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Low-grade serous epithelial ovarian cancer: a comprehensive review and update for radiologists
Insights into Imaging volume 12, Article number: 60 (2021)
Low-grade serous carcinoma (LGSC) is an infrequent subtype of ovarian cancer, corresponding to 5% of epithelial neoplasms. This subtype of ovarian carcinoma characteristically has molecular features, pathogenesis, clinical behaviour, sensitivity to chemotherapy, and prognosis distinct to high-grade serous carcinoma (HGSC). Knowing the difference between LGSC and other ovarian serous tumours is vital to guide clinical management, which currently is only possible histologically. However, imaging can provide several clues that allow differentiating LGSC from other tumours and enable precise staging and follow-up of ovarian cancer treatment. Characteristically, LGSC appears as mixed lesions with variable papillary projections and solid components, usually in different proportions from those detected in serous borderline tumour and HGSC. Calcified extracellular bodies, known as psammoma bodies, are also a common feature of LGSC, frequently detectable within lymphadenopathies and metastases associated with this type of tumour. In addition, the characterisation of magnetic resonance imaging enhancement also plays an essential role in calculating the probability of malignancy of these lesions. As such, in this review, we discuss and update the distinct radiological modalities features and the clinicopathologic characteristics of LGSC to allow radiologists to be familiarised with them and to narrow the differential diagnosis when facing this type of tumour.
Low-grade serous carcinoma (LGSC) is a rare subtype of ovarian cancer.
Imaging can provide several clues that suggest the diagnosis of LGSC.
Psammoma bodies can occur within serous tumours or metastases, especially in LGSC.
MRI enhancement patterns help to discriminate benign, borderline, and malignant ovarian tumours.
Malignancy’s predictive models contribute to the early diagnosis of ovarian cancer.
Epithelial neoplasms are the most frequent, accounting for 90–98% of ovarian tumours. According to the 2020 World Health Organization (WHO) Classification of Tumours, they are divided into serous tumours, which include high-grade serous carcinoma (HGSC) (70%) and low-grade serous carcinoma (LGSC) (5%); mucinous tumours (3–4%); endometrioid tumours (10%); clear cell tumours (10–12%); Brenner tumours (< 5%); and other carcinomas [2, 3].
LGSC is an invasive serous tumour presenting low-grade malignant features that is diagnosed at a young age (median age between 43 and 47), has an indolent clinical course, and is relatively chemoresistant [1, 4]. LGSC is also associated with longer progression-free survival and overall survival than HGSC .
The discrimination between HGSC and LGSC has a high impact on clinical management due to their diverse prognoses and treatment strategies. LGSC primary treatment is cytoreductive surgery, in contrast to HGSC, which is preferentially treated with chemotherapy and surgery .
Certain radiological features may provide important clues to the diagnosis of LGSC; however, the distinction between HGSC and LGSC is sometimes difficult (Table 1) [1, 4]. As such, radiologists must be aware of this entity and be familiarised with its radiological findings to optimise imaging protocols and provide adequate management and timely treatment to these patients.
Morphology and pathogenesis
Macroscopically, LGSC may present as bilateral adnexal tumours, often multicystic with nodular areas, excrescences, and papillary projections on the interior surface (Fig. 1). Some may be gritty due to the presence of calcifications .
Microscopically, LGSC can have a diversity of morphological patterns, such as small nests, glands, papillae, or micropapillae. Frequently, there are micropapillae floating within clear spaces. There is mild to moderate atypia, with uniform nuclei. Compared to HGSC, LGSC has fewer mitoses (1–2 mitoses/mm2), and necrosis is usually absent. As in many other neoplasms with papillary growth, LGSC often has psammoma bodies. Approximately 60% of LGSC can occur with serous borderline tumour (SBT) at diagnosis [2,3,4] (Fig. 2).
Immunohistochemically, LGSCs are diffusely positive for CK7, PAX8, ER, and WT1, and p16 expression is patchy. In this carcinoma, as opposed to HGSC, p53 exhibits a wild-type pattern .
LGSCs are often characterised by KRAS, NRAS, BRAF, USP9X, and EIF1AX mutations [1, 4, 6, 9]. Also, KRAS mutation may be related to tumour recurrence. Identification of these particular gene mutations may be useful for new clinical approaches and personalised treatments [2, 6, 9].
Signs and symptoms
The signs and symptoms of LGSC are similar to other forms of ovarian tumours [10,11,12]. The patient can be asymptomatic or present with significant symptoms, mainly due to mass effect, such as early satiety, bloating, dyspnoea, urinary urgency, and pain. In advanced cases, it may course with pleural effusion and/or bowel obstruction [11, 12].
Although CA-125 serum levels tend to be higher in HGSC than in LGSC, CA-125 serum levels are used in the diagnosis and follow-up of LGSC, as in any other serous epithelial malignant ovarian tumour .
Imaging findings of low-grade ovarian carcinoma
Imaging features used to predict malignancy include thick irregular walls (> 3 mm), papillary projections, and solid echogenic nodules, with flow on colour Doppler .
