Impact of FDG-PET and -PET/CT Imaging in the Clinical Decision-Making of Ovarian Carcinoma: An Evidence-Based Approach

Abstract

The most definitive role of fluorodeoxyglucose (FDG)-PET/computed tomography (CT) at present is surveillance and detecting recurrence in patients who have completed primary therapy but demonstrate a rising serum tumor marker (e.g., CA–125 levels). In this scenario, PET/CT demonstrates high sensitivity and accuracy in detecting lesions that are otherwise challenging, and appears superior (with less interobserver variability) compared with CT alone. Despite the fact that peritoneal deposits may be missed by PET/CT, the overall performance is better than CT alone, FDG-PET does not play a significant additional role in the primary diagnosis of ovarian cancers; however, the role of combined PET/CT modality has recently begun to be re-explored for initial disease staging, particularly because PET/CT can pick up small unsuspected lesions and thereby provide a better disease assessment of the whole body in a single examination, The baseline PET/CT also subserves an important role for future monitoring of therapy response. Therapy monitoring by PET could help to optimize neoadjuvant therapy protocols and to avoid ineffective therapy in nonresponders early in its course, although PET/CT has cost-effectiveness issues that need further evaluation. The prognostic value of FDG-PET/CT has been investigated in the following areas: in the preoperative setting to predict optimal cytoreduction; to assess the value of a positive FDG-PET following primary surgery; and when employed as a replacement for second-look laparotomy following completion of primary surgery and chemotherapy. The data, although promising, are still sparse in all the three domains for a definite recommendation.

Keywords

computed tomography fluorodeoxyglucose ovarian cancer ovarian carcinoma PET PET/computed tomography

Ovarian cancer is the sixth most common cancer among women [1,2]. Worldwide there are more than 200,000 new cases of ovarian cancer each year, accounting for around 4% of all cancers diagnosed in women [3]. A woman's risk of developing cancer of the ovaries by the age of 75 years varies between countries, ranging from 0.5 to 1.6%, corresponding to an age-standardized rate of five to 14 cases per year in 100,000 women. In Europe, ovarian cancer is the leading cause of gynecological cancer death; just over a third of women are alive 5 years after diagnosis [4], largely because most women with ovarian cancer present at an advanced stage when surgical cure is usually impossible [5].

The International Federation of Obstetricians and Gynecologists (FIGO) staging is used to describe the spread of the disease (Box 1). Fewer than 30% of women present with stage I or II ovarian cancer [6].

Management of carcinoma of the ovary involves evaluation and primary staging, followed by primary debulking surgery followed by adjuvant chemotherapy in the early stages, while chemotherapy (neoadjuvant) followed by interval debulking surgery in advanced disease with variations depending on the his to-pathological grade and the general condition of the patient [1].

Preoperative staging is done by imaging followed by surgical staging at laparotomy. Imaging by ultrasonography or computed tomography (CT)/MRI is widely acceptable for carcinoma of the ovary. Over the past few years, especially the past decade, with the advent of functional imaging using PET with ¹⁸F-fluorodeoxyglucose (FDG) imaging, diagnostic imaging in oncology has undergone a paradigm shift. With the advent of the routine clinical use of FDG-PET in the early nineties for staging and follow-up of various cancers, we have now arrived at the time of advanced molecular imaging using PET/CT, which combines both functional and anatomical information. Based on the increasing body of literature in the last few years, we now place PET/CT at a certain point in the management of ovarian carcinomas.

Box 1.

Description of the International Federation of Obstetricians and Gynecologists staging of ovarian cancer.

IA. Disease confined to one ovary with no capsular involvement. Peritoneal washings/cytology negative

IB. Disease confined to both ovaries with no capsular involvement. Peritoneal washings/cytology negative

IC. Disease confined to the ovary/ovaries but ovarian capsular involved or cyst rupture

IIA. Extension to uterus or fallopian tubes

IIB. Extension to other pelvic tissues

IIC. As for IIA or IIB but one or both ovaries have ruptured capsule or surface tumor; malignant ascites or positive peritoneal washings

IIIA. Histologically confirmed microscopic seeding of abdominal peritoneal surfaces and negative retroperitoneal lymph nodes

IIIB. Histologically confirmed implants of abdominal peritoneal surfaces less than 2 cm and negative retroperitoneal lymph nodes

IIIC. Histologically confirmed implants of abdominal peritoneal surfaces greater than 2 cm or positive retroperitoneal lymph nodes

IV. Distant metastases (including liver parenchyma/positive pleural fluid cytology)

Data taken from [6].

