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Diagnostic Applications of Nuclear Medicine: Uterine Cancers

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

Abstract

Cervical and uterine malignancies are a significant health issue for women worldwide. Uterine cancers are the most common gynecological cancers, although ovarian cancers have the highest mortality. The primary modalities for anatomic imaging are ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI). These imaging tools are used for the diagnosis, staging, and posttherapy follow-up for detection of recurrent disease; however, they lack biologic information. Positron emission tomography (PET) with [18F]fluoro-2-deoxy-D-glucose ([18F]FDG) imaging plays a critical role in the evaluation of cervical and uterine malignancies. A number of studies have established the role of [18F]FDG PET in the staging and prognosis of advanced cervical cancer. PET/MRI scanners with newer technology are available and in future may be the mainstay in assessment of gynecologic malignancies.

Radionuclide lymphoscintigraphy is an established technique for sentinel lymph node (SNL) mapping in vulvar cancer. For cervical and endometrial cancer, it can help prevent morbidities that follow lymphadenectomies and there is convincing evidence that SLN mapping can be useful in early-stage disease.

In this chapter, we discuss the role of nuclear imaging, especially [18F]FDG PET scanning, and summarize the initial experiences with PET/MRI in cervical and uterine cancers; we also discuss the use of lymphoscintigraphy in gynecological cancers.

Keywords

FDG PET/CT Cervical cancer Endometrial cancer Lymphoscintigraphy 

Glossary

[18F]FDG

2-Deoxy-2-[18F]fluoro-d-glucose

18F-FMISO

18F-fluoromisonidazole, 1-fluoro-3-(2-nitroimidazol-1-yl)-propan-2-ol

ADC

Apparent diffusion coefficient, a parameter of magnetic resonance imaging

AJCC

American Joint Committee on Cancer

ceCT

Contrast-enhanced computed tomography

CI

Confidence interval

CIN

Cervical intraepithelial neoplasia

CT

X-ray computed tomogaphy

DES

Diethylstilbestrol

EC

Endometrial cancer

FDA

United States Food and Drug Administration

FIGO

International Federation of Obstetrics and Gynecology

GLUT

Glucose transporter family

HIV

Human immunodeficiency virus

HK

Hexokinase

HPV

Human papilloma virus

IMRT

Intensity-modulated radiation therapy

IVP

Intravenous pyelography

LACC

Locally advanced cervical cancer

LSG

Lymphoscintigraphy

M

Metastasis status according to the AJCC/UICC TNM staging system

MIP

Maximum intensity projection

MRI

Magnetic resonance imaging

MTV

Metabolic tumor volume

N

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

NPV

Negative predictive value

OS

Overall survival

PALN

Para-aortic lymph nodes

PET

Positron emission tomography

PET/CT

Positron emission tomography/Computed tomography

PET/MRI

Positron emission tomography/Magnetic resonance imaging

PFS

Progression-free survival

PLN

Pelvic lymph nodes

PPV

Positive predictive value

SCC

Squamous cell carcinoma

SNL

Sentinel lymph node

SPECT

Single-photon emission computed tomography

SPECT/CT

Single-photon emission computed tomography/Computed tomography

SUV

Standardized uptake value

SUVmax

Standardized uptake value at point of maximum

T

Tumor status according to the AJCC/UICC TNM staging system

TLG

Total lesion glycolysis

UICC

Union Internationale Contre le Cancer (International Union Against Cancer)

US

Ultrasonography

Cervical Cancer

Epidemiology and Prevalence

Cervical cancer is the second most common cancer in women worldwide and the third most common gynecologic cancer in the United States with 12,990 new cases and 4,120 deaths predicted in 2016 [1]. Cervical cancer was once a leading cause of cancer death for women in the United States; however, the prevalence and mortality have decreased significantly in the past few decades largely as a result of effective screening with the Papanicolaou (Pap) smear test. A continuous decline in the death rate has been observed, at a rate of nearly 0.8% each year. Cervical cancer is uncommon in women younger than 20 years, and most often occurs in women younger than 50 years although about 15–20% cases may occur in women over 65 years. It is more common in Black and Hispanic women compared with non-Hispanic White women. The 5-year relative survival rate for early-stage invasive cervical cancer is 91.3%, while the overall 5-year survival rate for all stages is about 67.5% [1] (Fig. 1).
Fig. 1

Observed survival rates for 15,070 cases with carcinoma of the cervix uterus. Data from the National Cancer Data Base (Commission on Cancer of the American College of Surgeons and the American Cancer Society) diagnosed in years 2000–2002. Stage 0 includes 7,119 patients; Stage IA, 1,530; Stage IB, 2,249; Stage IIA 453; Stage IIB, 1,518; Stage IIIA, 191; Stage IIIB, 1,009; Stage IVA, 213; and Stage IVB, 788. (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)

Cervical cancer is associated with several risk factors such as human papilloma virus (HPV), cigarette smoking, chlamydia, and human immunodeficiency virus (HIV) infection, long-term use of oral contraceptives or exposure to diethylstilbestrol (DES), diet low in fruits and vegetables, low socioeconomic status, multiple pregnancies, and younger age at first pregnancy. The most important risk factor for cervical cancer is HPV infection. The high-risk viral types are HPV 16, HPV 18, HPV 31, HPV 33, and HPV 45, with about two thirds of all cervical cancers being associated with HPV 16 and 18 [2]. Vaccines have been developed to help prevent infection with some types of HPV; currently three HPV vaccines have been approved for use in the United States by the Food and Drug Administration (FDA) [2].

Pathophysiology and Clinical Presentation

There are generally no symptoms in women with precancerous lesions and early cervical lesions. Abnormal postmenopausal vaginal bleeding, including postcoital bleeding, intermenstrual bleeding, menorrhagia and spotting between periods, abnormal discharge, painful coitus, and bleeding after vaginal examination are some of the symptoms that are associated with advanced stages and invasive cancers. In some advanced-stage cases, symptoms of bowel obstruction or urinary tract obstruction may be found at presentation [3].

Cervical intraepithelial neoplasia (CIN) is a precursor lesion of cervical cancer and is graded into three groups based on cellular dysplasia: CIN 1 with minor dysplasia; CIN 2 with moderate dysplasia; and CIN 3 or carcinoma in-situ with severe dysplasia. Up to 40% of CIN 3 lesions could develop into invasive cervical cancer if left untreated.

Histologically, 80–90% of all cervical malignancies are squamous cell carcinoma (SCC) (Table 1), with 25% well-differentiated, keratinizing, large-cell SCC histology while 70% are moderately differentiated, non keratinizing, large-cell SCC. Small-cell undifferentiated carcinomas account for only about 5% of cases, but are associated with a poor prognosis. Adenocarcinomas arise from endocervical-type cells and constitute 5–20% of all cervical malignancies. The histologic patterns of adenocarcinoma include well-differentiated mucinous adenocarcinoma, papillary adenocarcinoma, and clear-cell types. Poorly differentiated and aggressive histologic subtypes of cervical adenocarcinoma are associated with a poorer prognosis compared with SCC. Miscellaneous, uncommon, or rare cancers of the cervix include variants of SCC and adenocarcinomas, mixed carcinomas, small-cell carcinoma, sarcoma, lymphoma, melanoma, and metastatic tumors. The most common metastases arise from endometrial primary tumors while others include the ovary, colon, and breast primaries [3, 4].
Table 1

Pathological types of cervical cancer

1. Squamous cell carcinoma

 a. Carcinoma in situ (CIN)

 b. Microinvasive carcinoma

 c. Invasive squamous cell carcinoma

2. Variants of squamous cell carcinoma

 a. Verrucous carcinoma

 b. Papillary squamous and transitional carcinoma

 c. Lymphoepithelioma-like carcinoma

3. Adenocarcinoma

 a. Early invasive

 b. Mucinous adenocarcinoma

  i. Endocervical variant

  ii. Intestinal type, signet ring and colloid variants

  iii. Minimal deviation variant (adenoma malignum)

  iv. Well-differentiated villoglandular variant

 c. Endometrioid adenocarcinoma

 d. Clear cell adenocarcinoma

 e. Serous adenocarcinoma

 f. Mesonephric adenocarcinoma

 g. Microcystic endocervical adenocarcinomas

4. Other epithelial tumors

 a. Adenosquamous carcinoma

 b. Glassy cell carcinoma

 c. Adenoid cystic carcinoma

 d. Adenoid basal epithelioma

 e. Neuroendocrine tumors

 f. Carcinoid tumors

5. Mixed epithelial and mesenchymal tumors

 a. Mullerian adenosarcomas

6. Other malignant tumors

 a. Sarcomas

 b. Secondary tumors

Preinvasive lesions can be treated with electrocoagulation, conization, cryotherapy, laser ablation, or local surgery, while invasive cancers require surgery (total hysterectomy, modified radical hysterectomy, or radical trachelectomy), radiation or chemotherapy, or combination therapy. The survival rate for women with localized cancer is about 91% at 5 years. However, it is lower for women with advanced disease with relative 1-year and 5-year survival rates of 88% and 73%, respectively. The 5-year survival rate is 57% when tumor has spread to surrounding tissues or organs and/or the regional lymph nodes and is only 16.8% in the presence of distant metastatic disease [1].

Diagnosis of Cervical Cancer

The Pap test is a very effective screening test that has led to the detection of a large number of cervical cancers at early stages. The American Cancer Society recommends screening for cervical cancer to start approximately 3 years after a woman begins to have vaginal intercourse, but no later than 21 years of age [2]. For women between 21 and 29 years of age, the Pap test is recommended every 3 years. At 30 or more years of age, both a Pap test and an HPV test should be performed every 5 years, or a Pap test only every 3 years. In women who have three normal test results in a row, screening may be performed every 2–3 years. Women with a higher risk such as those with HIV infection or a weak immune system may need to get screened more frequently. Women aged 65 years and older, who have had three or more consecutive normal Pap tests in the past 10 years and have not had any precancerous histology (CIN 2 or 3) detected in the previous 20 years, may choose to stop cervical cancer screening. Screening after total hysterectomy is not necessary, unless surgery was done for cervical cancer [2].

Patients with suspicious findings on Pap smear or patients with high-risk HPV strains could be further evaluated with colposcopy or colposcopy-directed biopsies of the suspicious areas and if necessary with conization to establish the diagnosis [2, 3, 4, 5]. Those diagnosed with cervical cancer should undergo clinical staging with imaging and detailed pathology followed by surgical staging.

