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Magnetic Resonance Imaging in the Diagnosis, Staging, and Surveillance of Cervical Carcinoma
Author's Accepted Manuscript
MRI in the Diagnosis, Staging, and Surveillance of Cervical Carcinoma Catherine Devine MD, Carly Gardner MD, Tara Sagebiel MD, Priya Bhosale MD
www.elsevier.com/locate/enganabound
PII: DOI: Reference:
S0887-2171(15)00039-6 http://dx.doi.org/10.1053/j.sult.2015.05.004 YSULT633
To appear in: Semin Ultrasound CT MRI
Cite this article as: Catherine Devine MD, Carly Gardner MD, Tara Sagebiel MD, Priya Bhosale MD, MRI in the Diagnosis, Staging, and Surveillance of Cervical Carcinoma, Semin Ultrasound CT MRI , http://dx.doi.org/10.1053/j.sult.2015.05.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
MRI in the Diagnosis, Staging, and Surveillance of Cervical Carcinoma
Authors Catherine Devine MD, Associate Professor, Diagnostic Radiology, UTMDACC Carly Gardner MD, Fellow, Abdominal Imaging, Diagnostic Radiology, UTMDACC Tara Sagebiel MD, Assistant Professor, Diagnostic Radiology, UTMDACC Priya Bhosale MD, Associate Professor, Diagnostic Radiology, UTMDACC
Abstract Cervical carcinoma remains a common gynecologic malignancy. Magnetic Resonance Imaging is a useful and accurate tool in the diagnosis, staging, and follow-up of cervical carcinoma. This article will describe the optimal techniques for MR evaluation of the cervix, illustrate the role of MRI in patients with known or suspected cervical carcinoma, and describe key aspects of staging and management of cervical carcinoma.
Introduction Cervical cancer is the third most common gynecological malignancy in females, following uterine and ovarian cancer. The number of cases of cervical cancer and the number of deaths from cervical cancer have decreased significantly in the past 40 years due to cervical screening.1 Currently, cervical cancer is diagnosed in one out of every 154 American women over her lifetime, with 12,900 new cases and 4,100 deaths estimated to occur in 2015.2 The five-year overall survival rates range from 93% for stage I disease to 15% for stage IV disease.3 Patients typically present in the fourth and fifth decades of life. Many patients with noninvasive cervical cancers are asymptomatic and are initially diagnosed due to screening with a Papanicolaou’s (Pap) smear. Patients with invasive cervical cancer frequently present with vaginal discharge and intermenstrual or postcoital bleeding. Human papilloma virus (HPV) infection is the most important etiologic factor in cervical cancer, and is present in nearly all cases of cervical squamous cell carcinomas.4 Several other risk factors have been reported, including early coitarche, multiple sexual partners, low socioeconomic status, and smoking.5
Histopathology There are 2 main histologic types of cervical carcinoma: squamous cell carcinoma, which accounts for the majority of cases, and non-squamous cell cancers, which account for only approximately 20% of cases.6 Squamous cell carcinomas arise from foci of dysplasia and atypia at the squamocolumnar junction. Nonsquamous cell cancers arise from the endocervical glands and include andenocarcinoma, adenosquamous carcinoma, adenocystic carcinoma, small-cell carcinoma, and lymphoma.7 While the incidence of
squamous cell carinomas has declined in recent decades, there has been an increase in relative and absolute incidence of adenocarcinoma and adenosquamous carcinoma of the uterine cervix during the same period.8 Adenoma malignum is a very rare subtype of cervical adenocarcinoma which carries a very poor prognosis. It is a multicystic lesion associated with copious watery vaginal discharge, and may be indistinguishable from nabothian cysts on MRI. Adenoma malignum is exceedingly uncommon and should not be diagnosed based on imaging findings alone.9
Anatomy The cervix is usually between 2-3 cm long and cylindrical in shape. The endocervical canal connects the uterine cavity and the lumen of the vagina via the internal os and external os, respectively. The lower part of the cervix, known as the vaginal portion, portio vaginalis, or ectocervix, is covered by stratified squamous epithelium as a continuation of the epithelial lining of the vagina. The endocervical canal is lined by columnar epithelium. These two epithelial linings meet at the squamocolumnar junction. Metaplasia at this junction results in squamous cell carcinomas. The squamocolumnar junction is located near the external os in young women, but migrates superiorly with advancing age. This movement accounts for a typical pattern of exophytic tumors in young women and endocervival tumors in older women.10 A thick layer of fibrous stroma underlies both types of epithelium. T2 weighted MR imaging demonstrates the distinct zones of the cervix: hyperintense mucous located centrally in the canal, hyperintense endocervical mucosa, and hypointense fibrous stroma forming the outer layer (figure 1). Cervical lymphatics initially drain to parametrial nodes. From this level, the drainage proceeds laterally to external iliac nodes, inferiorly to internal iliac nodes, or posteriorly along sacral nodes. All of these routes lead eventually to the common iliac nodes and the para-aortic nodes.7 There are three patterns of spread of squamous cell carcinoma of the cervix: direct invasion of adjacent organs, the most common; lymphatic dissemination to pelvic and para-aortic lymph nodes; and rarely, hematogenous spread to the lungs and bones.11
