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Diagnostic Applications of Nuclear Medicine: Ovarian Cancer

  • Neeta Pandit-TaskarEmail author
  • Sonia Mahajan
  • Weining Ma
Living reference work entry

Abstract

Ovarian malignancies are a leading cause of death in women in the United States and a significant health issue for women worldwide. Anatomic imaging with ultrasound, computed tomography, and magnetic resonance is a main tool for the diagnosis, staging, and follow-up of recurrent disease; however, it lacks biologic information. Nuclear imaging, primarily positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG), has been increasingly used for the detection of cancer. Encouraging data have emerged in recent years that support the use of [18F]FDG PET in a variety of clinical settings in ovarian cancer management.

Keywords

Ovarian cancer Imaging Staging Prognosis Response to therapy 

Glossary

[18F]FDG

2-[18F]fluoro-2-deoxy-D-glucose

AJCC

American Joint Committee on Cancer

BRCA1

Breast cancer type 1 susceptibility protein

BRCA2

Breast cancer type 2 susceptibility protein

CA-125

A tumor-associated marker for ovarian cancer (also known as carbohydrate antigen 125 or mucin 16)

CT

X-ray computed tomography

CTce

Contrast-enhanced computed tomography

FIGO

International Federation of Obstetrics and Gynecology

GLUT

Glucose transporter family

LBMI

Large bowel mesentery implants

LI

Labeling index

M

Metastasis status according to the AJCC/UICC TNM staging system

MIB-1

Marker of cell proliferation based on an antibody against an epitope of the nuclear protein different from that recognized by the Ki-67 antibody

MRI

Magnetic resonance imaging

MTV

Metabolic tumor volume

N

Lymph node status according to the AJCC/UICC TNM staging system

NPV

Negative predictive value

PET

Positron emission tomography

PET/CT

Positron emission tomography/computed tomography

PFS

Progression-free survival

PPV

Positive predictive value

RO

Right ovary

SLL

Second look laparotomy

SUV

Standardized uptake value

SUVmax

Standardized uptake value at point of maximum

T

Tumor status according to the AJCC/UICC TNM staging system

TAHBSO

Total abdominal hysterectomy with bilateral salpingo oophorectomy

TLG

Total lesion glycolysis

TNM

AJCC staging system based on parameters “T” (tumor status), “N” (lymph node status), and “M” (distant metastasis status)

TVUS

Transvaginal ultrasound

UICC

Union Internationale Contre le Cancer (International Union Against Cancer)

US

Ultrasonography

Ovarian Cancer

The American Cancer Society estimated 22,280 new cases of ovarian cancer and 14,240 deaths related to ovarian cancer in 2016 in the United States [1]. Ovarian cancer is the ninth most common non-skin-related cancer in women and the fifth most common cause of cancer deaths in women. Ovarian cancer is an insidious disease, and patients often present with an advanced stage of disease. Despite clinical advances and improved surgical techniques, it remains a form of gynecologic malignancy with the highest mortality (Fig. 1). Ovarian cancer represents the second most common gynecologic malignancy and leads to more than half of all deaths related to gynecologic cancer. There is no fully reliable screening tumor marker, but CA-125 has proven useful. Treatment with surgical debulking is critical. Surgery is usually followed by chemotherapy. However, there is high recurrence rate, and the overall 5-year survival rate for advanced disease is only 17% [2].
Fig. 1

Observed survival rates for 11,738 cases of primary ovarian epithelial cancer. Data from the National Cancer Database (Commission on Cancer of the American College of Surgeons and the American Cancer Society), diagnosed in the period 1998–2002. Stage 0 includes 60 patients; stage IA, 1, 415; stage IB, 160; stage IC, 878; stage IIA, 211; stage IIB, 304; stage IIC, 473; stage IIIA, 284; stage IIIB, 425; stage IIIC, 3,815; and stage IV, 3,773 (Used with the permission of the American Joint Committee on Cancer [AJCC], Chicago, IL. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC. http://www.springer.com)

Pathogenesis

The pathogenesis of ovarian cancer is multifactorial [1, 2, 3]. About 5–10% of ovarian cancers are familial and include three distinct hereditary patterns: breast–ovarian cancers (genetically linked to mutations in the BRCA1 and BRCA2 tumor suppressor genes), site-specific ovarian cancer, and ovarian and nonpolyposis colon cancers or Lynch syndrome II. The remaining 90% of ovarian cancers are sporadic.

Pathology

Ovarian neoplasms are classified according to their histogenesis (Table 1). Tumor derived from surface epithelium is most common with almost 90% of ovarian cancers originating from germinal epithelium. Other tumors include germ cell neoplasms, stromal neoplasms, and metastases, which comprise the remaining 10%. Epithelial ovarian cancer subtypes include serous, endometrioid, mucinous, clear cell, undifferentiated, and Brenner types. Serous tumors are the most common, accounting for approximately 40% of primary ovarian neoplasms and 40% of primary cancers. They occur in the age group of 15–50 years. Benign neoplasms tend to occur in younger women than malignant neoplasms. Serous tumors are frequently bilateral; 25% of benign, 30% of low malignant potential (borderline), and 70% of malignant serous tumors are bilateral. Mucinous tumors account for 20% of ovarian neoplasms and occur commonly in the age group of 15–50 years. These are mostly benign and more commonly unilateral. Mucinous cystadenocarcinoma accounts for 10% of ovarian cancers [2, 3].
Table 1

Ovarian cancer: histologic types

Tumor type

% of all tumors

Epithelial tumors

75

Serous tumors

40

  Benign serous cystadenoma

  Serous tumor of low malignant potential

  Serous cystadenocarcinoma

Mucinous tumors

20

  Benign mucinous cystadenoma

  Mucinous tumor of low malignant potential

  Mucinous cystadenocarcinoma

Endometrioid tumors

5

Carcinoma

 Clear cell carcinoma

2

 Brenner tumors

2

 Undifferentiated carcinoma

5–10

Germ cell tumors

20

 Teratoma

15

 Dysgerminoma

5

 Yolk sac carcinoma

Rare

 Embryonal carcinoma

Very rare

 Choriocarcinoma3

Very rare

Gonadal stromal tumors

5

 Granulosa–theca cell

2

 Fibrothecoma

3

 Sertoli–Leydig cell

Rare

Mixed germ and stromal cell

Rare

Metastatic neoplasms

Common

Endometrioid carcinoma accounts for 20% of malignant ovarian neoplasms and is frequently bilateral. It is defined by its microscopic resemblance to endometrial carcinoma. Associated endometriosis is found in about 25% of cases. In some cases, concurrent endometrial carcinoma is present, raising the question of whether the ovarian neoplasm is metastatic or a second independent primary. An origin from endometriosis has been demonstrated for some endometrioid carcinomas; however, the frequency with which this occurs is probably low, and in most cases the tumor is believed to represent endometrioid differentiation of a neoplasm derived from the celomic epithelium. Endometrioid carcinomas grossly appear as solid and cystic masses that frequently show areas of hemorrhage and necrosis. Microscopically, the cells resemble endometrial carcinoma. Squamous metaplasia is seen in 50% of cases [2, 3].