Role of Conventional Imaging

Patients are staged clinically according to the International Federation of Gynecologic and Obstetrics (FIGO) staging system (Table 2). Conventional imaging studies recommended for clinical staging include chest x-ray, barium enema, and intravenous urogram. However, ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) are increasingly being used. Intravenous pyelography (IVP) and barium enema are usually restricted for selective patients.
Table 2

TNM and FIGO classification of carcinoma of the cervix

TNM categories (FIGO stage)

Description

TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis a

Carcinoma in situ (preinvasive carcinoma)

T1 I

Cervical carcinoma confined to uterus (extension to corpus should be disregarded)

T1a b (IA)

Invasive carcinoma diagnosed only by microscopy. Stromal invasion with a maximum depth of 5.0 mm measured from the base of the epithelium and a horizontal spread of 7.0 mm or less. Vascular space involvement, venous or lymphatic, does not affect classification

T1a1 (IA1)

Measured stromal invasion 3.0 mm or less in depth and 7.0 mm or less in horizontal spread

T1a2 (IA2)

Measured stromal invasion more than 3.0 mm and not more than 5.0 mm with a horizontal spread 7.0 mm or less

T1b (IB)

Clinically visible lesion confined to the cervix or microscopic lesion greater than T1a/IA2

T1b1 (IB1)

Clinically visible lesion 4.0 cm or less in greatest dimension

T1b2 (IB2)

Clinically visible lesion more than 4.0 cm in greatest dimension

T2 (II)

Cervical carcinoma invades beyond uterus but not to pelvic wall or to lower third of vagina

T2a (IIA)

Tumor without parametrial invasion

T2a1 (IIA1)

Clinically visible lesion 4.0 cm or less in greatest dimension

T2a2 (IIA2)

Clinically visible lesion more than 4.0 cm in greatest dimension

T2b (IIB)

Tumor with parametrial invasion

T3 (III)

Tumor extends to pelvic wall and/or involves lower third of vagina, and/or causes hydronephrosis or nonfunctioning kidney

T3a (IIIA)

Tumor involves lower third of vagina, no extension to pelvic wall

T3b (IIIB)

Tumor extends to pelvic wall and/or causes hydronephrosis or nonfunctioning kidney

T4 (IVA)

Tumor invades mucosa of bladder or rectum, and/or extends beyond true pelvis (bullous edema is not sufficient to classify a tumor as T4)

Nodal stage

NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1 (IIIB)

Regional lymph node metastasis

Metastasis

M0

No distant metastasis

M1 (IVB)

Distant metastasis (including peritoneal spread, involvement of supraclavicular, mediastinal, or para-aortic lymph nodes, lung, liver, or bone)

aNote: FIGO no longer includes stage 0 (Tis)

bAll microscopically visible lesions, even with superficial invasion are T1b/IB

Surgical staging is generally done to assess pelvic and para-aortic lymph node (PALN) involvement, critical for further treatment and follow-up. Establishing the local extent of the primary tumor is very important and, while involvement of pelvic or para-aortic lymph nodes may not affect the FIGO staging, it identifies patients with a worse prognosis [6, 7, 8, 9]. Spread of cervical cancer occurs initially by direct extension to local structures and regional lymphatics, later disseminating hematogenously to distant organs, such as the lung, bone, liver, and brain. Nodal metastasis sequentially involves first the pelvic lymph nodes followed by para-aortic and supraclavicular lymph nodes. Scalene nodes can also be involved in up to 17% of the cases, seen more commonly in patients who have para-aortic nodal disease [6, 10, 11]. Bone metastasis occurs infrequently and therefore bone scans are not routinely indicated. Bone scans are indicated in patients with bone pain. For initial staging, imaging is critical to define the local extent of cervical cancer and detect local and distant nodal metastatic disease. Abdominal and pelvic CT provides high-resolution anatomic detail and is an integral part of routine staging. Disease in the cervix, uterus, parametrium and adnexa, as well as pelvic and abdominal nodes and extrapelvic disease sites, can be assessed with high sensitivity [12]. Evaluation of microscopic disease, however, is limited since the anatomic changes are subtle, thereby reducing the sensitivity of CT. In high-risk cases, CT of the chest is performed to detect lung and mediastinal disease.

MRI has superior soft tissue characterization and is preferred for assessment of the local extent of tumors (Figs. 2, 3, and 4). MRI can help predict endometrial involvement in about 84–96% of the cases compared with 55–80% for CT and has a high negative predictive value (NPV) [12, 13, 14]. Para-aortic nodal metastasis can be detected with high specificity; however, the sensitivity is only 50% [14]. Staging using physical examination, colposcopy, lesion biopsy, and cystoscopy or sigmoidoscopy may understage up to 30% of stage I and II cases and up to 40% of stage III cases. Conversely, it may overstage approximately 64% of patients with stage IIIB disease [8, 9, 15, 16, 17]. Accurate assessment of tumor size, especially in endocervical location, parametrial and pelvic sidewall invasion, lymph node and distant metastases is extremely important for prognosis. Although CT is an integral part of the clinical staging, useful to evaluate both local extent and metastatic disease [18], CT is limited, especially in early stage [9] disease. Additional imaging with MRI and [18F]FDG PET/CT can provide critical information for management of disease.
Fig. 2

Magnetic resonance imaging of the pelvis: axial T2-weighted (a) and sagittal T2-weighted images (b) show a large soft tissue mass in the cervix invading the parametrium bilaterally (white arrows), involving the upper third of the vagina (thick arrow), and abutting the anterior wall of the rectosigmoid colon (arrow head). No bladder or lower vaginal invasion is noted. Biopsy revealed well- to moderately differentiated squamous cell carcinoma

Fig. 3

Magnetic resonance imaging of the pelvis: (a) sagittal T2-weighted image shows a soft tissue mass (M) arising from cervical stump, status after prior supracervical hysterectomy for cervical cancer, invading posterior bladder wall (black arrows); (b) axial T2-weighted image shows cervical stump of recurrent mass again invading the posterior bladder wall (black arrow) and possibly invading anterior rectal wall, with obliteration of fat planes (white arrow). Surgical pathology showed squamous cell carcinoma, moderately or poorly differentiated

Fig. 4

Magnetic resonance imaging of the pelvis: (a, b) sagittal T2-weighted and axial T2-weighted images (c) show intermediate T2 signal intensity of cervical lesion consistent with cervical cancer (white thin arrows). The bulk of the lesion within the ventral aspect of the cervical canal demonstrates deep stromal invasion, without extension involving the parametrium. Then tumor extends into the posterior aspect of the cervix into the posterior fornix of the vagina (a, black arrow). Multiple nabothian cysts are seen in the cervical canal (a, white thick arrow). The tumor abuts the internal cervical os and no extension into the lower uterine segment is seen

[18F]FDG PET Imaging

PET/CT is useful in the staging of cervical cancer patients to assess local extent, pelvic nodal involvement, and detect distant metastases. This information is useful for planning surgery and/or for radiation therapy planning. It is useful in assessing response to neoadjuvant therapy and for identification of persistent/recurrent disease after treatment.

Primary Cervical Cancer

[18F]FDG avidly localizes in cervical cancer. The uptake of [18F]FDG in cervical cancer appears to be related to high GLUT-1 expression in tumor cells; however, there is no established correlation of PET/CT-based standardized uptake value (SUV) or GLUT-1 expression with the initial grade of histologic differentiation and FIGO staging. Higher GLUT-1 expression is seen in recurrent or persistent disease than in metastatic lymph nodes [19]. Similarly, a higher PET positivity has been noted in pathologically positive nodes with higher expression of GLUT-1 and HK-II [20].

Although most primary cervical cancers accumulate [18F]FDG (Fig. 5), poorly differentiated and squamous cell histology tumors are more [18F]FDG avid. In 240 patients with stage I–IV disease, a significant difference in uptake was seen in well vs. poorly differentiated lesions with a mean SUVmax of 8.58 for well-differentiated, 11.56 for moderately differentiated, and 12.23 for poorly differentiated tumors [19]. Higher uptakes were seen in squamous cell histology (average SUVmax of 11.91, range 2.50–50.39) than in non-squamous histology (average SUVmax of 8.05, range 2.83–13.92). A higher SUVmax is associated with an increased risk of nodal involvement: Patients with SUVmax < 5 had 24% nodal involvement compared with 59% for patients with SUVmax 5–14, and 72% for those with SUVmax > 14 [19]. Similar findings were noted for 43 patients with cervical cancer (stage IB–IVB) where, using a cut-off SUVmax value of 13.5 for defining high- vs. low-uptake groups, it was noted that lymph node metastasis, predominantly pelvic, was more commonly seen in the high SUVmax group (73%, 16/22) than in the low SUVmax group (38%, 8/21) [21].
Fig. 5

(a, b) Primary carcinoma of the cervix: extent of disease at diagnosis. A 50-year-old woman with cervical cancer. [18F]FDG PET/CT showed abnormal uptake (SUVmax 13.6) in the cervix and uptake in left external iliac node

Early studies used dedicated PET scanners without CT capability [22]. Fusion imaging with PET/CT scanners improves localization and hence diagnosis thereby leading to a decrease in equivocal results. This is especially relevant for gynecologic malignancies where peritoneal and serosal bowel implants may be obscured by physiological [18F]FDG activity. Early studies showed the increased accuracy of hybrid PET and CT imaging compared with side-by-side reading of CT and PET. These studies demonstrated improved accuracy in detecting nodal involvement and lesions adjacent to the chest or abdominal wall or bowel [23]. The hybrid method also improved characterization of physiological and inflammatory uptake [24].

In 13 primary and metastatic uterine cervical cancer patients, PET/CT provided more definite lesion localization in 30% and additional definite lesion characterization in 20% of patients compared with PET alone. There was higher diagnostic accuracy with PET/CT than with PET alone on a lesion-based analysis (92% vs. 78%), although no difference was noted for evaluation of metastatic disease [25].