Ovarian cancers are usually detected at advanced stages. They tend to recur despite adequate surgery and chemotherapy. Recurrent ovarian malignancies are difficult to detect and even if detected the prognosis is not very favorable in advanced disease with poor 5-year survival rates [4]. Despite these factors, detection of early stage disease, early detection of recurrence following completion of therapy and response to therapy are some of the important situations where PET/CT can play an important role for clinical decision making.

With this background, in this review we aim to discuss the impact of PET/CT in the management of ovarian carcinomas.

Basics of FDG-PET/CT imaging in oncology

PET imaging involves the injection of the tracer ¹⁸F-FDG, which is a glucose analog [7]. This is followed by imaging in a PET scanner with or without CT. However, most PET scanners today have an integrated CT component, which is useful for attenuation correction as well as anatomical correlation with coregistration. Organs show FDG uptake, which is dependant on the glucose metabolic status of the cells [7]. Glucose uptake is increased manifolds in malignant cells which forms the basis of increased FDG uptake and functional imaging with FDG-PET [7].

PET/CT in physiological conditions of the ovary

In the ovaries, a baseline FDG uptake and a spectrum of cyclical physiological and benign FDG uptake have to be considered in order to detect or diagnose malignant disease. There are known confounding factors of benign/physiological uptake by the ovaries in the various phases of the menstrual cycle [8 –11]; these need to be taken care of when PET /CT scans are performed for the diagnosis of ovarian carcinoma (TABLE 1). On FDG-PET imaging, the ovaries are prominent in the mid-cycle, with focal uptake located in the left or right side superior and posterior to the urinary bladder. Patients with irregular cycles have a low probability of intense uptake in the ovaries and this should be viewed with high suspicion. Corresponding CT correlation should be done in suspicious cases. Characteristic CT appearance is enhancing cyst and no lymphadenopathy.

Table 1.

Physiological uptake patterns of the ovaries on a fluorodeoxyglucose-PET scan.

Author (year)	Type of publication	Conclusion	Ref.
Liu (2009)	Review	Increased ovarian FDG uptake in phases of menstrual cycle; increased uptake in benign tumors; diagnostic CT correlation important	[8]
Nishizawa et al. (2007)	Retrospective analysis of 26 women with serial PET scans and MRI	Ovarian FDG uptake is seen even after hysterectomy; needs to be correlated with an anatomical imaging modality (in this study MRI)	[9]
Zhu et al. (2007)	Prospective study of 247 women included in various phases of the menstrual cycle	Ovarian uptake was more prominent in mid-cycle, with the foci of uptake in ovoid shape and located at the left and/or right side superior-posterior to the bladder; patients with irregular cycles have low probability of intense uptake in the ovary	[10]
Kim et al. (2005)	Retrospective analysis of ovarian uptake in 207 women	Increased FDG uptake in the ovary in the peri-ovulatory phase; FDG-PET scan should be planned postmenstrually	[11]

CT: Computed tomography; FDG: Fluorodeoxyglucose.

It is imperative that FDG-PET/CT scan for evaluation of ovarian/pelvic malignancies is performed in the postmenstrual phase in order to avoid ovarian as well as endometrial activity, which increases in the mid-cycle and menstrual phases, respectively. In postmenopausal women any ovarian uptake should be viewed with high suspicion.

PET/CT in the diagnosis & initial staging of ovarian cancers

Barring a few reports [12 –14], it is evident that FDG-PET only has no incremental role with regards to initial diagnosis of suspicious pelvic masses ( Table 2 ) [15 –20]. Transvaginal ultrasound/CT or MRI have been found to be more useful and cost-effective modalities in the initial diagnostic evaluation of ovarian malignancies or asymptomatic adnexal masses before the advent of PET/CT. FDG-PET did not reveal much incremental benefit over ultrasound, MRI or all three modalities in combination [15,16]. The poor resolution of PET was suggested to be a major cause for this impression.

Table 2.

Fluorodeoxyglucose-PET in the diagnosis of malignant ovarian lesions.

