Ultrasound in Med. & Biol., Vol. 41, No. 9, pp. 2303–2309, 2015 Ó 2015 Published by Elsevier Inc. on behalf of World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/$ - see front matter
http://dx.doi.org/10.1016/j.ultrasmedbio.2014.10.005
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Original Contribution THREE-DIMENSIONAL TRANSVAGINAL TOMOGRAPHIC ULTRASOUND IMAGING FOR CERVICAL CANCER STAGING XUE-SONG HAN,* CHUN-PING NING,y LI-TAO SUN,* XIAO-YING LI,* YAN-QING PENG,* and MEI-ZHENG DANG* * Department of Ultrasound, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People’s Republic of China; and y Department of Ultrasound, Affiliated Hospital of Qingdao University, Medical College, Qingdao, ShanDong Province, People’s Republic of China (Received 22 May 2014; revised 20 September 2014; in final form 13 October 2014)
Abstract—The objective of this study was to investigate the feasibility of using 3-D transvaginal tomographic ultrasound imaging (TUI) to stage patients with cervical carcinoma. Eighty women with cervical cancer who underwent transvaginal TUI examinations were enrolled. In all patients, cancer was confirmed pre-operatively by pathologic examination. Staging on the basis of clinical features, ultrasonography and magnetic resonance imaging was performed according to the International Federation of Gynecology and Obstetrics (FIGO) staging system. Clinical, TUI and magnetic resonance imaging staging was compared with that based on histology. Depth of invasion into the stroma was measured by TUI in 52 cases and compared with pathologic results. An interclass correlation coefficient was used to analyze reproducibility. In total, all 80 patients underwent surgical treatment. The accuracy of pre-operative staging, compared with histologic findings, was 92.50% for TUI, 82.50% for magnetic resonance imaging and 78.75% for clinical examination. The mean depth of lesions as measured with TUI was 12.5 ± 6.2 mm (range: 3.5–40.0 mm), and that measured on histology was 10.5 ± 8.0 mm (range: 3.0–40.0 mm). The interclass correlation coefficient of the two methods was 0.933 (95% confidence interval: 0.887–0.961). Preoperative TUI is promising as a method for pre-operative staging of cervical carcinomas. TUI can also reliably assess lesion depth. (E-mail: [email protected]) Ó 2015 Published by Elsevier Inc. on behalf of World Federation for Ultrasound in Medicine & Biology. Key Words: Tomographic ultrasonic imaging, Ultrasound, Cervical carcinoma, Staging.
excretory urography and barium enema (Creasman et al. 1998; Koh et al. 2013; Sheu et al. 2001). Compared with surgical/histologic staging, clinical staging for primary cervical cancer has an error rate ranging from 26% to 66% (Sheu et al. 2001). Therefore, a more accurate evaluation method is necessary for successful treatment. Although the revised staging system did not previously include imaging modalities, FIGO now encourages their use in the staging of cervical cancers (Haie-Meder et al. 2010). FIGO recommended the use of three imaging modalities to improve pre-operative evaluation, including computed tomography (CT), magnetic resonance imaging (MRI) and ultrasound. Compared with CT, which has inherently low contrast with soft tissue, MRI has been viewed as the ideal modality for pre-operative staging of cervical carcinomas (Delgado et al. 1990; Lagasse et al. 1980; Parkin et al. 2001). Several studies have reported that T2-weighted MRI is the best imaging modality to reveal cervical neoplasms (Bipat et al. 2003;
INTRODUCTION Cervical cancer is the third most common malignancy among females, with 85% of new cases occurring in developing countries and 150,000 new cases per year in China (Koh et al. 2013). Assessment of the infiltration limits and involvement of cervical stroma and adjacent organs is essential for individualized treatment (Pecorelli et al. 2009). The International Federation of Gynecology and Obstetrics (FIGO) recommends a clinical staging system for cervical carcinomas based on findings from physical examination, colposcopy, biopsy of lesions, chest radiography, cystoscopy, sigmoidoscopy
Address correspondence to: Li-Tao Sun, Department of Ultrasound, Second Affiliated Hospital of Harbin Medical University, No. 246, Xufu Road, Nangang Dis, Harbin 150081, Heilongjiang, People’s Republic of China. E-mail: [email protected] Conflicts of Interest: The authors declare that there are no conflicts of interest. 2303
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Boss et al. 2000; Hricak et al. 1993; Nicolet et al. 2000; Sheu et al. 2001). However, MRI is expensive and cumbersome and cannot be performed in those with certain intrauterine devices. Ultrasound is gaining more attention as a non-invasive alternative because it is less time consuming, easy to perform and less expensive than MRI. Moreover, ultrasound has been found to be similar to MRI in diagnostic accuracy. Some prospective studies have suggested that it might to be superior to MRI in identifying parametrial involvement (Byun et al. 2013; Fischerova et al. 2008; Ghi et al. 2007; Testa et al. 2009). Tomographic ultrasound imaging (TUI) is a relatively new technique that combines several advantages of CT, MRI and traditional ultrasound. It allows multiplanar scanning and continuous imaging of the uterus. Volumetric reconstruction can be performed from different angles, including transverse planes, to reveal structures that are not visible using traditional transvaginal ultrasound. TUI has been satisfactory in first-trimester fetal cardiac examinations and scanning of the pelvis (Fischerova 2011; Turan et al. 2009). The improved resolution of transvaginal sonography and TUI might allow cervical cancer staging. The study described here investigated whether 3-D transvaginal TUI can accurately and reliably stage cervical carcinomas. TUI was used to assess the presence and extent of tumors and their depth of invasion into the stroma. All imaging results were compared with pathologic results, which were considered the gold standard. METHODS Patients This protocol was approved by the ethics committee of Harbin Medical University. From December 2011 to June 2013, 87 patients (42 6 11 y, range: 19–71 y) at the 2nd Affiliated Hospital of Harbin Medical University with invasive cervical cancer confirmed by biopsy were enrolled in this study. Patients with recurrent cervical cancer were excluded. Patients who previously received chemotherapy and/or radiotherapy were also excluded. Ultrasound and pelvic MRI examinations were performed within 1 wk before surgery. All patients signed informed consent forms before enrollment. Ultrasonography Real-time transabdominal ultrasound was performed using a Voluson E8 (GE Healthcare, Wauwatosa, WI, USA) with a 4- to 8-MHz transabdominal probe. Patients were asked to lie in the supine position with their bladders moderately full. Visceral organs and peritoneal surfaces, including the omentum majus and lympth nodes surrounding the abdominal aorta and iliac arteries, were examined. Patients were then asked to empty their blad-
