Validation of ¹⁸F-FDG PET/MRI and diffusion-weighted MRI for estimating the extent of peritoneal carcinomatosis in ovarian and endometrial cancer -a pilot study

Ovarian cancer is the fifth most common cause of cancer-related deaths in women in Europe with a five-year survival of around 40% [1]. The age-standardised incidence rate is around 12–14/100.000 in the Nordic countries [2], with 751 cases diagnosed in Sweden in 2013 [3]. Ovarian cancer usually presents at an advanced stage, with intra-abdominal spread and peritoneal carcinomatosis at diagnosis. The mainstay of treatment is primary surgery, aiming at complete cytoreduction, followed by chemotherapy [4, 5]. Because of the widespread disease, surgery is often extensive and not suitable for all patients. It is of great value to identify patients with non-resectable tumours who preferably should benefit from neoadjuvant chemotherapy. Endometrial cancer is more seldom diagnosed in advanced stage, but in these women, the prognosis and treatment is similar to advanced ovarian cancer [6].

Carcinomatosis can be estimated intraoperatively by using the peritoneal cancer index (PCI) [7], which describes the distribution of tumours in the abdomen and pelvis. PCI correlates with the completeness of cytoreduction, and is associated with long-term survival [8, 9]. Furthermore, it has been suggested that it can be used to estimate operability; however, the cut-off point is yet to be determined. PCI has also been used in radiology in an effort to obtain this information preoperatively.

There is no universally accepted reference standard for imaging peritoneal carcinomatosis. Prospective studies comparing CT, PET-CT and MRI are few, and findings indicate minor differences between the methods [10]. Contrast-enhanced CT is to date the imaging modality of choice but has limitations in detecting carcinomatosis and small bowel involvement [11, 12]. PET-CT has been shown to be sensitive and specific to the detection of lymph node and distant metastases, and is therefore mostly used in detecting recurrent disease and response monitoring [13, 14]. MRI with diffusion-weighted imaging (DWI) has also been suggested for preoperative staging of abdominal carcinomatosis and might be more accurate than CT [15]. Recently, MRI including DWI has shown superior results to CT in preoperative assessment of suspected ovarian cancer [16].

A combination of PET and MRI was recently introduced, which may have advantages over PET/CT [17] as MRI is superior for morphology and adds functional information in terms of DWI [18]. The few studies available suggest the high diagnostic potential of PET/MRI for the assessment of recurrence of female pelvic malignancies [18, 19], and higher diagnostic confidence in discrimination between benign and malignant lesions compared with PET/CT [19]. However, previous published studies are few and heterogeneous, and to the best of our knowledge, no previous studies evaluating carcinomatosis with PET/MRI have been published.

The purpose of this prospective study was to validate integrated PET/MRI, in comparison with DW-MRI alone, for preoperative prediction of peritoneal carcinomatosis with gynaecological origin.

None of the authors declared any conflict of interest regarding the subject of this study. All patients were willing to participate in the study and signed written informed consent. The study procedures were in accordance with ethical standards for human experimentation and the study was approved by the local ethics committee.

To the best of our knowledge, this is the first study estimating the extent of peritoneal carcinomatosis with integrated PET/MRI.

We found PET/MRI and DW-MRI-determined total peritoneal cancer index to be well correlated with the gold standard, surgical PCI. The PET/MRI PCI was significantly closer to the operative total PCI than DW-MRI alone. PET/MRI was more accurate than DW-MRI when evaluating patients at primary diagnosis but no difference was noted in patients previously treated with chemotherapy. PET/MRI was also superior in inoperable patients with high tumour burden, and in clinical practice, this is the most important finding, since these women could be offered neoadjuvant chemotherapy and not be subjected to unnecessary diagnostic laparotomy. In the small bowel regions, there was a tendency of higher sensitivity but lower specificity in PET/MRI compared to DW-MRI.

Few studies have evaluated PET/MRI in gynaecological cancer, and most of them focus on recurrent pelvic malignancies where PET/MRI may have advantages over PET-CT in better defining of lesion margins [17]. It has been shown that PET/MRI and PET-CT have equivalently high diagnostic value in recurrent cervical and ovarian cancer, but PET/MRI offers higher diagnostic confidence in the discrimination of benign and malignant lesions [19, 20]. Furthermore, a higher lesion contrast for malignant lesions has been found with PET/MRI than MRI alone [21]. In 2014, Schwenzer et al. [22] used PET/MRI to characterise carcinomatosis of different histology and found significant differences in glucose uptake and diffusion characteristics, depending on the histology of the tumours.