These findings, integrated with additional clinical features, such as menopausal status and CA-125 level, allow risk stratification of adnexal lesions into likely malignant or benign by calculating the risk of malignancy index [1, 6, 8].
The International Ovarian Tumour Analysis (IOTA) group developed the Assessment of Different NEoplasias in the adneXa (ADNEX) model, which is a risk prediction model that involves three clinical and six ultrasound variables. This model can discriminate benign from malignant adnexal lesions with high sensitivity (97%) and specificity (71%) [1, 6]. However, about 25% of adnexal masses stay sonographically indeterminate even when evaluated by sonographic experts .
It is known that the number of papillary projections and solid components increases from SBT to LGSC and to HGSC . On ultrasound, LGSC usually appears as a multilocular cystic lesion with a higher number of solid components when comparing to SBT and with a lower number of solid components when compared to HGSC [1, 8, 10, 14] (Fig. 3). Calcifications corresponding to psammoma bodies are common in LGSCs and can be identified on ultrasound [3, 8]. On the other hand, HGSC appears more frequently as a non-papillary solid mass with areas of cystic change, necrosis, and/or haemorrhage [1, 10].
Doppler ultrasound may also be useful since HGSC tends to be more vascularised than LGSC and SBT . In elastography, LGSC is usually stiffer and less elastic than an HGSC. This fact can be explained by the frequent presence of necrosis in HGSC [1, 10].
Contrast-enhanced CT is the current imaging modality of choice for ovarian cancer staging and for treatment follow-up [1, 2, 13, 15]. It allows the detection of lymphadenopathy and peritoneal metastases with high diagnostic accuracy (89%) [1, 15, 16].
The use of oral contrast is generally recommended to detect adnexal lesions and is also useful to distinguish peritoneal metastases from the fluid-filled bowel [1, 2, 16]. Oral contrast is especially necessary in women with low body mass index or in premenopause, in whom ovaries might be difficult to detect . Generally, 1.5 L of diluted contrast or water is administered an hour before the study [2, 13].
The use of intravenous contrast allows optimal characterisation of adnexal lesions architecture and identification of pelvic vascular structures. Solid components and papillary projections should be assessed on the venous phase (70–90 s) as they may be missed in the early phase [1, 13].
LGSC can typically appears on CT as a large, complex, cystic mass with well-marginated septa, papillary projections, and solid components that may be found unilaterally or bilaterally [1, 2, 10, 17] (Figs. 4, 5, 6, 7). The number and complexity of serous tumours on solid tissue correlate with malignancy risk .
The classic psammoma bodies, calcified extracellular bodies, can occur within serous tumours or peritoneal metastases, especially in LGSCs (90% of cases) [4, 10,11,12, 17] (Figs. 5, 6, 7). These tiny calcifications are detected in 30% of tumours at histology but only in 12% of cases at CT . Several authors endorse the use of non-contrast CT and intestinal opacification with water to differentiate tiny calcifications from intestinal loops, particularly in LGSC [1, 13].
Brenner tumours can have calcifications similar to those of LGSCs, usually amorphous and central; however, distant metastases are generally not present, since in the vast majority of cases, these tumours are benign [1, 2, 4].
Peritoneal metastases, nodal calcifications, papillary projections in cystic lesions, and the presence of necrosis are findings that suggest malignancy and help to distinguish malignant serous tumours from benign lesions [1, 4, 17]. Ascites is also rarely identified in LGSC, whereas HGSC typically presents abundant ascites and diffuse peritoneal metastases (Figs. 6, 7) [1, 4, 8].
Iodine, a component widely used in CT contrast, is highlighted when low kiloelectron volt (KeV) values are used. This property enables distinguishing structures with this compound from others [21, 22].
Post-processing software also allows additional information to be obtained. One example is the selective removal of certain types of material from the image, that enables to create virtually unenhanced images without iodine, among other uses .
Benveniste et al. believe that DECT can be an essential tool in malignant adnexal lesion characterisation since their complexity stands out using iodinated contrast and low KeV values technique .
Calcified peritoneal metastases, frequently seen in LGSC, can also be better depicted on low KeV values and water-enhanced images when iodine-based oral contrast is used. In this scenario, intravenous and oral contrasts are removed with post-processing software resulting in virtual unenhanced images and allowing better conspicuity to detect calcified metastases, especially those in the bowel wall .
Positron emission tomography (PET)/CT
Fluoro-2-deoxy-d-glucose (FDG) PET/CT has a limited role in the primary diagnosis of adnexal masses since false-negative findings have been detected with borderline tumours, mucinous tumours, and other low-grade types of tumours. False-positive results have also been reported with bowel loops, follicular cysts, corpus luteum cysts, and in some benign ovarian tumours [1, 2, 10, 15]. Yet, despite this, FDG-PET/CT can help diagnose and stage advanced disease (stage IV disease), specially when CT is indeterminate [1, 13, 15]. FDG-PET/CT metabolic activity provides disease detection in small metastases or lymph nodes, which can be difficult to characterise only with CT [13, 15] (Fig. 8).