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ders and lie in the lithotomy position for the transvaginal examination. Transvaginal ultrasound imaging was performed using the Voluson E8 with a 5- to 9-MHz transvaginal transducer protected by a disposable condom. The transvaginal probe was placed in the posterior fornix to reveal the cervix and the tumor. Position, shape, size, depth of invasion into stroma and echogenicity of the cervical lesions were recorded. Color Doppler flow imaging (CDFI) was used to assess blood supply to the lesion. The highest sensitivity setting was used to detect blood flow signals with low velocities (#2 cm/s). Afterward, the clearest sagittal view was selected, and the system was switched to 3-D mode to perform TUI. The parameters were as follows: sweep angle, 120 ; sweep velocity, maximum quality; sensitivity, highest. Volumetric data sets with the following characteristics were considered satisfactory: (i) the image had to reveal both the tumor and its growth pattern (exophytic/endophytic) clearly; (ii) the distance between the tumor and the internal cervix of the mouth should be observable; and (3) both the bladder and the rectum must be included. Tissues surrounding the cervix should also be able to be viewed clearly on the coronal plane. After acquisition of volumetric data, off-line TUI analysis was performed using Voluson 4DView software (GE Healthcare). First, the sagittal image was rotated so that the scan line was perpendicular to the cervical canal. A reference point was placed in the center of the tumor. Second, a 3-D box was drawn to encompass the cervix plus 2 cm on each side. Then 3-D reconstruction was performed with a slice interval of 2 mm and 15–29 slices, to ensure that all study slices could be displayed on the screen. Examinations were performed in succession by a single sonographer who had more than 10 y of experience in ultrasound scanning. The sonographer was blinded to colposcopy, physical examination and MRI findings. Before analysis, the sonographer underwent a 1-motraining course on analytical procedures from General Electric. Evaluation of TUI All images were assessed by a single sonographer based on volumetric measurements. On volumetric sonography, parametrial involvement was suspected if (i) the limits between the cervix itself or the tumor and the surrounding tissue became unclear or discontinuous; (ii) the hyper-echoic pericervical fascia of the cervix became disrupted; or (ii) the hyper-echoic gap between the cervix and the bladder/rectum disappeared (Epstein et al. 2010). Rectal or bladder invasion was suspected when the limit between the cervical tumor and the rectum or bladder was unclear, or the serosa of the bladder or rectum was interrupted. When hypo-echoic masses extended to the
3-D tomographic US imaging in cervical cancer staging d X.-S. HAN et al.
vagina, vaginal invasion was suspected. When the interface between bladder or rectum and cervix was not clear, bladder or rectal invasion was suspected. To assess the depth of invasion, 52 cases of cervical cancer measured on histopathology were selected. The surgical specimens were examined according to previous protocols (Testa et al. 2009). The maximum depth of invasion was compared with the value obtained by TUI. Staging Three sets of stages were assessed in this study. All were defined according to the revised staging system proposed by the FIGO (Pecorelli et al. 2009; Koh et al. 2013) in 2009 (Table 1). According to the standard protocol of our department, clinical staging was performed by a gynecologist on the basis of clinical findings. Ultrasound staging was performed on the basis of information from both conventional ultrasound and TUI images. Ultrasound staging was compared with clinical, MRI and surgical/histologic staging. Statistical analysis Data were analyzed using SPSS software Version 17.0 (SPSS, Chicago, IL, USA). Fisher’s exact and c2 tests were used to compare the performance of the different staging methods. A p-value ,0.05 was considered to indicate statistical significance. A reproducibility analysis was performed by calculating the interclass correlation coefficient (ICC).
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RESULTS In total, 80 patients agreed to surgical treatment. Most of the enrolled patients had squamous cell carcinoma. Both the histotype and final stage results are provided in Table 2. Cervical cancer was staged by clinical examination, 3-D TUI and MRI separately. Results for each method were compared with the results from pathologic staging for accuracy. The overall accuracy of pre-operative staging was 78.75% for clinical examination, 78.75% for clinical examination, 92.50% for 3D TUI, and 82.50% MRI (Table 3). Five stage IA cervical carcinomas were missed by clinical staging, but cone biopsies revealed the lesions. Seven patients were understaged and 10 patients were overstaged. Three-dimensional TUI failed to detect tumors in two patients (both stage IA), but these lesions were also undetected by clinical examinations. Seventy-three of 80 patients were correctly staged by 3-D TUI compared with histopathologic staging. Five patients were overstaged and 2 patients were understaged. Compared with histopathologic staging, MRI staging failed to detect left stage IA lesions in 3 patients. Eight patients were overstaged and five patients were understaged. The overall accuracy of tumor staging by TUI examination was 92.50%. In Figure 1 are images of a cervical lesion diagnosed by transvaginal ultrasound and a cervical tumor with well-developed blood vessels. Figure 2b is a tomographic ultrasound image revealing parametrial invasion.
