Endometriosis and Ovarian Cancer:
Clinical, Biochemical and Imaging
Differentiation
A Review of Literature
Name: Seit Mei Chien
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TABLE OF CONTENTS
Page
1.0 ABSTRACT
3
2.0 INTRODUCTION
4
5–6
3.0 CLINICAL PRESENTATION
3.1 Endometriosis
5
3.2 Ovarian Cancer
5
7–8
4.0 SERUM TUMOUR MARKERS
4.1 CA-125
7
4.2 CEA
8
9 – 10
5.0 CLINICAL IMAGING
5.1 Ultrasonography and Magnetic Resonance Imaging
5.2 Combined Positron Emission Tomography and Computer
9
9 – 10
Tomography
11 – 12
6.0 DISCUSSION
6.1 Clinical Presentation
11
6.2 Serum Tumour Markers
11
6.3 Clinical Imaging
12
6.4 Our Findings
12
7.0 CONCLUSION
13
8.0 REFERENCES
14
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1.0 ABSTRACT
Introduction
Endometriosis is an enigmatic medical condition with clinical, biochemical and radiological
features resembling ovarian cancer.
Objective
A review of the literature in preoperative differentiation of endometriosis from ovarian cancer
based on clinical presentation, serum tumour marker levels and radiological imaging.
Design
All the literature in English language, over preceding 40 years were examined, using Ovid
databases. Clinical presentations, serum tumour markers and imaging characteristics of
both conditions were compared to establish differentiating features.
Results
Endometriosis is more common in patients of the reproductive age, presenting mostly with
pelvic pain, dysmenorrhoea, dysparaeunia, and menstrual irregularities. In contrast. ovarian
cancer is more common in the older age group with symptoms such as abdominal and/ or
pelvic pain, abdominal distension, dyspepsia, urinary symptoms and constitutional
abnormalities. In addition, patients with ovarian cancer are more likely to have raised and
higher levels of serum CA-125 and CEA compared with endometriosis. Imaging
differentiation could be challenging and no very reliable. However, PET/CT appear to have
the highest sensitivity and specificity compared to ultrasonography and MRI, in
differentiating endometriosis and ovarian cancer.
Conclusion
It is difficult to distinguish between endometriosis and ovarian cancer preoperatively.
However there are some clinical, biochemical and radiological features that can assist
clinician. PET-CT may have an important role in the future.
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2.0 INTRODUCTION
2.0 Introduction
Endometriosis is defined as the presence of endometrial glandular epithelium and stroma
outside the uterine cavity. It is a common gynaecological condition with an estimated
prevalence of 10.0% to 25.0% of women presenting with gynaecological symptoms.
Endometrial deposits are most commonly sited over the ovaries, uterosacral ligaments,
pouch of Douglas, bladder and pelvic peritoneum. Extrapelvic endometriosis has also been
reported in many areas such as the sciatic nerve and lung.
Although endometriosis is a benign gynaecological condition, it does possess traits of
malignancy, such as loss of control of cell proliferation and the ability to spread locally and
metastasize.
Other common factors of both endometriosis and malignancy are familial
predisposition, certain common genetic and immunobiological abbarations.
However,
endometriosis does not have the ability to cause catabolic disturbance and death, which is
the end result of advanced ovarian cancer. It is now widely accepted that endometriosis has
a potential to transform into ovarian cancer. The first case of suspected malignant
transformation in endometriosis was reported by Sampson in 1925. He showed three vital
criteria for the diagnosis of this malignant transformation: (i) demonstration of the occurrence
of carcinoma and endometriosis in the same ovary; (ii) a similar histological relationship to
each other and (iii) no other primary tumour sites are found.1
An interesting connection between endometriosis and ovarian carcinoma is the fact that
endometriosis increases a women’s risk of becoming infertile and hence nulliparous.
Nulliparity has been clearly shown to increases risk of ovarian cancer. This association may
explain why these two conditions can co-exist. This coexistence adds to the complexity in
differentiation between the two conditions preoperatively. Such differentiation is of great
clinical importance as the patients with suspected ovarian cancer are best to be managed in
specialist centres by cancer specialists, where as endometriosis can be managed locally,
with preservation of fertility, by general obstetrician and gynaecologist.
In this review, we will focus on how to distinguish between endometriosis and ovarian cancer
pre-operatively on their clinical presentations, CA-125 and CEA tumour marker levels, and
radiological imaging.