[18F]FDG PET in Staging of Cervical Cancer

Clinical studies have shown the usefulness of PET/CT in staging cervical cancer (Table 3). While the reported sensitivity is variable ranging from 38% to 86%, a definite advantage of [18F]FDG PET is the ability to detect (a) involvement of lymph nodes that are benign using size criteria and (b) distant metastases that were not detected by other imaging modalities [26], especially defining pelvic and distant nodal status [27, 28, 29]. In a retrospective analysis (n = 41) [18F]FDG PET showed 100% accuracy in detecting disease for initial staging, while for restaging, sensitivity and specificity were 82% and 97%, respectively [22]. MRI facilitates an excellent evaluation of local tumor and parametrial involvement, while PET is more useful for the evaluation of pelvic lymph nodes; however, microscopic disease is missed by both modalities [30]. An additional advantage of PET/CT over MRI includes the ability to image larger scanning areas allowing for an estimation of thoracic or suprathoracic disease in a single study. Tran and colleagues detected supraclavicular nodal involvement in about 8% of patients with a 100% positive predictive value (PPV) [11].
Table 3

Carcinoma of the cervix: staging/para-aortic and pelvic nodal assessment on [18F]FDG PET

Author and year

Type

Stage

Number of patients; Histology

Comparative imaging (CT or MRI)

Histopathology confirmation (Yes/No)

Sensitivity/specificity/accuracy

Driscoll et al. 2015

Prospective

IA (n = 9), IB1 (n = 38)

47; SCC (n = 31), Adenocarcinoma (n = 14), Adenosquamous (n = 2)

MRI (negative)

Yes

Patient based: 0%/100%/96% Node based: 0%/100%/99%

Gouy et al. 2013

Prospective

IB2 (n = 79), IIA (n = 10), IIB (n = 121), IIIA (n = 6), IIIB (n = 16), IVA (n = 5)

237; SCC (n = 199), Adenocarcinoma (n = 35), Adenosquamous (n = 1), Clear cell (n = 1), Glassy cell (n = 1)

MRI/CT/PET (negative)

Yes

NA/NA, False-negative rate – 12%

Leblanc et al. 2011

Prospective

IB2 (n = 43), IIA (n = 9), IIB(n = 46), IIIA (n = 2), IIIB (n = 13), IVA (n = 10), recurrent (n = 2)

125; SCC (n = 109), Adenocarcinoma (n = 14), Clear cell (n = 2)

MRI and CT (negative)

Yes

LN size >5 mm: 42%/93%, LN size <5 mm: 22%/91%

Lv et al. 2014

Retrospective

IA1 (n = 3), IA2 (n = 14), IB1 (n = 19), IB2 (n = 15), IIA (n = 26), IIB (n = 10)

87; SCC (n = 69), Adenocarcinoma (n = 12), Neuroendocrine (n = 2), Clear cell (n = 4)

MRI

Yes

Node based – [18F]FDG: 91%/NA/98% MRI: 37.3%/NA/95%. Patient based – [18F]FDG: 100%/NA/94.3% MRI: 44%/NA/69%

Perez-Medina et al. 2013

Prospective

IB2 (n = 17), IIA2 (n = 3), IIB (n = 18), IIIA (n = 3), IIIB (n = 8), IVA (n = 3)

52; SCC (n = 38), Adenocarcinoma (n = 13), Clear cell (n = 1)

MRI

Yes

FDG: 77.7%/94.1%/NA MRI: 66.7%/94.1%/NA

Monteil et al. 2011

Prospective

IA (n = 1), IB1 (n = 10), IB2 (n = 4), IIB (n = 22), IIIB (n = 2), IVA (n = 1)

40; SCC (n = 28), Adenocarcinoma (n = 12)

MRI

Yes

Pelvic LN metastases – [18F]FDG: 33%/92%/81%, MRI: 67%/84%/81% Para-aortic LN metastases – [18F]FDG: 100%/77%/70%, MRI: 60%/73%/70%

Ramirez et al. 2011

Prospective

IB2 (n = 16), IIA (n = 12), IIB (n = 16), IIIA (n = 4), IIIB (n = 12)

60; SCC (n = 48), Adenocarcinoma (n = 9), Neuroendocrine (n = 2), Transitional cell (n = 1)

CT/MRI (negative)

Yes

36%/96%/NA In patients with positive pelvic LN: 45%/91%/NA

Nogami et al. 2015

Prospective

IA (n = 5), IB (n = 62), IIA (n = 2), IIB (n = 1)

70; SCC (n = 41), Adenosquamous(n = 2), Mucinous adenocarcinoma (n = 20), Glassy cell (n = 2), Serous adenocarcinoma (n = 1), Endometroid (n = 1), Endometroid adenocarcinoma (n = 3)

None

Yes

Case based – 33.3%, 92.7% LN based – 30.6%, 98.9%

Yang, 2016

Retrospective

IB1 (n = 56), IB2 (n = 17), IIA1 (n = 35), IIA2 (n = 5)

113; NA

No

Yes

53.8%/95%/94.7%

NA not available, SCC squamous cell carcinoma

The sensitivity and accuracy of [18F]FDG for detection of lesions are higher for advanced disease but lower in early-stage disease including stage IA2–IIA, although abnormal lymph nodes may be detected better with [18F]FDG PET than with CT [31, 32, 33, 34].

[18F]FDG PET is more sensitive than CT or MRI for detecting lymph node metastases [27, 28, 32, 34, 35, 36, 37]. Using a cut-off SUVmax value of 2.5 on PET/CT and 1 cm or greater lesion size on MRI, higher sensitivity and accuracy for detecting lymph node metastases were noted with [18F]FDG PET compared with MRI (91% and 98%, respectively, vs. 37.3% and 95%, respectively). MRI yielded negative findings for 63% of positive lymph nodes diagnosed, and 56% (19/34) of patients were inappropriately classified. MRI also gave false-positive results in 16 lymph nodes [37]. However, the sensitivity for micrometastasis in early cervical cancer is low for both; in 120 patients who had a normal MRI for pelvic nodes, PET had low sensitivity for detection of micrometastasis;, all PET-undetected nodes had micrometastasis with a mean tumor focus of 4.0 × 3.0 mm (range 0.5 × 0.5 to 7 × 6 mm) [32]. Other groups have reported a false-negative lymph node detection rate for [18F]FDG PET between 13% and 32% cases, although detection was overall better compared with CT [33, 38, 39]. Higher sensitivity with MRI (93%) has been reported using iron oxide nanoparticles for contrast-enhanced imaging for nodal detection than when using the conventional size criteria (29%) [40].

In a study of 22 patients with stage IB–IVA cervical cancer, Choi et al. found that PET/CT had a higher sensitivity (57%) than MRI (33%) for lymph node detection, and that nodal size was critical for detection. In their study, the short-axis dimension of metastatic lymph nodes was 11.8 ± 3.5 mm while that of nonmetastatic nodes was (6.5 ± 4.6 mm); understandably, the detection of lymph node metastases was higher for areas of larger involvement. Regionwise, the overall sensitivity of MRI for detecting lymph node metastases (32.0%) appears to be lower than PET, with a detection rate of 42.9% and 54.5% for tumor diameters of 5–10 mm and >10 mm, respectively [41]. Some studies report a high number of false negatives (8/10 or 80%) in lesions smaller than 10 mm in diameter, noted on thin-slice examination of the pathological specimen [32]. Overall reported sensitivities for disease detection in cervical cancer are widely variable, possibly due to differences in the completeness of surgical staging and the number of lymph nodes removed.

The value of PET/CT in early-stage cervical cancer is limited and while not recommended as a routine evaluation for staging [32, 33, 42, 43], it has a high specificity especially for detecting nodal disease, although small-volume disease may be missed. In a study by Sironi et al., 47 patients with stage IA and IB disease were evaluated preoperatively. The overall patient-based sensitivity and specificity of PET/CT was 73% and 97%, respectively. The overall node-based specificity was 99.7% and while the overall sensitivity was lower (72%), a 100% sensitivity was seen for lymph nodes larger than 0.5 cm in diameter [44].

In a recent retrospective analysis of 113 patients, [18F]FDG PET/CT showed high accuracy in preoperative staging (94.7%) and was superior to clinical staging. Six patients were upstaged based on [18F]FDG findings. Nodal staging had lower sensitivity (53.8%) but was more specific (95%) [45]. The study evaluated use of metabolic tumor volume (MTV) for predicting stromal invasion and showed that an MTV cut-off of 8.76 had a sensitivity of 75.0% and specificity of 76.2% for predicting stromal invasion and may be a useful parameter. This, however, needs to be established in a larger study.

In a prospective study of 120 patients with newly diagnosed cervical cancer with FIGO stage ≥IB, [18F]FDG PET/CT had 75% sensitivity and 96% specificity for nodal status in those who underwent surgery [46]. For para-aortic nodal disease, the PPV was 94%, NPV 100%, sensitivity 100% and specificity 99%, while for distant metastasis PPV was 63%, NPV 100%, sensitivity 100%, and specificity 94%. This highlights the ability to decide on the management of patients: Those with PET-positive nodes can be offered radio/chemotherapy instead of surgery, and patients with para-aortic nodal involvement may be treated with extended-field radiotherapy [46]. In comparison with MRI, [18F]FDG PET shows higher sensitivity for the detection of para-aortic nodes and may be useful in guiding PALN dissection [47].

False-positive findings on [18F]FDG PET may be seen for lymph nodes with granulomatous involvement or in reactive nodes especially in sites such as the axilla and groin, which may raise concern for metastatic disease and lead to further evaluation. The limitations of [18F]FDG PET also include false-negative results related to low spatial resolution and micrometastasis, and false-positive results related to bowel uptake and urinary artifacts. Distant metastases are uncommon in sites like the neck or mediastinum, while metastases in the liver, lung, omentum, or bones are seen in more aggressive and higher-stage disease [46].

Pelvic and Para-Aortic Lymph Node Assessment at Initial Staging, in Locally Advanced and Advanced Cervical Cancer

The rate of PALN involvement in locally advanced cervical cancer (LACC) is 15–20%, and it carries a poor prognosis with an overall survival (OS) rate of only 17% [48, 49]. Early studies using [18F]FDG PET with 12 or more subjects and with a clinical follow-up of 6 months or longer, or histopathology as the reference standards, showed a pooled sensitivity of 79% (95% CI, 65–90%) and a pooled specificity of 99% (96–99%) for detection of pelvic or para-aortic lymph node metastasis in patients with newly diagnosed cervical cancer [27, 28, 29, 44, 50]. In comparisons of PET with MRI with CT, PET was superior to both [31, 33, 50]. CT had a pooled sensitivity of 47% (95% CI, 21–73%) and MRI had a pooled sensitivity of 72% (95% CI, 53–87%) and a pooled specificity of 96% (95% CI, 92–98%).