Table 1. Revised staging system used in this study* Stage
Surgical pathology staging
Clinical staging
IA IB
Confirmed by microscopy Lesion confined to cervix, or $ IA
IB1 IB2 IIA
Lesion size #4 cm Lesion size .4 cm Carcinoma extends beyond cervical canal, to upper two-thirds of vagina, no parametrial involvement
IIA1 IIA2 IIB
Lesion size #4 cm Lesion size .4 cm Parametrial involvement, but not onto pelvic sidewall
Confirmed by microscopyy Lesion confined to cervix, brittle, tissues around cervical canal are elastic and prone to bleeding Lesion size visible #4 cm Lesion size visible .4 cm Carcinoma extends beyond cervical canal, to upper two-thirds of vagina, vaginal fornix shortened, tissues around cervical canal are elastic Lesion size visible #4 cm Lesion size visible .4 cm Vaginal fornix shortened, parametria thickened and hard or with nodules
IIIA IIIB
Involvement of lower third of vagina without pelvic sidewall extension Extension onto pelvic sidewall
Involvement of lower third of vagina, pelvic sidewall difficult to determine Hydronephrosis or non-functioning kidney
IVA
Spread to adjacent pelvic organs
IVB
Spread to distant organs
Clinical involvement of bladder and/or rectal mucosa Spread to distant organs
Ultrasound imaging Tumor not seen or same as IB Heterogeneic hypo-echoic area or mass confined to cervix, cervical canal destroyed, serosa continuous Lesion size visible #4 cm Lesion size visible .4 cm Hypo-echoic mass extends to upper two-thirds of vagina, cervical canal destroyed, serosa continuous Lesion size #4 cm Lesion size .4 cm Heterogeneic mass, boundary not clear, serosa continuous or extruding outside, or nodes in parametrium Heterogeneic mass extending into lower vagina, but not onto pelvic sidewall Nodes on pelvic sidewall or hydronephrosis/ non-functioning kidney Loss of perivesical and perirectal normal echo Spread to distant organs
* Adapted from FIGO Committee on Gynecologic Oncology. Vascular space invasion and lymph node metastasis should not alter staging. y Extension to the uterine corpus should be disregarded.
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Table 2. Characteristics of enrolled patients (n 5 80) Histotype Squamous Adenocarcinoma Adenosquamous Glassy cells FIGO stage IA1 IA2 IB1 IB2 IIA IIB
70 5 4 1 1 4 46 4 15 10
Histopathologic evaluation revealed lymph node metastases in 10 patients. They were staged as IIB (3 patients), IB (4 patients) and IIA (3 patients). Combined D TUI and transabdominal ultrasound revealed lymph node involvement in 2 patients (accuracy 5 20%). MRI revealed lymph node involvement in 5 patients (accuracy 5 50%). Reproducibility analyses comparing depths of invasion of lesions measured by TUI and histopathology included 52 cases in which both histopathology and TUI revealed the tumor. The mean depth of lesions was 12.5 6 6.2 mm (range: 3.5–40.0 mm) as measured with TUI and 10.5 6 8.0 mm (range: 3.0–40.0 mm) as measured on histopathology. The ICC of the two methods was 0.933 (95% confidence interval: 0.887–0.961). DISCUSSION Cervical cancer is a major health problem for women worldwide. Successful treatment that improves outcomes in cervical cancer requires accurate evaluation (Fischerova 2011). There has been a great deal of research on pre-operative assessment in patients with cervical cancer (Cobby et al. 1990; Zalewski et al. 2010), and imaging is complementary to clinical assessment. Despite being used in gynecology for a relatively short period, transvaginal ultrasound shows promise as a method for staging invasive cervical cancer. Recent
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publications have reported acceptable accuracy for ultrasound examinations for pre-operative staging of cervical cancer (Fischerova et al. 2008; Gaurilcikas et al. 2011; Innocenti et al. 1992). A review of 12 studies describing the accuracy of MRI staging of cervical carcinoma reported a mean accuracy of 79% (rang: 47%–90%) (Boss et al. 2000). Our results agree with these studies. In our study, we evaluated the staging performance of clinical examination, 3-D transvaginal TUI and MRI in early invasive cervical cancers. Our results indicated that the overall accuracy of pre-operative staging was 92.50% for 3-D transvaginal TUI, which was higher than that for MRI (82.5%). Vaginal involvement can be easily detected by physical or colposcopy examinations. (Boss et al. 2000; Nicolet et al. 2000). However, clinical evaluation of parametrial infiltration is considered unreliable as it is highly subjective and examiner dependent (Benedet et al. 2003). It has been reported that clinical examination could underestimate one-third of cases of parametrial invasion (Delgado et al. 1990; Lagasse et al. 1980), whereas MRI could accurately detect 53% cases (Hricak et al. 2005). For the 10 patients with stage IIB disease in our study, 9 p were staged correctly by TUI, 6 were staged correctly by MRI and only 3 were staged correctly by clinical staging. The accuracy of 3-D transvaginal TUI was actually superior to that of MRI. Lateral extension of the tumor toward the cervical parametria could be detected more easily in the transverse section. We believe that altered echogenicity of the pericervical fascia, with or without nodular or irregular tumor signal intensity extending into the parametrium, is a reliable sign of parametrial invasion. Therefore, pre-operative 3-D transvaginal TUI might be promising as a method for the evaluation of cervical cancer with parametrial infiltration. Although this study did not include patients who denied or were not candidates for surgical treatment in the final statistics, we observed several useful indicators that can be used to detect rectal or bladder involvement. The presence of narrow echogenic stripes of fibrous and fat tissue between
Table 3. Comparison of clinical, US and MRI staging Clinical staging Stage IA IB IIA IIB Accuracy Comparisons Clinical vs. US US vs. MRI
Final staging
Accurate
5 50 15 10
5 42 13 3
Understaged — 2 — 5 (63/80) 78.75%
US 5 ultrasound; MRI 5 magnetic resonance imaging.
US staging Overstaged
Accurate
— 6 2 2
1 48 15 10
Understaged
MRI staging Overstaged
Accurate
2 2 — 1
0 45 15 6
2 — — — (74/80) 92.50%
c2 5 4.902, p 5 0.022 c2 5 2.686, p 5 0.079
Understaged 3 1 — 2 66/80 (82.50%)
Overstaged 2 4 — 2
3-D tomographic US imaging in cervical cancer staging d X.-S. HAN et al.
