-menopausal women. Although ovarian cancer is a significant cause ofmortality in menopausal women, large population-based studies demonstrate that the majority of adnexal masses are benign.Despite this, the appearance of an adnexal mass is a concern for the patient and an insight exercise for physicians. In mostcases, an adnexal enlargement is an incidental finding, generally corresponding to a benign cyst and easily diagnosed byconventional ultrasound. Exceptionally an ovarian tumour may be malignant and should be treated as early as possible.When conventional ultrasound renders complex morphology other diagnostic tools must be used such as: colour Dopplerand functional tumour vessel properties, serum CA 125 levels, nuclear magnetic resonance imaging and in some caseslaparoscopy. Several new tumour markers are being studied for clinical application, although there are presently no clearrecommendations. Adnexal masses with benign morphological and functional properties must be periodically monitored asan alternative to surgery since malignant transformation is exceptional.

Keywords: Menopause, adnexal mass, ovarian cancer, ultrasound scan, Doppler, CA 125, incidental ovarian cyst

Introduction

Ovarian cancer is the most lethal disease of the female

reproductive tract. Risk for ovarian malignancy in-

creases with age, and decreases with pregnancy.

Lifetime risk is about 1.6%, while women with affected

first-degree relatives have a 5% risk, those with a

mutated BRCA1 or BRCA2 gene or hereditary non-

polyposis colorectal cancer (Lynch syndrome) have a

25–60% risk depending on the specific mutation

[1–3]. Contrary to this, most ovarian cysts are never

noticed and resolve without women ever knowing so.

Prevalence of ovarian and paraovarian cysts is high in

both peri- and post-menopausal women, and while

most cases are benign [4–6], other incidental adnexal

masses are infrequent [7,8]. Hormonal changes taking

place around the menopause may predispose the

development of these benign ovarian cysts [9,10].

Proposal for ovarian cancer screening have failed or

have not been cost-effective; therefore, aside from

clinical trials, screening is not currently recom-

mended in the general populations [11–13]. Routine

ultrasound in pre- and post-menopausal women

allows diagnosing many ovarian cysts that are devoid

of any significant clinical symptom. An incidental

ovarian finding produces concern in many women

and should be differentiated from ovarian cancer.

When a cyst causes symptoms, pain is by far the most

common one. This pain may be due to cyst rupture,

rapid growth and stretching, intracyst bleeding and/or

torsion around its blood supply. The most common

type of ovarian cyst is the follicular caused by a follicle

growth. Other types include the haemorrhagic or

endometrioid. Dermoid cysts are infrequent around

the menopause [14]. Ovarian cancer is a silent killer,

especially affecting women above 50 years; although

presentation is often vague and non-specific, symp-

toms are definitely present. Therefore, a proper

clinical examination and appropriate tests should be

carried out upon onset in peri- and post-menopausal

Correspondence: Faustino R. Perez-Lopez, Facultad de Medicina, Department of Obstetrics and Gynaecology, Universidad de Zaragoza, Hospital Clınico de

Zaragoza, Zaragoza 50009, Spain. Tel: þ34-976-76-1734. Fax: þ34-976-76-1735. E-mail: faustino.perez@unizar.es

Gynecological Endocrinology, September 2010; 26(9): 631–643

ISSN 0951-3590 print/ISSN 1473-0766 online ª 2010 Informa UK Ltd.

DOI: 10.3109/09513590.2010.487611

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women. This study will update and assess the

available evidence concerning the management of

incidental adnexal masses around the menopause in

otherwise healthy women. Since women with heredi-

tary ovarian cancer risk may also have breast and colon

cancer risks and receive especial clinical recommen-

dations [15–17], hereditary cancer will not be

addressed.

Structure of the human menopausal ovary:

focussing on epithelial neoplastic capability

Ovarian plasticity has been postulated to facilitate

neoplastic transformation, tumour heterogeneity and

the complex pattern of its clinical course [18]. The

most common ovarian cancer is the epithelial with

three sub-types: mucinous, serous and endometrioid.

Germ cell and sex-cord stromal tumours are less

frequent types. Epithelial types of cancers derive

from the ovarian surface epithelium and its inclusion

cysts. Borderline ovarian tumours also arise from the

ovarian epithelium and show histological features

that are intermediate between benign and malignant

tumours. The surface epithelium is embryologically

formed from the invagination of the coelomic

mesothelium over the gonadal ridges [19], which

can migrate into the ovarian stroma to create

inclusion cysts. However, cysts can also develop

from periovarian and peritubal adhesions [20]. The

exposure of an inclusion cyst to the ovarian environ-

ment may cause phenotypic changes to the epithe-

lium commonly found in these cysts [21,22].