Staging

Staging is surgically based. Both the International Federation of Obstetrics and Gynecology (FIGO) and the TNM classification of ovarian cancer are based on the intraoperative findings [4, 5, 6] (Table 2). Early-stage ovarian cancer is treated with comprehensive staging laparotomy, whereas advanced but operable disease is treated with primary cytoreductive surgery (debulking) followed by adjuvant therapy. Patients with unresectable disease may benefit from neoadjuvant (preoperative) chemotherapy before debulking. Factors that generally indicate inoperable disease include: invasion of the pelvic sidewall, rectum, sigmoid colon, or bladder; tumor deposits greater than 1–2 cm in the porta hepatis; intersegmental fissure of the liver, lesser sac, gastrosplenic ligament, gastrohepatic ligament, subphrenic space, mesenteric root, and presacral space; suprarenal adenopathy; and hepatic parenchymal, pleural, or pulmonary metastases.
Table 2

International Federation of Obstetrics Gynecology (FIGO) and TNM staging for ovarian cancer

Primary tumor (T)

TNM

FIGO

Tx

 

Primary tumor cannot be assessed

T0

 

No evidence of primary tumor

T1

I

 

Tumor limited to the ovaries (one or both)

T1a

IA

 

Tumor limited to one ovary; capsule intact, no tumor on surface; negative washings

T1b

IB

 

Tumor limited to both ovaries; rest same as IA

T1c

IC

 

Tumor limited to one or both ovaries with any of the following: surgical spill; capsule rupture; tumor on ovarian surface; malignant cells in ascites or peritoneal washings

 

IC1

Tumor limited to one or both ovaries with surgical spill

 

IC2

Tumor limited to one or both ovaries with ruptured capsule or tumor on ovarian surface

 

IC3

Tumor limited to one or both ovaries with malignant cells in ascites or peritoneal washings

T2

II

 

Tumor involving one or both ovaries with pelvic extension

T2a

IIA

 

Extension and/or implants on uterus and/or fallopian tube

T2b

IIB

 

Extension and/or implants on other pelvic tissues

T2ca

IIC

 

a

T3

III

 

Tumor involving one or both ovaries with histologically or cytologically confirmed peritoneal spread outside pelvis and/or metastasis to retroperitoneal lymph nodes

T3aa

IIIA

 

Positive retroperitoneal lymph nodes and/or microscopic metastases outside pelvis

 

IIIA1

Positive retroperitoneal lymph nodes

 

 IIIA1(i)

Size ≤10 mm

 

 IIIA1(ii)

Size >10 mm

 

IIIA2

 

Microscopic peritoneal spread outside pelvis and/or retroperitoneal lymph nodes

T3b

IIIB

 

Macroscopic peritoneal spread (metastases ≤2 cm) and/or positive retroperitoneal lymph nodes. Including extension to liver/splenic capsule

T3c

IIIC

 

Macroscopic peritoneal spread (metastases >2 cm) and/or positive retroperitoneal lymph nodes. Including extension to liver/splenic capsule

Regional lymph nodes (N)

TNM

FIGO

  

Nx

 

Regional lymph nodes cannot be assessed

N0

 

No regional lymph node metastasis

N1

IIIC

 

Regional lymph node metastasis

Distant metastasis (M)

TNM

FIGO

 

M0

 

No distant metastasis

M1a

IV

Distant metastasis (excluding peritoneal metastasis)

IVA

Pleural effusion with positive cytology

IVB

Hepatic and/or splenic parenchymal metastasis, metastasis to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside of the abdominal cavity)

aChanges made to FIGO staging criteria have not yet been resolved by TNM system. FIGO stage IIC has been eliminated

Diagnosis of Ovarian Cancer

Pelvic or transvaginal ultrasonography and CA-125 tumor marker levels are used in combination for identification of ovarian carcinoma in early stages. There is some evidence that supports the use of these screening tools in high-risk populations, i.e., women with genetic predisposition or positive family history [6, 7]. The impact of such routine screening on reducing the mortality of patients with ovarian carcinoma is not yet clearly established.

In women presenting with a suspected ovarian mass, confirmation should be obtained pathologically by either biopsy or laparoscopic removal [6].

Role of Conventional Imaging in Primary Ovarian Cancer

Ovarian cancer usually presents as: unilateral or bilateral adnexal complex cystic masses with a thick, irregular wall; thick septations greater than 3 mm in thickness; and mural nodularity, papillary projections, or a solid component with variable degree of necrosis. Advanced stages of ovarian cancers are often associated with pelvic organ invasion, ascites, and peritoneal carcinomatosis.