Fig. 1. (a) Transvaginal ultrasound image of cervical cancer. (b) Color Doppler flow imaging reveals increased blood flow.
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the tumor and the rectum or bladder wall can exclude involvement of these structures. In addition, the echogenic pericervical fascia near the bladder also could be seen clearly (Fig. 3). Three-dimensional TUI and MRI results were similar in the remaining 7 patients who denied or were ineligible for surgical treatment. Three-dimensional TUI failed to detect microscopic metastasis in lymph nodes that appeared to be of normal size, but this should not be considered a clinical obstacle. One reason is that vascular invasion and lymph node metastasis do not affect staging. In addition, pelvic lymphadenectomies in the presence of invasive cervical cancer are mandatory, whether or not positive lymph nodes are detected pre-operatively. Transabdominal ultrasonography may be a useful supplement in evaluation of lymph nodes. In our study, we detected para-aortic lymph nodes in 3 slender patients using a transabdominal probe. The depth of invasion into the stroma was also an important prognostic factor. It is useful in the preoperative staging of cervical cancer and ultrasoundguided biopsy. We compared depths of invasion in 52 patients measured with TUI and histologically. Reproducibility analysis revealed that the correlation between the two methods was excellent (ICC 5 0.933, 95% confidence interval: 0.887–0.961). Moreover, TUI allowed off-line analysis after high-resolution imaging of cervical tumors. Unlike conventional 2-D transvaginal
Fig. 2. Images of the uterine cervix of a 39-y-old woman confirmed as having invasive cervical squamous cell carcinoma on pathologic examination. The tumor was classified as stage IIB. (a) Two-dimensional transvaginal ultrasound image revealing cervical cancer with a clear cervical margin, suggesting non-parametrial invasion. (b) Tomographic ultrasound image revealing disrupted echogenic pericervical fascia on the left cervix and involvement of the left parametria. (c) Histopathology confirmed left parametrial involvement.
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Fig. 3. Evaluation of the bladder. (a) Arrows point to a clear bladder–serosa margin and fat tissue between the cervix and bladder. (b) Arrowhead points to a mass involving the fat tissue between the cervix and bladder. (c) Magnetic resonance image revealing the same result as in (b).
sonography, with TUI the cervix is imaged in a simultaneous multiplanar fashion and the images are displayed on a single screen. Conventional 2-D transvaginal ultrasound requires meticulous scanning and precise operating skills, such as setting the probe at appropriate angles to visualize the relationship between the tumor and surrounding tissues; TUI makes acquisition of cervical tumor images much easier and less operator dependent. In this study, we did not compare the differences in clinical performance between conventional 2-D transvaginal ultrasound and 3-D transvaginal TUI. Because a satisfactory 3-D tomographic ultrasound image is reconstructed from 2-D images, we felt that the two methods were inseparable and complement each other clinically. Therefore, 3-D transvaginal TUI has a significant role in pre-operative staging of cervical cancer. It can provide objective and useful findings for staging and treatment.
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Byun JM, Kim YN, Jeong DH, Kim KT, Sung MS, Lee KB. Threedimensional transvaginal ultrasonography for locally advanced cervical cancer. Int J Gynecol Cancer 2013;23:1459–1464. Cobby M, Browning J, Jones A, Whipp E, Goddard P. Magnetic resonance imaging, computed tomography and endosonography in the local staging of carcinoma of the cervix. Br J Radiol 1990;63: 673–679. Creasman WT, Zaino RJ, Major FJ, Disaia PJ, Hatch KD, Homesley HD. Early invasive carcinoma of the cervix (3–5 mm invasion): Risk factors and prognosis. A Gynecologic Oncology Group study. Am J Obstet Gynecol 1998;178:62–65. Delgado G, Bundy B, Zaino R, Sevin BU, Creasman WT, Major F. Prospective surgical-pathologic study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix: A Gynecologic Oncology Group study. Gynecol Oncol 1990;38:352–357. Epstein E, Dilegge A, M asb€ack A, Lindqvist PG, Kannisto P, Testa AC. Sonographic characteristics of squamous cell cancer and adenocarcinoma of the uterine cervix. Ultrasound Obstet Gynecol 2010;36: 512–516. Fischerova D. Ultrasound scanning of the pelvis and abdomen for staging of gynecologic tumors: a review. Ultrasound Obstet Gynecol 2011;38:246–266. Fischerova D, Cibula D, Stenhova H, Vondrichova H, Calda P, Zikan M, Freitag P, Slama J, Dundr P, Belacek J. Transrectal ultrasound and magnetic resonance imaging in staging of early cervical cancer. Int J Gynecol Cancer 2008;18:766–772. Gaurilcikas A, Vaitkiene D, Cizauskas A, Inciura A, Svedas E, Maciuleviciene R, Di Legge A, Ferrandina G, Testa AC, Valentin L. Early-stage cervical cancer: Agreement between ultrasound and histopathological findings with regard to tumor size and extent of local disease. Ultrasound Obstet Gynecol 2011;38: 707–715. Ghi T, Giunchi S, Kuleva M, Santini D, Savelli L, Formelli G, Casadio P, Costa S, Meriggiola MC, Pelusi G. Three-dimensional transvaginal sonography in local staging of cervical carcinoma: Description of a
3-D tomographic US imaging in cervical cancer staging d X.-S. HAN et al. novel technique and preliminary results. Ultrasound Obstet Gynecol 2007;30:778–782. Haie-Meder C, Morice P, Castiglione M. ESMO Guidelines Working Group. Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010;21(Suppl 5): v37–v40. Hricak H, Quivey JM, Campos Z, Gildengorin V, Hindmarsh T, Bis KG, Stern JL, Phillips TL. Carcinoma of the cervix: Predictive value of clinical and magnetic resonance (MR) imaging assessment of prognostic factors. Int J Radiat Oncol Biol Phys 1993;27:791–801. Hricak H, Gatsonis C, Chi DS, Amendola MA, Brandt K, Schwartz LH, Koelliker S, Siegelman ES, Brown JJ, McGhee RB Jr, Vitellas KM, Snyder B, Long HJ III, Fiorica JV, Mitchell DG. Role of imaging in pre-treatment evaluation of early invasive cervical cancer: Results of the intergroup study American College of Radiology Imaging Network 6651–Gynecologic Oncology Group 183. J Clin Oncol 2005;23:9329–9337. Innocenti P, Pulli F, Savino L, Nicolucci A, Pandimiglio A, Menchi I, Massi G. Staging of cervical cancer: Reliability of transrectal US. Radiology 1992;185:201–205. Koh WJ, Greer BE, Abu-Rustum NR, Apte SM, Campos SM, Chan J, Cho KR, Cohn D, Crispens MA, DuPont N, Eifel PJ, Gaffney DK, Giuntoli RL II, Han E, Huh WK, Lurain JR III, Martin L, Morgan MA, Mutch D, Remmenga SW, Reynolds RK, Small W Jr, Teng N, Tillmanns T, Valea FA, McMillian NR, Hughes M. Cervical Cancer. J Natl Compr Canc Netw 2013;11:320–343.