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3.0 CLINICAL PRESENTATION
3.0 Clinical Presentation
3.1 Endometriosis
Endometriosis is common in women of reproductive age, with a peak incidence between
30 and 45 years old. The presenting symptoms differ depending on the affected
anatomical sites but not the volume of the disease. The most common presenting
symptoms are pelvic pain, dysmenorrhoea, dysparaeunia, infertility and chronic fatigue.
However, about 20% to 50% patients with endometriosis have no symptoms, hence
making the differentiation from ovarian cancer challenging.
3.2 Ovarian Cancer
Ovarian cancer most commonly presents in post-menopausal women, with an incidence
which peaks at 50 to 70 years old. About 18.0% to 20.0% of women with early stage
ovarian cancer have no symptoms. For those with symptoms, the most commonly
reported symptoms are pelvic pain, dyspepsia, constitutional symptoms, abdominal
distension, urinary symptoms and vaginal bleeding. Goff et al. reported that women with
malignant masses typically experienced abdominal and/or pelvic pain, abdominal
distension, fatigue, urinary tract symptoms and constipation, 20 to 30 times per month,
with higher severity and more recent onset than women with benign lesions. The
combination of bloatedness, increased abdominal size, and urinary symptoms was found
in 43.0% of those with ovarian cancer. On physical examination, 60.0% to 70.0% of such
patients had palpable abdominal masses.
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Table 1: Comparison of frequency of the common symptoms between patients with
endometriosis and patients with ovarian cancer.2
Endometriosis
Ovarian Cancer
Likely Frequency (%)
Likely Frequency (%)
Abdominal/ pelvic pain
21 - 94
30 - 77
Dysmenorrhoea
60 - 80
18
87
34
Dyspareunia
25 - 75
13
Infertility
20 - 50
2.67a
Menstrual irregularities
10 - 50
-
Dyspepsia
19
70
Weight loss
-
50
Loss of appetite
-
20 - 40
19
17 - 36
Urinary symptoms
1-3
14 - 34
Constipation
1-2
20 - 24
10 - 20
20
-
13
<4
9
Symptom
Fatigue
Abdominal distension
Vaginal bleeding
Post-menopausal bleeding
Rectal bleeding
a
Odds ratio
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4.0 SERUM TUMOUR MARKERS
4.0 Serum Tumour markers
Based on the current literature, cancer antigen 125 (CA-125), carcinoembryonic antigen
(CEA), alpha-fetoprotein (AFB) and human chorionic gonadotrophin (hCG) are the main
serum tumour markers that are routinely measured in patients with suspected ovarian
cancer and in clinical endeavours to differentiate benign from malignant pelvic pathologies.
4.1 CA-125
CA-125, is a glycoprotein that is expressed in all mesodermal tissue. Raised Ca 125
level has been associated with many benign and malignant gynaecological disorders. In
a study by Rosen et al. found that about 20.0% of ovarian cancer patients lack
expression of the antigen.3 CA-125 is not a sensitive marker with a sensitivity thought to
range between 24.0% to 94.0%.
It has been shown that patients with endometriosis rarely have elevated serum CA-125
of more than 100 IU/ml, except in event of ruptured endometriotic cyst, when the
recorded levels can be as high as 106 IU/ml. In addition, most patients with severe,
advanced endometriosis will have a raised serum CA-125 levels, which is similar to the
levels reported in ovarian cancer. It has also been shown that there is a link between
decreasing CA-125 serum levels following surgery and the amount of resected
endometriosis. Therefore, although it cannot be used solely to diagnose benign or
malignant disease, it remains a useful test to warrant further investigation with clinical
imaging or monitoring response to treatment.
Other confounding factors include variation in CA-125 levels with age and menstruation.
CA-125 is more likely to be elevated in the elderly group or during menstruation in young
patients. In order to overcome these limitations, some have suggested parallel
measurements of other markers in the blood serum (CA 19-9, and CEA) to provide more
information for the differential diagnosis of endometriosis from malignant tumours.