Author (year)	Type of study	Number of patients	Study aim	Conclusion	Ref.
Kawahara et al. (2004)	Prospective	38	FDG-PET: comparison with MRI for initial diagnosis of suspicious lesions	PET provides no incremental benefit over MRI	[15]
Fenchel et al. (2002)	Prospective	99	Diagnosis of malignancy in asymptomatic adnexal masses: comparison of US, PET, MRI and histopathology findings	Sensitivity of US is the same as PET, MRI or all three combined	[16]
Reiber et al. (2001)	Prospective	103	Suspicious adnexal lesions: evaluation by US, MRI and PET; comparison with histopathology	PET showed no incremental value; US, MRI or surgery recommended	[17]
Grab et al. (2000)	Prospective	101	Accuracy of US vs MRI and PET for the characterization of adnexal masses	Combination of MRI or PET with US may improve diagnostic accuracy, but does not rule out malignancy	[18]
Kubik-Huch et al. (2000)	Prospective	19	Accuracy of PET, CT and MRI for diagnosis (n = 8) and recurrence (n = 11)	No significant difference between all three modalities; poor resolution of PET has a disadvantage; none can replace surgical staging	[19]
Fenchel et al. (1999)	Prospective	85	Asymptomatic adnexal masses with PET and MRI	Limited usefulness; sensitivity and specificity 50 and 78%, respectively	[20]

FDG: Fluorodeoxyglucose; US: Ultrasound.

With the advent of FDG-PET/CT in recent years, the role of PET imaging is being re-explored. PET/CT has been proven to provide incremental information in comparison with CT/MRI only and may play a role in the preoperative staging of carcinoma of the ovary ( Table 3 ) [21 –25]. This means a better initial staging, which would provide a better outlook for the surgeon before embarking upon primary debulking surgery ( Figure 1 ).

Figure 1.

¹⁸F-fluorodeoxyglucose-PET at initial diagnosis. A 45-year-old female patient who was diagnosed with a case of ovary carcinoma with ¹⁸F-fluorodeoxyglucose (FDG)-PET scan performed at initial presentation, demonstrating bulky FDG concentrating lesions in the pelvis with multiple satellite lymph node, regional nodal metastasis and multiple para-aortic lymph node involvement. There is tracer retention within the proximal urinary system of both kidneys. Also noted is intense FDG uptake in the spleen, which is usually observed in the postchemotherapy setting due to extramedullary hematopoiesis related to the effect of colony-stimulating factors [67]. This was unexplained in this case.

Table 3.

PET/computed tomography in initial staging of ovarian cancers.

Author (year)	Number of patients and type of study	Study aim	Conclusion	Ref.
Nam et al. (2010)	133 patients; prospective	Comparison of PET/CT, US, CT and MRI for diagnosis and staging	PET/CT is better for preoperative staging and to pick up metastasis (15.8% more than radiological staging) and also unexpected tumors (in 3.8% cases)	[21]
Kitajima et al. (2008)	40 patients; prospective	Comparison of PET/CT and only CT	PET/CT is more sensitive than CT (69.4 vs 37.6), more specific (97.5 vs 97.1) and more accurate (94 vs 89.7)	[22]
Yamamoto et al. (2008)	30 patients; prospective	Efficiency of PET/CT to differentiate between benign and malignant in selected suspicious lesions by clinical US and tumor markers	High efficiency for differentiating between benign and malignant; but poor for differentiating between borderline malignant and benign	[23]
Castellucci et al. (2007)	50 patients; prospective	Efficiency of PET/CT for diagnosis vs TVUS and with CT for staging	PET/CT provided incremental value in both diagnosis and staging for ovarian carcinoma	[24]
Risum et al. (2007)	101 patients; prospective	Efficiency of PET/CT for diagnosis of malignancy in pelvic masses	PET/CT is the modality of choice for initial diagnosis of suspicious mass on US	[25]

CT: Computed tomography; TVUS: Transvaginal ultrasound; US: Ultrasound.

Overall, PET/CT has a better lesion detection rate than CT or MRI alone, better efficiency to differentiate benign from malignant lesions – except for borderline lesions - and to pick up other unexpected tumors. Thus, the incremental value of PET/CT has been well proven in initial staging workup although surgery still remains the gold standard.