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Lagasse LD, Creasman WT, Shingleton HM, Ford JH, Blessing JA. Results and complications of operative staging in cervical cancer: Experience of the Gynecologic Oncology Group. Gynecol Oncol 1980;9:90–98. Nicolet V, Carignan L, Bourdon F, Prosmanne O. MR imaging of cervical carcinoma: A practical staging approach. Radiographics 2000; 20:1539–1549. Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000: The global picture. Eur J Cancer 2001;37(Suppl 8):S4–S66. Pecorelli S, Zigliani L, Odicino F. Revised FIGO staging for carcinoma of the cervix. Int J Gynaecol Obstet 2009;105:107–108. Sheu MH, Chang CY, Wang JH, Yen MS. Preoperative staging of cervical carcinoma with MR imaging: A reappraisal of diagnostic accuracy and pitfalls. Eur Radiol 2001;11:1828–1833. Testa AC, Ludovisi M, Manfredi R, Zannoni G, Gui B, Basso D, Dilegge A, Licameli A, Dibidino R, Scambia G, Ferrandina G. Transvaginal ultrasonography and magnetic resonance imaging for assessment of presence, size and extent of invasive cervical cancer. Ultrasound Obstet Gynecol 2009;34:335–344. Turan S, Turan OM, Ty-Torredes K, Harman CR, Baschat AA. Standardization of the first-trimester fetal cardiac examination using spatiotemporal image correlation with tomographic ultrasound and color Doppler imaging. Ultrasound Obstet Gynecol 2009;33:652–656. Zalewski K, Doniec J, Baranowski W, Bidzinski M. Revised FIGO staging systems for gynecologic malignancies—2009 update. Ginekol Pol 2010;81:778.
http://dx.doi.org/10.1016/j.ultrasmedbio.2014.10.005
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Original Contribution THREE-DIMENSIONAL TRANSVAGINAL TOMOGRAPHIC ULTRASOUND IMAGING FOR CERVICAL CANCER STAGING XUE-SONG HAN,* CHUN-PING NING,y LI-TAO SUN,* XIAO-YING LI,* YAN-QING PENG,* and MEI-ZHENG DANG* * Department of Ultrasound, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People’s Republic of China; and y Department of Ultrasound, Affiliated Hospital of Qingdao University, Medical College, Qingdao, ShanDong Province, People’s Republic of China (Received 22 May 2014; revised 20 September 2014; in final form 13 October 2014)
Abstract—The objective of this study was to investigate the feasibility of using 3-D transvaginal tomographic ultrasound imaging (TUI) to stage patients with cervical carcinoma. Eighty women with cervical cancer who underwent transvaginal TUI examinations were enrolled. In all patients, cancer was confirmed pre-operatively by pathologic examination. Staging on the basis of clinical features, ultrasonography and magnetic resonance imaging was performed according to the International Federation of Gynecology and Obstetrics (FIGO) staging system. Clinical, TUI and magnetic resonance imaging staging was compared with that based on histology. Depth of invasion into the stroma was measured by TUI in 52 cases and compared with pathologic results. An interclass correlation coefficient was used to analyze reproducibility. In total, all 80 patients underwent surgical treatment. The accuracy of pre-operative staging, compared with histologic findings, was 92.50% for TUI, 82.50% for magnetic resonance imaging and 78.75% for clinical examination. The mean depth of lesions as measured with TUI was 12.5 ± 6.2 mm (range: 3.5–40.0 mm), and that measured on histology was 10.5 ± 8.0 mm (range: 3.0–40.0 mm). The interclass correlation coefficient of the two methods was 0.933 (95% confidence interval: 0.887–0.961). Preoperative TUI is promising as a method for pre-operative staging of cervical carcinomas. TUI can also reliably assess lesion depth. (E-mail: [email protected]) Ó 2015 Published by Elsevier Inc. on behalf of World Federation for Ultrasound in Medicine & Biology. Key Words: Tomographic ultrasonic imaging, Ultrasound, Cervical carcinoma, Staging.