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4.2 CEA
CEA is another glycoprotein like CA-125, which is involved in cell adhesion and is
produced during foetal development. A study by Cirkel et al. demonstrated that none of
the women with endometriosis have increased serum CEA levels. As for ovarian cancer,
serum CEA level was increased significantly, with highest incidence of 77.0% found in
those patients with serous cystadenocarcinoma. Furthermore, about 94.0% of the poorly
differentiated ovarian tumours have an increased serum CEA level. One study has also
shown that all squamous cell carcinomas and 66.7% of mucinous cystadenocarcinomas
had increased serum CEA of more than 5 ng/ml.4
Table 2: Comparison of incidences of increased common serum tumour markers between
patients with endometriosis and patients with ovarian cancer and their levels.4
Endometriosis
Serum Tumour
Stage
Marker
Incidence
Level
(%)
CA-125 (IU/ml)
Stage I
8.0
Stage II
19.6
Stage III
44.7
Stage IV
86.7
Stage I
Stage II
CEA (ng/ml)
Stage III
Stage IV
Stage I
AFP
Stage II
(ng/ml)
Stage III
Stage IV
73.4 (11.26)a
248.4 (58.72)a
0.0
0.8 (0.68)a
0.0
0.9 (1.28)a
0.0
1.9 (1.04)a
Stage I
-
(fmol/mg for
Stage II
-
endometriosis)
Stage III
-
(IU/L for ovarian
Stage IV
-
Incidence
(%)
50.0
90.0
92.1
93.9
Mean (SD)
b
Median (quartiles)
243 (113 - 389)b
719 (289 - 1071)b
0.0 - 48.0
8.5 (2.88)a
9.1 - 56.0
16.6 (7.64)a
67.0 - 91.0
10.2a
90.0 - 100.0
-
50.0
> 20.0
0.61 (0.21)a,c
-
4.5
-
3.5
-
2.5
0.28 (0.71)a,c
-
cancer)
a
Level
2.2 (2.36)a
0.0
hCG
Ovarian Cancer
c
Luteinising hormone concentration
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6.0
5.0 CLINICAL IMAGING
5.0 Clinical Imaging
Currently, the gold standard diagnostic technique for endometriosis is laparoscopy. Whilst,
this is an accurate and effective method for diagnosis, a less invasive test is needed to
differentiate accurately between benign and malignant diseases.
5.1 Ultrasonography and Magnetic Resonance Imaging
Ultrasonography is the first line imaging method used to diagnose adnexal masses,
whether benign or malignant. However, it is only effective at diagnosing endometriomas
of more than 2.0 cm, and bladder endometriosis. If a multilocular mass is picked up on
ultrasound with diffuse, low level internal echoes and hyperechoic foci in the wall, an
endometrioma is highly likely to be the diagnosis. Masses with solid or mixed
components are highly suggestive of malignancy and should warrant further investigation
with magnetic resonance imaging (MRI).
The accuracy of MRI in diagnosing benign or malignant adnexal mass is between 83.0%
and 93.0%. MRI is able to diagnose endometriosis at any anatomical sites, provided the
lesions are more than 5.0 mm. Mural nodules within a cystic mass found at the time of
MRI are suggestive of malignancy as opposed to endometriosis. MRI allows the
examiner to map out the endometriotic lesions. Therefore, it should be performed preoperatively to allow better surgical planning and to avoid surgical complications.
A large (> 4 cm), bilateral, predominantly solid mass seen on MRI is highly suspicious
signs of malignancy. Other features on MRI suggestive of malignancy include evidence
of free fluid, omental or peritoneal disease, and enlarged nodes. In a young patient, if
these features are not seen, but the patient is symptomatic, the possibility of a diagnosis
of endometriosis should be considered.
5.2 Combined Positron Emission Tomography and Computer Tomography
Combined positron emission tomography and computed tomography (PET/CT) is a new
technology, which integrates functional images by PET into anatomical images by CT.
Several studies have shown that the sensitivity and specificity for PET/CT in diagnosing
a malignant pelvic tumor ranges from 87.0% to 100.0% and from 92.5% to 100.0%,
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respectively.5 The use of PET/CT has proven to be more superior than ultrasonography
or MRI for diagnosis of ovarian cancer. Ultrasonography and MRI lack ability in
distinguishing benign reactive changes from cancer. However, PET/CT allows
differentiation of benign peritoneal nodules resulting from endometriosis from malignant
peritoneal nodules.
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6.0 DISCUSSION
6.0 Discussion
6.1 Clinical Presentation
Endometriosis is most common in patients between the age of 30 to 45 years old
whereas ovarian cancer occur mostly in patients 50 to 70 years old. Table 1,
demonstrate great overlap in presentation of endometriosis and ovarian cancer.