PET/CT in disease prognostication

PET/CT has been found to be of some incremental value in prognostication and prediction of disease [26 –32] after primary treatment, although it does not stand a very strong hold in this area ( Table 4 ) [27,28,31]. Risum et al. demonstrated that factors for predicting sub optimal cytoreduction include large bowel mesenteric deposits, which could be picked up on PET/CT with high sensitivity prior to surgery and thus help in prognostication [27]. However, the few studies done in this area cannot be very strong contenders to replace second-look laparotomy [31,32]. Presently, Phase III randomized trials are still ongoing to examine if the information generated based on the results of PET/CT will be useful in predicting and selecting a specific management plan in this scenario [26]. The primary aim here would be to see if PET/CT could replace second-look laparotomy. There is still not enough data to conclude that this is so.

Table 4.

Incremental role of PET or PET/computed tomography in prognostication of ovarian cancers.

Author (year)	Number of patients and type of study	Aim	Conclusion	Ref.
Risum et al. (2008)	179 patients; prospective	To find predictors for suboptimal cytoreduction in primary ovarian cancer before surgery	Factors for prediction of suboptimal cytoreduction were found by PET/CT. LBMI was found to be an independent predictor of incomplete cytoreduction; recommends to use PET/CT only for preoperative evaluation and not for withholding cytoreductive surgery	[27]
Kurosaki et al. (2006)	18 patients; prospective	Followed after primary surgery for mean 2.5 years with PET/CT and CA-125 for prediction of relapse	PET/CT positive had a less favorable prognosis than PET/CT negative; but CA?125 was found to be a more useful predictor of prognosis	[28]
Kim et al. (2004)	55 patients; retrospective	Follow-up of two groups after primary surgery and chemotherapy; SLL in one group and PET in the other	PET was found to have similar prognostic value to SLL in follow-up of ovarian carcinomas	[31]

CT: Computed tomography; LBMI: Large bowel mesenteric implants; SLL: Second-look laparotomy.

PET/CT in detecting disease recurrence of ovarian carcinoma

The highest impact of PET/CT in ovarian cancers is in the detection of recurrence as this is one of the most common malignancies to recur despite adequate therapy (Figures 2 & 3). There are extensive data in this area ( Table 5 ) [33 –50]. Various studies [33,34] have revealed the significant alteration in the management of patients (>50%) with suspected disease recurrence by the introduction of PET/CT. PET/CT reveals lesions in nodal, peritoneal and subcapsular liver disease with higher sensitivity and accuracy, which are otherwise challenging to interprete with CT alone [41]. Only one study favored MRI and has shown a better sensitivity and accuracy of MRI in comparison with PET/CT, but the details of the study (e.g., selection of patients, interpretation skills and sample size) need to be considered in larger multicentric trials [39]. It should be observed that in this area PET alone as well as PET/CT have both been reported to perform well [42].

Figure 2.

¹⁸F-fluorodeoxyglucose-PET for disease surveillance in patient with a raised level of serum tumor marker. Post-treatment follow-up ¹⁸F-fluorodeoxyglucose (FDG)-PET in a 40-year-old female patient; diagnosed case of carcinoma ovary with abnormally elevated serum CA-125 (535 U/ml). Whole-body FDG-PET demonstrating abnormal foci, suggesting active disease in the para-aortic and pelvic group of lymph nodes on the right side. Initial scan had urinary tracer collection interfering with the disease foci, which were well delineated on the postfurosemide regional PET study. (A) Baseline whole-body FDG-PET image. (B) Postfurosemide regional FDG-PET.

Figure 3.

¹⁸F-fluorodeoxyglucose-PET documenting disease recurrence after a prolonged complete remission. A 52-year-old female who previously had a case of breast carcinoma but was post-treatment and had been in complete remission for 10 years, developed carcinoma of both the ovaries. The patient underwent total abdominal hysterectomy and bilateral salphingo-oophorectomy with chemotherapy. Follow-up assessment 4 years post-treatment revealed abnormally elevated CA-125 (105 U/ml). Whole-body ¹⁸F-fluorodeoxyglucose-PET scan demonstrating focal abnormal tracer concentration within the right lobe of the liver. Also noted is prominent blood pool activity in the heart and major vessels including the upper limb vessels, which is at times observed incidentally.

Table 5.

PET and PET/computed tomography in recurrent ovarian cancers.

