**2.13. Interpretation of positron emission tomography-computed tomography (PET/ CT) scans**

Abnormal FDG hypermetabolism is analysed on the PET/CT images, starting from a survey of the maximum intensity projection (MIP) 3D image of the PET component. Regions commonly evaluated to detect nodal spread and distant metastases include the pelvic, abdominal and inguinal lymph nodes; the uterus, urinary bladder, peritoneum, omentum, bowel, liver, lungs and bones. Adnexal lesions frequently have a variable FDG uptake irrespective of their histopathological origin. For instance, mucinous carcinomas do not demonstrate avid FDG uptake compared to serous tumours [44]. It is postulated that indolent (Type I) and aggressive (Type II) ovarian cancers may arise from different cell lines [5]. Thus, Type I tumours do not demonstrate significantly elevated SUVmax values.

The sensitivity, specificity, PPV and NPV of PET/CT in detecting OC metastases are 87, 100, 81 and 100% respectively [45]. Moreover, PET/CT has improved accuracy at detecting peritoneal seeding, sub-diaphragmatic involvement, distant organ metastasis, bowel invasion and extra-abdominal lymph node involvement which has led to a reduction in the rate of second look surgery [46]. A negative PET/CT has NPV of 90% for detection of recurrence within a two-year follow-up period [2]. PET/CT scan in axial, coronal and sagittal views was able to detect bowel invasion (red arrow) in an advanced ovarian cancer disease (white arrow) (**Figure 4**). Therefore, it can aid in the decision-making for primary debulking surgery followed by platinum-based chemotherapy as opposed to treatment using neoadjuvant chemotherapy.

with internal calcifications as seen in **Figure 5b**. Mucinous adenocarcinomas often have low FDG uptake as seen in **Figure 5c** and represent a diagnostic caveat against dismissing them

**Figure 5.** PET/CT scans in axial view demonstrating malignant ovarian tumours. White arrow shows markedly increased

**Figure 4.** PET/CT scan demonstrating an advanced ovarian cancer. White arrows show a large adnexal tumour with

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heterogeneous FDG uptake. Red arrow shows bowel involvement.

The current theory postulates that high grade serous ovarian carcinoma (HGSC) originate from the fimbrial end of fallopian tubes [47]. It has sparked interest as to whether risk-reducing opportunistic salpingectomy could be performed to preserve fertility in a premenopausal

**2.14. Limitations and future research in positron emission tomography-computed** 

as benign lesions.

**tomography (PET/CT) scans**

FDG uptake within the solid component of the tumour.

PET/CT is also able to demonstrate the heterogeneity of ovarian cancers. (**Figure 5**) There is moderate FDG uptake noted in serous adenocarcinomas of the ovary as seen in **Figure 5a**. Endometrioid adenocarcinomas often have multiple cystic areas within and can be associated

standardised uptake values (SUVmax) are frequently detected in the ovaries in the luteal phase of the menstrual cycle. This is considered as normal physiological FDG metabolism and should not be mistaken for pathology. Therefore, PET/CT scans should be scheduled right

PET/CT scans are performed using a hybrid PET/CT scanner commonly using 3D lutetium oxy-orthosilicate crystals as detectors for the PET component. It is recommended that the examination include a diagnostic contrast-enhanced computed tomography (CECT) scan by the administration of low osmolar iodinated contrast media. Apart from enabling attenuation correction, and anatomical localisation; CECT is essential for performing diagnostic clinical staging [1]. Patients are instructed to fast for a minimum of 6 h before scanning, and blood glucose is checked before the scan. Subsequently, 18F-FDG will be administered and subjects are kept in a dark room for approximately 60 min to allow for uptake time. Subjects are given approximately 100 mL (2 ml/kg body weight) of iodinated contrast media during the CECT scan. Immediately after the CT, PET images acquisition will be performed over the same anatomic regions. The attenuation corrected CECT images will then be fused with PET images. The combined images will be utilised for visual interpretation, tumour size and maximum

after the menstruation to minimise this observed effect in premenopausal women.

**2.13. Interpretation of positron emission tomography-computed tomography (PET/**

Abnormal FDG hypermetabolism is analysed on the PET/CT images, starting from a survey of the maximum intensity projection (MIP) 3D image of the PET component. Regions commonly evaluated to detect nodal spread and distant metastases include the pelvic, abdominal and inguinal lymph nodes; the uterus, urinary bladder, peritoneum, omentum, bowel, liver, lungs and bones. Adnexal lesions frequently have a variable FDG uptake irrespective of their histopathological origin. For instance, mucinous carcinomas do not demonstrate avid FDG uptake compared to serous tumours [44]. It is postulated that indolent (Type I) and aggressive (Type II) ovarian cancers may arise from different cell lines [5]. Thus, Type I tumours do not