However, symptoms such as dysmenorrhoea, chronic fatigue, dysparaeunia, infertility
and menstrual irregularities are more common in patients with endometriosis than
ovarian cancer. Ovarian cancer, like endometriosis can present with abdominal or pelvic
pain but unlike endometriosis patients can have dyspepsia, abdominal distension,
urinary symptoms and constitutional symptoms such as fatigue, weight loss and loss of
appetite,. Such symptoms although may raise the possibility of malignancy but still
remains non specific and not diagnostic.
6.2 Serum Tumour Markers
Out of the four serum tumour markers examined in the literatuer CA-125 and CEA
provide the most valuable information in differentiating endometriosis from ovarian
cancer. Table 2 shows that overall incidence of raised CA-125 and CEA levels are higher
in all stages of ovarian cancer than in endometriosis. When comparing serum CA-125
and CEA levels within each stage of ovarian cancer and endometriosis, the levels
appear to be higher in ovarian cancer than endometriosis.
There is very limited data on AFP and hCG levels as a means of differentiating between
the two condition. Many experimental studies have shown various serum, peritoneal fluid
and immunological markers in association with endometriosis. However, none have so
far been introduced into cliincal practice due to primarily lack of validating data from
other centres. Future proteomic studies looking at a whole host of serum proteins may
prove to be beneficial in differntial diagnosis between these two conditions.
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6.3 Clinical Imaging
Ultrasonography and MRI have been used extensively as supplementary diagnostic tools
to aid in the diagnosis of endometriosis and ovarian cancer. Recently, PET/CT has
shown to be more superior than ultrasonography and MRI, with a high sensitivity and
specificity. Furthermore, PET/CT gives additional information to ultrasonography for the
differential diagnosis of benign from malignant pelvic lesions. Therefore, PET/CT should
be considered as a non invasive modality of choice when ultrasonography or MRI
demonstrates a suspecious pelvic mass prior to invasive measures such as laparotomy.
6.4 Our findings
We have collected and looked at data from the last eight years in the West of Scotland.
We found that about 1.0% of ovarian cancer cases were associated with endometriosis.
Clinical presentation of abdominal pain appeared to be more common in the group of
patients with only endometriosis as opposed to the group with dual pathology of
endometriosis and ovarian cancer (56.7% vs. 15.9%). Furthermore, ovarian cancer in
association with endometriosis, presented in the older age group; mostly in their fifth and
sixth decades. In terms of serum tumour markers, CA-125 levels were shown to be of
little value. However, CEA levels were noted to be elevated in the group with dual
pathology. These findings need to be further evaluated in a prospective study. In our
centre, ultrasonography and CT imaging remain the main stay of pre-operative
assessment. We also found that the presence of bilateral adnexal lesions, peritoneal
implants, omental disease and para-aortic lymphadenopathy are more suggestive of
ovarian malignancy than endometriosis.
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7.0 CONCLUSION
7.0 Conclusion
Differentiation between endometriosis and ovarian cancer remains a challenge. Despite
great similarities, there are clinical, radiological and serological differences that clinicians
need to be aware of. At present PET-CT imaging appear to be the most promising
radiological investigation.
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8.0 REFERENCES
1. Sampson J. Endometrial carcinoma of the ovary, arising in endometrial tissue of that
organ. Arch Surg 1925;10:1-72.
2. Bankhead C, Collins C, Stokes-Lampard H, Rose P, Wilson S, Clements A, et al.
Identifying symptoms of ovarian cancer: a qualitative and quantitative study. BJOG. 2008
Jul;115(8):1008-14.
3. Rosen D, Wang L, Atkinson J, Yu Y, Lu K, Diamandis E, et al. Potential markers that
complement expression of CA125 in epithelial ovarian cancer. Gynecol Oncol. 2005
Nov;99(2):267-77.
4. A. H. Askalani, H. A. Meabid, Saad El Sadek M El Sadek, Nabil M El Tabbakh & M. S.
Osman . A Monoclonal Antibody Quantitative Measurement And Immunohistochemical
Localisation Of Carcinoembryonic Antigen In Ovarian Neoplasia . The Internet Journal of
Gynecology and Obstetrics. 2002 Vol. 1 No. 2
5. Risum S, Høgdall C, Loft A, Berthelsen A, Høgdall E, Nedergaard L, et al. The diagnostic
value of PET/CT for primary ovarian cancer--a prospective study. Gynecol Oncol. 2007
Apr;105(1):145-9.
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