Metaplastic epithelium may also initiate neoplastic

changes which may be, under certain circumstances,

the pathway for developing an epithelial carcinoma

[23–25]. Characteristics of the epithelium surface of

early and advanced ovarian cancer have been

classified according to gene expression in attempt

to find the causes for cancer progression [26–31].

Despite this, no reasonable explanation for the

carcinogenesis process has been elucidated. Serous

borderline tumours are a separate category and in

most cases probably do not progress to authentic

carcinomas [32].

Assessment of the risk of developing ovarian

carcinoma has been performed by comparing the

histological ovarian features of women with high and

low risk. Ovaries removed from women with in-

creased risk of developing ovarian cancer contained

atypical features such as: surface epithelial pseudoes-

tratification, surface papillomatosis, deep epithelium

cortical surface invagination, multiple papillar pro-

jections with small cysts, epithelial inclusion cysts,

cortical stromal hyperplasia and hyperthecosis, in-

creased follicular activity, corpus luteum hyperplasia

or hiliar cell hyperplasia [33–35]. An early disruption

of the ovarian hormonal balance may exist in women

with pre-disposition to ovarian cancer that favours

the expression of certain genes and tumour growth

[36–38]. However, there are no clear ovarian

carcinoma precursors [20,32]. Risk factors for

sporadic ovarian cancer include age and a family

history of the disease, while increasing parity, oral

contraceptive (OC) use, oophorectomy, and breast-

feeding have protective effects. Modifiable risk

factors for epithelial ovarian cancer include lifestyle

ones such as, high body mass index, central obesity,

cigarette smoking, alcohol consumption, recreational

activities and post-menopausal hormone treatment

(HT) [39–49].

In young women, the ovarian surface epithelium is

a single layer of mesothelial cells that covers the

surface of the ovary, which is cyclically submitted to

conspicuous changes due to the ovulatory rupture

and repair process. This continuous process pro-

duces biochemical changes to date unknown that

may favour carcinogenic transformation. There is a

large number of biochemical candidates that may

initiate genetic alterations and progression, including

steroids, cytokines, prostaglandins, caspases, apop-

totic regulators and growth factors [50–52]. The

reduction of the number of ovulations due to

multiparity or OC use have protective effects against

epithelial ovarian cancer risk through the annulations

of repetitive rupture-reparation process in the cell

surface ovarian epithelium. Experimental (in-vitro

animal studies), epidemiological and clinical evi-

dence have shown that normal ovaries and many

ovarian tumours are influenced by endocrine factors

are hormone dependent or may be submitted to HT.

However, the relationships between ovarian hormone

function and carcinogenesis are still not clear. The

presence of oestrogen (ER) and androgen receptors

have been documented in a great number of primary

ovarian cancers (63% and 69%, respectively), while

progesterone receptors are reported in half of

tumours and glucocorticoid receptors in up to 88%

of ovarian cancers [53–56].

Oestrogen acts on the ovary by the two ER, a and bwhich are present in the ovary, although ER-bmRNA is the most abundant. Specific roles for each

ER at the ovarian level have yet to be established.

However, a reduction of ER-b has been suggested to

be associated to severity and prognosis of ovarian

cancer. The importance of ER signals in the ovarian

function has been postulated in the oestrogen

depleted aromatase knockout mouse. Although it

remains to be determined what genes are regulated

by ER-b in the human ovary [57]. Gene expression

profile (24 genes) differs in ovarian cancer cell lines

with different ER-a and ER-b populations, by adding

oestradiol or genistein. It seems that in-vitro oestro-

gens play a role in ovarian carcinogenesis in

association with unidentified cofactors [58]. Mole-

cular factors involved in epithelial ovarian cancer

have been studied by microarray techniques to

632 F. R. Perez-Lopez et al.

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identify gene expression profiles that participate in

cell signalling, proteinase secretion, cell adhesion and

proliferation, extracellular matrix formation and

apoptosis [59,60]. Clinicopathological correlates

have tried to determine malignant disease develop-

ment, growth, infiltration and progression. However,

the mechanisms underlying gene alterations and the

specific role of involved proteins remain to be

elucidated.