Author (year)	Number of patients	Aim	Conclusion	Ref.
Risum et al. (2009)	60 patients; prospective	To compare PET/CT, US and CT for detection of recurrence	PET/CT has higher diagnostic value than US and CT for recurrence; accurate for depiction of solitary recurrences	[33]
Markman (2009)	90 patients; prospective	Multicentric study; to see impact of PET/CT in suspected recurrence	For women with previously treated ovarian carcinoma with recurrent disease, PET/CT can: alter management in close to 60% of patients; detect more sites of disease than abdominal and pelvic CT; is superior in the detection of nodal, peritoneal and subcapsular liver disease; and offers the opportunity for technology replacement in this setting	[34]
Cuenca Cuenca et al. (2008)	40 patients; prospective	Impact of PET/CT in suspected recurrence	FDG-PET has high sensitivity and clinical impact in patients with suspicion of recurrent ovarian cancer; better results were obtained in patients with increased tumor markers and negative MIT	[35]
Fagotti et al. (2008)	70 patients; prospective	Best strategy for diagnosis of recurrence and management strategy between PET/CT and staging laparoscopy	Both combined have a significant effect and are recommended as a multimodal modality approach; both found to be complementary	[36]
Lenhard et al. (2008)	70 patients; prospective	Role of PET/CT in recurrent ovarian cancer	Reliable for detection; however, for prediction of resectibility it has limited use, but surgical planning is helpful to select resectable areas	[37]
Gu et al. (2008)	Review	PET alone, PET/CT CA?125, CT and MRI in diagnosis of recurrent ovarian cancer	PET/CT useful in detection of recurrence; CT component shown to have limited additional value	[38]
Kim et al. (2007)	36 patients; prospective	Comparison of PET/CT with MRI for detection of recurrence	MRI (86%) found to be more sensitive than PET/CT (66%)	[39]
Sheng et al. (2007)	26 patients; prospective	Performance of PET/CT for early detection of recurrence, in rising CA-125 levels	High accuracy of PET/CT for detection of recurrence in combination with CA-125 levels; also increases accuracy of recytoreductive surgery	[40]
Sebastian et al. (2008)	51 patients; prospective	PET/CT vs CT alone for recurrence	PET/CT demonstrates greater accuracy and less interobserver variability than CT alone	[41]
Garcia-Velloso et al. (2007)	86 patients; retrospective	PET for detection of recurrence compared with conventional radiological imaging	PET can detect recurrence earlier with more sensitivity and accuracy than conventional radiological imaging	[42]
Thrall et al. (2007)	39 patients; retrospective	PET/CT for detection of recurrence	PET/CT high detection of recurrence especially in rising CA-125 and negative conventional imaging	[43]
Mangili et al. (2007)	32 patients; retrospective	PET/CT vs CT for suspected recurrence	PET/CT detected more recurrences and altered management in 44% of patients	[44]
Chung et al. (2007)	77 patients; prospective	PET/CT for recurrence correlated with histology (surgical findings)	PET/CT sensitive modality, aids decision-making	[45]
Simcock et al. (2006)	56 patients; prospective	PET/CT in follow-up for recurrence	PET/CT modifies the assessment of the distribution of recurrent ovarian cancer and alters patient management in a substantial proportion of patients; PET/CT offers prognostic information	[46]
Hauth et al. (2005)	19 patients; prospective	PET, CT and PET/CT compared for recurrence	PET/CT detects more lesions than PET or CT alone	[47]
Bristow et al. (2005)	14 patients; retrospective	PET/CT showed high sensitivity and positive predictive value in identifying recurrent ovarian cancer among patients with rising CA-125 levels and negative or equivocal conventional imaging (e.g., CT) findings	PET/CT has a high positive predictive value in this region known for occult recurrence	[48]
Nanni et al. (2005)	41 patients; prospective	PET/CT done after primary treatment; for recurrence in addition to CA-125, CT/MRI/USG	PET/CT showed a good sensitivity (88.2%), specificity (71.4%) and accuracy (85.4%), for detection of recurrence (early study)	[49]
Bristow et al. (2003)	22 patients; prospective	PET/CT for detection of clinically occult recurrence FIGO IIIC-IV	PET/CT showed high sensitivity and positive predictive value in identifying potentially resectable, macroscopic recurrent ovarian cancer among patients with biochemical evidence of recurrence and negative or equivocal conventional CT findings	[50]

CT: Computed tomography; FDG: Fluorodeoxyglucose; FIGO: International Federation of Obstetricians and Gynecologists; MIT: Morphologic imaging tests; US: Ultrasound; USG: Ultrasonography.

