The limitation of IOTA ADNEX in Differentiating Rare Ovarian Tumour: a Case Study

of Meigs’ Syndrome

Leonardo Alexandra, Tricia Dewi Anggraeni, Adianty Kartika, Muhammad Luthfiyanto

Gynecology Oncology Division, Dept. Obstetrics & Gynecology, National General Hospital

Dr. Cipto Mangunkusumo, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia

Correspondence: Leonardo Alexandra; leonardo.alexandra93@gmail.com,

ABSTRAK

Diagnosis pre-operasi tumor ovarium sangatlah sulit terutama pada kasus langka. Disini kami

melaporkan seorang wanita 60 tahun para 1, post menopause dengan sindrom Meigs.

Sindrom Meigs merupakan suatu trias yang terdiri dari tumor ovarium jinak (fibroma),

ascites dan efusi pleura yang mana akan pulih setelah pengangkatan tumor. Fibroma ovarium

seringkali salah diagnosis dengan myoma uteri atau kanker ovarium oleh karena sifatnya

yaitu tumor padat. Ultrasonografi merupakan salah satu metode yang mudah dan dapat

digunakan untuk mendiagnosa fibroma ovarium dan sindrom Meigs dengan akurat. Menurut

International Ovarian Tumor Analysis (IOTA) group terdapat beberapa indicator yang dapat

digunakan untuk menilai suatu masa ovarium, indikatornya adalah: diameter maksimum dari lesi,

diameter maksimum bagian padat, jumlah papil, jumlah lokulus, ekogenisitas dan skor dari

banyaknya aliran darah serta kadar serum CA125. IOTA group baru saja mempublikasi suatu model

matematika baru yang disebut ADNEX (Assessment of Different NEoplasias in the adnexa) yang

dikembangkan untuk dapat membedakan berbagai subtipe dari massa ovarium. Kami

menemukan bahwa IOTA ADNEX terkadang dapat menginterpretasikan data yang

dimasukan kedalam modelnya terutama pada kasus fibroma. Pada penelitian retrospektif

didapatkan beberapa temuan ultrasonografi yang tipikal pada fibroma ovarium, antara lain:

1
massa adneksa yang hipoekoik dengan batas tegas dengan bayangan akustik dan aliran darah

minimal yang dinilai dari USG Doppler.

Kata Kunci: Sindroma Meigs, fibroma ovarium, IOTA, ADNEX

ABSTRACT

Preoperative diagnosis of ovarian tumours is challenging, especially in a rare case. Here we

present a 60 years old para 1, post-menopause lady with Meigs’ syndrome. M’ syndrome is a

triad of benign ovarian tumour (fibroma), ascites, and pleural effusion, which resolves after

removal of the tumour. The ovarian fibroma is often misdiagnosed for uterine leiomyoma or

ovarian malignancy due to its nature as a solid tumour. A convenient method of ultrasound

can be used to accurately diagnose ovarian fibroma and Meigs’ syndrome. According to

International Ovarian Tumour Analysis (IOTA) group, there are several indicators to be

assessed during adnexal mass ultrasound examination, those indicators are the maximal

diameter of the lesion, the maximum diameter of the solid part, number of papillation,

number of locules, echogenicity and the score of amounts of blood flow also the level of

serum CA125. The IOTA group recently published a new mathematical model

called ADNEX (Assessment of Different NEoplasias in the adneXa) to further

differentiate various subtypes of an ovarian mass. We found that the IOTA ADNEX model

sometimes falsely interprets the data submitted especially ovarian fibroma. In a retrospective

study, several typical ultrasounds finding for ovarian fibroma is introduced, those

are adnexal hypoechoic masses with clear border and acoustic attenuation and minimal

Doppler flow signals.

Keywords: Meigs’ syndrome, ovarian fibroma, IOTA, ADNEX,

2
INTRODUCTION

Ovarian tumours are classified into three different groups based on its cell origin: surface

epithelium stroma, sex cord stroma and germ cell. Sex cord stroma tumours account for 3%

to 5% of all ovarian malignancies. Ovarian fibromas are solid tumours that classified to sex-

cord stromal cell tumour of the ovary and the most common benign solid tumours

constituting 1 to 4% of all ovarian tumours. The ovarian fibroma is difficult to diagnose

preoperatively and often misdiagnosed as uterine leiomyoma and ovarian malignancy. About

1 % of ovarian fibromas can present with Meigs’ syndrome. Meigs’ syndrome is a triad of

benign ovarian tumour (fibroma), ascites, and pleural effusion, which resolves after removal

of the tumour1. The International Ovarian Tumour Analysis (IOTA) group published a new

model to evaluate adnexal mass called ADNEX (Assessment of Different NEoplasias in the

adnexa). The IOTA study (International Ovarian Tumour Analysis) is a multicentre

collaborative project for the pre-operative characterisation of ovarian tumours.