Clinical Staging and Prognosis Staging of cervical cancer aims at assessing tumor resectability and is currently based on the guidelines of the International Federation of Gynecology and Obstetrics (FIGO) (table 1).12 The FIGO classification is a clinical approach based on findings from physical examination. Many studies have demonstrated the value of cross-sectional imaging over clinical staging, and MRI is significantly better than clinical examination in ruling out parametrial invasion.13,14 The most recent update to FIGO staging system encourages, but does not mandate the use of diagnostic imaging techniques.15 The FIGO staging system is used as a predictor of patient survival, but has limitations.16 Studies have shown a poor correlation between the clinical stage and surgical-pathologic findings. These limitations are due inaccurate estimation of tumor size, poor detection of parametrial, pelvic sidewall, bladder and rectal wall invasion, and non-detection of distant metastases.7 In addition, nodal status, known to be one of the most important prognostic factors, is not included in the current FIGO staging system.17,18
Accurate staging influences clinical management. Current FIGO guidelines suggest surgical treatment or radiotherapy alone for patients with early disease, stages IA, IB1, and IIA with tumor size less than or
equal to 4 cm. Patients who have more extensive early disease, stages IB2 and IIA with tumor size greater than 4 cm, may require radiation and/or chemotherapy. Furthermore, stage IIB (limited extrauterine extension to the parametrium) disease or greater precludes curative surgical treatment.
Imaging Modalities Physical examination remains the central component of cervical cancer evaluation, but often fails in the accurate estimation of tumor size, the detection of parametrial, pelvic sidewall, bladder and rectal wall invasion, and metastases to distant organs.7 CT, PET/CT, Ultrasound, and MRI all have roles in assessing local extent and distant spread of disease. The advantages of MRI include excellent soft tissue resolution, wide field of view, and lack of ionizing radiation. MRI is far more reliable than physical exam in assessing tumor size, with accuracy close to 90%.19 MRI has a high negative predictive value for parametrial invasion, approaching 100% in some studies.20, 21 The positive predictive value of MRI for parametrial invasion is lower, due to the difficulty in distinguishing benign reactive changes adjacent to the cervix from actual tumor invasion. MRI is highly accurate in diagnosing bladder and rectal invasion.22
MRI Technique Proper patient preparation and MR imaging technique are critical in obtaining high quality images. The patient should be instructed to fast for 4 hours prior to the study to reduce bowl motion artifact. Some institutions advocate the use of an anti-peristaltic agent, such as 1 mg of glucagon intramuscularly, to further minimize bowl motion. The bladder should neither be empty, nor uncomfortably full. A partially distended bladder can helpfully displace loops of bowel out of the pelvis. The patient should be imaged supine with a surface phased-array coil on a high field magnet (1.5 Tesla or higher). Once the patient is positioned on the table, approximately 20-30 cc of warm ultrasound gel is instilled into the vagina via a catheter. The high signal intensity of the vaginal gel creates excellent contrast, highlighting the contour of the vaginal portion of the cervix on the T2 weighted sequences. The T2-weighted sequences are the mainstay of cervical cancer imaging, namely sagittal and axial oblique thin-section, small field of view, high-resolution T2 weighted sequences. Dynamic gadoliniumenhanced T1-weighted imaging has been shown to improve detection of small cervical tumors and may be especially useful for the evaluation of depth of stromal invasion and bladder wall invasion.23, 24 Additional sequences may include an axial T1-weighted sequence with a large field of view to evaluate the entire pelvis and lower abdomen for lymphadenopathy and bone marrow abnormalities, a large field of view SSFSE T2 weighted sequence to include the kidneys, and diffusion weighted images. (Table 2)
MRI appearance of cervical cancer The normal cervix demonstrates three discrete zones on high-resolution T2-weighted images, a central hyperintense zone formed by the endocervical mucosa, a hypointense middle layer of fibromuscular stroma, and a low to intermediate signal intensity outer layer of fibromuscular stroma. The three layers cannot be distinguished onT1-weighted images, but after the administration of intravenous gadolinium contrast, the endocervical mucosa enhances more rapidly than the fibromuscular stroma.25