Ultrasound (US) is usually an initial imaging modality for detection and characterization of adnexal masses and pelvic ascites (Figs. 2 and 3). Computed tomography (CT) is the imaging modality of choice for preoperative staging. Magnetic resonance imaging (MRI) better characterizes adnexal lesions (Fig. 4) and is especially helpful in cases with inconclusive US findings and those with complex changes or involvement of nodes and adjacent organs (Fig. 5); it is also the modality of choice for evaluation of pelvic side wall invasion (Fig. 6). MRI increases the specificity of detection for indeterminate lesions on US and decreases the incidence of resections for benign lesions (Fig. 7). CT is more useful in staging and treatment planning once malignancy is proven (Fig. 8).
Fig. 2

(a) Contrast-enhanced axial computed tomography of the pelvis shows prominent right ovary (RO) and adjacent uterus (U). (b, c) Transvaginal pelvic ultrasound shows right ovarian hypoechoic solid mass (white arrow) with internal vascularity (black arrow) on color Doppler image (c). Surgical pathology analysis of the right ovary proved to be metastatic signet ring cell adenocarcinoma of the stomach

Fig. 3

(a) Transvaginal pelvic ultrasound color Doppler images show a left ovarian complex cystic mass containing vascular thick septations (white arrows) and vascular solid components (black arrows); (b, c). Surgical pathology analysis from the left ovarian cystectomy showed papillary serous tumor, a borderline tumor

Fig. 4

Magnetic resonance imaging of the pelvis. (a) Coronal T2-weighted and (b) axial T2-weighted images show a large pelvic multiloculated/septated complex cystic mass (white arrow) containing a large soft tissue component (dashed white arrow), probably arising from the left adnexa. Histopathology revealed bilateral ovarian high-grade serous carcinoma

Fig. 5

Magnetic resonance imaging of the pelvis. (a) Axial T2-weighted and (b) gadolinium-enhanced axial T1-weighted images show a large right adnexal mass containing an enhancing component (black arrows) that is inseparable from the rectum (small white arrow), bilateral external iliac enlarged lymph nodes (large white arrows), and pelvic ascites. Pathology confirmed high-grade serous carcinoma

Fig. 6

Patient with high grade papillary serous carcinoma. MRI Pelvis (a) axial T2-weighted and (b) Gadolinium-enhanced axial T1 weighted images showed a left adnexal complex mixed cystic and solid mass invading adjacent rectum (small white arrows), uterus (black arrow) and left pelvic side wall (large white arrows).

Fig. 7

MRI pelvis (a) Gadolinium-enhanced sagittal T1 weighted (b) sagittal T2 weighted and (c) Gadolinium-enhanced axial T1 weighted images showed a right adnexal large complex cystic mass containing an enhancing solid component (large white arrows). Surgical pathology revealed right ovarian Sertoli Leydig cell tumor (right ovarian sex cord stromal tumor).

Fig. 8

Contrast enhanced axial CT abdomen and pelvis of 58 yo woman who presented with intermittent abdominal pain and increased CA-125 (~169.9) showed (a) hepatic metastases [black arrow], perihepatic implant (dashed white arrow), (b) serosal implant in the left paracolic gutter (white arrow) (c) perisplenic implant (white arrow), (d) right external iliac lymph node (white arrow) and minimal pelvic ascites (black arrow). Histopathology was positive for high grade ovarian adenocarcinoma.

[18F]FDG PET Imaging

Normal Variants and Limitations

Increased uptake of 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) can be seen in some benign lesions and physiological conditions. Functional uptake in ovaries related to cyclical changes and maturing or growing follicles is frequently seen [8] (Fig. 9-old edition Fig. 22.6). This is commonly noted in younger females of reproductive age. Physiologic ovarian uptake may also be seen during cyclical variation in premenopausal females. Increased ovarian uptake may be seen in nonmalignant lesions such as serous and mucinous cyst adenoma, dermoid cyst, endometriosis, inflammation, teratoma, and schwannoma [9, 10]. An absolute standardized uptake value (SUV) to distinguish benign from malignant lesions is not known, but in general malignant lesions show higher uptake although a significant overlap is seen. Cutoff SUVmax values ranging between 2.75 and 3 have been suggested. In an analysis of 160 patients, Tanizaki et al. demonstrated that a cutoff SUVmax of 2.9 had a sensitivity and specificity of 80.6% and 94.6%, respectively, for differentiating between benign and malignant ovarian tumors [11]. Only three of 79 cases (3.8%) with benign tumors were PET positive (SUVmax >2.9). Castellucci et al. suggested a cutoff SUVmax of 3 (sensitivity and specificity of 87% and 100%, respectively) [12], and Kitajima et al. found that a cutoff SUVmax of 2.75 (sensitivity and specificity of 86.3% and 73.7%, respectively) [13] could help distinguish benign/borderline from malignant ovarian masses. Contrary to these findings, Lermann and colleagues determined an SUV of 7.9 for determining benign versus malignant uptake, with a sensitivity of 57% and a specificity of 95% [14]. The SUV for those with ovarian cancer was on average 9.1 ± 4 and in premenopausal females without known ovarian malignancy it was 5.7 ± 1.5. This variation may likely be due to differences in the sample size of patients that were evaluated. Increased ovarian uptake in postmenopausal patients is associated with malignancy and should be further evaluated when visualized. It is therefore important that any uptake in the ovaries be correlated with clinical history and corresponding CT findings. Demonstration of a functional ovarian cyst on CT and correlation with menstrual history can help in identifying functional cysts. Focal uptake in the pelvis can also be seen related to fallopian tubes predominantly in premenopausal women at mid-menstrual cycle, owing to the influence of estrogen on the fallopian tubes [15] (Fig. 10).
Fig. 9

Physiologic [18F]FDG uptake in the right ovary and uterine cavity (arrows). No abnormality was detected on follow-up. Findings consistent with uptake related to cyclical changes in the uterus and corpus luteal cyst in the right ovary

Fig. 10

Variable uptake in uterine fibroids. CT images (left) show heterogeneously enlarged uterus with lesions that have calcificationconsistent with fibroids. [18F]FDG PET/CT (right) shows no uptake in the region of calcified fibroid and mild heterogeneous activity associated with the remainder of the enlarged uterus

In the primary diagnosis and staging of ovarian cancer, the role of [18F]FDG PET is limited by size resolution. Although [18F]FDG-avid ovarian uptake in postmenopausal women is considered suggestive of malignancy, PET/CT is not recommended for primary cancer detection because of the high false–positive rates [16]. Most primary lesions show high [18F]FDG activity (Fig. 11) although detection of small lesions and peritoneal deposits is still limited. Earlier studies using only PET reported a positive predictive value (PPV) of 86–96% and a negative predictive value (NPV) of 76% with an overall accuracy of about 90% [17, 18]. PET does seem to add incremental value to conventional imaging in staging ovarian cancer either through confirmation of disease or exclusion of distant disease [19] (Fig. 12).
Fig. 11

A 60-year-old woman with breast cancer and elevated CA-125 level referred for evaluation of a left ovarian cyst. PET/CT shows intense [18F]FDG uptake in the mildly enlarged left ovary. Pathology showed poorly differentiated serous adenocarcinoma of the left ovary