The sensitivity, specificity, PPV and NPV of PET/CT in detecting OC metastases are 87, 100, 81 and 100% respectively [45]. Moreover, PET/CT has improved accuracy at detecting peritoneal seeding, sub-diaphragmatic involvement, distant organ metastasis, bowel invasion and extra-abdominal lymph node involvement which has led to a reduction in the rate of second look surgery [46]. A negative PET/CT has NPV of 90% for detection of recurrence within a two-year follow-up period [2]. PET/CT scan in axial, coronal and sagittal views was able to detect bowel invasion (red arrow) in an advanced ovarian cancer disease (white arrow) (**Figure 4**). Therefore, it can aid in the decision-making for primary debulking surgery followed by platinum-based chemotherapy as opposed to treatment using neoadjuvant

PET/CT is also able to demonstrate the heterogeneity of ovarian cancers. (**Figure 5**) There is moderate FDG uptake noted in serous adenocarcinomas of the ovary as seen in **Figure 5a**. Endometrioid adenocarcinomas often have multiple cystic areas within and can be associated

standard uptake value (SUVmax) measurements.

184 Ovarian Cancer - From Pathogenesis to Treatment

demonstrate significantly elevated SUVmax values.

**CT) scans**

chemotherapy.

**Figure 4.** PET/CT scan demonstrating an advanced ovarian cancer. White arrows show a large adnexal tumour with heterogeneous FDG uptake. Red arrow shows bowel involvement.

**Figure 5.** PET/CT scans in axial view demonstrating malignant ovarian tumours. White arrow shows markedly increased FDG uptake within the solid component of the tumour.

with internal calcifications as seen in **Figure 5b**. Mucinous adenocarcinomas often have low FDG uptake as seen in **Figure 5c** and represent a diagnostic caveat against dismissing them as benign lesions.

#### **2.14. Limitations and future research in positron emission tomography-computed tomography (PET/CT) scans**

The current theory postulates that high grade serous ovarian carcinoma (HGSC) originate from the fimbrial end of fallopian tubes [47]. It has sparked interest as to whether risk-reducing opportunistic salpingectomy could be performed to preserve fertility in a premenopausal woman with high risk of developing ovarian cancer. There is a need to explore the role of PET/ CT or rather MR/PET, which may be able to detect disease at an earlier stage especially when it is still localised to the fallopian tubes.

Apart from 18F-FDG, other tracers have also been studied to assess for recurrent or residual ovarian cancer. These include 11C-Choline which can help better delineate pelvic lesions [48]; as well as 16α-18F-fluoro-17β-estradiol (FES) which have the potential to evaluate the response to hormonal therapy for ovarian cancer [44]. Another tracer also in the experimental stage, is 3′-deoxy-3′-18F-fluorothymidine (FLT) that distributes rapidly in the extracellular fluid and is phosphorylated by thymidine kinase 1(TK-1) and becomes trapped in tumours with increased cellular proliferation activity. The role of FLT PET/CT may be in assessing and predicting response to an antitumour type of therapy, where it has been shown to be superior to 18F-FDG PET/CT [49].

#### **2.15. Other research-based imaging techniques and work in progress**

Positron Emission Tomography/Magnetic Resonance (PET/MR) is an emerging technique, which uses scanners that acquire MR and PET data either simultaneously or sequentially. Simultaneous acquisition devices, some called the mMR scanners, allow for concurrent imaging of the same body region. Alternatively, sequential scanning is done using two different scanners during one examination session, and the images are fused later. PET/MR acquisition protocol for assessment of a gynaecological tumour includes whole-body Dixon and a dedicated pelvic MRI exam that includes dynamic intravenous gadolinium administration [50]. It is suitable for assessment of the loco-regional extent of a pelvic tumour and evaluates the entire body for metastases, albeit having a very long scanning time of approximately 1.0–1.5 h [50].

Additionally, PET/MRI may be a more useful modality as compared to PET/CT for the detection of miliary disseminated metastases in cases of suspected OC recurrence [2]. As evident in **Figure 6** in which PET/MRI demonstrates FDG avid uptake in the para-aortic lymph nodes (**Figure 6**). Furthermore, PET/CT potentially gives high false negative results in the case of small volume disease which predisposes it to miss low-grade tumours and early adenocarcinomas [51]. Therefore, it is recommended to be used in conjunction with transvaginal ultrasound or MRI for characterisation of adnexal masses and the detection of OC.