In fact, this is one definitive clinical indication that has been shown to be cost-effective as well. The use of PET/CT in the group of patients with suspected recurrent disease is cost-effective and can be allowed to redirect the clinical management of patients towards more appropriate therapeutic choices [51].

PET/CT in peritoneal metastases

In patients with metastatic ovarian carcinoma, disease sensitivity of both ¹⁸F-FDG-PET and CT for the detection of peritoneal metastases is low; however, with regards to better specificity of FDG-PET, it is preferred for evaluation of residual/recurrent disease with better sensitivity for the retroperitoneal region than the intraperitoneal region ( Figure 4A & B ). Surgical staging remains the gold standard [52].

Figure 4.

¹⁸F-fluorodeoxyglucose-PET imaging of ovarian carcinoma demonstrating different sites of disease involvement including the peritoneum. (A) A 50-year-old female patient with a diagnosed case of carcinoma of the ovary. ¹⁸F-fluorodeoxyglucose (FDG)-PET study demonstrating extensive ¹⁸F-FDG concentrating lesions of varying size and intensity involving the liver, the peritoneum, lymphatic and extra-lymphatic soft tissue in the abdomen and pelvis, (B) A 40-year-old female patient diagnosed with a case of carcinoma of the ovary post-treatment assessment with whole-body ¹⁸F-FDG-PET, demonstrating extensive residual ¹⁸F-FDG-concentrating large lesions in the epigastric region, multiple focal hepatic lesions of varying size and intensity, multiple peritoneal deposits and a few small lesions with necrotic areas in the pelvis on the right side.

Performance of PET has been found to be a useful tool for the detection of the peritoneal deposits [53 –56]. This is due to two factors, in particular: detection of peritoneal carcinomatosis is difficult with CT due to poor sensitivity. Detection with peritoneal biopsy is also fraught with high incidence of sampling errors. Two distinct abnormal scintigraphic patterns of focal and uniform ¹⁸F-FDG uptake corresponding to nodular and diffuse peritoneal disease on pathologic examination have been observed for peritoneal carcinomatosis on FDG-PET [57].

PET in assessing response to therapy

FDG-PET uptake in the tumor prior to therapy and after neoadjuvant chemotherapy or chemo-radiotherapy in advanced ovarian cancers has been studied [58,59]. Standardized uptake value (SUV)-based assessment of response has been found to be accurate; however, the role of PET in the context of patient management and the cost–effectiveness of this approach needs further evaluation [59,60]. Therapy monitoring by PET could help to optimize neoadjuvant therapy protocols and to avoid ineffective preoperative therapy in nonresponders, but this has to be proven in a larger number of patients and in different neoadjuvant settings such as chemotherapy, radiation therapy, hormone therapy or a combination of these [61]. The results of PET/CT in this situation could also translate into prognostication of the disease. There is relatively less defined course in terms of therapeutic intervention with positive PET/CT results in this clinical setting when compared with other malignancies. This is one of the main reasons why PET/CT is not yet popular in this area [60].

PET in metastatic ovarian cancer & in the setting of rising CA-125 levels

Ovarian cancer can spread locally within the pelvis with subsequent spread within the peritoneal cavity to the rest of the abdomen. Tumor spread can also occur via lymphatics and hematogenously. Lymphadenopathy can be seen in the inguinal, pelvic and para-aortic regions. Hematogenous sites of spread include the liver and lung [62].

Distant metastasis is also seen in the liver, pleura, mediastinum and supraclavicular lymph nodes ( Figure 5 ) [24]. Kim et al. broadly classified recurrent ovarian tumors in the abdomen and pelvis based on site as follows: local pelvic recurrence; peritoneal lesion; lymph nodal metastasis; and distant metastasis [39]. PET/CT showed an excellent sensitivity and specificity of nearly 100% for detection for all sites of metastasis viz local spread, peritoneal lesions, inguinal and pelvic lymph nodes and distant metastasis in liver and lungs, except for the para-aortic lymph nodes where PET performance was observed to be relatively low [37]. Overall, PET/CT has been found to have better sensitivity than CT alone for the detection of distant metastasis [24,62].