HT use has been related to ovarian cancer risk in

post-menopausal women [61–63]. A meta-analysis of

8 cohort and 19 observational studies examined the

relation between menopausal HT and ovarian

cancer, estimating the risks for less than 5 years,

6–10 and more than 10 years use as 1.02, 1.13 and

1.21, respectively [64]. A more recent systematic

review examined a total of 14 publications, including

case–control, cohort and randomised studies con-

cerning the use of oestrogen-alone (ET) or oestrogen

associated to progestin treatment (EPT) and the risk

of ovarian cancer. The use of ET and EPT for 5 years

significantly increased this risk (RR: 1.22 and 1.10,

respectively) [63]. It seems that progestin addition

may slightly reduce cancer risk related to ET. The

Danish National Cancer Registry provides interest-

ing information regarding HT and ovarian cancer

incidence in a total of 909,946 of women. During a

follow up of 8 years, there were 3068 incident ovarian

cancers, of which 2681 were epithelial ones. Among

current HT users ovarian cancer incidences were

1.38 and 1.44 for epithelial ovarian cancers. In-

creased ovarian cancer risk was independent of

treatment duration, formulations, progestin used

and route of administration. It seems that cancer

risk disappears more than 2–4 years after HT

discontinuation. Incidence rates in current and never

HT users were respectively 0.52 and 0.40 per 1000

years [62].

New aspects regarding carcinogenesis are emer-

ging, including the importance of tumour origin and

distribution. Thus, it has been postulated that some

serous tumours may originate in the fimbria or

peritoneoum where p53 tumour suppressor gene

mutations have been found [65].

Clinical symptoms of the asymptomatic killer

It is assumed that early ovarian cancer diagnosis

results in better survival and also assumed that stages

I and II progress to stage III and IV. However,

neither of the two assumptions has been clearly

demonstrated. Early stages of ovarian cancers have

an insidious onset and cause no or non-specific

symptoms. Most women with ovarian cancer have

one or several symptoms, including abdominal pain

or discomfort, bloating, back pain, urinary urgency,

pelvic pain, abnormal genital bleeding and abdom-

inal mass or unjustified weight loss [66–69]. Because

of the lack of early symptoms or non-specific nature

of these, about two-thirds of patients with ovarian

cancer present in FIGO stages III and IV, having

tumour dissemination in the abdominal cavity, with

or without varying degrees of pleural effusion.

Pavlik et al. [70] have reported the value of clinical

symptoms as compared to ultrasound for the early

detection of ovarian cancer malignancy. Hence, in a

selected group of women, clinical symptoms were

correlated with ultrasound vaginal findings, being

respectively sensitivity 73% versus 20%. Clinical

symptoms have higher specificity (91%) in benign

tumours than in malignant ones (74%). In this

regard, studied tumours that are negative by both

symptom and ultrasound assessment are likely to be

benign, and by adding to symptoms information

ultrasound malignancy assessment increases sensi-

tivity only 3.3%.

Ultrasound features of incidental adnexal

masses

The diagnosis of an adnexal mass is usually

established by ultrasound. Prevalence of adnexal

masses is influenced by the number of scanned

women, the inclusion criteria used in each study, and

may increase with some endocrine treatments

[71,72] Simple cysts are more common than

previously thought (2.5–14%) and are frequently

diagnosed incidentally [4,8,73–75]. In many cases,

bidimensional (2D) ultrasound examination is suffi-

cient to give a clear diagnosis of benign or malignant

ovarian lesions. However, in clinical practice there

are many overlapping situations. Thus, some malig-

nancies are detected as simple cyst without a

complex morphological image, and contrarily some

very complex images may correspond to benign

pathological findings.

Three-dimensional (3D) sonography is currently a

major development in ultrasound imaging with a

significantly higher sensitivity, specificity and accu-

racy as compared to 2D ultrasound [76]. 3D

ultrasound characterises an entire soft tissue volume

by storing multiple 2D images. Computer software

then rapidly creates a tridimensional image. Despite

the fact that 3D ultrasound is gaining clinical

acceptance it seems, however, that in routine practice

it will not replace conventional 2D ultrasound.

Indeed those who support 3D ultrasound vascular

assessment for the differential diagnosis of an adnexal

mass consider this procedure still under research

[74,76]. To improve results, colour Doppler assess-

ment of intratumoural blood flow has been proposed.