Cervical carcinoma appears as a high signal intensity mass on T2 weighted sequences, disrupting the normal T2 hypointense fibromuscular stroma. The tumor usually cannot be distinguished on T1-weighted images. Cervical carcinoma is hyperintense on diffusion-weighted images with corresponding low signal intensity on the apparent diffusion coefficient (ADC) map. While T2-weighed sequences provide the key images for staging, diffusion-weighted images can be helpful to localize very small tumors. MRI Staging Stage I Stage IA microinvasive tumors are not reliably visualized on MRI, although they may be detected as a focus of early enhancement on dynamic contrast-enhanced images. For macroscopic tumors, MRI provides excellent measurement of the size of primary tumor, coming within 5 mm of pathologic measurements of surgical specimens with 83-93% accuracy.26, 27 Treatment decisions hinge on the size of small tumors, which should be measured in all 3 planes. In early-stage cervical carcinoma (≤ IB1 and distance of >5mm from the internal os) treatment with trachelectomy (which removes the cervix, but leaves the uterine body intact) can be considered to preserve fertility. Involvement of the internal os is a contra-indication to such treatment. Tumor involvement of the internal os is best evaluated on sagittal T2weighed images, with reported sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 91%, 97%, 81%, 98% and 96%, respectively.28 (figures 2 and 3) Stage II Tumor which extends beyond the uterine cervix, but not to the pelvic sidewall or lower vagina, is classified as stage II. Tumor infiltration into the vagina can be seen as T2-hyperintensity interrupting the normally hypointense vaginal walls. The location should be described as anterior or posterior, and whether it is confined to the upper two-thirds, or extends to the lower one-third of the vagina. Physical exam is often more accurate than MRI in assessing the vaginal fornices.29 Once the tumor breaches the cervical stoma and extends into the parametrium, it is classified as IIB. (figure 4) The stromal ring is best evaluated with axial oblique T2 weighted images perpendicular to the long axis of the cervix. The presence of an intact cervical stromal ring excludes parametrial extension with a negative predictive value of 94-100%.7 With early parametrial extension, the interface between the cervix and the parametrium becomes irregular and spiculated. More advanced parametrial extension is seen as an actual mass in the fatty parametrium. MRI is superior to physical exam in detecting parametrial extension, particularly early extension, with reported sensitivity of 69% and specificity of 93%.30 MRI is prone to overestimate parametrial invasion in large tumors with an accuracy of 70% versus an accuracy of 96% in small tumors due to stromal edema caused by tumor compression and inflammation.30 Nonetheless, MRI is considerably more accurate for staging than physical exam, which as an accuracy of approximately 50%.7 Stage III Tumor which extends to the lower vagina or to the pelvic side wall is classified as stage III. Stage IIIA disease involves the lower vagina, but not the pelvic sidewall. Stage IIIB disease extends to the pelvic sidewall or causes hydronephrosis. Pelvic sidewall involvement can be seen as tumor coming within 3mm or less from the pelvic sidewall musculature. The internal obturator, levator ani, and pyriformis muscles will demonstrate hyperintense infiltration when involved with tumor. Encasement of the iliac vessels is an additional sign of pelvic sidewall involvement. Involvement of the ureters resulting in hydronephrosis is automatically stage IIIB disease. (figure 5)
Stage IV Tumor which involves adjacent organs (bladder or rectum) or has distant metastases is classified as stage IV. Adjacent organ invasion is suspected if there is loss of the plane of fat separation between the cervix and the bladder or rectum. Abnormal high signal intensity in the bladder wall is suspicious for tumor involvement, but must be confirmed with cystoscopy, as bullous edema can mimic tumor. Frank tumor growth invading the bladder or rectum is unequivocally stage IV. (figure 6)
Lymph Node Involvement Although not included in the FIGO staging system, nodal involvement is one of the most important prognostic factors in cervical cancer. In surgically treatable disease, survival rates decline from 85–90% to 50–55% if nodal metastases are present. 7,11 MRI determination of metastatic lymph nodes is primarily based on size criteria, with a short-axis diameter of 1 centimeter or more indicating metastatic involvement. The limitations of morphologic assessment are well known, as enlarged lymph nodes may be reactive, and small nodes may contain microscopic foci of disease. Nodal metastases are typically seen initially in the pelvis with an orderly progression superiorly to involve retroperitoneal nodes. Rarely there are direct metastases to para-aortic nodes.31 (figure 7)