Figure 5.

¹⁸F-fluorodeoxyglucose-PET in assessing response to chemotherapy. A 59-year-old female patient diagnosed with a case of carcinoma of the ovary with advanced disease. She underwent radical surgery (total abdominal hysterectomy with bilateral saphingo-ophorectomy) and multiple cycles of chemotherapy. Follow-up assessments demonstrated abnormal and rising levels of CA-125. Hence the patient was subjected to whole-body ¹⁸F-fluorodeoxyglucose (FDG)-PET in the third year since initiation of treatment (A). This demonstrated focal abnormal tracer uptake in the left supraclavicular lymph node and multiple para-aortic lymph nodes. Follow-up whole-body FDG-PET scan done 18 months after previous PET scan postchemotherapy (B), demonstrating resolution of supraclavicular disease with persistent residual para-aortic nodal disease. This case demonstrates the role of FDG-PET scan in monitoring post-treatment disease with rising tumor marker and response assessment postchemotherapy.

Although we have discussed the role of PET/CT in detecting recurrent/metastatic disease, the area of rising CA-125 levels (tumor markers) with normal anatomical imaging (CT/MRI) deserves special mention ( Figure 6 ). CT has been shown to have quite a low negative predictive value for recurrence suspected owing to rising CA-125 levels [37]. Makhija et al. reported that PET/CT could identify recurrent disease in 62% of patients with negative CT scans [63]. Soussan et al. have shown that PET/CT imaging allows for better restaging than CT and induces a change in clinical management in over a third of patients with suspected ovarian carcinoma recurrence with increased CA-125 [64].

Figure 6.

Superiority of ¹⁸F-fluorodeoxyglucose-PET/computed tomography compared with diagnostic contrast-enhanced computed tomography alone. A 68-year-old woman presented with rising CA-125 levels and normal findings on computed tomography (CT). (A-B) At restaging, transaxial PET/CT slice through the chest (A) demonstrates moderate (same as blood pool) ¹⁸F-fluorodeoxyglucose (FDG) uptake in the right hilum, corresponding to a 1.6 cm in size lymph node on CT, consistent with metastasis; transaxial PET/CT slice through the focus of ¹⁸F-FDG uptake in the right lower quadrant (B) demonstrates moderate ¹⁸F-FDG uptake in the 0.5-cm right serosal implant, consistent with metastasis. This lesion was identified on CT retrospectively because of ¹⁸F-FDG uptake. (C-D) 3 months post chemotherapy, transaxial PET/CT slice through the chest (C) demonstrates more intense (greater than blood pool) ¹⁸F-FDG uptake in the right hilar lymph node and a slight increase in size, consistent with progressive disease; transaxial PET/CT slice through the pelvis (D) demonstrates more intense ¹⁸F-FDG uptake in the right serosal implant, consistent with progressive disease. Reproduced with permission from [68].

Overall, better lesion detection in rising tumor markers has been seen with PET/CT than with CT alone [35,40].

Other issues: differentiation of benign versus malignant lesions in ovarian tumor imaging

This is an extension of the initial point discussed under the section, ‘PET/CT in the diagnosis & initial staging of ovarian cancers.‘ Hypermetabolic ovarian lesions, more intense than the physiological hepatic uptake have been considered positive for malignancy in most studies, although in our experience significant overlap can be observed in practice. A cut-off value of SUV greater than or equal to three has been seen to be highly suggestive of malignancy in some studies [62]. SUVs ranging from 3 to 27 have been seen in malignant lesions proven by histopathology [65]. The SUV cut-off-based diagnosis, however, would require more validation. Lesions within SUV of less than two have been considered to be benign by some authorities even if other imaging modalities are positive, for example in borderline ovarian tumors [66]. We believe that more data with PET/CT imaging needs to be accrued in this area for a definitive conclusion.