It is based upon assigning red colour to flow directing

toward the transducer and blue colour for flow

directing away. Colour Doppler flow imaging is very

useful in the detection of uterine adnexal malignan-

cies because of the frequent neovascularisation found

Menopause and ovarian cancer 633

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in these cases [7–9,77,78]. However, considerable

overlapping exists between benign and malignant

adnexal masses in terms of resistance (RI) and

pulsatility (PI) indices. Therefore, colour Doppler

RI measurements cannot be used alone for the

detection of malignant ovarian tumours. Further-

more, results from ultrasound explorations are highly

dependent on individual operator dedication and

technical expertises [79]. The use of power Doppler

3D implies new haemodynamic indices, such as the

flow index, vascularisation index and the flow

vascularisation index, which replace the traditional

RI and PI. This allows performing flow volumetric

calculations. Vascular tridimensionality may be

assessed and the mean vascular density calculated

for any tumoural area calculated. In this sense, the

most recent technology constitutes the virtual organ

computer-aided analysis that allows to automatically

obtaining angiographic volumes of spherical or

regular structures, as well as of irregular ones.

Ultrasonographic morphological features of incidental

adnexal masses

The morphological characteristics found at ultra-

sound may suggest the type of lesion. Complex

intracystic ovarian masses, including solid and

parietal irregularities, are associated with ovarian

carcinoma, suggesting these findings as significant

markers of malignancy [4]. Sonographic character-

istics of an incidental early ovarian cancer include

multilocular or multiple cysts, irregular thick septa or

walls, poor-defined borders, papillar growths, solid

elements and echogenic components [77,80,81].

Transvaginal sonography has relatively low positive

predictive value for ovarian cancer, in some studies

with a 10% value in post-menopausal women

[81,82]. The presence of a purely solid tumour is

highly suspicious of metastatic cancer rather than a

primary ovarian cancer [78]. The presence of ascites

is suggestive of malignancy but may be related to

other causes. Careful examination of the abdominal

cavity should be performed to detect the extent of

the disease.

Paraovarian (peritoneal inclusion close to the

ovary) and paratubal cysts constitute up to 10% of

all adnexal masses [83], being more frequent in

young women than in menopausal ones. Upon

ultrasound examination they may be separately

identified from ovaries (76%) as thin walled,

anechoic and unilocular cysts. Most usually in these

cases ovaries are normal [84]. However, sometimes

they display solid nodular areas within the cyst,

septations, thick or irregular walls [85,86].

Sonographical features of incidentally detected

small ovarian dermoids are better detected by means

of transvaginal ultrasound. They generally appear as

a solid homogeneous or heterogeneous hyperechoic

image, sometimes with a full fluid area and a

hyperechoic focus in its wall, an inconstant mixed

pattern with solid and liquid areas or calcifications

and a frequent posterior or lateral acoustic shadow-

ing [87]. Ultrasonographic morphology has a high

accuracy and specificity in differentiating dermoid

cysts from other adnexal masses [88].

Ovarian cystadenofibromas are infrequent epithe-

lial tumours that include fibrous stroma as the

dominant element and usually appear during the

fourth and fifth decade of life. Although in many

cases they are simple cysts, sometimes they may have

solid and liquid components, therefore simulating

upon ultrasound assessment as malignant neoplasms

[89]. Ovarian Brenner tumours may also be often

incidentally found in women in their 60s, being in 2–

5% of cases malignant [90]. During ultrasound

assessment, these tumours are in two-third of cases

solid, multilocular and partially cystic epithelial

nests; sometimes affecting both ovaries, and asso-

ciated to other benign ovarian neoplasms [91].

Borderline ovarian tumours show similar ultra-

sonographic morphological findings as malignant

lesions (89%), including intracystic papillae, diffuse

internal echogenicity, intracystic septs, heteroge-

neous images and a solid pattern [92]. However,

neither papillae nor other sonographic features

are sensitive ultrasound markers for borderline

tumours [93].

Vascular Doppler assessment of ovarian tumours

Tumour angiogenesis is an essential part of tumour

growth and development. Angiogenesis in early small

tumours may be studied with Doppler ultrasound by

measuring resistive indices that show the down-

stream impedance to blood flow within a vessel.

Doppler ultrasound findings include: a dominant

cyst mass, solid papillar projections and vascularisa-

tion. The latter is present in almost half of cases

appearing with a typical peripheral pattern and

vessels of high blood impedance [72,77–79]. In

some cases, malignant tumours display low potential

for inducing an angiogenic response or vessels are so

small and fail in being detected by color and pulsed

Doppler. Specificity for cancer diagnosis may reach

97% and the positive predictive value 91% [94,95].