The identification of metabolic activity in infracentimetric metastases and the detection of disease between intestinal loops, especially after surgery, are recognised limitations of PET [1, 15]. Despite this, the anatomical resolution and metabolic activity of FDG-PET/CT outperform those of CT and MRI in detecting lymph nodes recurrent disease and unresectable sites [1, 15].
Magnetic resonance imaging
The imaging findings used to predict malignancy and the ancillary findings that improve diagnostic confidence are listed in Table 2 [2, 24]. However, each of these criteria alone does not have sufficient specificity to diagnose ovarian cancer [2, 24].
Malignant serous tumours are less frequently cystic compared to borderline (respectively 25% and 44%). They tend to be complex mixed lesions with indistinct solid-cystic interfaces  (Figs. 1, 3, 4, 7, 9).
Although diffusion-weighted imaging (DWI) characteristics of benign and malignant adnexal lesions may overlap, DWI can be helpful in excluding malignancy when low signal intensity is identified on high b-value images [2, 6, 8]. It is also known that the solid components of LGSCs present lower T2 signal intensity and lower ADC values than SBTs [2, 5] (Fig. 1).
The evaluation of MRI contrast enhanced sequences is an essential step in tumour characterisation. It allows a more detailed assessment of the papillary projections seen on serous tumours and the characterisation of their vascularisation patterns . It also confirms or excludes the presence of necrosis .
The characterisation of the solid components of complex adnexal masses using a semiquantitative multiphase-dynamic contrast-enhanced MRI technique has shown to discriminate benign, borderline, and malignant ovarian tumours [2, 6, 8, 25]. Solid components that show a rapid and high enhancement level are associated with a very high malignancy likelihood .
This technique identifies three types of enhancement curves by comparing the solid enhancement pattern of the lesion with myometrial enhancement [2, 6, 8, 26, 27] (Fig. 10). Type II curves (early and moderate uptake of gadolinium, not exceeding the myometrial signal, followed by a plateau) are typical of borderline tumours, whereas type III curves (avid and early contrast uptake, more accentuated than the myometrium’s, followed by washout) are more commonly seen in malignant epithelial ovarian tumours, such as LGSCs (Fig. 11). Type I curves (gradual uptake of contrast) are characteristic of benign lesions [2, 6, 8, 27].
Recently, a multicentre study validated the Ovarian-Adnexal Reporting and Data System (O-RADS) MRI risk stratification scoring system, which allows the standardisation of risk stratification and provides indications for follow-up of adnexal masses using MRI and the O-RADS ultrasound score. This score showed high sensitivity and specificity (93% and 91%) to diagnose malignant lesions amongst indeterminate masses detected by ultrasound [28,29,30].
MRI has gained value as an alternative technique for staging ovarian cancer when DWI is used with standard sequences . MRI is preferred over CT if there are contraindications to iodine contrast and in pregnant and young women [1, 2, 13].
MRI is also helpful in evaluating treatment response and in excluding recurrent disease, as dynamic contrast-enhanced (DCE) MRI allows detection of residual and recurrent peritoneal disease with a sensitivity of 90% and specificity of 88% .
Generally, ovarian cancer peritoneal metastases, such as those from LGSC, demonstrate high signal intensity on DWI and low signal intensity on ADC and are best evaluated 5–10 min after paramagnetic contrast administration  (Figs. 3, 4).
DWI also showed high sensitivity in detecting small peritoneal metastases, mainly in the pouch of Douglas and the left upper quadrant.
LGSC is a rare subtype of epithelial serous tumour. LGSC and HGSC have a distinct histogenesis, clinical behaviour, sensitivity to chemotherapy, and prognosis; therefore, preoperative discrimination between LGSC and other serous tumours is fundamental to guide patient care and treatment strategies.
Although differentiation between these subtypes is only entirely possible histologically, imaging can provide clues that may suggest the diagnosis of LGSC.
LGSCs can appear as a solid, mixed solid cystic, or complex cystic adnexal mass. Classic psammoma bodies are frequent in this type of tumour and can occur within the adnexal mass, lymph nodes and peritoneal metastases. Moreover, MRI evaluation of lesion enhancement pattern can also provide important tips to discriminate benign, borderline, and malignant ovarian tumours.
As such, in addition to be aware of the most frequent radiological findings of LGSC, radiologists must also be familiarised with the pathology, biology, and characteristic markers of this tumour to optimise the interpretation of images and provide adequate management and timely treatment to these women.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.
Assessment of Different NEoplasias in the adnexa
High-grade serous carcinoma
International Ovarian Tumour Analysis
Low-grade serous carcinoma
Magnetic resonance imaging
Ovarian-Adnexal Reporting and Data System
Positron emission tomography/Computed tomography
Serous borderline tumour
World Health Organization
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The authors would like to acknowledge Dr. Mariana Horta (Radiologist), who helped improve the article's English and clarity.
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Amante, S., Santos, F. & Cunha, T.M. Low-grade serous epithelial ovarian cancer: a comprehensive review and update for radiologists. Insights Imaging 12, 60 (2021). https://doi.org/10.1186/s13244-021-01004-7
- Low-grade serous carcinoma
- Epithelial ovarian carcinoma
- Computed tomography
- Magnetic resonance imaging