Pelvic masses are routinely encountered in gynaecological practice and pose diagnostic and management challenges for both general practitioners and gynaecologists.
While the majority of pelvic masses are benign and may not require active intervention, a small proportion harbour malignancy that requires timely and appropriate surgical management. Pelvic masses and non-gynaecological origin; therefore, it is paramount that clinicians be aware of the differential diagnosis and have an understanding of the significance and accuracy of diagnostic techniques (see Table 1).
The purpose of triage is to differentiate benign from malignant masses, develop a suitable management strategy and facilitate referral to a gynaecological oncologist. Gynaecologic oncologists are specifically trained to complete the operative management of malignant and suspected malignant conditions of the female genital tract. In the presence of a malignant or clinically suspicious mass, a pre-operative consultation with a gynaecological oncologist is important so that the patient can eceive a realistic explanation of their cancer risk and understand the potential extent of surgical procedures, including associated risks and benefits of gastrointestinal or genitourinary surgery. It also obviates the likelihood of re-operation when an unstaged or incompletely cytoreduced malignancy is diagnosed.1-6 Furthermore, studies confirm that women treated by a gynaecological oncologist in a multidisciplinary setting have decreased morbidity and mortality and increased overall survival.4-6
After excluding malignancy, the goal is then to differentiate masses that would require active surgical intervention from those that can be managed medically or observed clinically for spontaneous resolution, for example, follicular cysts, corpus luteal cysts and hemorrhagic cysts of the ovary. Functional ovarian cysts arise from unruptured follicle or corpus luteum and invariably undergo spontaneous resolution. An internal haemorrhage within these cysts may delay resolution as it progresses through the stages of acute haemorrhage, clot formation, clot retraction and complete resolution. Physiological cysts are commonly seen in young girls and women in the reproductive age group; however, they can also be encountered in perimenopausal women who are amenorrhoeic, but rarely in postmenopausal women. Meanwhile, pelvic inflammatory diseases, tuberculosis and endometriomas can be managed with medical treatment, occasionally requiring surgery in exceptional circumstances.
For triage, epidemiological and genetic risk factors, evaluation of clinical symptoms and clinical examination with careful selection and interpretation of diagnostic tests should be considered and applied accordingly in a given clinical context.1-3
Risk factors for ovarian cancer
The lifetime risk of ovarian cancer in the general population of women is 1.4 per cent and the age-adjusted incidence rate is 12.9 cases per 100 000 women.7 Nulliparity, early menarche, late menopause, infertility and a BMI ≥30kg/m2 are some epidemiological factors associated with an increased risk of ovarian cancer. Meanwhile, the use of oral contraceptive pills, breastfeeding, multiparity and tubal ligation are some protective factors associated with reduced risk of ovarian cancer.
Table 1. Differential diagnoses of pelvic masses.
|Functional or physiological||Ovarian follicles Haemorrhagic cyst Corpus luteum|
|Inflammatory||Pelvic inflammatory disease Endometrioma|
|Other benign conditions||Paratubal cysts Para-ovarian cysts Hydrosalpinx Polycystic ovaries Ectopic pregnancy Ovarian torsion|
|Benign neoplasms||Germ cell tumours||Mature cystic teratoma|
|Sex cord stromal tumour||Fibroma Thecoma|
|Malignant neoplasms||Epithelial ovarian cancer||Borderline or low malignant potential tumour
Invasive epithelial adenocarcinoma
|Germ cell tumour||Dysgerminoma Immature teratoma Yolk sac tumour
(Endodermal sinus) Choriocarcinoma
|Sex cord stromal tumour||Granulosa cell
from gastric, breast
Age is the most important independent risk factor for epithelial ovarian cancer (EOC). The median age of diagnosis is 60 years old for sporadic cases and ten years earlier in women with a hereditary ovarian cancer syndrome (BRCA or HNPCC/Lynch syndrome).7,8
EOC is uncommon in women <40 years of age. Low malignant potential tumours or borderline tumours occur more frequently in younger premenopausal women compared to post menopausal women. Similarly, sex cord stromal tumours and germ cell tumours are more common in younger women aged 10–30 years.
Of women with ovarian cancer, ten to 15 per cent have an inherited germline mutation in a tumour suppressor gene. BRCA1, BRCA2 and hereditary nonpolyposis colorectal cancer (HNPCC) are the most common germline mutations. The risk of EOC is increased by 40–45 per cent with BRCA1, ten to 25 per cent with BRCA2 and nine to 12 per cent with HNPCC gene mutations. In the absence of formal genetic testing, family history can provide an insight into the risk of cancer. A woman with a single relative affected by EOC has a four to five per cent risk of developing the disease, while one with two affected relatives has a seven per cent risk. In contrast, women with hereditary ovarian cancer syndromes, defined as having at least two first-degree relatives with EOC, have a lifetime probability as high as 25–50 per cent for developing EOC.