Nevertheless, overlaps in terms of findings between

malignant and benign cases have been long recog-

nised. Medeiros et al. [96] carried out a systematic

review to estimate the accuracy of colour Doppler

sonography in the diagnosis of ovarian tumours.

Diagnosis was confirmed by paraffin-embedded

pathology study. The pooled sensitivity was 0.87

(95% CI: 0.84–0.90) and the specificity was 0.92

(95% CI: 0.87–0.90). Receiver operating character-

istic curves demonstrated that colour Doppler is a

valid tool prior to surgery in predicting the diagnosis

634 F. R. Perez-Lopez et al.

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of ovarian tumours. Colour Doppler imaging for

borderline ovarian tumours have lower PI and RI

compared to benign lesions [92].

3D ultrasound in combination with power Dop-

pler provides better morphologic visualisation of

complex ovarian masses (the tumour per se or its

vascularisation), significantly improving preoperative

diagnostic accuracy of suspected ovarian lesions. A

significant problem with power Doppler is that

information regarding speed and flow direction is

lacking, and the technique is highly dependent on

operator expertise. To define an ovarian malignancy

the presence of at least two of the following findings

have been proposed: irregular branching, vessel

diameter changes, microaneurysms and vascular

lakes [79].

Paraovarian, paratubal or peritoneal pseudocysts

may be diagnosed by 2D and 3D ultrasound. In one

retrospective study, pathological paraovarian cyst

findings were assessed preoperatively with 2D

sonography and power Doppler evaluation. In 30%

of cases there were papillary projections within the

cyst, and in a quarter of these cases the papillae had

blood vessels. Malignancy risk is low in cases without

papillar growths; however, when wall proliferations

are found this may correspond to borderline ovarian

tumours [86].

Assessing the Doppler flow characteristics of

dermoid cysts has been intended to differentiate

benign ovarian cystic teratoma from malignant cases.

Thus, intratumoural blood flow is more frequent in

malignant teratomas compared to benign ones.

Malignant teratomas usually have RI less than 0.4

and PI less than 0.6, while peak systolic velocity

values are similar in benign and malignant teratomas

[97]. Ovarian struma ovarii represent 5% of cases of

ovarian dermoid cysts, and most women are pre-

menopausal with a mean lesion diameter of 5 cm and

normal CA 125 values. Although blood flow signals

may be present and low resistance to flow may be

more common in struma ovarii, it is difficult to

distinguish between struma ovarii and dermoid cysts

on the basis of their sonographic appearance [98].

Figure 1 presents the general morphological

characteristics of incidental adnexal masses found

at ultrasound. Finally, a need to emphasise that there

are ovarian cancers that – very early in its develop-

ment – produce peritoneal dissemination without

significant ovarian growth, and therefore, a normal

ovarian ultrasound exploration is not synonymous of

absence of malignant disease. Van Nagell et al. [99]

have clearly established this possibility in their long

term ultrasound follow up of the Kentucky cohort.

Tumour markers

Elevation alone of serum tumour markers are not diag-

nostic, only suggestive of malignancy or related

lesions, and some markers are so non-specific that

their increase may be associated to benign conditions.

Ovarian tumour markers should ideally be specific for

each one, indicating what type of cancer is present, or

predicting treatment outcome. However, markers

may be non-specifically produced in high levels by

different cells – ovarian or extraovarian – which suffer

various alterations in their biochemical machinery.

Unfortunately, a unique and ideal tumour marker is

currently not available. Genomic advances may

improve ovarian cancer detection in the near future

when used with diagnostic imaging.

CA 125, tumour-associated trypsin inhibitor, afoetoprotein and chorionic gonadotrophin

Initial optimism for markers such as CA 125, CA

19.9, CA 72-4, CASA, CYFRA and others to be

Figure 1. General morphologic characteristics of incidental adnexal masses in peri- and post-menopausal women according to ultrasound

findings.

Menopause and ovarian cancer 635

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used in combination with ultrasound, has been

confronted because of their non-specific nature in

detecting ovarian malignant lesions and borderline

tumours [100–103]. Serum CA 125 is the only

validated marker for ovarian cancer, and it is useful

for follow up purposes and evaluating treatment

response or disease recurrence. However, it is not a

diagnostic or prognostic marker [104]. The utility of

serum CA125 in the identification of early stages of

epithelial ovarian cancer is shadowed by the fact that

not all cancers display elevated levels [105], and

since isolated CA125 values lack adequate sensitivity

or specificity [106]. CA 125 screening for the general

population is impaired by the low cancer incidence

and the high rates of false positive [107]. Several

benign gynaecological conditions, such as first

trimester pregnancy, pelvic inflammatory disease,

uterine fibroids, ovarian cysts, pelvic adhesions and

endometriosis may be associated to elevated CA 125

levels [108,109]. These conditions are exceptional in

post-menopausal women. Therefore, CA 125 may

regain some application in this population for the

detection of ovarian malignancies. In addition, serial

CA 125 determinations at 3–4 week intervals may

detect increases associated to malignant growth.