CASE ILLUSTRATION

A 60 years old para 1, post-menopause woman was referred to the tertiary health centre with

solid ovarian neoplasm suspected advanced-stage ovarian cancer. She complained of

abdominal enlargement since three months ago before she was referred. She also complained

of dyspnoea, loss of appetite and 10 kg weight lost, nausea and vomiting also complained.

She had done ascites punctured and pleural punctured at the previous hospital with cytology

result negative form malignancy. Several tumour markers also examined with result CA125

of 745.5, CEA 1, β-hCG 4.7, AFP 3.33.

The second ascites and pleural punctured was done on July 2019 with cytology result

negative for malignancy. The third ascites punctured was done on August 2019 with cytology

result negative for malignancy. On August 2019 a maternal-foetal ultrasound examination

3
was done with the result of pleural effusion and ascites with bilateral solid ovarian neoplasm

correspond to malignancy (with abdominal invasion). Another laboratory examination for

CA125 was done with the result of 1163.2.

On September 2019 she performed thorax CT-scan with a result of bilateral pleural

effusion with atelectasis component at inferior lobes of both lungs, hepatomegaly at the left

lobe of the liver, ascites at perihepatic and peri-splenic, simplex cyst at the upper pole of the

left kidney (Bosniac I). She also referred to our tertiary health centre National General

Hospital Dr. Cipto Mangunkusumo and oncology ultrasound examination was done with the

result of on the right ovary a regular solid mass with cystic components was found with size

14.58 x 13.58 x 18.93 cm and the volume was 1962.35 cm 3, colour score 1, acoustic shadow

was positive on the posterior border of the mass, massive ascites was found without

enlargement of bilateral pelvic and para-aortic lymph node, the left ovary was within normal

limits.

Figure 1. Pre-operative ultrasound showing

acoustic attenuation or shadowing
4
Figure 2. Pre-operative ultrasound showing multiple
tumour implant at peritoneum of Douglas pouch with
pseudocyst appearance

Figure 3. Pre-operative ultrasound

showing normal right ovary

5
 IOTA easy description criteria did not fulfil and simple rules were then used, both

benign and malignant features existed so the conclusion for simple rules was inconclusive.

IOTA ADNEX model was performed with the result for risk of benign tumour 73.6%, risk of

malignancy 26.4%, and borderline 2.3%. She was then planned for laparotomy total

hysterectomy and bilateral salphingo-oophorectomy with frozen section.

She underwent MRI scan on November 2019 with the result of heterogeneous mass at

pelvic cavity until abdomen suspected malignancy came from ovarium, ascites and

peritoneum nodule with differential diagnoses of peritoneal metastasis, left para-iliac and

bilateral inguinal lymph nodes enlargement, multiple nodules at liver suspect for metastasis,

bilateral pleural effusion, and bilateral multiple kidney cysts.

Figure 4. Pre-operative MRI

Exploratory laparotomy was performed on her on January 2020 with histopathology

result from frozen section was mesenchymal ovarian tumour with atypical focus. The

intraoperative finding was serous yellowish ascites of 1500 ml with firm-cystic mass sized 20

6
x 20 x 20 cm with a smooth surface, and nodular implant at Douglas pouch sized 2 x 2 x 2

cm.

Figure 5. Intra-operative specimen Figure 6. Post-operative specimen

One month after the operation the patient returned to oncology clinic with

histopathology result of right ovarian fibroma, no metastasis tumour at tissue from Douglas

pouch and multiple leiomyomas. The ascites cytology result was negative for malignancy. At

follow up her complaints were resolved; no mass was palpated on abdominal &

gynaecological examination.

DISCUSSION

Ovarian tumours are classified into three different groups based on its cell origin: surface

epithelium stroma, sex cord stroma and germ cell. Although 90% of all ovarian cancers are

derived from surface epithelium stroma, sex cord stroma tumours account for 3% to 5% of all

ovarian malignancies.

7
 Ovarian fibromas are solid tumours that classified to sex-cord stromal cell tumour of

the ovary with spindle shape fibroblastic cells and abundant collagen. Ovarian fibromas are

the most common benign solid tumours constituting 1 to 4% of all ovarian tumours.

According to the World Health Organization classification of ovarian neoplasms, ovarian

fibromas belong to ovarian thecoma-fibroma groups (OTFG) neoplasm. The ovarian fibroma

is difficult to diagnose preoperatively and often misdiagnosed as uterine leiomyoma and

ovarian malignancy because of its nature of the solid mass, low incidence and diverse clinical

syndromes. Ovarian fibromas vary in size and often arise unilaterally. Ovarian fibromas can

occur in any age group but the average age is in the fifth decade of life2,3.