Fig. 12

A 56-year-old woman with ovarian cancer referred for staging. Uptake is seen in the primary tumor in the pelvis and pelvic adenopathy (black arrow). [18F]FDG PET images show uptake in the right retrocrural (white long arrow) and preaortic (white short arrow) node that were not suspicious based on size criteria

Most epithelial tumors show intense accumulation of [18F]FDG. There was no positive correlation of SUV with clinical stage, tumor grade, cell proliferation, and glucose metabolism in 17 patients suspected of having ovarian epithelial cancer . Intensity of GLUT-1 expression, MIB-1 LI, and histologic grading score showed statistically significant positive correlations with [18F]FDG uptake. GLUT-1 transporter expression was the strongest parameter to predict positive [18F]FDG uptake [20]. For distinguishing malignant from benign pelvic lesions, [18F]FDG PET/CT is similar to transvaginal ultrasound (TVUS) in sensitivity; however, it is more specific (100% vs. 61%). In staging ovarian cancer, PET/CT appears to be superior to CT alone. When correlated with final pathological staging, PET was concordant in 22 of 32 (69%) patients as compared with CT, which was concordant in 17 of 32 (53%) patients. Staging was modified correctly suing PET, leading to upstaging four out of six patients by detecting distant metastasis in the liver, pleura, mediastinum, and left supraclavicular lymph nodes [12].

A prospective study by Hynninen et al. found that PET/CT provided incremental information to CT in the detection of intra-abdominal disease, particularly mesenteric and subdiaphragmatic peritoneal disease, and was more effective for detection of extra-abdominal disease. In 35 patients with ovarian cancer, the overall site-based sensitivity, specificity, and accuracy for [18F]FDG PET/CT were 51%, 89%, and 64% and for CT 41%, 92%, 57% [21]. Dauwen et al. assessed the value of [18F]FDG PET/CT in evaluating suspicious ovarian masses. In comparison with CT, [18F]FDG PET had higher specificity (77% vs. 38% for CT) for detecting malignant tumors and extra-abdominal metastases [22].

[18F]FDG PET/CT has a low diagnostic value in differentiating between borderline malignant or benign tumors and other malignant ovarian tumors. The reported sensitivity and specificity of [18F]FDG PET/CT in detecting malignant lesions are as high as 100% and 85.0%, respectively, while the rates for borderline tumors are only 71.4% and 81.3%, respectively. The SUVmax of borderline tumors is generally lower than that of malignant tumors and is very similar to benign tumors, making it difficult to conclusively reach the diagnosis [23]. Mucinous tumors and germ cell tumors are also generally less avid. It is important to be aware of this variation so that false negatives can be recognized. In a retrospective study of 98 patients, PET/CT had high sensitivity and specificity in detecting primary tumors. PET/CT yielded true-positive findings in 87 of 94 patients and true-negative findings in four of four patients with benign lesions [24]. PET/CT can be a useful adjunct to conventional imaging, especially in equivocal cases. It has incremental value in staging through detection of disease in normal-sized or small nodes and metastatic disease especially at distant sites. In comparison with Doppler US, CT, or MRI, PET/CT was concordant with surgical staging in 78% of patients and revealed 15 (15.8%) cases of unpredicted extra-abdominal lymph node metastasis in 95 patients with ovarian cancer. Furthermore, PET/CT was more specific in distinguishing malignant from benign lesion, although overall sensitivity did not vary significantly between the three modalities. In detecting malignant lesions in the extra-ovarian pelvis and the abdomen, the sensitivity was similar (94.6% vs. 94.1%), but specificity was significantly higher for PET/CT at 82.8% than for CT at 71.4% [25]. In detecting malignant nodes, including the bilateral pelvic and the para-aortic lymph nodes, both the sensitivity and specificity of PET/CT were higher (83.8%, 92.6%, respectively) than for CT or MRI (62.5%, 83.6%, respectively). PET/CT was shown to have higher accuracy than pelvic US, CT, or MRI (0.749; p = 0.013). False-negative findings on PET/CT included bowel mucosal invasion, small peritoneal seeding, and adjacent adnexal invasion [25]. Physiologic activity in the bowel and low resolution are known to lead to false negatives. Unknown supra-diaphragmatic metastases were found in 15 cases of which ten (66.6%) were supraclavicular lymph node metastasis [25]. Michielsen et al. evaluated the role of whole-body diffusion-weighted MRI in staging and compared it with CT and [18F]FDG PET/CT in 32 patients with suspected ovarian cancer. Comparable accuracy was similar for all modalities; however, the specificity for characterizing primary lesions was the highest with MRI [26]. PET/CT is valuable in staging as it can detect unexpected sites and can lead to stage migration [27]. In a large prospective study of 101 patients with primary ovarian cancer, Risum and colleagues reported a high sensitivity of PET/CT in detecting malignant pelvic tumor of ~100% (57/57) with a specificity of 92.5% (37/40) and an incremental value in staging. In three of five patients (60%) with stage IV disease, metastases were found only on PET/CT, located in an inguinal lymph node and in a supraclavicular lymph node [28]. In limited studies, a combination of PET with contrast-enhanced CT (CTce) was shown to improve detection. A comparison of modalities (CTce vs. PET/CTce) in 40 patients showed improvement in overall lesion-based sensitivity from 37.6% (32/85) to 69.4% (59/85), while the specificity between CTce and PET/CTce was comparable (97.1% and 97.5%, respectively) [29].

[18F]FDG PET/CT is useful in detecting lymph node involvement in patients with ovarian cancer. In a meta-analysis of 18 studies analyzing 882 patients, the diagnostic performance of CT, MRI, and PET was compared. [18F]FDG PET or [18F]FDG PET/CT was more accurate than CT and MRI in the detection of lymph node metastasis in patients with ovarian cancer (sensitivity and specificity were 73.2% and 96.7% for [18F]FDG, 42.6% and 95% for CT, and 54.7% and 88.3% for MRI, respectively) [30]. Nodal staging in 68 patients (stage IA–IIIC) revealed a sensitivity of 83.3%, a specificity of 98.2%, and an NPV of 96.5% for [18F]FDG PET/CT; however, the sample size was small with nodal disease found in only 12 patients. All false–negative results were seen in patients with a nodal size less than 5 mm. Sensitivity in detecting pelvic nodes (63.6%) was lower compared with that for para-aortic nodes (82.3%), which is likely attributable to the difficulty in assessing the pelvic region because of the close anatomy of the ovarian primary tumor [31].

