Endometriosis and Ovarian Cancer: Clinical, Biochemical and Imaging Differentiation
A Review of Literature
Name: Seit Mei Chien
TABLE OF CONTENTSPage
1.0 ABSTRACT / 3
2.0 INTRODUCTION / 4
3.0 CLINICAL PRESENTATION / 5 – 6
3.1 Endometriosis / 5
3.2 Ovarian Cancer / 5
4.0 SERUM TUMOUR MARKERS / 7 – 8
4.1 CA-125 / 7
4.2 CEA / 8
5.0 CLINICAL IMAGING / 9 – 10
5.1 Ultrasonography and Magnetic Resonance Imaging / 9
5.2 Combined Positron Emission Tomography and Computer Tomography / 9 – 10
6.0 DISCUSSION / 11 – 12
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
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 cancerbased 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 symptomsandconstitutional 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.
2.0 INTRODUCTION2.0 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 immunobiologicalabbarations. 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 ofthe 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 factthat 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.
3.0 CLINICAL PRESENTATION3.0 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, infertilityand 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 cancerhave no symptoms.For those with symptoms, the most commonlyreported symptomsare pelvic pain, dyspepsia, constitutional symptoms, abdominal distension,urinary symptoms and vaginal bleeding.Goffetal. reported that women with malignant masses typically experiencedabdominal 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 womenwith benign lesions. The combination of bloatedness,increased abdominal size, and urinary symptoms was found in43.0% of those with ovarian cancer. On physical examination, 60.0% to 70.0% of such patients had palpable abdominal masses.
Table 1: Comparison of frequency of the common symptoms between patients with endometriosis and patients with ovarian cancer.2
Symptom / Endometriosis / Ovarian CancerLikely Frequency(%) / Likely Frequency (%)
Abdominal/ pelvic pain / 21 - 94 / 30 - 77
Dysmenorrhoea / 60 - 80 / 18
Fatigue / 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
Abdominal distension / 19 / 17 - 36
Urinary symptoms / 1 - 3 / 14 - 34
Constipation / 1 - 2 / 20 - 24
Vaginal bleeding / 10 - 20 / 20
Post-menopausal bleeding / - / 13
Rectal bleeding / < 4 / 9
aOdds ratio
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.3CA-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 suggestedparallel measurements of other markers in the blood serum (CA 19-9, and CEA) toprovide more information for the differential diagnosis of endometriosis from malignant tumours.
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
Serum Tumour Marker / Stage / Endometriosis / Ovarian CancerIncidence (%) / Level / Incidence (%) / Level
CA-125 (IU/ml) / Stage I / 8.0 / 73.4 (11.26)a / 50.0 / 243 (113 - 389)b
Stage II / 19.6 / 90.0
Stage III / 44.7 / 248.4 (58.72)a / 92.1 / 719 (289 - 1071)b
Stage IV / 86.7 / 93.9
CEA(ng/ml) / Stage I / 0.0 / 0.8 (0.68)a / 0.0 - 48.0 / 8.5 (2.88)a
Stage II / 9.1 - 56.0 / 16.6 (7.64)a
Stage III / 0.0 / 0.9 (1.28)a / 67.0 - 91.0 / 10.2a
Stage IV / 90.0 - 100.0 / -
AFP
(ng/ml) / Stage I / 0.0 / 1.9 (1.04)a / 50.0 / 20.0
Stage II
Stage III / 0.0 / 2.2 (2.36)a
Stage IV
hCG
(fmol/mg for endometriosis)
(IU/L for ovarian cancer) / Stage I / - / 0.61 (0.21)a,c / - / 4.5
Stage II / - / - / 3.5
Stage III / - / 0.28 (0.71)a,c / - / 2.5
Stage IV / - / - / 6.0
aMean (SD)
bMedian (quartiles)
cLuteinising hormone concentration
Table 2: Comparison of incidences of increased common serum tumour markers between patients with endometriosis and patients with ovarian cancer and their levels.4
5.0 CLINICAL IMAGING5.0 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 pre-operatively to allow better surgical planning and to avoid surgical complications.
A large (>4cm), 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 from87.0% to 100.0% and from 92.5% to 100.0%, respectively.5The use of PET/CT has proven to be more superior than ultrasonographyor 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.
6.0 DISCUSSION6.0 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 asdysmenorrhoea, chronic fatigue, dysparaeunia, infertility and menstrual irregularities are more common in patients with endometriosis than ovarian cancer. Ovarian cancer, like endometriosis can present with abdominalor 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.
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 anon invasive modality of choice when ultrasonographyor 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.
7.0 CONCLUSION7.0 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.
8.0 REFERENCES1. 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.
Glasgow Obstetrical & Gynaecological Society Medical Student Prize