Plain Computerized Tomography (CT) scan shows hypodensity or isodensity of the

tumours while contrast-enhanced CT scan mainly shows no enhancement or delayed mild

enhancement. Low signals of the tumours are shown by T1-weighted and T2-weighted

Magnetic Resonance Imaging (MRI), slightly enhanced by MRI contrast agent. There’s little

research investigating the connection between ultrasound features and pathologic features of

ovarian fibromas2.

About 1 % of ovarian fibromas can present with Meigs’ syndrome. Meigs’ syndrome

is a triad of benign ovarian tumour (fibroma), ascites, and pleural effusion, which resolves

after removal of the tumour1. Meigs’ syndrome was first published in 1852 by Blin in the

Société de Biology de Paris, in 1887 a Demons of Bordeaux, France also reported to Société

de Chirurgie de Paris that 9 of 50 patients with ovarian cyst were cured of their ascites and

hydrothorax by removal of the adnexal cyst. In 1937, an American professor of the Harvard

school of medicine of Gynaecology, Joe Vincent Meigs drew widespread attention of the

medical community to the syndrome. He used seven cases to highlight the association

between ovarian fibroma, ascites and hydrothorax. Meigs’ syndrome was coined first in 1937

by Rhodes and Terrell4.

8
 Ultrasound is an easy, convenient and broadly available tool to evaluate adnexal

masses. Recently International Ovarian Tumour Analysis (IOTA) group published a new

model to evaluate adnexal mass called ADNEX (Assessment of Different NEoplasias in the

adnexa). With the previous model easy descriptor and simple rules, we can continuously use

these three models and called three-step approach. The first step is using easy descriptor to

distinguish benign and malignant mass. If the criteria of this first step failed to differentiate

the adnexal mass then the next step is using simple rules which define malignancy if there is

one or more malignant features without benign features, if the mass is benign then the criteria

of at least one benign features without malignant features must be fulfilled, while if the mass

fulfilled malignant and benign features or no malignant or benign features fulfilled

simultaneously then the result is inconclusive and ADNEX model should then be used.

The IOTA study (International Ovarian Tumour Analysis) is a multicentre

collaborative project for the pre-operative characterisation of ovarian tumours. IOTA conduct

several phases of researches; the first phase was conducted between 1999 and 2002 and

developed several mathematical models which perform excellently with areas under the ROC

curves of more than 0.94. The second phase of IOTA conducted between 2005 and 2007 with

bigger sample size and conducted in more centres, this phase of IOTA concluded that a

subgroup of “uncertain” tumours needs a reliable second stage test to help even experienced

ultrasound examiner. The third phase of the IOTA study was conducted in 2010 to validate

the added value of mathematical models as a new diagnostic tool in the prediction of ovarian

cancer in clinical practice in centres that were involved in IOTA phase 1 or 2. In phase 4 of

IOTA study, they conduct randomised controlled trial in 7 London hospital to assess the

efficacy, referral pattern, and cost of IOTA logistic regression models LR2 versus the

routinely used Risk of Malignancy Index. The fifth phase of IOTA conducted to examine the

9
short and long term outcomes of the conservative management of benign-looking adnexal

masses and the pre-operative characterisation of ovarian tumours5.

IOTA consortium published the ADNEX model in 2015 the first risk model that

differentiates between benign and four types of malignant ovarian tumours: borderline, stage

I cancer, stage II-IV cancer and secondary metastatic cancer 6. The IOTA ADNEX model

consists of three clinical predictors and six ultrasound predictors. The clinical predictors are

age (years), serum CA125 (U/mL) and type of centre to which the patient has been referred

for ultrasound examination which divided into oncology centre and non-oncology centre. The

ultrasound predictors are the maximal diameter of the lesion (mm), the proportion of solid

tissue (%) which defined as the ratio of the maximal diameter of the largest solid component

and the maximal diameter of the lesion, number of papillary projections (0, 1, 2, 3, >3),

presence of over 10 cyst locules (yes/no), acoustic shadow (yes/no) and also the presence of

ascites (yes/no)6.

Figure 7. Ultrasound predictors in IOTA ADNEX model

10
 IOTA ADNEX model’s ability to discriminate between benign and malignant adnexal

masses, the area under the receiver operating characteristic (ROC) curves (AUC) of the

ADNEX model was 0.954 (95% CI 0.947 to 0.961) on the development data. Using a cut-off

of 10% the sensitivity for malignancy was 96.5% and specificity 71.3% on the validation

data. IOTA ADNEX model discriminates benign tumour and each of four types of

malignancy with AUC between 0.85 (benign versus borderline) and 0.99 (benign versus stage

II-IV cancer). IOTA ADNEX compared with the previous model which are LR2 and simple

rules performance seems similar and even slightly better. ADNEX model was published to

differentiates between benign and four types of malignant ovarian tumours and the AUCs

were varied between 0.71 and 0.95. In the final histological outcome about the average

predicted risk the ADNEX model had difficulties with abscesses, rare benign tumours and

fibromas, with average predicted probabilities of being benign of around 70%6.