[18F]FDG PET/CT may be limited in detecting small lesions and peritoneal disease. De Iaco et al. compared the sensitivity of [18F]FDG PET with histopathology for detecting peritoneal disease in 40 patients with ovarian cancer. PET/CT yielded positive results in 268 of 360 quadrants, with a sensitivity and specificity of 78% and 68%, respectively, and a PPV of 95%. False–negative results were seen in those with adhesions and in lesions smaller than 5 mm such as in carcinomatosis [32]. Some have found PET/CT comparable to MR and multidetector CT in assessing peritoneal carcinomatosis and have reported an added value of PET in detecting small peritoneal implants in patients with ascites due to a better separation of bowel loops, allowing for easier distinction between physiological intestinal activity and pathological uptake [33].

Impact on Management at Staging

Primary treatment for ovarian cancer is primary cytoreduction, which when performed optimally has prognostic value. Presence of disease outside the abdomen can have significant implications in further management of ovarian cancer. Detecting distant metastases is therefore critical. The current FIGO staging system allows for the use of any imaging modality to evaluate metastatic disease. A number of studies have shown the value of PET and PET/CT in detecting previously unrecognized distant metastases [28, 29, 34, 35].

[18F]FDG PET/CT can help identify disease in sites that may prevent primary cytoreductive surgery; in six of 21 cases, [18F]FDG PET detected previously unknown hepatic hilar infiltration (4/6) and disease in the mesenteric root (2/6) that was confirmed at surgical exploration [36].

PET/CT, through more accurate staging, provides prognostic information. Of 201 patients with primary ovarian cancer, the overall survival and prognostic variables were analyzed in 66 patients (n = 64, stage III; n = 2, stage IV). Using PET/CT, 51% (39/66) of the patients were diagnosed as having stage III and 41% (27/66) as having stage IV disease. With a median follow-up of 30.2 months and using univariate analysis, a lower stage on PET/CT was a significant prognostic variable besides optimal debulking and performance status; however, it was not an independent prognostic factor. The study was somewhat limited owing to the lack of histological correlation for distant metastatic sites detected on PET [27].

Preoperative PET/CT may help predict surgical outcomes. In a prospective study of 179 patients, the predictive value of ten parameters of preoperative PET/CT findings were evaluated for optimal versus suboptimal cytoreduction [37]. In 77% of women undergoing incomplete cytoreduction, PET/CT showed LBMI or ascites. In 31% of women undergoing incomplete cytoreduction, PET/CT showed pleural effusion, and in 89%, PET/CT showed peritoneal carcinomatosis that were predictors of incomplete cytoreduction. Using multivariate analysis, LBMI was the only independent predictor of incomplete cytoreduction, and no predictor of suboptimal cytoreduction was found. PET/CT can be a useful supplementary imaging modality before surgery in primary ovarian cancer and may also have a role in the appropriate selection of patients for neoadjuvant chemotherapy [38].

Imaging in Recurrent Ovarian Cancer

Approximately 50% of patients with ovarian cancer will present with recurrence after cytoreductive surgery and first-line chemotherapy. The presentation is pelvic masses, recurrence at the vaginal cuff or pelvic side wall, peritoneal tumor implants, malignant ascites, lymphadenopathy, or distant metastases including of the lung, pleura, liver, or bone (Figs. 13 and 14). CT is the most commonly used modality for detection of recurrent tumor (Fig. 15), while MRI provides superior information on the local extent of disease including evaluation of the involvement of other organs, the pelvic side wall, and vascular invasion.
Fig. 13

Recurrence of ovarian carcinoma. A 62-year-old woman with ovarian cancer, submitted to TAHBSO, referred for evaluation of metastatic disease. Whole-body images show focal [18F]FDG uptake in the pelvis and mid-abdomen localizing to the nodes in common iliac region and para-aortic region (arrow)

Fig. 14

A 64-year-old woman with ovarian carcinoma and rising CA-125 level referred for assessment of disease extent. [18F]FDG uptake is seen in the lower anterior pelvic peritoneal disease, small peritoneal implant in the left abdomen (white short arrow), and right perihepatic implants

Fig. 15

Contrast-enhanced axial computed tomography of the abdomen in a 68-year-old woman with recurrent ovarian carcinoma shows omental disease (caking; white arrow) and small loculated ascites (black arrow) in the left hemiabdomen. Pathology showed high-grade serous ovarian carcinoma

In general clinical practice, [18F]FDG PET has been a secondary imaging modality after CT and MRI, with [18F]FDG PET indicated only in cases with equivocal findings by other imaging modalities or cases with negative findings on other imaging in the presence of rising tumor markers.

There are significant data published on the utility of [18F]FDG PET in recurrent ovarian cancer including in the surveillance and assessment of patients with rising tumor markers as well as in management decisions (Table 3). [18F]FDG PET has been shown to be superior to CT or MRI in the detection of recurrent disease, with reported sensitivity and specificity of 83–91% and 66–93% for [18F]FDG PET, respectively, versus 45–91% and 46–84% for CT or MRI [39, 40]. [18F]FDG PET helps identify disease in those with rising CA-125 levels. In a retrospective study by Dragosavac et al., PET/CT detected disease in 42 of 45 patients and unsuspected lesions in 20 of 45 patients; 11 of these patients had normal conventional imaging. [18F]FDG PET/CT was true negative in the remaining three patients. A limitation of this study was the lack of histopathological confirmation of the lesions, although the conclusion was supported by concurrent clinical data and follow-up [41].
Table 3

Fluorodeoxyglucose (FDG) in the assessment of recurrent ovarian carcinoma

Author and year

Type

FIGO stage

Total number of patients studied

Comparative imaging (CT or MRI)

Number of cases with negative/equivocal CT and MRI findings

Histopathology confirmation (yes/no)

Sensitivity/specificity/accuracy

Rusu et al. (2015)

Retrospective

II (n = 1), III (n = 41)