excretory urography and barium enema (Creasman et al. 1998; Koh et al. 2013; Sheu et al. 2001). Compared with surgical/histologic staging, clinical staging for primary cervical cancer has an error rate ranging from 26% to 66% (Sheu et al. 2001). Therefore, a more accurate evaluation method is necessary for successful treatment. Although the revised staging system did not previously include imaging modalities, FIGO now encourages their use in the staging of cervical cancers (Haie-Meder et al. 2010). FIGO recommended the use of three imaging modalities to improve pre-operative evaluation, including computed tomography (CT), magnetic resonance imaging (MRI) and ultrasound. Compared with CT, which has inherently low contrast with soft tissue, MRI has been viewed as the ideal modality for pre-operative staging of cervical carcinomas (Delgado et al. 1990; Lagasse et al. 1980; Parkin et al. 2001). Several studies have reported that T2-weighted MRI is the best imaging modality to reveal cervical neoplasms (Bipat et al. 2003;
INTRODUCTION Cervical cancer is the third most common malignancy among females, with 85% of new cases occurring in developing countries and 150,000 new cases per year in China (Koh et al. 2013). Assessment of the infiltration limits and involvement of cervical stroma and adjacent organs is essential for individualized treatment (Pecorelli et al. 2009). The International Federation of Gynecology and Obstetrics (FIGO) recommends a clinical staging system for cervical carcinomas based on findings from physical examination, colposcopy, biopsy of lesions, chest radiography, cystoscopy, sigmoidoscopy
Address correspondence to: Li-Tao Sun, Department of Ultrasound, Second Affiliated Hospital of Harbin Medical University, No. 246, Xufu Road, Nangang Dis, Harbin 150081, Heilongjiang, People’s Republic of China. E-mail: [email protected] Conflicts of Interest: The authors declare that there are no conflicts of interest. 2303
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Boss et al. 2000; Hricak et al. 1993; Nicolet et al. 2000; Sheu et al. 2001). However, MRI is expensive and cumbersome and cannot be performed in those with certain intrauterine devices. Ultrasound is gaining more attention as a non-invasive alternative because it is less time consuming, easy to perform and less expensive than MRI. Moreover, ultrasound has been found to be similar to MRI in diagnostic accuracy. Some prospective studies have suggested that it might to be superior to MRI in identifying parametrial involvement (Byun et al. 2013; Fischerova et al. 2008; Ghi et al. 2007; Testa et al. 2009). Tomographic ultrasound imaging (TUI) is a relatively new technique that combines several advantages of CT, MRI and traditional ultrasound. It allows multiplanar scanning and continuous imaging of the uterus. Volumetric reconstruction can be performed from different angles, including transverse planes, to reveal structures that are not visible using traditional transvaginal ultrasound. TUI has been satisfactory in first-trimester fetal cardiac examinations and scanning of the pelvis (Fischerova 2011; Turan et al. 2009). The improved resolution of transvaginal sonography and TUI might allow cervical cancer staging. The study described here investigated whether 3-D transvaginal TUI can accurately and reliably stage cervical carcinomas. TUI was used to assess the presence and extent of tumors and their depth of invasion into the stroma. All imaging results were compared with pathologic results, which were considered the gold standard. METHODS Patients This protocol was approved by the ethics committee of Harbin Medical University. From December 2011 to June 2013, 87 patients (42 6 11 y, range: 19–71 y) at the 2nd Affiliated Hospital of Harbin Medical University with invasive cervical cancer confirmed by biopsy were enrolled in this study. Patients with recurrent cervical cancer were excluded. Patients who previously received chemotherapy and/or radiotherapy were also excluded. Ultrasound and pelvic MRI examinations were performed within 1 wk before surgery. All patients signed informed consent forms before enrollment. Ultrasonography Real-time transabdominal ultrasound was performed using a Voluson E8 (GE Healthcare, Wauwatosa, WI, USA) with a 4- to 8-MHz transabdominal probe. Patients were asked to lie in the supine position with their bladders moderately full. Visceral organs and peritoneal surfaces, including the omentum majus and lympth nodes surrounding the abdominal aorta and iliac arteries, were examined. Patients were then asked to empty their blad-
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ders and lie in the lithotomy position for the transvaginal examination. Transvaginal ultrasound imaging was performed using the Voluson E8 with a 5- to 9-MHz transvaginal transducer protected by a disposable condom. The transvaginal probe was placed in the posterior fornix to reveal the cervix and the tumor. Position, shape, size, depth of invasion into stroma and echogenicity of the cervical lesions were recorded. Color Doppler flow imaging (CDFI) was used to assess blood supply to the lesion. The highest sensitivity setting was used to detect blood flow signals with low velocities (#2 cm/s). Afterward, the clearest sagittal view was selected, and the system was switched to 3-D mode to perform TUI. The parameters were as follows: sweep angle, 120 ; sweep velocity, maximum quality; sensitivity, highest. Volumetric data sets with the following characteristics were considered satisfactory: (i) the image had to reveal both the tumor and its growth pattern (exophytic/endophytic) clearly; (ii) the distance between the tumor and the internal cervix of the mouth should be observable; and (3) both the bladder and the rectum must be included. Tissues surrounding the cervix should also be able to be viewed clearly on the coronal plane. After acquisition of volumetric data, off-line TUI analysis was performed using Voluson 4DView software (GE Healthcare). First, the sagittal image was rotated so that the scan line was perpendicular to the cervical canal. A reference point was placed in the center of the tumor. Second, a 3-D box was drawn to encompass the cervix plus 2 cm on each side. Then 3-D reconstruction was performed with a slice interval of 2 mm and 15–29 slices, to ensure that all study slices could be displayed on the screen. Examinations were performed in succession by a single sonographer who had more than 10 y of experience in ultrasound scanning. The sonographer was blinded to colposcopy, physical examination and MRI findings. Before analysis, the sonographer underwent a 1-motraining course on analytical procedures from General Electric. Evaluation of TUI All images were assessed by a single sonographer based on volumetric measurements. On volumetric sonography, parametrial involvement was suspected if (i) the limits between the cervix itself or the tumor and the surrounding tissue became unclear or discontinuous; (ii) the hyper-echoic pericervical fascia of the cervix became disrupted; or (ii) the hyper-echoic gap between the cervix and the bladder/rectum disappeared (Epstein et al. 2010). Rectal or bladder invasion was suspected when the limit between the cervical tumor and the rectum or bladder was unclear, or the serosa of the bladder or rectum was interrupted. When hypo-echoic masses extended to the
3-D tomographic US imaging in cervical cancer staging d X.-S. HAN et al.