After the incubation time, usually 10–15 min, the sentinel nodes can be visualised by either colorization (blue lymph nodes can be identified) and/or with a gamma probe that detects the radioactive tracer. The pathological examination of the sentinel node is an indication of the nodal status of the remaining nodes; when the sentinel node is negative, one can presume that the remaining nodes are also not involved. As a consequence, the patient may be spared from

**Figure 6.** PET/MRI scan demonstrating recurrent ovarian cancer with para-aortic lymph nodes involvement. MRI gives

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Conventional diagnostic imaging modalities lack specificity and sensitivity in the detection of small primary and disseminated tumours in the peritoneal cavity. Using the knowledge that HER-2 receptors are overexpressed in ovarian tumours, a near infrared (NIR) optical imaging approach for detection of ovarian tumours using a HER-2 targeted nanoparticle-based imaging agent in an orthotopic mouse model of ovarian cancer has been conducted achieving

Furthermore, the overexpression of folate receptor-α (FR-α) in OC, has prompted the investigation of intra-operative tumour-specific fluorescence imaging. It has potential applications in

undergoing radical lymphadenectomy, and thus the morbidity associated with it.

good soft tissue resolution of the FDG avid lymph nodes noted at central abdomen.

improved detection of smaller lesions [54].

PET/MRI ideally has added value in oncologic imaging due to its improved soft-tissue resolution. Furthermore, sophisticated sequences such as diffusion-weighted imaging, functional MRI, and MR spectroscopy can all be incorporated with molecular imaging, giving further information but with less radiation exposure. This can provide a significant reduction in radiation dose and exposure in patients who require follow-up imaging [3].

Some other imaging techniques are performed intra-operatively, namely the sentinel node procedure (SNP). SNP is sometimes conducted in patients with a high likelihood of having an OC in whom a median laparotomy and a frozen section analysis is planned. The concept of SNP is to determine whether the OC has spread to the very first lymph node (sentinel node). If the sentinel node is negative for cancer cells, then there is a high likelihood that the cancer has not spread to other lymph nodes [52]. Blue dye and radioactive colloid are injected into either the ovaries or the ovarian ligaments to perform the SNP [53].

woman with high risk of developing ovarian cancer. There is a need to explore the role of PET/ CT or rather MR/PET, which may be able to detect disease at an earlier stage especially when it

Apart from 18F-FDG, other tracers have also been studied to assess for recurrent or residual ovarian cancer. These include 11C-Choline which can help better delineate pelvic lesions [48]; as well as 16α-18F-fluoro-17β-estradiol (FES) which have the potential to evaluate the response to hormonal therapy for ovarian cancer [44]. Another tracer also in the experimental stage, is 3′-deoxy-3′-18F-fluorothymidine (FLT) that distributes rapidly in the extracellular fluid and is phosphorylated by thymidine kinase 1(TK-1) and becomes trapped in tumours with increased cellular proliferation activity. The role of FLT PET/CT may be in assessing and predicting response to an antitumour type of therapy, where it has been shown to be superior

Positron Emission Tomography/Magnetic Resonance (PET/MR) is an emerging technique, which uses scanners that acquire MR and PET data either simultaneously or sequentially. Simultaneous acquisition devices, some called the mMR scanners, allow for concurrent imaging of the same body region. Alternatively, sequential scanning is done using two different scanners during one examination session, and the images are fused later. PET/MR acquisition protocol for assessment of a gynaecological tumour includes whole-body Dixon and a dedicated pelvic MRI exam that includes dynamic intravenous gadolinium administration [50]. It is suitable for assessment of the loco-regional extent of a pelvic tumour and evaluates the entire body for metastases, albeit having a very long scanning time of approximately 1.0–1.5 h [50]. Additionally, PET/MRI may be a more useful modality as compared to PET/CT for the detection of miliary disseminated metastases in cases of suspected OC recurrence [2]. As evident in **Figure 6** in which PET/MRI demonstrates FDG avid uptake in the para-aortic lymph nodes (**Figure 6**). Furthermore, PET/CT potentially gives high false negative results in the case of small volume disease which predisposes it to miss low-grade tumours and early adenocarcinomas [51]. Therefore, it is recommended to be used in conjunction with transvaginal ultra-

**2.15. Other research-based imaging techniques and work in progress**

sound or MRI for characterisation of adnexal masses and the detection of OC.

ation dose and exposure in patients who require follow-up imaging [3].

either the ovaries or the ovarian ligaments to perform the SNP [53].

PET/MRI ideally has added value in oncologic imaging due to its improved soft-tissue resolution. Furthermore, sophisticated sequences such as diffusion-weighted imaging, functional MRI, and MR spectroscopy can all be incorporated with molecular imaging, giving further information but with less radiation exposure. This can provide a significant reduction in radi-

Some other imaging techniques are performed intra-operatively, namely the sentinel node procedure (SNP). SNP is sometimes conducted in patients with a high likelihood of having an OC in whom a median laparotomy and a frozen section analysis is planned. The concept of SNP is to determine whether the OC has spread to the very first lymph node (sentinel node). If the sentinel node is negative for cancer cells, then there is a high likelihood that the cancer has not spread to other lymph nodes [52]. Blue dye and radioactive colloid are injected into

is still localised to the fallopian tubes.