42

CT

23

Yes

[18F]FDG: 92.2%/100%/92.5%; CT: 60.8%/NA/52.8%

Dragosavac et al. (2013)

Retrospective

I (n = 2), II (n = 3), III (n = 34), IV (n = 6)

45

US/CT/MRI

23

Yes

[18F]FDG: 100%/100%/NA

Antunovic et al. (2012)

Retrospective

NA

121

US/CT/MRI

41

Yes

[18F]FDG: 82%/87%/83%; CA-125: 59%/80%/63%; conventional imaging: 69%/47%/66%

Sanli et al. (2012)

Retrospective; Assessed detection of peritoneal implants by [18F]FDG PET

NA

47

MRI

NA

Yes

Overall:

[18F]FDG: 97.5%/100%/97.8%; MRI; 95%/85.7%/93.6%

For implants 0.5-1 cm: [18F]FDG: 95.4%/100%/97.8%; MRI: 50%/100%/78.7%

For implants >3 cm: [18F]FDG: 100%/100%/100%; MRI: 87.5%/100%/97.8%

Pan et al. (2011)

Prospective

I (n = 7), III (n = 23), IV (n = 7)

37

None

NA

Yes

[18F]FDG: 100%/84%/94%; CA-125: 58%/100%/72%; CA15-3: 29%/100%/54%

Bilici et al. (2010)

Retrospective

I (n = 8), II (n = 6), III (n = 43), IV (n = 3)

60

CT

20

Yes

[18F]FDG – 95.5%/93.3%/95%. CT – 55.5%/66.6%/58.3%

The role of [18F]FDG PET has, however, been uncertain owing to variable results. Its role is limited in the detection of microscopic and small-volume disease where earlier studies reported low sensitivity in detecting disease. A study by Rose et al. of 17 ovarian cancer patients reported poor results for [18F]FDG PET [42]. The study was done with patients who had optimal primary cytoreduction, using PET only, and most of the lesions not detected were smaller than 6 mm. In 36 patients, Kim et al. observed an overall significant difference in lesion-based sensitivity for PET/CT (66%) and MRI (86%). MRI was, however, more accurate than PET in detecting peritoneal lesions, with the overall lesion-based sensitivity and accuracy of PET/CT being 43% and 86% and that for MRI being 75% and 94%, respectively [43]. For peritoneal implants that are slightly larger, the results have been variable, although some authors have reported equivalent or higher sensitivity for [18F]FDG PET. In a recent study, the sensitivity of PET/CT was better than MRI in detecting small to medium-sized peritoneal implants (<2 cm); the reported sensitivity was 95.4% for [18F]FDG versus 50% for MRI (for sizes of 0.5–1 cm) [44]. In a meta-analysis of 29 studies involving 1,651 patients, the pooled sensitivity and specificity of [18F]FDG were 88.6% and 90.3%, respectively, for detection of recurrence in ovarian carcinoma [45].

Detection is improved with combined PET/CT than with PET alone (Figs. 16 and 17). Reported sensitivities for the detection of peritoneal disease range between 57% and 88%, although with higher specificity for PET than for CT (94% vs. 77%, respectively). In these studies, the combined sensitivity ranged from 88% to 100% and the specificity from 79% to 93% [46, 47, 48, 49, 50].
Fig. 16

A 67-year-old patient with papillary serous adenocarcinoma of the left ovary, who underwent s/p total abdominal hysterectomy/bilateral salpingo-oopherectomy, was referred for PET/CT for restaging in view of rising CA-125 levels (34 U/ml). The patient was clinically asymptomatic and had normal findings on conventional imaging. Maximum intensity projection image (a, arrow) shows focal abnormal [18F]FDG uptake in the right side of the pelvis localizing to a right para-iliac soft tissue nodule measuring 1.5 × 1.1 cm (b, carrows; SUVmax, 7.3), likely a lymph node. No other metabolically active lesion was noted elsewhere. Pathology findings were positive for metastatic carcinoma

Fig. 17

A 66-year-old patient with ovarian carcinoma, who underwent and s/p primary (total abdominal hysterectomy/bilateral salpingo-oopherectomy) and secondary (partial resection of transverse colon/omentectomy) cytoreduction was referred for restaging in view of rising CA-125 levels (from 11 U/mL to17 U/mL in 3 months). PET/CT (panel I) shows a peritoneal nodule in the pelvis (a, barrow; SUVmax: 6.2) suggestive of recurrence. The patient was treated with chemotherapy. A follow-up PET/CT (panel II), however, shows progression (g, harrow) with appearance of new peritoneal nodules in the perihepatic portacaval region (c, darrow; SUVmax: 4.2) and in the left upper abdominal peritoneum (e, farrows; SUVmax: 8.2)

[18F]FDG PET can help in the early detection of disease in patients who are asymptomatic with normal CA-125 levels as well as in those with rising CA-125 levels and normal conventional imaging including CT scan or MRI [50, 51, 52]. A single study reported a sensitivity of 100% with a specificity of 85% for this modality; however, this was a study with a very small number of patients who underwent exploratory laparotomy (n = 22) or diagnostic laparoscopy (n = 15) [50]. In a meta-analysis, Gu et al. compared data from 34 studies to evaluate the accuracy of CA-125, PET alone, PET/CT, CT, and MRI in diagnosing recurrent ovarian carcinoma. Pooled data showed the highest specificity for CA-125 at 0.93 (95% CI: 0.89–0.95), while PET/CT had the highest pooled sensitivity at 0.91 (95% CI: 0.88–0.94). There was significant heterogeneity among studies and evidence of publication bias. The pooled sensitivity of PET alone was 0.88 (0.84–0.92), not statistically significant from PET/CT [47]. The combined pooled data supported the use of PET/CT as a supplement to current surveillance techniques, particularly for those patients with an increasing CA-125 level and normal CT or MRI findings.