Sugawara et al. in a study of 21 patients with cervical cancer of stages IB to IVA, reported a sensitivity of 86% for [18F]FDG PET in pelvic lymph node and PALN metastasis detection, which was higher than CT ( 57% sensitivity) [51]. Rose et al. studied presurgical patients with stages IIB–IVA and reported a sensitivity of 75% and specificity of 92% for [18F]FDG PET in depicting PALN metastasis. In these studies there was overall higher sensitivity (100%) for PLN detection than for PALN metastases [27].

In prospective studies comparing [18F]FDG PET imaging for PALN metastasis with histopathology after para-aortic lymphadenectomy, the pooled sensitivity of PET for the detection of PALN metastasis was 84% (95% CI, 68–94%) and the pooled specificity was 95% (89–98%) [33, 52, 53, 54]. Pooled data from 15 studies on [18F]FDG PET in cervical cancer showed 84% sensitivity (range 68–98%) and 95% specificity (range 89–98%) for PALN metastasis, with a 79% sensitivity (range 65–90%) and 99% specificity (range 96–99%) for PLN metastasis [55].

In a meta-analysis of PALN detection, data from ten studies involving 385 patients showed the overall specificity of [18F]FDG PET to be as high as 97% (95% CI, 93–99%), but with a low overall sensitivity that was highly variable among the studies (average 34%; 95% CI, 10–72%). In the five studies with a prevalence of PALN metastasis greater than 15%, the estimated sensitivity and specificity were 73% (95% CI, 53–87%) and 93% (95% CI, 86–97%), respectively. With this diagnostic performance and assuming a 15% prevalence, the calculated false-positive and false-negative rates were 35% and 5%, respectively. This suggests a greater value of PET in those with high clinical probability of PALN metastasis than when used for patients with a low risk of PALN involvement [35]. [18F]FDG PET may be of value in patients with normal CT or MRI of the abdomen [52, 53, 56]. In a small-sized study of patients with locally advanced (FIGO stage IIB-IVA) cervical squamous cancer with normal, conventional CT findings, PET/CT scans were done prospectively, followed by surgery. Based on histopathological confirmation, the accuracy, sensitivity, specificity, PPV, and NPV of PET/CT for PALN metastasis were 75%, 50%, 83.3%, 50%, and 83.3%, respectively. Change of management based on PET/CT findings occurred for four of 16 (25%) patients [56]. Compared with the histopathological analysis of pelvic and para-aortic nodes from 22 patients, two of the four para-aortic metastatic nodes were missed on preoperative PET/CT imaging [31]. The false-negative rate for detection of PALN involvement by PET can vary between 4% and 17%, most likely related to small lesions and micrometastasis, which should be considered before planning radiation treatment. In 98 patients with LACC (stage IB2–IVA), 8.4% of patients with negative PET/CT findings had metastatic disease within PALN; all of the patients also had no evidence of extrapelvic disease detected on preoperative CT or MRI. Nodal metastases of 5 mm or smaller were found in four patients and larger than 1 cm in the other four patients [57]. Similar results were noted from other studies, which found a low sensitivity (33–36%) for the detection of microscopic involvement and disease in small nodes [58, 59]. Of the 27 patients with positive pelvic nodes but negative PALN on PET/CT, six patients (22%) had histopathologically positive PALN. PALN dissection should be part of pretherapeutic staging for every LACC patient before undergoing definitive concurrent chemoradiotherapy [57, 58, 59, 60].

For pelvic nodal assessment, the use of [18F]FDG PET imaging for routine staging prior to radical hysterectomy and PLN dissection is still controversial, although the high specificity and NPV of [18F]FDG PET may be helpful in planning the appropriate surgical procedure [61]. In a retrospective review, PET/CT was found to have limited sensitivity (36.4%) but high specificity for predicting PLN metastasis. With a median number of harvested lymph nodes of 29 (range 13–57), 17 (50.0%) had PLN metastases. The overall region-specific sensitivity and specificity of PET/CT was 36.4% and 98.8%, respectively [61].

Overall, PET is of value in nodal assessment and can also guide management. While microscopic disease and small nodes may be missed, the clinical significance and impact of such findings in conjunction with normal conventional imaging remains to be determined in view of systemic therapy that may be instituted.

Prognostic Value of PET/CT

High uptake of [18F]FDG in the primary disease may influence the outcome and is linked to survival and recurrence. In 44 patients with FIGO clinical stage IB–IIA, SUVmax was significantly higher in patients with deep stromal invasion, lymph-vascular space invasion, and a tumor size of more than 4 cm. An SUVmax greater than or equal to 13.4 correlated with a reduced disease-free survival rate and was a significant independent predictor of recurrence. If validated in larger studies, the uptake and cut-off may be used in planning a more aggressive multimodal treatment [62].

Recent studies have evaluated and shown prognostic value of volume-based quantification of tumor [18F]FDG uptake in patients with cervical cancer. In a comparison between MRI and PET findings, quantitative MRI parameters such as mean apparent diffusion coefficient (ADC) on pretreatment diffusion-weighted MRI, MTV (with threshold 42%), and total lesion glycolysis (TLG) from PET/CT showed a significant correlation with adverse prognostic factors such as advanced FIGO stage and lymph node metastases, disease-free survival, and OS, while no correlation was found for the SUVmax value of the lesions [63]. Chung et al. demonstrated that preoperative MTV more than or equal to 23.4 ml was a better predictor of disease-free survival and recurrence in patients with early-stage disease [64]. In 73 patients (stage IB1–IVA), a primary tumor TLG cut-off value of 7,600 was better than SUVmax for identifying patients with higher risk of recurrence [65]. Overall, there is variation in the TLG and MTV cut-off values correlated with prognostic factors. Several studies have shown TLG cut-off values of 215 or 562 to be an independent predictor of recurrence-free survival [66, 67]. In a more recent study, lower values of MTV larger than 5.6 ml and TLG greater than 21.6 ml were significantly associated with OS and progression-free survival (PFS) [68].

Nodal uptake and extent detected by [18F]FDG PET in cervical cancer also stratifies patients for recurrence and survival outcomes. Assessment of PALN metastasis is prognostically important and is related to PFS in advanced cervical cancer. The presence of nodal disease on the [18F]FDG PET scan can help predict cause-specific survival, prognosis, and OS. In a study of 47 patients with FIGO stage IIIB cervical cancer who were evaluated before therapy, the 3-year cause-specific survival was highest for patients without nodal metastasis at 73%, lower for those with only PLN metastasis at 58%, 29% for patients with pelvic and PALN disease, and the lowest (0%) for those with pelvic, para-aortic, and supraclavicular lymph node metastasis [69]. Similar findings were noted in a larger prospective study of patients with newly diagnosed cervical cancer patients (n = 560, stage IA2–IVA) that showed decreased survival with nodal involvement for all stages and an increased risk of recurrence with the number and site of distant nodal metastasis being the highest for supraclavicular nodal involvement and lowest for pelvic nodal disease only [70]. Distant nodal uptake is linked to an adverse prognosis. Involvement of the supraclavicular node or scalene nodes can be seen in about 0–17% of patients, more commonly in those who have para-aortic node disease [71, 72] with a PPV as high as 100% [72]. Therefore, PET findings might help in selecting suitable patients for curative primary and/or salvage treatment. In a follow-up study by the same group, recurrence-free survival, disease-specific survival, and OS were correlated with PET-based cervical tumor volume, SUVmax, and lymph node status. Lymph node status had the highest influence on patient outcome, followed by cervical tumor volume [73].

A number of studies have shown an adverse effect on outcomes and higher recurrence rates in patients with PALN disease. In a retrospective study of 336 patients, OS at 2 years was significantly lower for patients who were surgically or imaging positive for PALN on PET or CT compared with those who were negative for PALN disease by surgery or imaging [10]. [18F]FDG uptake in nodes on PET studies has also been correlated with outcomes. SUVmax in PALN is also a significant prognostic factor; in 70 patients with FIGO stage I–IV, SUVmax greater than or equal to 3.3 for PALN was a significant adverse factor [74]. SUVmax values of PLN have been correlated with PALN recurrence and survival after chemoradiotherapy; an SUVmax cut-off value of 3.85 or more was found to be an independent risk factor and those with SUVmax greater than 3.85 had significantly worse PFS than those with lower SUVmax [75]. The definitive SUVmax cut-off that can be universally applied clinically is not yet definite, as others have noted higher SUVmax cut-off values of up to 7.5 correlating with recurrences [76].

In multivariate analysis, the detection of nodes by imaging was independently associated with a poorer prognosis compared with those detected at surgery only [77]. A recent meta-analysis including 14 studies (n = 1,150) summarized the findings on prognostic indicators in imaging. While there is variation in the methodology and descriptions of SUVmax cut-off and some studies have found no significant correlation [78, 79, 80], the majority of data support the association of a higher risk of recurrence and poor outcomes with a higher SUVmax of the primary or nodal lesions [81]. Only limited studies have shown the value of SUVmax in PLN and PALN as a single independent predictor of outcomes [82, 83, 84]. Outcomes following chemoradiation therapy were found to be best for patients without PALN by surgical and radiographic imaging. In multivariate analysis, detection of metastatic lymph nodes by imaging was independently associated with a poorer prognosis for disease progression compared with nodal positivity at surgery only [77].

In patients with LACC , PET and MRI were compared with FIGO staging for impact on outcomes measured by OS, relapse-free survival, time to failure, local failure, nodal failure, and distant failure. In 206 patients the OS rate was 59% at 5 years. Local failure was mostly associated with adenocarcinoma, and involvement of the corpus on MRI was significantly associated with nodal involvement. Nodal status on PET was a major predictor of outcome in LACC undergoing chemoradiation and was superior to FIGO staging, while MRI tumor volume was a predictor of locoregional relapse [85].