Hence, it is very important for the clinicians to thoroughly evaluate a patient’s family history and be alert if a patient has either multiple relatives or a first-degree relative with early age onset (<50 years) of breast and/or ovarian cancer (with BRCA1/2 mutations) or colon, endometrial, gastrointestinal, pancreatic or renal malignancies (with Lynch/HNPCC syndrome).7,8
Symptoms and clinical examination
The non-specific nature of the symptoms of ovarian cancer has led to it being termed the ‘silent killer’. Studies suggest that approximately 93 per cent of women experience symptoms prior to diagnosis; therefore it is vital to establish symptoms and signs and initiate diagnostic tests that allow women to be directed towards an appropriate clinical pathway. The following symptoms are commonly experienced by women with ovarian cancer9:
- Abdominal or pelvic pain
- Abdominal bloating
- Abdominal distension
- Abdominal mass/swelling
- Urinary frequency or urgency
- Postmenopausal/abnormal bleeding
- Loss of appetite
These symptoms may indicate ovarian cancers, especially if they are new and occur frequently: more than 12 times per month.10 Although symptom assessment is not an efficient screening tool for the general population, persistent symptoms in high-risk patients with or without a palpable pelvic mass should raise the index of suspicion for malignancy.1-3
In premenopausal women, only five to 18 per cent of palpable pelvic masses prove to be malignant, in contrast to 30–60 per cent in postmenopausal women. The higher predictive value for discrimination of malignant from benign disease in postmenopausal women is due to the higher prevalence of cancer and lower prevalence of disorders that mimic malignancy.11,12
The presence of a solid, irregular, fixed pelvic mass or nodularity in the posterior vaginal fornix on pelvic examination is highly suggestive of an ovarian malignancy. If the physical examination identifies the presence of ascites, the patient should immediately be referred to a gynaecological oncologist.2,3
In my experience, a thorough examination – including a general physical examination, breast examination, per-abdominal, per-speculum, per-vaginal and a per-rectal examination – often helps in reaching a correct diagnosis.
Ultrasound (US) scan through both transabdominal (TA) and transvaginal (TV) routes has a well-established role in the initial evaluation of an ovarian mass or pelvic symptoms. The technique has many advantages as it is widely available, inexpensive, involves no exposure to radiation and can be used effectively to differentiate a benign from a complex mass and facilitate triage of patients with a suspicious mass. Besides providing multiplanar imaging, TVUS has a higher resolution, which allows better visualisation of the ovaries independent of body habitus and is associated with a relatively short examination time. However, the sensitivity of US is to an extent observer dependent. Size, morphologic features such as presence of septae, irregular cyst wall, thickness, internal vegetations, solid areas and mural nodules are taken into consideration while interpreting USS results and ovarian volumes of 20cm3 in premenopausal women and 10cm3 in postmenopausal women are taken as upper cut-off limits.13,14
Both TAUS and TVUS, however, have low specificity for detecting malignancy, owing to overlap in the imaging appearances of benign, borderline and malignant diseases. Thickened cyst walls, internal separations and mural nodules are sometimes present in benign cyst adenomas, haemorrhagic cysts and cystadenofibromas of the ovary. Similarly benign fibromas, Brenner tumours and fibrothecomas of the ovaries often appear as solid tumours. However, if there
are associated ascites, hydronephrosis or peritoneal implants diagnosis of malignancy is more likely.14 Supplementation of Doppler arterial measurements to morphologic features of the ovary improves specificity, thereby decreasing the number of false-positive cases ending up in surgery.15 The use of both non-targeted and targeted micro bubbles is being evaluated to analyse their ability to discriminate between benign and malignant ovarian lesions. The contrast agents increase the reflectivity of blood, which helps assess blood flow and tissue perfusion at the microvascular levels enabling better detection than the conventional US Doppler.16,17
A computed tomography (CT) scan, although not a primary imaging tool in early diagnosis of ovarian cancer, is a common imaging modality used after the US, because of its widespread availability. It provides information about peritoneal and lymphatic dissemination of ovarian cancer in the thorax and upper abdomen. A magnetic resonance imaging (MRI) scan helps to define indeterminate lesions on US masses. It has a specificity of 98 per cent versus 82 and 87 per cent with US and CT scan, respectively. Contrast-enhanced MRI with soft tissue contrast results in better tissue characterisation and accuracy when diagnosing endometriomas and dermoid cysts.18
Table 2. Risk of malignancy index (RMI).
|RMI combines three pre-surgical features||Ultrasound score (U)
Menopausal status (M)
Serum CA-125 level (IU/ml)
|U is scored one point for each of the following characteristics||Multi-locular cysts, solid areas, bilateral lesions, ascites and intra-abdominal metastasis
0 = no abnormality1= one abnormality
3 = two or more abnormalities
|M is scored by menopausal status||Premenopausal = 1
Postmenopausal = 3
|RMI score = U x M x CA 125 value. Score ≥200 = high risk of malignancy.|
Table 3. Risk of malignancy algorithm (ROMA).