Similar results were seen for PET in more recent studies of patients who were clinically disease-free [46, 49]. PET compared with conventional imaging and serum CA-125 levels showed superior results than conventional imaging, with a sensitivity of 86.9% and a specificity of 78.8% versus 53.3% and 81.8%, respectively. [18F]FDG PET detected disease in 23 patients with positive serum CA-125 levels but who had normal findings on other imaging modalities and in 11 patients with negative serum CA-125 levels and other imaging [46]. Murakami and colleagues reported the detection of disease using PET in 46 patients (51%); in eight of 41 patients (19.5%) with normal CA-125 levels, disease was seen with PET only. The sensitivity of the combination of PET and CA-125 was highest at 97.8%. PET detected intraperitoneal and retroperitoneal metastases and normal-sized nodal metastases and was able to detect recurrence at relatively low titers of CA-125 [49]. In a more recent study, Antunovic et al. evaluated 121 patients for recurrence using [18F]FDG PET/CT and conventional imaging with a sensitivity of 82% and 70%, respectively. Of these patients, only 55 had serum CA-125 levels greater than 35 U/mL, whereas 52 patients presented with CA-125 levels in the normal reference range [51]. The detection rates with [18F]FDG PET are generally higher with a greater increase in the CA-125 level; the reported detection rates were around 53% for CA-125 levels less than 30 U/mL compared with 89% for CA-125 levels greater than 286 U/mL [52].

PET/CT may be considered for the evaluation of patients suspected of having recurrent disease [6].

Impact on Management of Recurrent Disease

The use of PET/CT in conjunction with conventional imaging has potential impact on management [53]. It has also been suggested that the combination of PET/CT and staging laparoscopy has a significant effect on the multimodal approach through its complementary role in the assessment of disease (Fig. 18).
Fig. 18

A 58-year-old patient with stage-III high-grade papillary serous carcinoma who underwent s/p partial primary cytoreduction and chemotherapy. PET/CT performed after completion of therapy (panel I) does not show evidence of any [18F]FDG-avid disease (ad). In view of rising CA-125 levels 4 months later, the patient was referred for PET/CT scan (panel II, arrows) revealing hypermetabolic disease in the peritoneum (eharrows) and retroperitoneal lymph nodes. No other distant metastases were seen in the whole-body scan. She was started on chemotherapy and underwent a second debulking procedure

Fagiotti and colleagues evaluated [18F]FDG PET and staging laparoscopy in identifying surgically treatable or untreatable patients in 70 recurrent ovarian cancer cases [54]. The sensitivity and specificity of PET were 93.0% and 55.6%, respectively, versus 95.0% and 64.0% for staging laparoscopy. Combined radiological and laparoscopic evaluation improved all parameters, with an NPV of 88.9% and a sensitivity of 95.3%.

[18F]FDG PET/CT may be helpful in optimizing the selection of patients for site-specific treatment, including radiation treatment planning and selection of optimal surgical candidates. In a retrospective review of 39 ovarian cancer patients, [18F]FDG PET/CT detected disease in three patients with clinical symptoms of recurrence but normal CA-125 levels, while in four patients with no clinical evidence of recurrent disease, PET was true negative in all cases [55]. PET/CT facilitated the accurate localization of disease, guided treatment, and helped avoid surgery in four patients in whom additional disease was detected in unresectable anatomic areas. In five of eight patients, PET confirmed the presence of disease following treatment [55]. In another study, PET/CT led to a change in the clinical management in 44% of cases when PET/CT information was added to conventional follow-up findings [56]. For 32 patients, both CTce and PET/CT were performed: PET/CT yielded positive findings in 91% of cases compared with 63% for CT. Intermodality changes in management were indicated for 14 of 32 (44%) patients undergoing PET, with the decision changed from observation in five, further examinations in three, and chemotherapy in six additional patients [56].

In a larger study of 132 women, the combination of CTce with PET improved the diagnosis, resulting in a change of management for 51 of the 132 patients (39%). In comparison, CTce alone changed management in 12% while PET/CT (non-contrast) affected management in only 2% of cases [57]. For patient-based analysis, the sensitivity, specificity, and accuracy of PET/ceCT was the highest and significantly different at 78.8%, 90.9%, and 84.8%, respectively, whereas those of PET/non-contrast-enhanced CT were 74.2%, 90.9%, and 82.6%, respectively, and those of CTce were 60.6%, 84.8%, and 72.7%, respectively [57].

Similar results were reported by Chung and colleagues in their study where PET/CT modified the diagnostic or treatment plan for 19 patients (24.7%), by leading to the use of previously unplanned therapeutic procedures in 11 (57.9%) and the avoidance of previously planned diagnostic procedures in eight (42.1%) patients [58].

In 56 women with elevated CA-125 levels of more than 35 IU/mL, all but one had a positive finding on PET/CT. PET/CT altered the known disease distribution in 40 scans (64%). Overall, PET/CT showed less disease in six scans (9%) and more disease in 34 scans (52%). Regardless of the value of CA-125, PET/CT identified a subgroup of women with apparently localized disease or no definite evidence of disease. This group had improved survival compared with women shown to have systemic disease. PET/CT resulted in a major change of management plan in 34 patients (58%) [59]. In a recent study, [18F]FDG PET/CT changed the management of 31 patients (51.6%), leading to the use of previously unplanned treatment procedures in 19 patients (61.2%) and the avoidance of previously planned therapeutic procedures in 12 patients (38.8%) [60].

When pre- and post-PET/CT questionnaires completed by the oncologists were examined for the impact of PET/CT results on decision-making, there was a statistically significant change in the decision-making for ten patients (34%, p < 0.0001). PET had positive findings in 93% of patients compared with the CT scan (76%) and it modified the disease distribution for 16 patients (55%; p < 0.001) compared with CT [61].

In a recent prospective, multicenter, cohort study where referring doctors were asked to specify a management plan pre- and post-PET imaging, PET/CT affected management in 60% of cases (49% high, 11% medium impact) and identified 168 more lesions than conventional imaging that were mostly nodal or peritoneal sites of disease. Patients in whom more disease was detected with PET/CT were more likely to experience disease progression in the following 12 months [62].

Role in Assessment Before Second-Look Laparotomy or Secondary Debulking

At second-look laparotomy (SSL), about 36–73% of patients are found to have persistent ovarian cancer [42]. Even patients with negative results from second-look procedures have a relapse rate of 30–50% with a mean interval of 24 months. About 60% of recurrence is in the peritoneal cavity [63]. Careful monitoring of the patients is therefore mandatory. SLL is performed on patients without clinical evidence of disease in order to assess tumor response. If SLL cannot confirm presence of disease, then adjunctive therapy is discontinued while reductive surgery is performed on those with residual disease before further chemotherapy [64, 65]. Some feel that the clinical impact of the diagnostic SLL is limited because even when there is no disease (negative SLL), 40–60% of patients relapse within 5 years [66, 67]. Additional drawbacks include invasive surgical procedure, associated complications and morbidity, risk of anesthesia, and all the associated expenses leading to an overall more costly management [67].