Contrarily benign adnexal masses should not associ-

ate to abrupt marker increases but rather stable or

diminishing values.

The natural history of ovarian cancer development

in relation to changes in serum CA 125 level has been

studied in the Shizuoka Cohort Study on Ovarian

Cancer Screening. In this study, CA 125 measure-

ment was performed to 396 women with ovarian

cancer 4.1 years (mean) before confirming diagnosis.

The change of CA125 level before the diagnosis of

ovarian cancer could be clearly separated into two

groups according to the length of the following

intervals: 47% (107/228) of patients with non-serous-

type ovarian cancers develop secondarily from slightly

elevated CA125 level (355CA1255 65 U/ml), with

a mean interval of 3.8 years. On the other hand, 75%

(126/168) of patients with serous-type ovarian cancer

seem to develop suddenly from a normal CA125 level

(CA1255 35 U/ml), with a mean interval of 1.4 years

(p¼ 0.011) [110]. In a small number of cases,

ultrasonographic abnormalities associated to normal

CA 125 values result in cancer found at surgery [111].

Therefore, depending on the tumour type CA 125

elevation may present a different behaviour and

elevation velocity, or even with low values a cancer

may be present. These possibilities should be care-

fully considered when evaluating incidental ovarian

masses.

Tumour-associated trypsin inhibitor (TATI) has

been considered as a potential polypeptide tumour

marker for mucinous ovarian carcinomas, colorectal

cancer and other tumours [112,113]. In mucinous

ovarian tumours, TATI has an 89% specificity and

an 86% positive predictive value for malignancy.

However, less than half of ovarian cancers – even at

advanced stages7 express tissue trypsinogen-1 and 2

and TATI, although TATI tissue expression is an

adverse prognostic factor, independent of cancer

clinical stage and histological tumour type [114]. In

patients with epithelial ovarian carcinoma, using a

cut-off of 21 ng/ml TATI had a 63% sensitivity and

72% specificity, as compared – respectively – to 80%

and 82% for CA 125 at a cut-off value of 35 U/ml.

When measurement of both markers were combined

(TATI4 21 ng/ml or CA 1254 35 U/ml) specificity

was 65% [115]. It seems that despite its limitations,

CA 125 is the single marker of choice for suspicious

epithelial ovarian malignancy. TATI measurement

may be helpful as an additional marker in combina-

tion with CA 125 when mucinous carcinomas are

suspected.

Human a foetoprotein (AFP) and chorionic

gonadotrophin are the main tumour markers for

germ cell tumours, including ovarian and extragona-

dal germ cell tumours as well as malignant teratomas

of any location. In females, germ cell tumours

represent a third of ovarian tumours, but only 1–

3% are malignant tumours [116]. These tumours are

infrequent in menopausal women. In recent years

several messenger RNA AFP isoforms have been

described, opening new insights for the development

of specific diagnostic possibilities for the cited

ovarian tumours [117].

New tumour markers

In recent years concerns have been reported

regarding the validation of new biomarkers and

risks. Inhibin may complement CA 125 in the

assessment of malignant ovarian cancers; although

there is limited information since studies have been

confined to advanced cases [118,119]. Inhibin is

elevated in post-menopausal women with granulose

cell tumour and in mucinous epithelial cancers, and

less frequently in epithelial serous and endome-

trioid ovarian carcinoma subtypes [118,120,121].

In peri-menopausal women, inhibin measurements

are of less value for ovarian cancer detection

because it may be elevated in relation to the

menstrual cycle. Serum anti-mullerian hormone

levels have been studied for the diagnosis and

follow-up of granulose cell tumours [119]. This

serum hormone is a more specific parameter than

inhibin for granulose cell cancers, since inhibin may

also increase in some mucinous epithelial ovarian

tumours [122].