[18F]FDG PET in Cervical Cancer: Impact on Management and Treatment Planning

[18F]FDG PET/CT can alter management by detecting nodal disease or unknown metastatic sites (Figs. 6 and 7) [71, 86, 87]. Patients with cervical cancer whose CT and MRI studies showed metastases limited to para-aortic, inguinal, and/or supraclavicular lymph nodes were prospectively evaluated for the impact of the addition of PET or PET/CT on management. PET had a positive clinical impact in 21 (44.7%) of the 47 patients, including detection of additional curable sites (n = 8), down-staging (n = 6), offering metabolic biopsy (n = 4), or change of treatment to palliation (n = 3) [71]. In a more recent study, [18F]FDG PET led to a major change in management in 32% patients owing to the detection of more extensive local nodal involvement, occult metastatic disease, synchronous tumors, or exclusion of otherwise equivocal lymph nodes on MRI [87].
Fig. 6

A 22-year-old female patient diagnosed with invasive squamous cell carcinoma of the cervix was e valuated for recurrence. [18F]FDG PET/CT scan (A, black arrow) shows uptake in the cervix consistent with a recurrence. Additional uptake was noted in the right external iliac node (SUVmax 5.1) (a, bwhite arrow, SUV 13.3) that was confirmed on pathology. She was treated with chemotherapy. A follow-up scan at the end of treatment showed an increase in size of an external iliac node (MIP – B, black arrows and c, white arrows, SUV 8.5) and depicted a new left abdominal anterior peritoneal nodule (d, arrow, SUV 7.8). The patient was treated with pelvic and para-aortic radiotherapy and chemotherapy. Follow-up PET/CT scan (C) showed metabolic resolution of right external iliac node, partial metabolic response in pelvic sidewall metastases (e, farrows SUVmax 7.4), and peritoneal nodules (g, harrows SUVmax 2.93)

Fig. 7

A 33-year-old female patient with poorly differentiated invasive squamous cell carcinoma of the cervix. [18F]FDG PET/CT maximum intensity projection (MIP; A) shows abnormal uptake in the pelvis (black arrow) corresponding to primary lesion in the cervix (a, bwhite arrows, SUVmax 6.2). The patient was treated with chemoradiotherapy. On follow-up PET/CT scan, whole-body MIP (B) shows resolution of the primary lesion in the cervix (c, dwhite arrows) suggestive of complete metabolic response to therapy

An accurate status of nodal involvement is critical for treatment planning. For those patients with PET-negative lymph nodes, there is no benefit of combined treatment with radiation therapy and chemotherapy vs. radiation therapy alone [88]. PET/CT maximizes patient triage to correct therapy in pretreatment of early-stage disease; combined MRI and PET/CT spares patients unnecessary trimodality therapy [89].

[18F]FDG PET has been useful for management and therapy planning in about 14–35% of cases [90, 91]. Pretherapeutic assessment with [18F]FDG PET is useful in guiding therapy [50, 87]. PET/CT led to modifications of the radiotherapy dose or field in 32–34% and to major alterations in treatment plans in 23% of patients with widespread disease, with a reported minor impact in 8% of patients [50, 87].

Pretreatment [18F]FDG PET improves the detection of extrapelvic metastasis, mainly PALN, and helps select patients for extended-field radiotherapy [92]. [18F]FDG PET has been increasingly used for radiation treatment planning with intensity-modulated radiation therapy (IMRT) and brachytherapy enabling the use of higher radiation doses while sparing adjacent normal organs and tissues [93, 94]. The concept of prophylactic extended radiotherapy based on PET guidance has been examined; the rate of para-aortic failure in patients with only pelvic node involvement was 2.5%. The study shows that routine application of extended-field IMRT with concurrent chemotherapy can lower the rates of PALN relapse [95].

Persistent uptake of [18F]FDG after therapy is linked to poor outcome and the need for more aggressive treatment and follow-up [96]. The ratio of posttreatment vs. pretreatment SUVmax is, as expected, lower for those who achieve complete response and have better outcomes; a cut-off SUVmax of 4.0 yielded a sensitivity and specificity of 92% and 94%, respectively [96].

[18F]FDG PET in Recurrent Cervical Cancer

[18F]FDG PET has a high sensitivity in the detection of recurrent disease (Figs. 8 and 9; Table 4). The overall sensitivity and specificity for detection of recurrence are reported to be 86% and 94%, respectively [97, 98, 99, 100, 101, 102]. While detection of small-volume disease is limited, owing to the lack of resolution, peritoneal disease can be detected when metabolically active [103]. [18F]FDG PET increases physician confidence and decision-making in cases with equivocal findings on conventional imaging [104]. However, some have questioned the cost-effectiveness of [18F]FDG PET in this clinical scenario and further data are needed [105].
Fig. 8

A 32-year-old woman with carcinoma of the cervix, stage IIa, treated with chemoradiation therapy, was referred for PET/CT evaluation of residual disease and restaging. Focal 18[F]FDG PET uptake is seen in the cervix consistent with residual/recurrent disease

Fig. 9

A 60-year-old female patient with invasive squamous cell carcinoma of the cervix, after total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAH/BSO) and chemoradiotherapy, referred for evaluation of recurrent disease. Whole-body MIP (a, black arrows) shows multiple foci of increased [18F]FDG uptake in the neck, chest, abdomen, and pelvis localizing to disease in the surgical bed (b), consistent with recurrence. [18F]FDG-avid lesions are also noted in the peritoneum (b, cwhite arrows, SUVmax 11.3) and retrocrural lymph node (d, ewhite arrows, SUVmax 7.05); additional lesions are noted in retroperitoneal nodes, mediastinal nodes, including prominent uptake in left upper paratracheal node. Additional distant nodes are also noted in the left axillary and left supraclavicular regions (f, gwhite arrows, SUVmax 5.6)

Table 4

FDG PET in cervical cancer

Author and Year

Design

Number of patients; disease stage evaluated

Pathology

Indication

Comparative imaging (CT or MRI)

Histopathology confirmation (yes/no)

Sensitivity/specificity/accuracy

Cut-off SUVmax identified on posttreatment PET scan (yes/no)/value

Median follow-up time (range) months

PFS/OS

Havrilesky et al. 2003

Retrospective

28; IB (n = 7), IIA (n = 1), IIB (n = 10), IIIB (n = 9), IVB (n = 1)

SCC (n = 23), Adenocarcinoma (n = 4), Unknown (n = 1)

Recurrence

None

Yes

85.7%/86.7%/NA

No/NA

14.3(3.6–235)

NA

Ryu et al. 2003

Retrospective

249; IB (n = 100), IIA (n = 49), IIB (n = 83), III/IV (n = 17)

SCC (n = 226), Adenocarcinoma (n = 10), Adenosquamous (n = 5), Others (n = 8)

Recurrence in asymptomatic/negative CI

Yes

Yes

90.3%/76.1%/NA

No/NA

30(6–282)

NA

Unger et al. 2004

Retrospective

47; IB(n = 29), IIA(n = 4), IIB(n = 9), IIIA(n = 1), IIIB(n = 4)

NA

Recurrence

None

Yes

Asymptomatic: 80%/100%/NA Symptomatic: 100%/85.7%/NA

No/NA

16.4(6–33)

NA

Sironi et al. 2007

Prospective

25; Cervical Ca (n = 12; Stage IIB (n =6), IIIA (n =5), IIIB (n =1), Endometrial Ca (n = 13; Stage IC (n =1), IIB (n =8), IIIA (n =3), IIIB (n =1)

NA

Recurrence

CT/MRI

Yes

Patient based 92.9%/100%/96%, Lesion based 94.7%/99.5%/99%

No/NA

15.3(12–23)

NA

van der Veldt et al. 2008

Retrospective

40; Stage IB (n = 13), IIA (n = 3), IIB(n = 6), IIIA (n = 1), IIIB (n = 13), IVA (n =1), IVB (n = 1), Unknown (n = 2)

SCC (n = 25), Adenocarcinoma (n = 11), Large cell (n = 2), Glassy cell (n = 1), Unknown (n = 1)

Recurrence

CT/MRI

Yes

92%/93%/NA

No/NA

18(10–37)

NA

Kitajima et al. 2008

Prospective

52; Stage I (n = 12), II (n = 15), III (n = 21), IV (n = 4)

SCC (n = 42), Adenocarcinoma (n = 8), Adenosquamous cell carcinoma (n = 2)

Recurrence

None

Yes

FDG PET/CT 92%/92.6%/92.3%, PET 80%/77.8%/78.8%

No/NA

17(12–25)

NA

Pallardy et al. 2010

Retrospective

40; I (n = 7), II (n = 16), III (n = 13), IV (n = 4)

SCC (n = 39), Adenosquamous (n = 1)

Recurrence

Yes

Yes

FDG PET/CT94%/75%/92.5% CI 42.5%/71.5%/47.5%

No/NA

25(3–312)

NA

Chung HH et al. 2012

Retrospective

276; IA2 (n = 30), IB (n = 134), II (n = 86), III (n = 11), IV (n = 15)

SCC (n = 235), Adenocarcinoma(n = 27), Adenosquamous(n = 8), Others (n = 6)

Recurrence

None

Yes

94.7%, 87.8%, 90.2%

Yes/5.25

49(6–345)

5 years −98.62%/99.31%

Choi et al. 2014

Retrospective

136; IB1 (n = 2), IB2 (n = 1), IIA (n = 5), IIB (n = 97), IIIA (n = 2), IIIB (n = 15), IVA (n = 7), IVB (n = 7)

SCC (n = 124), Adenocarcinoma (n = 9), Other (n = 3)

Residual disease

MRI

No

92%/95%/NA

Yes/4

NA

NA

SCC squamous cell carcinoma, PFS progression-free survival, OS overall survival, CI conventional imaging, NA not available

Combining PET with contrast-enhanced CT (ceCT) may improve detection, although the increment in value may not be significant depending on the distribution of the disease. In 100 women with either uterine cervical (n = 55) or endometrial cancer (n = 45), while there was no significant difference in sensitivity or specificity between contrast-enhanced and low-dose CT [99], PET/ceCT led to better delineation of equivocal lesions; four equivocal regions by PET/low-dose CT (local recurrence, PLN metastasis, liver metastasis and muscle metastasis) were correctly interpreted as positive by PET/ceCT [99]

[18F]FDG PET has a high sensitivity for detecting recurrence; the sensitivity in asymptomatic women is lower than that for symptomatic women (80% vs. 100%) [101, 106] and in those with rising markers with normal conventional imaging enabling institution of early therapy or management [107]. [18F]FDG PET is not routinely performed or recommended for surveillance. In asymptomatic patients treated with radiation, [18F]FDG PET can help in early detection of recurrent disease, or help confirm disease in those with abnormal serum tumor marker values. In such patients, the sensitivity for the detection of extrapelvic lymph node metastases was extremely high (100%); by contrast, the sensitivity and specificity for lung and bone lesions were 75.0% (12/16) and 33.3% (1/3), respectively [108]. Chang et al. [109] reported the detection of disease in 94% of patients with normal conventional imaging, leading to institution of earlier therapy.