Prior to cytoreductive surgery, [18F]FDG PET/CT may be helpful in confirming discrete macroscopic disease in those cases where conventional imaging is unable to detect disease or has equivocal results. It can also help localize the sites of disease so that surgery or biopsy can be directed better. This is useful in cases where detection by conventional imaging fails because of postsurgical changes. Use of a PET probe in the operating room can aid identification and localization of disease sites for resection and help establish the completeness of surgical resection. In a feasibility study, intraoperative gamma probe detection, specimen PET/CT, and postoperative PET/CT verified complete resection of the clinical and hypermetabolic lesions and helped identify disease sites when the extent of disease was not fully apparent intraoperatively by gross palpation or inspection. The intraoperative gamma probe also helped characterize extensive, unresectable disease in the porta hepatis and celiac axis of a patient, much of which was not recognized with the initial intraoperative survey [68]. This, however, needs to be validated in larger studies.

[18F]FDG PET is cost-effective for the evaluation of recurrent disease and helps guide surgical management; reported change may be affected in about 50–60% patients [40, 69]. In their study of 42 patients, Rusu et al. noted a change in therapeutic procedures in 30 out of 53 (56.6%) cases, leading to a change from surgical intervention to conservative treatment in 11, while three patients were eligible for surgery contrary to the prior plan of either systemic treatment or observation [40].

The high NPV of PET scanning may be useful for avoiding second-look surgery, and by better selection of patients for secondary cytoreductive surgery [18F]FDG PET may be a substitute for second-look surgery [70, 71, 72]. In a prospective evaluation of 60 patients, Risum and colleagues compared [18F]FDG PET/CT with abdominal/TVUS and CT performed before secondary cytoreductive surgery. All patients had a CA-125 level greater than 50 U/mL or more than 15% over the baseline level. The sensitivities of US, CT, and PET/CT for diagnosing recurrence were 66%, 81%, and 97%, respectively. The specificity of US, CT, and PET/CT for diagnosing recurrence was 90% for all three modalities. PET/CT detected recurrence in ten (50%) of 20 patients without evidence of recurrence on CT. Multiple versus solitary tumors were found using PET/CT on 27 of 39 (69%) patients compared with 19 of 39 (48%) by CT [72].

Smith et al. demonstrated a reduction in unnecessary invasive staging procedures and health-care costs following the introduction of [18F]FDG PET. PET led to a decrease in unnecessary laparotomies from 70% to 5%; 35% of patients underwent the less-invasive laparoscopy instead of laparotomy [71]. Mansueto and colleagues also reported on the cost-effectiveness of using PET/CT in recurrent disease through accurate detection of disease sites and its ability to direct the clinical management [70]. The study compared treatment strategies based on CT only, PET/CT for those with normal CT scans, and PET/CT for all cases. The expected costs, avoided surgery, and incremental cost-effectiveness ratio were calculated to identify the most cost-effective strategy. PET/CT reoriented physician choice in 31% and 62% of patients compared with normal CT cases and all PET/CT cases. While applying PET/CT in all cases adds to the cost, it is offset by cases where surgery is avoided. In this study, surgery was avoided in three cases [70].

PET/CT offers a noninvasive method for assessing and predicting full resectability of recurrent disease when planning cytoreductive surgery and hyperthermic intraperitoneal chemotherapy [73]. In 206 patients with recurrent ovarian cancer who were evaluated with either [18F]FDG PET or conventional imaging (n = 103 each), those who had secondary cytoreductive surgery guided by PET/CT had fewer residual lesions and showed prolonged overall survival (43 months vs. 22 months) and progression-free survival (median 20 months vs. 9 months, respectively) compared with those who underwent conventional imaging [74]. When compared with a scoring system based on clinical parameters of resectability, PET/CT showed a higher sensitivity of 100% and an NPV of 100%, although overall specificity at 60% was low. A very good prediction of full resectability was shown for patients undergoing concordant PET/CT and clinical scoring, with a sensitivity of 100% (63–100), specificity of 75% (20–96%), PPV of 89%, and NPV of 100%. PET/CT can provide complimentary information to clinical parameters or score and may be a noninvasive tool for the assessment of resectability [75].

Response Assessment and Prognostication

Limited data exist on the role of monitoring treatment response. In a small study of ovarian cancer patients receiving neoadjuvant therapy, response using [18F]FDG PET was retrospectively analyzed in eight patients and compared with histopathological parameters to identify responders or nonresponders. Posttherapy SUV in responders was significantly lower than that in nonresponders, and an SUV cutoff of 3.8 on posttherapy scans differentiated responders and nonresponders, with a sensitivity of 90%, a specificity of 63.6%, and an accuracy of 76.2%; a percent change in SUV of 65 as the cutoff showed a sensitivity of 90%, a specificity of 81.8%, and an accuracy of 85.7% for differentiating responders from nonresponders [76]. More data and studies are needed to consolidate and define the role of [18F]FDG PET in assessing treatment response.

Quantitative PET parameters may be useful for prognostication and assessing treatment outcomes although their role is yet to be fully understood and defined in routine practice. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) are some parameters associated with outcomes of surgery and prognosis. In 175 patients with primary disease, TLG was an independent prognostic factor for progression-free interval [77]. For presurgical staging, MTV and TLG values were inversely associated with clinical outcome. Patients with values higher than the cutoff value of 70 for MTV and 563 for TLG were associated with worse outcome and shorter progression-free interval compared with those with lower values [78]. Similar results were also shown in patients with recurrent disease [79, 80]. While there are data available on this topic, many of the studies are limited owing to their retrospective design and small cohort of patients. The use of such parameters and relevance in routine practice remains to be established.

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Copyright information

© Springer International Publishing AG 2016

Authors and Affiliations

  • Neeta Pandit-Taskar
    • 1
    • 2
    Email author
  • Sonia Mahajan
    • 1
  • Weining Ma
    • 1
  1. 1.Department of RadiologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  2. 2.Department of RadiologyWeill Cornell Medical CollegeNew YorkUSA

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