Peritoneal cancer index is a known prognostic indicator for operability of ovarian cancer [8]. Nevertheless, tumour load is not the only factor deciding surgical operability; the location of the tumour is also important. Massive small bowel infiltration is often the crucial factor that renders patients inoperable. It has previously been shown that the most difficult area for assessing carcinomatosis with radiology is the small bowel [12]. In our study, the sensitivity for carcinomatosis in the small bowel was higher for PET/MRI than for DW-MRI alone. One of the possible reasons is that the fusion of morphological, functional and metabolic information is highly accurate when acquired simultaneously in a hybrid PET/MRI system. However, PET/MRI overestimated peritoneal carcinomatosis in some bowel regions. This can be explained by the fact that bowels may appear hyper-intense in DWI due to long T2 relaxation times, impeded water movement, or both [23]. In addition, it is well known that FDG uptake in the gastrointestinal tract varies between individuals [24] with varying degrees of FDG uptake, usually with a diffuse and linear pattern but also with a focal pattern [25]. The mechanism of increased FDG uptake in the GI tract is unclear. It can be related to physiological activity in the bowel, to metabolically active smooth muscle, to reactive lymphocytes in the terminal ileum and cecum, or to swallowed secretions. These benign or physiological activities can be misinterpreted as malignant lesions and vice versa [26]. In addition, neoadjuvant therapy may induce increased FDG uptake because of inflammation simulating residual tumour.

In our clinical experience small bowel involvement is almost always associated with high overall tumour burden, consequently a low-moderate PCI and isolated small bowel involvement is rare. This is illustrated in this study where all four inoperable patients had a total PCI score > 33. In a recently published study by our group, total PCI was found an excellent predictor of incomplete cytoreductive surgery [27] hence we suggest that the radiologic evaluation could focus on estimating total tumour burden instead of separate tumour implants such as small bowel infiltration. This is in line with the findings in the current study with excellent correlation between PET/MRI and surgical evaluation especially when it comes to patients with high tumour burden who were considered inoperable.

With both PET/MRI and DW-MRI, tumour burden in the individual regions differed from surgery. For example, peritoneal lesions assigned to region 5, the location of the sigmoid colon, were actually localised in the adjacent anatomic region or “lower jejunum”, and vice versa. These discrepancies might be explained by the fact that the surgeon moves organs to exactly define the location of peritoneal implants, but the radiologist interprets static images (Fig. 3). Nevertheless, the total PCI scores ended up similar, indicating that the tumour burden was equally well visualised even if its exact location was differently estimated. Two other common problems that led to mislocalisation were displacement of abdominal structures by large ovarian tumours and excessive amounts of ascites. However, sometimes ascites helped to correctly localise peritoneal lesions by separating otherwise adjacent structures (Fig. 4).

In the ten patients that had received neoadjuvant chemotherapy before radiology, we could not see any difference between the two methods, so presumably the additional advantage of PET is erased when the tumour activity is suppressed.

The study has its limitations, most importantly the relatively few patients and with the inclusion of both patients who had received neoadjuvant chemotherapy and those primarily operated on. Its strength lies in patients all having carcinomatosis of gynaecological origin, the majority being in the late FIGO stage. The same two surgeons assessed all patients during surgery in a standardised manner and two very experienced radiologists interpreted the images, further blinded to the patients’ medical history and surgical findings. Further, information on DWI-MRI and PET/MRI are gathered from the same individuals at the same time (with one examination) making patients their own controls and the examinations comparable.

In the present study PET/MRI was superior to DW-MRI in estimating total peritoneal cancer index especially in patients with high tumour burden without previous chemotherapy. We further suggest that the radiologic evaluation could focus on estimating the total tumour burden instead of separate tumour implants, as it has an excellent correlation with operability. The exact role of PET/MRI in carcinomatosis of gynaecological origin cannot be defined by our study alone but our results are promising and justify similar studies with larger cohorts. We believe that PET/MRI could be a useful tool to help physicians when deciding about operability in ovarian cancer patients.