[18F]FDG PET has the advantage of facilitating the identification of extrapelvic metastases with high sensitivity and specificity [110] and plays a complimentary role to conventional imaging. In 150 patients who had findings suggestive of recurrence on CT or MRI, or elevated serum squamous cell carcinoma antigen SCC-Ag levels, an additional benefit from [18F]FDG PET over CT–MRI was seen in 73.8% of patients; in particular, [18F]FDG PET CT led to the correction of false-negative findings on CT-MRI in 74.2% and of false-positive findings on CT-MRI in 25.8% of cases. About 75.4% of these lesions were extrapelvic. In 26.2% patients, CT-MRI findings were discrepant from [18F]FDG PET, which was able to confirm false-negative lesions in nine patients and exclude disease in 19; most of these lesions were extrapelvic.

[18F]FDG PET provides useful prognostic information in patients with recurrent disease [104, 111]. The most significant prognostic factor was the presence of more than three [18F]FDG-positive lesions. The median survival for those with more than three PET-positive lesions was shorter than for those with a normal scan or fewer lesions on PET [111]. Similarly, posttreatment [18F]FDG PET/CT is also useful for prognosis and planning management. In a retrospective study involving 276 patients, the 5-year PFS and OS in patients with negative scan findings for recurrence were significantly better than those with positive scan findings (98.6% vs. 17.8%, p < 0.0001 for PFS, 99.3% vs. 85.3%, p = 0.0015 for OS) [112].

Increasingly, [18F]FDG PET is being used for radiation treatment planning in recurrent cervical cancers. Using PET/CT, radiation dose to various organs like the stomach, liver, and colon could be significantly reduced, while radiation to other structures such as the spinal cord, kidneys, and small intestine was possible but depended on the beam sparing [113]. PET/CT-guided treatment planning for IMRT and brachytherapy allows for dose escalation without harming the surrounding tissues [93, 94]. Such escalated treatments may have better outcomes [114, 115], and a similar approach has been effectively used by others [95, 116].

Hypoxia is known to be a limiting factor in response to therapy (especially radiation therapy), and is increasingly recognized as an important aspect of treatment planning. It is associated with an increased likelihood of local recurrence and distant metastasis and heralds poor response to therapy [117, 118]. The phenomenon has also been recognized in cervical and uterine cancers and is associated with a more aggressive tumor phenotype [111]. Tumor hypoxia can be measured through the tumor PO2 levels using oxygen probes; however, this technique is invasive and needs special instruments and technical expertise.

A number of PET tracers are under investigation for noninvasive assessment of tumor hypoxia. Radiocopper-labeled diacetyl-bis(N(4)-methylthiosemicarbazone) [64Cu-ATSM] has been described as a potential tracer for imaging hypoxia [119, 120]. In cervical cancer, an inverse correlation between outcome and uptake of 64Cu-ATSM has been shown [121]. Hypoxic tumors have a significantly increased risk of nodal or distant metastases, and noninvasive methods of metabolic imaging would be critical in providing guidance for management. Another tracer for hypoxia evaluation is [18F-]fluoromisonidazole (18F-MISO), which has been extensively evaluated in cervical cancer. The feasibility of combined [18F]FDG and 18F-MISO PET/MRI was recently evaluated in LACC. Combined metabolic [18F]FDG and hypoxia PET imaging with 18F-MISO in conjunction with MRI can help identify discordant areas and tumor heterogeneity and also help direct radiation dose escalation to the hypoxic regions [122].

There is an emerging role of PET/MRI in gynecologic tumors. In cervical cancer, it can improve the detection of nodal involvement compared with PET/CT [123, 124] and helps in better assessment of local disease extent for staging [125]. MRI has superior soft tissue contrast resulting in better characterization of lesions with PET/MRI [126]. An additional advantage includes the reduction in radiation dosage. While the sensitivity is high, PET/MRI is likely to show more false-positive lesions. In a total of 79 patients where 553 nodal groups were assessed, PET/MRI detected an additional six positive nodal groups compared with PET/CT; however, it gave false-positive results in eight nodal groups [124]. In comparison with MRI alone, PET/MRI can help identify more disease (92% vs. 100%, respectively) and shows better characterization of lesions (88.8% vs. 98.9%, respectively) [127]. Specifically, PET/MRI is superior in the characterization and detection of lesions in the liver, peritoneum, and lymph nodes; however, it is limited in the assessment of lung lesions compared with PET/CT [128, 129].

Endometrial Cancers

Epidemiology and Prevalence

Endometrial cancer is the most common female pelvic malignancy, and the fourth most common cancer in women after breast, gastrointestinal, and lung cancer. It is more common in postmenopausal women, in Western countries, and is linked to exposure to unopposed estrogen. In 2016, 60,050 new cases and 10,470 deaths were predicted. The overall 5-year survival rate is estimated to be 81.7% – 95.4% for patients with localized disease, 68.7% for those with regional spread, and 16.8% for distant metastatic disease [1]. There is a slight increase in death rates annually, at a rate of 1.2% per year.

Pathophysiology and Clinical Presentation

Endometrial cancer results in abnormal bleeding in about 80% of patients. About 15% of postmenopausal women presenting with abnormal bleeding have endometrial carcinoma [3, 4]. Uterine cancer most commonly presents as polypoid fungating masses in the endometrial cavity causing asymmetric enlargement of the uterus. Invasion occurs directly into the myometrium, while distant spread of the tumor occurs through blood vessels or lymphatics. Prognostic factors include histology, tumor grade, depth of endometrial invasion, extension into the cervix or vascular space or adnexa, and pelvic or aortic node involvement. Surgical staging is definitive and nodal sampling is routinely performed. Clinical staging is commonly based on the FIGO classification (Table 5).
Table 5

AJCC and FIGO staging for endometrial cancer

Stage I: cancer confined to the corpus uteri

 IA: invasion to less than 50% of the myometrium

 IB: invasion to greater than 50% of the myometrium

Stage II: cancer involves stromal connective tissue of the cervix but has not extended outside the uterusa

Stage III: extension beyond the uterus but not beyond the true pelvis

 IIIA: tumor invades serosa and/or adnexa and/or positive peritoneal cytology

 IIIB: vaginal involvement (direct extension or metastasis) or parametrial involvement

 IIIC: metastases to pelvic and/or para-aortic lymph nodes

  IIIC1: pelvic lymph node involvement

  IIIC2: para-aortic lymph node involvement (with or without pelvic nodes)

Stage IV: involves the bladder or bowel mucosa or has metastasized to distant sites

 IVA: tumor invasion of bladder and/or bowel mucosa

 IVB: distant metastases, including intra-abdominal and/or inguinal lymph nodes

Grading:

 G1: no more than 5% of a nonsquamous or nonmorular solid growth pattern

 G2: 6–50% of a nonsquamous or nonmorular solid growth pattern

 G3: >50% of a nonsquamous or nonmorular solid growth pattern

FIGO staging

 Tumor limited to corpus

  Stage IA; G123: tumor limited to endometrium

  Stage IB; G123: invasion to less than 50% of the myometrium

  Stage IC; G123: invasion to greater than 50% of the myometrium

 Tumor extends beyond the uterus, within the pelvis

  Stage II; G123: cervical stromal invasion

 Extension beyond the uterus but not beyond the true pelvis

  Stage IIIA; G123: tumor invades serosa and/or adnexa and/or positive peritoneal cytology

  Stage IIIB; G123: vaginal metastases

  Stage IIIC; G123: metastases of pelvic and/or para-aortic lymph nodes

 Extension to bladder, intestinal mucosa or distant metastasis

  Stage IVA; G123: tumor invasion of bladder and/or bowel mucosa

  Stage IVB; distant metastases including intra-abdominal and/or inguinal lymph nodes

aEndocervical glandular involvement should only be considered as stage I and no longer as stage II

The most common histological type is adenocarcinoma (Table 6), which is seen as areas of irregular glands lined by malignant columnar epithelial cells. Although most adenocarcinomas are well-differentiated, areas of squamous differentiation can occur and are prominent in adenoacanthomas. Squamous areas that are poorly differentiated and show cytologic features of malignancy are seen in adenosquamous carcinoma. Endometrial carcinomas are graded according to their degree of histologic differentiation. Well-differentiated carcinomas are grade 1. The presence of large solid areas qualifies the tumors as grade 2, and poor differentiation is grade 3; both grades 2 and 3 carry a worse prognosis. Papillary serous adenocarcinoma is a variant that resembles ovarian serous carcinoma and has a worse prognosis than adenocarcinoma.
Table 6

Endometrial carcinoma: histopathologic types

1. Endometrioid adenocarcinoma

 a. Papillary villoglandular

 b. Adenocarcinoma with squamous differentiation

 c. Secretory

 d. Ciliated cell

2. Mucinous adenocarcinoma

3. Serous carcinoma

4. Clear cell carcinoma

5. Squamous carcinoma

6. Undifferentiated carcinoma

7. Mixed cell type

8. Secondary tumors

Leiomyosarcoma is a rare uterine neoplasm, accounting for 3% of all uterine malignancies and the most common uterine sarcoma arising from smooth muscle of the myometrium. These are generally bulky, fleshy masses that commonly occur in older women and have a high incidence of local recurrence and hematogenous metastases. Hemorrhage and necrosis are seen, with marked cytologic pleomorphism and atypia with a high rate of mitotic cells, which is diagnostic.

Role of Conventional Imaging

The diagnosis is generally made by obtaining an endometrial biopsy specimen [130]. Transvaginal ultrasonography may be used initially to evaluate those who cannot undergo biopsy. Ultrasound allows for a quick early preliminary examination that may be performed on patients with abnormal bleeding. A thickened and heterogeneous endometrium suggesting the presence of hyperplasia, polyps, or suspicious lesions may be noted that can be further evaluated by biopsy. In premenopausal women, the thickness of the endometrium varies with menstrual phase; however, a thickness of more than or equal to 5 mm in postmenopausal patients with bleeding should be considered abnormal and investigated further [131]. Recent studies, however, advocate the use of a 3–4-mm cut-off [132, 133, 134].

Chest imaging /CT of the chest may be performed for initial assessment to exclude disease. MRI is helpful in evaluating the disease extent to the cervix. MRI and CT of the abdomen and pelvis are performed before surgery to assess the presence of extrauterine disease [135]. MRI is sensitive in detecting myometrial invasion and involvement of the lower uterine segments, and it should be considered for the presurgical evaluation of patients who are suspected to have gross cervical involvement, thus affecting further management. CT and/or MRI of the abdomen and pelvis is specifically helpful in evaluating endometrial stromal tumors to assess the extent of the primary tumor and the presence of extrauterine disease including pelvic and para-aortic nodal involvement [135].