186 Ovarian Cancer - From Pathogenesis to Treatment

to 18F-FDG PET/CT [49].

**Figure 6.** PET/MRI scan demonstrating recurrent ovarian cancer with para-aortic lymph nodes involvement. MRI gives good soft tissue resolution of the FDG avid lymph nodes noted at central abdomen.

After the incubation time, usually 10–15 min, the sentinel nodes can be visualised by either colorization (blue lymph nodes can be identified) and/or with a gamma probe that detects the radioactive tracer. The pathological examination of the sentinel node is an indication of the nodal status of the remaining nodes; when the sentinel node is negative, one can presume that the remaining nodes are also not involved. As a consequence, the patient may be spared from undergoing radical lymphadenectomy, and thus the morbidity associated with it.

Conventional diagnostic imaging modalities lack specificity and sensitivity in the detection of small primary and disseminated tumours in the peritoneal cavity. Using the knowledge that HER-2 receptors are overexpressed in ovarian tumours, a near infrared (NIR) optical imaging approach for detection of ovarian tumours using a HER-2 targeted nanoparticle-based imaging agent in an orthotopic mouse model of ovarian cancer has been conducted achieving improved detection of smaller lesions [54].

Furthermore, the overexpression of folate receptor-α (FR-α) in OC, has prompted the investigation of intra-operative tumour-specific fluorescence imaging. It has potential applications in patients with OC for improved intra-operative staging and more radical cytoreductive surgery [55]. Additionally, optical coherence tomography (OCT) is another emerging high-resolution imaging technique that utilises an infrared light source directed to the tissues being examined. A novel prototype intra-operative OCT system combining positron detections; namely utilising Caesium (Tl204/Cs137) sources as well as 18F-FDG have shown potential for the development of a miniaturised laparoscopic probe to detect small volume disease of OC. This can offer simultaneous functional localisation and structural imaging for improved early cancer detection [56].

**Acknowledgements**

**Author details**

Subapriya Suppiah

**References**

[cited 2017 Sept. 6]

I would like to express my gratitude to the Dean of the Faculty of Medicine and Health Sciences, Universiti Putra Malaysia (UPM), Professor Dato' Dr. Abdul Jalil Nordin; and the Lead Consultant from the Nuclear Medicine Department at the Royal Liverpool and Broadgreen University Hospitals, NHS Trusts, Liverpool, the United Kingdom of Great Britain, Professor Dr. Sobhan Vinjamuri, my mentors; for their invaluable comments during preparation of this manuscript. I would also like to acknowledge Universiti Putra Malaysia research grant GP/IPM/2014/9404000 and GP/2017/9549800 that helped fund this project; and the fellowship training scholarship awarded by the International Atomic Energy Agency (IAEA) that enabled the collaboration with the United Kingdom counterparts. I would also like to thank the Director of the Centre for Diagnostic Nuclear Imaging, UPM; Associate Professor Dr. Fathinul Fikri Ahmad Saad for giving permission to use images from the centre as well as the Director General of Health, Ministry of

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Health Malaysia for giving permission to use images from Serdang Hospital, Malaysia.

Centre for Diagnostic Nuclear Imaging, Universiti Putra Malaysia, Serdang, Malaysia

Malaysian Journal of Medicine and Health Sciences. 2017;**13**(1):1-8

[2] Ovarian Cancer: Recognition and Initial Management. 2011. NICE.org.uk

of Nuclear Medicine. 2017;**16**(3):176-185. DOI: 10.4103/wjnm.WJNM\_31\_17

[1] Suppiah S, Asri AAA, Saad FFA, Hassan HA, CWL NM, Mahmud R, Nordin AJ. Contrastenhanced 18F-FDG PET/CT in preoperative assessment of suspicious adnexal masses and proposed diagnostic imaging algorithm: A single centre experience in Malaysia.

[3] Suppiah S, Chang WL, Hassan HA, Kaewput C, Asri AAA, Saad FFA, Nordin AJ, Vinjamuri S. Systematic review on the accuracy of positron emission tomography/computed tomography and positron emission tomography/magnetic resonance imaging in the management of ovarian cancer: Is functional information really Needed? World Journal

[4] Shih I-M, Kurman RJ. Ovarian tumorigenesis: A proposed model based on morphological and molecular genetic analysis. The American Journal of Pathology [Internet]. 2004;**164**(5):1511-1518. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15111296

[5] Kurman RJ, Shih IM. The origin and pathogenesis of epithelial ovarian cancer: A proposed unifying theory. The American Journal of Surgical Pathology [Internet]. 2010;

Address all correspondence to: subapriya@upm.edu.my