vagina, vaginal invasion was suspected. When the interface between bladder or rectum and cervix was not clear, bladder or rectal invasion was suspected. To assess the depth of invasion, 52 cases of cervical cancer measured on histopathology were selected. The surgical specimens were examined according to previous protocols (Testa et al. 2009). The maximum depth of invasion was compared with the value obtained by TUI. Staging Three sets of stages were assessed in this study. All were defined according to the revised staging system proposed by the FIGO (Pecorelli et al. 2009; Koh et al. 2013) in 2009 (Table 1). According to the standard protocol of our department, clinical staging was performed by a gynecologist on the basis of clinical findings. Ultrasound staging was performed on the basis of information from both conventional ultrasound and TUI images. Ultrasound staging was compared with clinical, MRI and surgical/histologic staging. Statistical analysis Data were analyzed using SPSS software Version 17.0 (SPSS, Chicago, IL, USA). Fisher’s exact and c2 tests were used to compare the performance of the different staging methods. A p-value ,0.05 was considered to indicate statistical significance. A reproducibility analysis was performed by calculating the interclass correlation coefficient (ICC).
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RESULTS In total, 80 patients agreed to surgical treatment. Most of the enrolled patients had squamous cell carcinoma. Both the histotype and final stage results are provided in Table 2. Cervical cancer was staged by clinical examination, 3-D TUI and MRI separately. Results for each method were compared with the results from pathologic staging for accuracy. The overall accuracy of pre-operative staging was 78.75% for clinical examination, 78.75% for clinical examination, 92.50% for 3D TUI, and 82.50% MRI (Table 3). Five stage IA cervical carcinomas were missed by clinical staging, but cone biopsies revealed the lesions. Seven patients were understaged and 10 patients were overstaged. Three-dimensional TUI failed to detect tumors in two patients (both stage IA), but these lesions were also undetected by clinical examinations. Seventy-three of 80 patients were correctly staged by 3-D TUI compared with histopathologic staging. Five patients were overstaged and 2 patients were understaged. Compared with histopathologic staging, MRI staging failed to detect left stage IA lesions in 3 patients. Eight patients were overstaged and five patients were understaged. The overall accuracy of tumor staging by TUI examination was 92.50%. In Figure 1 are images of a cervical lesion diagnosed by transvaginal ultrasound and a cervical tumor with well-developed blood vessels. Figure 2b is a tomographic ultrasound image revealing parametrial invasion.
Table 1. Revised staging system used in this study* Stage
Surgical pathology staging
Clinical staging
IA IB
Confirmed by microscopy Lesion confined to cervix, or $ IA
IB1 IB2 IIA
Lesion size #4 cm Lesion size .4 cm Carcinoma extends beyond cervical canal, to upper two-thirds of vagina, no parametrial involvement
IIA1 IIA2 IIB
Lesion size #4 cm Lesion size .4 cm Parametrial involvement, but not onto pelvic sidewall
Confirmed by microscopyy Lesion confined to cervix, brittle, tissues around cervical canal are elastic and prone to bleeding Lesion size visible #4 cm Lesion size visible .4 cm Carcinoma extends beyond cervical canal, to upper two-thirds of vagina, vaginal fornix shortened, tissues around cervical canal are elastic Lesion size visible #4 cm Lesion size visible .4 cm Vaginal fornix shortened, parametria thickened and hard or with nodules
IIIA IIIB
Involvement of lower third of vagina without pelvic sidewall extension Extension onto pelvic sidewall
Involvement of lower third of vagina, pelvic sidewall difficult to determine Hydronephrosis or non-functioning kidney
IVA
Spread to adjacent pelvic organs
IVB
Spread to distant organs
Clinical involvement of bladder and/or rectal mucosa Spread to distant organs
Ultrasound imaging Tumor not seen or same as IB Heterogeneic hypo-echoic area or mass confined to cervix, cervical canal destroyed, serosa continuous Lesion size visible #4 cm Lesion size visible .4 cm Hypo-echoic mass extends to upper two-thirds of vagina, cervical canal destroyed, serosa continuous Lesion size #4 cm Lesion size .4 cm Heterogeneic mass, boundary not clear, serosa continuous or extruding outside, or nodes in parametrium Heterogeneic mass extending into lower vagina, but not onto pelvic sidewall Nodes on pelvic sidewall or hydronephrosis/ non-functioning kidney Loss of perivesical and perirectal normal echo Spread to distant organs
* Adapted from FIGO Committee on Gynecologic Oncology. Vascular space invasion and lymph node metastasis should not alter staging. y Extension to the uterine corpus should be disregarded.