Role of [18F]FDG PET in Endometrial Carcinoma

Increased uterine [18F]FDG uptake is commonly seen in young premenopausal patients related to cyclical changes in the endometrium. Intense uptake is frequently detected during active menstruation, while focal endometrial uptake is common in the late follicular and early luteal phases (Fig. 10) [136]. Careful interpretation is needed especially when focal uterine uptake is noted in close proximity to a known cervical tumor so as to differentiate physiological activity from uterine invasion. Variable [18F]FDG uptake has also been demonstrated in different benign pathologies of the uterus such as fibroids and polyps (Fig. 11) [137].
Fig. 10

Physiologic uptake in the uterus. Woman with lung malignancy imaged with [18F]FDG PET for restaging. Uptake is seen in the uterine cavity (arrows). Patient was menstruating at the time of the scan, consistent with physiologic uptake

Fig. 11

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

[18F]FDG accumulates in uterine tumors [138, 139] (Table 7). Presurgical assessment with [18F]FDG PET for staging in high-grade endometrial cancer allows for the detection of extrapelvic sites of disease and distant metastasis (Fig. 12). Preoperative [18F]FDG PET/CT detects primary lesions with a high sensitivity. In high-risk malignancy, while there is lower sensitivity for detection of nodal disease (57.1%), the detection of distant disease is high (sensitivity 100%). The specificity, however, is high for both nodal disease (100%) and distant disease (96%) [140].
Table 7

Role of FDG PET CT in endometrial cancer

Author and year

Type

Disease stage evaluated

Indication

Number of cases

Comparative imaging (CT or MRI)

Histopathology confirmation (yes/no)

Sensitivity/specificity/accuracy

Antonsen et al. 2013

Prospective

Atypical endometrial hyperplasia (n = 18), I

Staging

318

MR, TV 2D US

Yes

For myometrial invasion [18F]FDG – 93%/49%/61% MRI -

Kitajima et al. 2009

Prospective

Endometrial: Stage I (n = 12), II (n = 8), III (n = 10) Cervical: I (n = 7), II (n = 8)

Staging

45 (30 Endometrial and 15 cervical carcinoma)

None

Yes

Overall: 51.1%/99.8%/98.7% Pelvic LN: 52.2%/99.8%/98.9% Para-aortic LN: 50%/99.7%/98.3%

Nakamura et al. 2011

Prospective

IA (n = 18), IB (n = 31), IC (n = 18), IIA (n = 3), IIB (n = 11), IIIA (n = 9), IIIB (n = 1), IIIC (n = 11), IVB (n = 4)

Staging

106

None

Yes

For LN metastasis 96.8%/69.2%/93.4%

Husby et al. 2015

Prospective

I (n = 96), II (n = 17), III (n = 12), IV (n = 4)

Staging

129

None

Yes

For lymph node metastases 77–85%/91–96%/89–93%

Nogami et al. 2015

Prospective

I (n = 36), II (n = 5), III (n = 10), IV (n = 2)

Staging

53

MRI

Yes

Patient based – 50%/93.9%/NA LN based – 45%/99.4%/NA

Signorelli et al. 2015

Prospective

IA (n = 36), IB (n = 17), II (n = 7), IIIA (n = 7), IIIB (n = 4), IIIC1 (n = 10), IIIC2 (n = 7), IVB (n = 5)

Staging

93

None

Yes

73.7%/98.7%/93.6%

Sharma et al. 2012

Retrospective

I (n = 63), II (n = 26), III (n = 10), IV (n = 2)

Recurrent disease

101

CT/MRI

Yes

88.9%/93.6%/94.1%

TV 2DUS transvaginal 2D ultrasonography, NA not available

Fig. 12

A 50-year-old female patient with a history of recurrent endometrial adenocarcinoma was noted to have a pelvic lesion on CT. The patient was treated with chemoradiation, but the lesion persisted, although there was a decrease in size. The patient was referred for PET/CT imaging for response evaluation and to rule out extrapelvic disease. The scan revealed a mildly [18F]FDG-avid (b, c, white arrow, SUVmax 2.8) pelvic mass adjacent to the urinary bladder with central necrosis. No other [18F]FDG-avid lesions were noted elsewhere (MIP, a). Patient underwent surgery; pathology confirmed necrotic tumor. Teaching point: [18F]FDG PET has lower uptake and sensitivity for necrotic or cystic lesions and will be generally photopenic. [18F]FDG PET helped rule out other disease sites

[18F]FDG PET/CT is more useful than MRI for assessing lymph node metastasis [141]. In a prospective multicenter study, the diagnostic performance of PET/CT, MRI, and transvaginal ultrasound was assessed preoperatively in 318 women with endometrial cancer. For lymph node metastases, the sensitivity and specificity were 74% and 93%, respectively, for PET/CT while for MRI it was 59% and 93%, respectively [141].

The SUVmax of [18F]FDG PET correlates with histological grade, tumor size, and glucose transporter GLUT-1 expression. In 44 patients, the mean SUVmax of the primary endometrial cancer tumors was 17.6 (range, 3.04–34.74) [142]. In 106 patients, the SUVmax of the primary tumor was inversely correlated with disease-free survival and OS rates. A mean SUVmax cut-off of 16.4 of the primary tumor was found to delineate prognostic groups [143].

In patients with high clinical risk and early-stage endometrial cancer, [18F]FDG PET has a high NPV that can serve as a guide in selecting patients for lymphadenectomy and thus minimize operative and surgical complications in others. PLN metastases were found at histopathological analysis in nine of 37 patients (24.3%). Patient-based sensitivity and specificity of [18F]FDG PET for detection of nodal disease were 77.8% and 100.0%, respectively, while nodal lesion site-based sensitivity and specificity were 66.7% and 99.4%, respectively [144]. In more recent and larger studies, high PPV and NPV for pelvic lymph node metastases have been reported, up to 93% and 94%, respectively [145]. The specificity for nodal detection was also high ranging between 91% and 99% [146, 147].

Preoperative [18F]FDG PET with ceCT is superior to conventional imaging in detecting metastatic disease, but it is limited in the assessment of small lymph nodes. In 45 patients with endometrial carcinoma, the overall node-based sensitivity and specificity were 51.1% and 99.8%, respectively. For smaller lymph nodes, the sensitivity was only 12.5% for nodes below 4 mm, 66.7% (16/24) for nodes 5–9 mm in size, and 100.0% for nodes 10 mm or larger(5/5) [148].

In uterine cancers [18F]FDG PET is useful for postsurgical monitoring and surveillance for recurrent disease (Figs. 13, 14, and 15). Belhocine and colleagues retrospectively analyzed findings from 34 women (41 scans) with suspected recurrence based upon tumor markers or findings of other radiographic imaging. PET confirmed recurrence in 88% of the cases; it also helped localize the site of disease and detected asymptomatic recurrences in 12% of patients. Moreover, in nine of 26 patients (35%) additional metastatic sites were detected with PET, a finding which significantly altered the treatment choice [149]. Similar results were noted in a larger study involving 101 posttherapy patients; the reported sensitivity and specificity were 89% and 94%, respectively [150].
Fig. 13

A 57-year-old female patient with endometrial carcinoma was referred for evaluation of recurrent disease. MIP images show large area of abnormal activity superior to the bladder. Axial CT and fused [18F]FDG PET/CT images show large left pelvic mass consistent with recurrent disease (a) and a node (b). Follow-up study shows resolution of [18F]FDG avidity and a decreased size of the pelvic mass (c) after chemoradiation

Fig. 14

A 61-year-old female patient with endometrioid adenocarcinoma referred for [18F]FDG PET/CT for restaging. The patient had presented with vaginal spotting and slightly elevated CA-125 markers (~43 ng/mL); CT imaging showed new subcentimeter pulmonary nodules, limited in the PET assessment, negative for uptake in the lungs (b, c; arrows). PET/CT MIP (a, black arrows) demonstrated splenic hilar implant (d, e,arrows, SUVmax 20.1), peritoneal nodules (f, arrow; SUVmax 10.1), and pelvic nodes (g, h, arrows, SUVmax 16.9). Additionally PET/CT showed suspicious lesions in bilateral axillary nodes (i, arrow, SUVmax 7.4 on the right) and a bilobed mass in the vaginal cuff (j, karrow; SUVmax 31.3), which was later confirmed to be recurrent disease on histopathology. Teaching point: [18F]FDG PET/CT helps identify distant sites of disease involvement. Small lesions including subcentimeter lesions may be limited in assessment due to size

Fig. 15

A 59-year-old patient with stage I endometrioid adenocarcinoma, s/p TAH/BSO, with suspected recurrence underwent [18F]FDG PET/CT for restaging. MIP images (a, black arrows) revealed hypermetabolic implants in the parahepatic region (d, e,arrows SUVmax 9.5) and left paracolic gutter (f, g,arrows SUVmax 3.3). A small supradiaphragmatic lymph node was also noted (white arrowb, c). No other lesions were noted elsewhere. The patient underwent surgery and all the [18F]FDG-positive lesions were confirmed metastasis. Teaching point: [18F]FDG PET excluded extensive disease and distant organ metastasis that would have otherwise required systemic therapy

Earlier studies in a small number of patients showed superior results with [18F]FDG PET compared with conventional imaging or tumor markers for recurrent disease. In 21 patients with 30 studies, PET showed 100% sensitivity and 88% specificity, compared with 85% sensitivity and 86% specificity for conventional imaging, or 100% sensitivity and 70.6% specificity with tumor markers. [18F]FDG-PET affected the patient management in one third of the cases, and patients with negative PET results had a trend to show longer disease-free courses [151]. The combination of [18F]FDG PET with ceCT is superior in categorizing the lesions as malignant vs. benign in comparison with low-dose CT owing to decreasing equivocal results, although no significant difference was noted in overall accuracy [99]. In a more recent follow-up study of 35 patients, PET/CT was compared with manually fused PET/MRI; while no significant difference was noted in diagnosing primary tumors, PET/MRI detected the extent of disease better than PET/CT (83% vs. 53.3%, respectively) [152].

Metabolic parameters derived from preoperative [18F]FDG PET/CT can help in the characterization of endometrial carcinomas. In 129 patients, preoperative [18F]FDG PET-derived MTV, using an absolute SUVmax threshold of 2.5, and TLG significantly correlated with deep myometrial invasion, lymph node metastases, and high histological grade. The potential cut-off value of MTV for predicting deep myometrial invasion and lymph node metastases was 30 ml (85% sensitivity, 76% specificity) [146]. A similar evaluation in patients with recurrent disease (n = 84) calculated an MTV cut-off of 17.5 ml (75% sensitivity, 58% specificity) and a TLG of 56.43 g (75% sensitivity, 53% specificity) as useful parameters [153].