Conclusion

Theoretically, fusing functional and anatomical information can be of significant benefit for the detection of abdominal lesions such as that in ovarian cancer. Hence, this modality needs to be utilized to its greatest potential in this malignancy. At present, PET/CT does not play a significant additional role in the primary diagnosis of ovarian cancers and holds a position similar to transvaginal ultrasound/CT for this purpose. Primary staging of diagnosed primary ovarian tumors can be better staged using PET/CT before any form of treatment as it adds valuable information regarding the number and extent of lesions. The monitoring of therapy response with PET/CT has cost-effectiveness issues, which need further evaluation. The most definite role of PET/CT is in the surveillance of patients who have received primary therapy with rising CA-125 levels or even normal CA-125 levels with high clinical suspicion. It does perform relatively poorly in peritoneal carcinomatosis, but the overall performance is better than CT alone. PET/CT can pick up unsuspected lesions whether nodal, in the peritoneum or subcapsular liver disease.

Future perspective

The wide application of current generation PET/CT scanners with better resolution in routine clinics will likely increase the role and reliability of this imaging modality in this group of tumors. We speculate the areas in which PET/CT may develop a role in the clinical management of ovarian carcinoma in the future are: as a promising technique in monitoring response to therapy; initial staging of the disease (particularly the metastatic disease burden) with better accuracy that would guide the correct therapeutic strategy; and disease prognostification especially as a replacement of second-look laparotomy following completion of primary therapy.

In these areas, presently this is not used in routine clinics but might change with better results with the application of combined structure-function approach and better quantification techniques. This would, however, be determined by results from more clinical studies, evidence based approach and the availability of newer salvage treatment modalities.

Executive summary

Background

Ovarian cancers being the sixth most common cancer among women with notoriety to being detected at advanced stages and to recur despite adequate treatment, makes them a challenging disease.

Evaluation with primary staging (according to the International Federation of Obstetricians and Gynecologists), followed by chemotherapy and surgery is the usual course of management of these malignancies.

PET/computed tomography in physiological conditions of the ovary

Ovaries show physiologically increased uptake of ¹⁸F-fluorodeoxyglucose (FDG) in midcycle of menstruation, which does not happen in patients with irregular cycles or postmenopausal women and thus should be reviewed with suspicion in such patients.

It is thus imperative to image these malignancies in the postmenstrual phase.

PET/computed tomography in initial disease staging

The transvaginal ultrasound and computed tomography (CT)/MRI have been the most popular modalities for diagnosis of the primary and initial staging in contrast to FDG-PET only.

With the advent of FDG-PET/CT, it is being observed that fusion imaging does provide incremental information in contrast to only anatomical imaging for initial disease staging as a whole-body modality (especially with regard to metastatic disease burden).

PET/CT has better lesion detection rates and better differentiation of benign from malignant and the probability to pick up unexpected tumors.

PET/CT in disease prognostication

Primary aim is to see if PET/CT could replace second-look laparotomy for which Phase III randomized trials are ongoing and results require evaluation.

FDG-PET & PET/CT in the setting of rising CA-125 levels (detection of disease recurrence/metastatic disease)

Ovarian cancers could spread or recur locally within the pelvis whereas metastatic involvement includes peritoneal cavity spread, lymphatic spread to inguinal, pelvic and para-aortic nodes or hematogenous spread to liver and lungs.

PET/CT shows highest impact in this area where it demonstrates higher sensitivity and accuracy in detecting disease involvement in areas like nodal, peritoneal and subcapsular liver disease, which are challenging otherwise with conventional imaging. The assessment of whole-body status is a distinct advantage of this modality in the detection of distant metastasis.

Rising CA-125 with normal anatomical imaging thus forms a definitive indication for FDG-PET/CT imaging. The application results in change in clinical management of over a third of such patients.

PET/CT in peritoneal metastasis

Though both PET and CT perform low in this area, PET-CT has been found to be more useful than CT alone and, hence, should be preferred compared with anatomical imaging alone.

FDG-PET/CT shows two distinct patterns of uptake (i.e., focal and uniform uptake for nodular and diffuse peritoneal disease, respectively).

PET in assessing response to therapy

Standardized uptake value based response monitoring has been found to be accurate early in the course of therapy; however, there are cost-effectiveness issues in this area.

Differentiation of benign versus malignant ovarian lesions

Always a challenge in FDG-PET imaging; validation with more studies needs to be continued. Standardized uptake values have been used in most studies and a value of three or more have been suggested to be highly suggestive of malignancy; however, this requires to be critically determined. Combined PET-CT and dual time point imaging may help.

Footnotes

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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