Human epididymis protein 4 (HE4) is a protease

overexpressed by patients with epithelial ovarian

cancers and found elevated in circulating blood

[123]. Serum HE4 measurements allow to dif-

ferentiate epithelial ovarian cancers from benign

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pathology, including endometriosis [124,125]. Ser-

um HE4 levels have equal sensitivities as CA 125 for

ovarian malignancy detection [126]. However, it

seems that HE4 sensitivity increase when combined

with CA 125 or other marker [127–129]. There is a

group of ovarian cancer cases that do not express Ca

125 nor HE4, and perhaps combining both markers

could be complementary by improving sensitivity for

detecting epithelial cancers [130,131].

Mesothelin is a glycoprotein expressed by normal

mesothelial cells, and overexpressed in different types

tumours including ovarian carcinomas. It is also a

potential target for cancer immunotherapy [132].

Women with diagnosed ovarian cancer show a cor-

relation between high mesothelin levels and che-

moresistance and poor survival [133]. It has been

postulated that the interaction between mesothelin

and CA 125 may be involved in the peritoneal disse-

mination, although the available information is limi-

ted [134]. There are at least three mesothelins, and by

means of flow cytometry the most frequent molecule

in ovarian cancer cells is mesothelin 1 [135].

Decoy receptor 3 (DcR3) or DD-C248 is a

protein member of the tumour necrosis receptor

family that prevents apoptosis via direct binding of

Fas-ligand. Elevated DcR3 tumour tissue and/or

serum levels have been reported in gastrointestinal

and ovarian cancers. In advance ovarian cancers

with ascites, DcR3 has been associated with

negative outcomes [136,137]. B7-H4 or protein

DD-O110 is expressed in activated T-cells and is

involved in cell mediated immunity [138]. This

protein has been demonstrated in ovarian and

breast cancer cells using immunohistochemical

techniques [139]. Patients with ovarian cancer

show elevated serum levels as compared to those

with benign gynaecological disease or healthy

women. The value of B7-H4 measurements seems

to rely as a complement to CA 125 determination

in the detection of early stage ovarian cancer [140].

Spondin 2 or protein DD-P108 has been demon-

strated in prostate and ovarian cancers [136,141].

New diagnostic markers have not yet been

validated for clinical use [142–144]. The utility of

combining several biomarkers is currently under

study. Recent results point out to the fact that a

panel of different markers may inform about ovarian

cancer existence before symptoms appear [145]. It

seems that CA 125, HE4 and mesothelin began to

slightly increase some 3 years before diagnosis;

however, detectable elevations only were present

within the final year before diagnosis. Nosov et al.

[146] have reported that a serum panel including Ca

125, apolipoprotein A-1, transthyretin and transfer-

rin are useful for the detection of early-stage cancer

(I–II), being the highest sensitivity for the endome-

trioid subtype. However, as authors concluded

prospective clinical studies are needed.

Optimism of these results should be carefully

considered to prevent massive testing which later

might demonstrate to be cost ineffective, stressful

and useless, as occurred in the past. In fact,

Anderson et al. [145] insist in the low discriminatory

power of their used markers. Although these studies

are scientifically encouraging, they are difficult to

extrapolate to the early diagnosis and clinical

management of ovarian cancer of any individual

subject due to the low prevalence of the disease,

tumour heterogeneity and the psychosomatic impli-

cations of implementing a screening programme with

non-standardised tests.

Proteomic technology

Proteomic technology may allow studying new

biomarkers for the early diagnosis of malignant

and pre-malignant stages. These targets may

theoretically be the first step in the development

of new diagnostic and therapeutical tools. Tu-

mour tissue, plasma and ascitis samples have

been studied to delineate the signals involved in

ovarian cancer [147–151]. However, attempts to

link genetics, molecular characterisation of the

system and clinical measures has not yet been

successful [152–155]. There is a need for further

developments in serum proteomic analysis to

develop more specific screening methods for

ovarian cancer and to differentiate from benign

lesions.

Magnetic resonance imaging

Although sonography is the primary imaging

approach for the diagnosis of adnexal masses,

magnetic resonance imaging (MRI) provides

additional information on the composition of

soft-tissue masses [156–158]. Normal ovaries and

dysfunctional cysts have been detailed by MRI at

different ages [159]. MRI has a 90–98% overall

accuracy for differentiating benign from malignant

adnexal tumours. Simple and complex cysts may be

clearly identified by MRI with a high degree of

precision [160–163]. Benign solid lesions may

include fat, haemorrhage or fibrous components.