Uterine sarcomas constitute less than 5% of the uterine corpus malignancies, and, based on the type of cell they developed from, belong to three groups: endometrial stromal sarcomas, uterine leiomyosarcomas, and uterine carcinosarcomas. These tumors are very aggressive and have high mortality. MRI is presently the most accurate imaging modality for these lesions. Leiomyosarcomas are [18F]FDG avid [154]. When compared with MRI in five patients, PET was positive in all five patients vs. four for MRI. The uptake in most cases was high, with a mean SUV of 4.5. In 53 patients with either uterine sarcomas, endometrial carcinomas, or leiomyomas, [18F]FDG uptake (SUVmax) was higher in uterine sarcomas and endometrial carcinomas than for leiomyomas; however, there was no significant difference in SUVs among endometrial carcinomas, carcinosarcomas, and leiomyosarcomas [155]. The diagnostic accuracy for leiomyosarcomas was only 73%. Sarcomas had higher GLUT-1 expression than endometrial carcinomas (EC). However, frequently, the uptake in leiomyomas can be very high, too, making it difficult to distinguish malignant from benign lesions based on uptake alone (Fig. 16).
Fig. 16

PET/CT fused image in a patient with nongynecologic malignancy. Intense [18F]FDG uptake (a, SUVmax 8.5) seen in the uterus localizing to posteriorly lying fibroid on CT image (b), which increased in comparison with prior study 1 year earlier (c). MRI and further evaluation confirmed intense uptake within the dominant intramural posterior leiomyomata. Teaching point: Fibroids may show variable uptake and intensity may vary with time. It is difficult to distinguish between benign and malignant lesions based on [18F]FDG uptake alone

In summary, the role of [18F]FDG PET is primarily in the evaluation of nodes or lesions in cases of equivocal conventional imaging and for detection of pelvic and distant disease in high-grade disease and high-risk patients.

Lymphoscintigraphy

Sentinel node mapping for cervical and uterine malignancies has been evaluated over the past decade for its feasibility and accuracy in early cervical and uterine cancers, and more clinical data are emerging of its use to prevent morbidity associated with nodal dissections [156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167]. Vascular and neural injuries with pain and paresthesia, formation of lymphoceles and seromas, and late and chronic sequelae of lymphedema associated with lymphadenectomies cause significant morbidity.

Lymph node status in cervical and endometrial cancer remains the most important prognostic factor for recurrence and survival and a major decision criterion for adjuvant therapy [168, 169]. In cervical cancer of stage IA1, the rate of lymphatic/vascular invasion is less than 1% [170]. Pelvic node metastases are detected in 0–4.8% of patients with stage IA disease, in 0–17% of those with stage IB disease, and in approximately 20–40% of stage II cervical cancers [49, 171]. In stage I and occult stage II endometrial cancers, the incidence of lymph node metastases is approximately 10% [172]. Accurate assessment of the disease status of pelvic and para-aortic lymph nodes preoperatively is suboptimal and requires surgical staging [31]. Routinely performed extensive nodal dissection in patients who otherwise have a low likelihood of nodal metastasis suggests that a number of patients undergo dissection without clinical benefit and with a potential for increased complications and morbidity [173, 174]. The incidence of nodal metastasis is low in patients presenting with a low-grade endometrioid adenocarcinoma [175] and the overall prognosis is excellent [176]. The use of lymphatic mapping and SLN identification in these patients may help reduce the morbidity of surgery without compromising the identification of patients who require adjuvant treatment [157, 177, 178, 179, 180, 181].

Lymphoscintigraphy (LSG) is a noninvasive and convenient technique that can be performed either on the day of surgery or 1 day before surgery to map the nodal drainage. Various injection techniques of radiolabeled colloids have been applied for nodal mapping in cervical and endometrial cancers. Generally, they involve injecting 1–2 mCi of radiocolloid in 1–1.5 mL volume at the site of the lesion; filtered 99mTc-sulfur colloid is generally used in the United States, while 99mTc-albumin nanocolloid is has been more commonly applied in Europe and elsewhere. More recently, 99mTc-tilmanocept, a node-seeking tracer that targets the mannose receptor CD206 has been approved for use in a variety of tumors [182, 183]. More recently, fluorescent dyes such as indocyanine green have been explored in both cervical and endometrial cancer, providing an advantage of better intraoperative visualization of SLN with infrared light [184, 185].

For cervical cancer, submucosal injection of tracer is carried out around the lesion or in four quadrants of the cervix using a 3.5-inch-long spinal needle. Imaging is acquired immediately after injection, and dynamic flow and static imaging in anterior, posterior, and lateral images are obtained. Handheld gamma probes have been used to detect “hot nodes” for removal during surgery. In vivo and ex vivo counts are recorded over the node. Generally, those with counts more than ten times the background levels are considered sentinel. The optimal site to inject radiotracer during LSG in patients with endometrial cancers is not well established and various techniques have been used including cervical, fundal, or hysteroscopic injections for SLN mapping [157, 178, 186, 187]. Cervical injection for SLN mapping has several advantages over the other methods such as being easily accessible, less invasive, and having fewer chances of being influenced by anatomic variation in the uterus that may affect fundal injection and tumor infiltration [188].

External iliac and obturator nodes are more frequently seen on LSG, and bilateral nodal drainage is common. Using LSG alone, the detection rate is between 80% and 93% while combined blue dye and colloid scintigraphy increases the detection rate with a reported range of 78–100% [157, 179, 178]. False-negative rates are very low, with an overall rate of less than 1% and a high NPV reported up to 100% [177].

Single photon emission computed tomography (SPECT) provides three-dimensional imaging information that, when combined with CT imaging (fusion imaging), can help to improve localization of SLNs (Fig. 17). This is more helpful in endometrial and cervical cancers, owing to the complex pelvic anatomy. Detection of SLNs with the hand-held probe requires experience. If the site of cervical injection is close to the sites of SLN basins in the pelvis, detecting the SLN uptake can be difficult because of scatter from the site of injection in the cervix. The closer the injected radiolabeled colloid is to the nodal sites, the more likely the interference with the hand-held probe. For similar reasons, a nodal basin like the parametrium (that is closer to the injection site) would be difficult to assess both by planar imaging and by probe counting. This is also true for blue dye, since the blue dye diffuses easily into the parametrium and can make it difficult to identify parametrial SLNs.
Fig. 17

Cervical carcinoma patient referred for lymphoscintigraphy. Planar images (a) show intense tracer activity in the injection site in the cervix. Two foci are seen superolaterally to the injection site localizing to the external iliac nodal region on SPECT/CT images (b). Additional focus seen faintly in the right side on planar images that localizes to the right common iliac nodal region on SPECT/CT (c)

Several studies have shown that SPECT imaging for SLN detection in endometrial and cervical cancer is superior to planar imaging and improves the sensitivity of detection and localization of SLN [188]. Using SPECT imaging, there was increased sensitivity of SLN detection, with a 100% detection rate using SPECT/CT compared with either planar LSG, hand-held probe, or blue dye alone (75%, 92.5%, and 82.5%, respectively, for endometrial cancer and 70%, 90%, and 90%, respectively, for cervical cancer), as well as compared with combined imaging plus probe and blue dye injection (94.2%). A recent meta-analysis of data from eight studies (n = 208) for SLN in early-stage cervical cancer showed an overall SLN detection rate of 98.6% for SPECT/CT vs. 85.3% for planar LSG, although bilateral nodal site localization was similar (69% vs. 67%) [189]. Accurate anatomic localization of SLNs preoperatively can also aid in probe-directed surgery and in reducing operator-dependent variation and time involved in surgery. SPECT/CT helps achieve faster intraoperative localization and SLN removal; an average time advantage of 25 min in lymph node retrieval was noted with the use of SPECT/CT [190]. Similarly, in a group of 59 patients with early-stage cervical cancer, Klapdor et al. demonstrated a detection rate of 84.3% for planar imaging and 92.2% for SPECT/CT [191, 192].

A similar advantage of SPECT/CT was shown in SLN mapping in early-stage endometrial cancer: The detection rate for planar imaging ranges between 50% and 67% while with SPECT/CT the range is 84–91% [193] [186]. With SPECT/CT, fewer false-positive findings are seen and localization of para-aortic and pelvic nodes is superior to planar imaging [188, 194], leading to a change in location in 37% of patients and in 22% of nodal sites compared with planar imaging. A recent study of 136 women with low-to-intermediate-risk endometrial carcinoma detected SLN with micrometastasis that resulted in upstaging of 22 patients and a higher risk group identified in ten cases, influencing management [195].

Certain limitations and potential issues with SPECT must be understood; for example, detection of multiple nodes can occur depending on the time of imaging, injection volume, and rate. Therefore, all these parameters should be standardized. Nodal localization may be seen on both sides of the pelvis, the first most intense node on each side may be regarded as the SLN; however, more data are needed to establish this clearly. With the current data, there is incremental value in using SPECT/CT and it should be employed in conjunction with planar imaging whenever possible and especially in patients with negative findings on planar imaging, to enhance SLN detection and localization.

LSG can identify patients with an atypical drainage pattern and identify unusual sites of SLN. In a prospective SENTICOL study comprising 139 patients with early-stage cervical disease, about 57% patients were noted to have atypical sites of SLN localization using LSG compared with 38% by intraoperative mapping. About 49% of patients with atypical SLN sites on LSG also had atypical sites detected by intraoperative mapping. In 13 patients, a parametrial SLN was seen with LSG only; 3% of patients also showed common iliac and para-aortic SLNs with LSG only [196].

In the SENTI-ENDO study, SLN mapping was performed on 118 of 133 patients with early endometrial cancers, for whom delayed imaging was performed at 120 min after injection (long protocol) vs. 90 min after injection (short protocol).The overall detection rate of LSG was 74.6% (88/118) with no significant difference in overall detection rate; however, a higher detection of para-aortic SLN was seen in patients imaged with the long protocol [197].

In summary, the feasibility of LSG in cervical and endometrial cancers has been documented. The overall detection rates with LSG are high and superior when used in conjunction with blue dye. Recent developments and the increasing use of fluorescent dyes may influence the future applications and use of LSG.

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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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