|Uses CA-125 value, HE4 value and menopausal status. Calculates the risk percentage using the following equations:|
|Premenopausal||Predictive index (PI) = -12.0+2.38*LN(HE4)+0.0626*LN(CA-125)|
Predicted probability exp (PI)/[1+ exp(PI)]
|Cut off values (specific to Abbott Laboratory)|
|Premenopausal||≥7.4% High risk of finding EOC
<7.4% Low risk of finding EOC
|Premenopausal||≥25.3% High risk of finding EOC
<25.3% Low risk of finding EOC
The serum glycoprotein CA-125 concentration (normal <35 units/mL) values are found to be elevated in 30–50 per cent cases with early-stage ovarian cancer and in over 80 per cent of women with advanced ovarian cancer. It has the advantages of being non-invasive, reproducible and relatively inexpensive and is the first test to be performed in presence of a pelvic mass. However, its specificity is limited, with the levels elevated in one per cent of healthy women, fluctuating during menstrual cycle and being elevated in the presence of benign and other malignant conditions, such as endometriosis, pelvic inflammatory disease, fibroid uterus, ulcerative colitis, liver cirrhosis, pericardial and pleural diseases and cancers of the endometrium, breast, lungs and pancreas. The test is more useful for predicting malignancy in postmenopausal women, in whom it has sensitivity of 69–87 per cent, specificity of 81–100 per cent and positive predictive value (PPV) of 73–100 per cent.19 CA-125 combined with sonographic features of the adnexal mass has a higher specificity for ovarian malignancy than CA-125 alone.12,19,20
Human epididymis protein 4 (HE4) is a protein expressed in clear, serous and endometriod ovarian cancer tissues. In contrast to CA- 125, it is minimally expressed in normal or benign ovarian tissue; hence it is not elevated in women with endometriosis. Studies suggest that the addition of HE4 testing to ovarian cancer risk assessment with CA-125, pelvic imaging and menopausal status increases the sensitivity for detection of malignant pelvic masses. HE4 is superior to CA-125 in triaging patients with an incidental finding of a pelvic mass who are asymptomatic and medically compromised, thus sparing elderly and unfit patients from surgery. While patients with high
CA-125 and negative HE4 can be referred to a gynaecologist, all patients with a normal or positive CA-125 and positive HE4 should be referred to a gynaecological oncologist.21-23
The tumour markers AFP (alpha-fetoprotein), LDH (lactate dehydrogenase) and beta human chorionic gonadotrophin are exclusive to endodermal sinus tumour, dysgerminoma and nongestational choriocarcinomas, respectively, and should be performed routinely in young women with a solid or solid and cystic adenexal mass to exclude these germ cell tumours.
Other tumour markers, such as carcino-embryonic antigen (CEA), may be elevated in the presence of gastrointestinal and especially colorectal malignancies and this helps in the differential diagnosis of pelvic masses of non-gynaecological origin. Further evaluation by proper history, risk assessment, colonoscopy and or upper GI endoscopy may be required for accurate diagnosis.
Individual tests alone are not sufficient for triage. The combination of elevated CA-125 value and ultrasound morphology provides better specificity of ovarian malignancy rather than the individual tests alone.19,20 Various combined methods for evaluating the risk of malignancy have been proposed. The risk of malignancy index (RMI) was originally developed in 1990, based on menopausal status, ultrasound and CA-125 (see Table 2).20 Patients with a RMI score greater than 200 had, on average, 42 times the background risk of cancer compared to those with a lower value.20
A number of modifications to the RMI have been proposed and scoring systems have incorporated additional variables such as pelvic examination, Doppler studies and serum Ca 72.4 values.12 All of these systems rely to a greater extent on expertise in ultrasonography, and even with a specificity of 92 per cent it does not help avoid unnecessary surgery in women with benign masses.
Combination of CA-125 and HE4 has the greatest sensitivity of 76.4 per cent and specificity of 95 per cent and outperforms every other tumour marker in regards to prediction of malignancy, making it the most effective dual combination.21,23 A combination of CA-125 and HE4 can be used as an aid in risk stratification for women presenting with pelvic mass by using the risk of ovarian malignancy algorithm (ROMA). The ROMA value estimates the probability of ovarian cancer in women with a pelvic mass, based on the patient’s HE4 and CA-125 levels and their menopausal status. There are two different ROMA formulas and cut offs based on the patient’s menopausal status (see Table 3).22 Women with ROMA levels above the cut off have an increased risk of ovarian cancer and should be evaluated by a gynecological oncologist. In a study by Moore et al24, ROMA was compared to RMI and found to have higher sensitivity than RMI for detecting epithelial ovarian cancer.24 Studies have shown HE4 and ROMA to improve the detection of ovarian cancer, however, further studies and validation is required in different population subsets.
A methodical approach is best for the management of pelvic masses. While the majority of theses masses are benign, it is of utmost importance that malignant cases are diagnosed efficiently and managed with proper investigation and interventions. Intermediate-risk adenexal masses pose various diagnostic challenges. For appropriate triage and management of these cases, careful consideration of clinical risks, evaluation of clinical symptoms, clinical examination (general physical, breasts, per abdominal, per vaginal, per rectal) and correct interpretation of diagnostic procedures is essential. When presented with a diagnostic dilemma one should not be hesitant in seeking an opinion from gynaecological oncology colleagues.