Thus, mature teratomas possessed high fat content

and contained derivatives of all three germ layers,

although with predominance of ectodermal compo-

nents [164]. Ovarian fibromas and cystadenofibro-

mas have a dense fibrous tissue [165,166]. Using

MRI, paraovarian and paratubal cysts located near

the ipsilateral round ligament and the uterus may be

separately defined from the ovary [167]. Although

preoperative MRI is not free of misinterpretations

when correlating adnexal mass images with patholo-

gical findings, malignancy diagnosis is often not

[168,169].

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Clinical management of incidental adnexal

masses

Clinical management of an adnexal mass is a con-

troversial issue in gynaecology that depends on the

symptoms, ultrasound findings, age and clinical course.

Guidelines or algorithms are general clinical recom-

mendations that should be individualised for each

patient (Figure 2). Although in peri-menopausal

women the prevalence of ovarian cancer is low, adnexal

masses (endometriomas or chronic sequel of inflam-

matory processes) are generally benign. Ultrasound

examination may show complex images sometimes

with morphological features suggestive of malignancy.

Doppler evaluation may be useful along with serum CA

125 determination to establish their nature. Malignancy

risk is low in unilocular cysts of up to 10 cm displaying

normal tumour marker levels and normal Doppler

evaluation. Ovarian malignancies are rare in post-

menopausal women yet more common than in younger

ones. Simple ovarian cysts of less than 5–6 cm in

diameter may stay stable or decrease in size. Although

there are no unanimous accepted recommendations for

follow up, the characteristics of such cysts may be

checked after 4–6 weeks, and at 3, 6 and 12 months.

The majority of small cysts will resolve but this may take

many months. When size increases or changes from a

simple to a complex aspect, complementary evaluation

and/or surgery should be considered for both diagnosis

and treatment. Unilocular ovarian cysts less than

5 cm – even up to 10 cm – in average diameter were

associated with minimal, if not insignificant, risk of

ovarian cancer in a follow up period of 5 years in

asymptomatic women older than 50 years [4,8,73–

76,170]. However, it is unknown if these lesions on

the long run progress to an ovarian cancer.

In complex cysts, MRI and/or laparoscopy evalua-

tion may be necessary to define their nature.

Variegated masses upon ultrasound exploration or

suspected diagnosis of cancer – associated or not to

high CA 125 levels – are an indication for surgery and

pathological analysis of the adnexal mass. In selected

cases, laparoscopy may serve both as diagnostic and

therapeutic tools. In some cases, especially when

findings are inconclusive, additional assessment at

frequent intervals is sometimes necessary. Women

using hormone treatment have an increased risk of

ovarian cancer [61–64]. These women are likely to be

submitted for routine pelvic exams more often than

non-hormone treatment users.

The majority of ovarian cancers demonstrate a very

rapid growth which may be detectable during a 4- to 6-

month period between initial detection and follow-up

scanning [8]. Malignancy risk of an adnexal mass has

been studied by models combining several of the

complementary tests to increase diagnostic efficacy

and precision. Thus, the combination of 3D Doppler

vascular evaluation, CA 125 measurement and meno-

pause status renders an 88% in the prediction of

malignancy with a sensitivity of 99% [171]. However,

in some circumstances 3D power Doppler adds little

to the correct diagnosis of malignancy [76,172].

Adnexal masses suspicious of cancer may be safely

managed by laparoscopy or open surgery, allowing

immediate and adequate pathological diagnosis,

surgical and systemic treatment, according to the

disease stage and other factors. The use of prophy-

lactic oophorectomy has increased in women at high

risk for familial hereditary breast and ovarian cancer.

Recent studies have shown that it does not only

reduce the risk of ovarian cancer yet also appears to

decrease breast cancer risk as well. Nevertheless,

even after oophorectomy there is still a risk of

developing peritoneal serous carcinomas [173,174].

Since the information produced by the differ-

ent explorations – and at the same time their

Figure 2. General clinical assessment of an adnexal mass for asymptomatic peri- and post-menopausal women. Dotted lines represent

optional examinations used when there are doubts upon confirming an ovarian cancer.

638 F. R. Perez-Lopez et al.

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limitations – patients should know the advantages and

risk of a conservative management in complex cysts.

Surgery and pathologic study will give assurance in

those cases which are not clear or present overlapping

benign and malignant features. As in many medical

aspects clinical management of adnexal masses

should be guided by evidence. Furthermore, clinical

management should consider full diagnostic and

therapeutic opportunities provided by available tools,

not by biased selection of a technique or procedure.

Acknowledgements

This study was partially supported by the B/017543/

08 AECID (Agencia Espanola de Cooperacion

Internacional para el Desarrollo) grant.

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