In a retrospective study conducted by Chen et.al 2 found several typical ultrasounds

finding to describe ovarian thecoma-fibroma group, it was adnexal hypoechoic masses with

clear border and acoustic attenuation and minimal Doppler flow signals. On this retrospective

research they found that 63.93% occurred after menopause with 65.57% in women aged 51 to

70 years old, the tumours 91.80% were unilateral. They also found the correlation analysis

revealed that the diameter of tumours was statistically significantly correlated with CA125

level and the amount of ascites fluid (p < 0.05). They also hypothesized that the ascites

formation may be due to transudation through the tumour surface which exceeds the

peritoneum’s resorptive capacity, irritation of the peritoneal surface by the tumour may also

explain the increased level of CA125.

The ultrasound featured varied by tumour components and degeneration or

complicated with other cystic lesions. Large tumours were often showed mixed echogenic

11
masses. Acoustic attenuation is presumably because of the low sound propagation of

fibroblast tissue. According to Chen et. al2 accurate diagnoses can be made based on

sonographic characterizations such as adnexal hypoechoic masses with clear border, posterior

echo attenuation and minimal or moderate blood flow signals inside the tumours. In their

study ultrasound examination made 72.12% correct diagnosis of OTFG before surgery.

In a recent prospective study done by Jeong, et.al 7 to compare the IOTA ADNEX

model with a gynaecologic expert in differentiating ovarian diseases found that when

comparing two AUCs of IOTA ADNEX model and the expert’s subjective analysis with a

nonparametric approach there were no significant differences between the IOTA ADNEX

model and the expert’s subjective assessment (p = 0.391 in all participants and p = 0.407 in

the surgical group)7. They also found the optimal cut-off point determined by the Youden

index method was 47.3%, with the specificity of 0.980 (95% CI: 0.892-0.999) and 90%

sensitivity7. They conclude that the IOTA ADNEX model is a promising ultrasound software

in precisely differentiating benign and malignant ovarian tumour and is equal to gynecologic

ultrasound experts in term of preoperatively characterizing ovarian tumours7.

CONCLUSION

This simple pre-operative ultrasound assessment is hoped to help clinicians to

differentiate benign, malignant and various subtype of ovarian tumours in everyday clinical

settings. In ovarian fibroma cases, the assessment using the IOTA ADNEX model is delicate

even the model was developed to differentiate between benign and another subtype of

malignant ovarian tumours. For rare benign tumour like ovarian fibroma subjective

assessment of expert might give higher value in detecting the rare ovarian tumours compared

to IOTA ADNEX model. Further study to evaluate rare ovarian tumours using the IOTA

ADNEX model is needed.

12
13
REFERENCE

1. Quinlan DJ. Meigs’ Syndrome. J Obstet Gynaecol Canada [Internet]. 2012;34(4):311.

Available from: http://dx.doi.org/10.1016/S1701-2163(16)35204-5

2. Chen H, Liu Y, Shen L fei, Jiang M jiao, Yang Z fang, Fang G ping. Ovarian thecoma-

fibroma groups: clinical and sonographic features with pathological comparison. J

Ovarian Res [Internet]. 2016;9(1):1–7. Available from:

http://dx.doi.org/10.1186/s13048-016-0291-2

3. Parwate NS, Patel SM, Arora R, Gupta M. Ovarian Fibroma: A Clinico-pathological

Study of 23 Cases with Review of Literature. J Obstet Gynecol India. 2016;66(6):460–

5.

4. Meigs ’ and Pseudo-Meigs ’ syndrome. 2012;15(February):29–31.

5. Bourne T, Valentin L, Timmerman D, Bourne T, College I, Testa AC, et al.

International Ovarian Tumour Analysis ( IOTA ) Phase 5.

6. Van Calster B, Van Hoorde K, Froyman W, Kaijser J, Wynants L, Landolfo C, et al.

Practical guidance for applying the ADNEX model from the IOTA group to

discriminate between different subtypes of adnexal tumors. Facts, views Vis ObGyn

[Internet]. 2015;7(1):32–41. Available from:

http://www.ncbi.nlm.nih.gov/pubmed/25897370%0Ahttp://www.pubmedcentral.nih.g

ov/articlerender.fcgi?artid=PMC4402441

7. Jeong SY, Park BK, Lee YY. Validation of IOTA-ADNEX Model in Discriminating

Characteristics of Adnexal Masses : A Comparison with Subjective Assessment.

14