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Table 2. Characteristics of enrolled patients (n 5 80) Histotype Squamous Adenocarcinoma Adenosquamous Glassy cells FIGO stage IA1 IA2 IB1 IB2 IIA IIB
70 5 4 1 1 4 46 4 15 10
Histopathologic evaluation revealed lymph node metastases in 10 patients. They were staged as IIB (3 patients), IB (4 patients) and IIA (3 patients). Combined D TUI and transabdominal ultrasound revealed lymph node involvement in 2 patients (accuracy 5 20%). MRI revealed lymph node involvement in 5 patients (accuracy 5 50%). Reproducibility analyses comparing depths of invasion of lesions measured by TUI and histopathology included 52 cases in which both histopathology and TUI revealed the tumor. The mean depth of lesions was 12.5 6 6.2 mm (range: 3.5–40.0 mm) as measured with TUI and 10.5 6 8.0 mm (range: 3.0–40.0 mm) as measured on histopathology. The ICC of the two methods was 0.933 (95% confidence interval: 0.887–0.961). DISCUSSION Cervical cancer is a major health problem for women worldwide. Successful treatment that improves outcomes in cervical cancer requires accurate evaluation (Fischerova 2011). There has been a great deal of research on pre-operative assessment in patients with cervical cancer (Cobby et al. 1990; Zalewski et al. 2010), and imaging is complementary to clinical assessment. Despite being used in gynecology for a relatively short period, transvaginal ultrasound shows promise as a method for staging invasive cervical cancer. Recent
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publications have reported acceptable accuracy for ultrasound examinations for pre-operative staging of cervical cancer (Fischerova et al. 2008; Gaurilcikas et al. 2011; Innocenti et al. 1992). A review of 12 studies describing the accuracy of MRI staging of cervical carcinoma reported a mean accuracy of 79% (rang: 47%–90%) (Boss et al. 2000). Our results agree with these studies. In our study, we evaluated the staging performance of clinical examination, 3-D transvaginal TUI and MRI in early invasive cervical cancers. Our results indicated that the overall accuracy of pre-operative staging was 92.50% for 3-D transvaginal TUI, which was higher than that for MRI (82.5%). Vaginal involvement can be easily detected by physical or colposcopy examinations. (Boss et al. 2000; Nicolet et al. 2000). However, clinical evaluation of parametrial infiltration is considered unreliable as it is highly subjective and examiner dependent (Benedet et al. 2003). It has been reported that clinical examination could underestimate one-third of cases of parametrial invasion (Delgado et al. 1990; Lagasse et al. 1980), whereas MRI could accurately detect 53% cases (Hricak et al. 2005). For the 10 patients with stage IIB disease in our study, 9 p were staged correctly by TUI, 6 were staged correctly by MRI and only 3 were staged correctly by clinical staging. The accuracy of 3-D transvaginal TUI was actually superior to that of MRI. Lateral extension of the tumor toward the cervical parametria could be detected more easily in the transverse section. We believe that altered echogenicity of the pericervical fascia, with or without nodular or irregular tumor signal intensity extending into the parametrium, is a reliable sign of parametrial invasion. Therefore, pre-operative 3-D transvaginal TUI might be promising as a method for the evaluation of cervical cancer with parametrial infiltration. Although this study did not include patients who denied or were not candidates for surgical treatment in the final statistics, we observed several useful indicators that can be used to detect rectal or bladder involvement. The presence of narrow echogenic stripes of fibrous and fat tissue between
Table 3. Comparison of clinical, US and MRI staging Clinical staging Stage IA IB IIA IIB Accuracy Comparisons Clinical vs. US US vs. MRI
Final staging
Accurate
5 50 15 10
5 42 13 3
Understaged — 2 — 5 (63/80) 78.75%
US 5 ultrasound; MRI 5 magnetic resonance imaging.
US staging Overstaged
Accurate
— 6 2 2
1 48 15 10
Understaged
MRI staging Overstaged
Accurate
2 2 — 1
0 45 15 6
2 — — — (74/80) 92.50%
c2 5 4.902, p 5 0.022 c2 5 2.686, p 5 0.079
Understaged 3 1 — 2 66/80 (82.50%)
Overstaged 2 4 — 2
3-D tomographic US imaging in cervical cancer staging d X.-S. HAN et al.
Fig. 1. (a) Transvaginal ultrasound image of cervical cancer. (b) Color Doppler flow imaging reveals increased blood flow.
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the tumor and the rectum or bladder wall can exclude involvement of these structures. In addition, the echogenic pericervical fascia near the bladder also could be seen clearly (Fig. 3). Three-dimensional TUI and MRI results were similar in the remaining 7 patients who denied or were ineligible for surgical treatment. Three-dimensional TUI failed to detect microscopic metastasis in lymph nodes that appeared to be of normal size, but this should not be considered a clinical obstacle. One reason is that vascular invasion and lymph node metastasis do not affect staging. In addition, pelvic lymphadenectomies in the presence of invasive cervical cancer are mandatory, whether or not positive lymph nodes are detected pre-operatively. Transabdominal ultrasonography may be a useful supplement in evaluation of lymph nodes. In our study, we detected para-aortic lymph nodes in 3 slender patients using a transabdominal probe. The depth of invasion into the stroma was also an important prognostic factor. It is useful in the preoperative staging of cervical cancer and ultrasoundguided biopsy. We compared depths of invasion in 52 patients measured with TUI and histologically. Reproducibility analysis revealed that the correlation between the two methods was excellent (ICC 5 0.933, 95% confidence interval: 0.887–0.961). Moreover, TUI allowed off-line analysis after high-resolution imaging of cervical tumors. Unlike conventional 2-D transvaginal
Fig. 2. Images of the uterine cervix of a 39-y-old woman confirmed as having invasive cervical squamous cell carcinoma on pathologic examination. The tumor was classified as stage IIB. (a) Two-dimensional transvaginal ultrasound image revealing cervical cancer with a clear cervical margin, suggesting non-parametrial invasion. (b) Tomographic ultrasound image revealing disrupted echogenic pericervical fascia on the left cervix and involvement of the left parametria. (c) Histopathology confirmed left parametrial involvement.
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Fig. 3. Evaluation of the bladder. (a) Arrows point to a clear bladder–serosa margin and fat tissue between the cervix and bladder. (b) Arrowhead points to a mass involving the fat tissue between the cervix and bladder. (c) Magnetic resonance image revealing the same result as in (b).
sonography, with TUI the cervix is imaged in a simultaneous multiplanar fashion and the images are displayed on a single screen. Conventional 2-D transvaginal ultrasound requires meticulous scanning and precise operating skills, such as setting the probe at appropriate angles to visualize the relationship between the tumor and surrounding tissues; TUI makes acquisition of cervical tumor images much easier and less operator dependent. In this study, we did not compare the differences in clinical performance between conventional 2-D transvaginal ultrasound and 3-D transvaginal TUI. Because a satisfactory 3-D tomographic ultrasound image is reconstructed from 2-D images, we felt that the two methods were inseparable and complement each other clinically. Therefore, 3-D transvaginal TUI has a significant role in pre-operative staging of cervical cancer. It can provide objective and useful findings for staging and treatment.
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