Distant Metastases Cervical carcinoma metastasizes hematogenously to the lungs, liver, and bones. Bone metastases are typically lytic. Distant metastases indicate a poor prognosis with a 5-year survival rate of 16%.1
Imaging Treatment Response Early-stage cervical cancer is treated surgically. Locally advanced tumors are treated with external beam radiation therapy with concurrent chemotherapy and integrated brachytherapy.32 MR imaging is the modality of choice for monitoring treatment response and for evaluating recurrent disease.33 Following radiation therapy, cervical tumors decrease in size and T2 signal intensity. Treatment effect may be seen rapidly (3 months) or after a delay (6-9 months), particularly in larger tumors. Complete treatment response is indicated by the return of the normal low-signal intensity cervical stroma and normal cervical zonal anatomy.33 (figure 8) If MR imaging is performed prior to 3 months post-radiation therapy, it can be difficult to distinguish between residual tumor and post-radiation edema and inflammation, both of which are seen as high T2 signal intensity. Recurrent disease often occurs in the cervix itself, and in the vaginal cuff, parametrium, and pelvic sidewall.34 MRI is useful to detect recurrences and may be able to distinguish recurrent tumor from radiation-induced fibrosis. Recurrent tumors are often heterogeneous masses with high signal intensity on T2 weighted sequences and variable degrees of enhancement. Radiation fibrosis has lower signal intensity on T2 weighted sequences, does not enhance significantly, and should regress or remain stable over time.35 Recurrent disease may be treated with radiation if it recurs in a non-radiated field. When the recurrence develops in the radiated field, pelvic exenteration may be considered as salvage therapy. Pelvic exenteration is a radical surgery with en bloc resection or all pelvic organs, the distal urinary tract, and anorectum. Due to the extremely high morbidity of this radical surgery, an exenteration is performed with curative intent and only when a complete resection with disease-free margins is expected.36
Conclusion MRI is widely accepted as an ideal modality for local staging of cervical carcinoma, and it has very high accuracy when performed with appropriate technique and image quality. MRI is useful in determining the feasibility of fertility-sparing surgery, as well as determining whether or not a patient is a surgical candidate based on parametrial involvement. MRI is useful in treatment planning, monitoring response to therapy, and assessing for recurrent disease. Factors contributing to prognosis, such as nodal involvement, tumor volume, and advanced stage disease can be evaluated with MRI. Finally, MRI has been shown to be cost-effective by eliminating the need for additional imaging or surgical procedures.37
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9. Yamashita Y, Takahashi M, Katabuchi H, et al: Adenoma malignum: MR appearances mimicking nabothian cysts. AJR Am J Roentgenol 162:649-650, 1994.
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11. Cheng X, Cai S, Li Z, et al: The prognosis of women with stage IB1-IIB node-positive cervical carcinoma after radical surgery. World J Surg Oncol 18:47, 2004.
12. Figo Committee on Gynecologic Oncology: Figo staging for carcinoma of the vulva, cervix and corpus uteri. Int J Gynaecol Obstet 125:97-98, 2014.
13. Subak LL, Hricak H, Powell CB, et al: Cervical carcinoma: computed tomography and magnetic resonance imaging for preoperative staging. Obstet Gynecol 86:43-50, 1995.
14. Thomeer MG, Gerestein C, Spronk S, et al: Clinical examination versus magnetic resonance imaging in the pretreatment staging of cervical carcinoma: systematic review and meta-analysis. Eur Radiol 23:2005-2018, 2013.
15. Pecorelli S, Zigliani L, Odicino F: Revised FIGO staging for carcinoma of the cervix. Int J Gynaecol Obstet 105:107-108, 2009.
16. Benedet JL, Odicino F, Maisonneuve P, et al: Carcinoma of the cervix uteri. Int J Gynaecol Obstet 83:41-78, 2003.
17. Freeman SJ, Aly AM, Kataoka MY, et al: The revised FIGO staging system for uterine malignancies: implications for MR Imaging. Radiographics 32:1805-1827, 2012.
18. Narayan K: Arguments for a magnetic resonance imaging-assisted FIGO staging system for cervical cancer. Int J Gynecol Cancer 15:573-582, 2005.
19. Tirumani SH, Shanbhogue AK, Prasad SR: Current concepts in the diagnosis and management of endometrial and cervical carcinomas. Radiol Clin North Am 51:1087-1110, 2013.
20. Hricak H, Gatsonis C, Chi DS, et al: Role of imaging in pretreatment 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 23:9329-9337, 2005.
21. Follen M, Levenback CF, Iyer RB, et al: Imaging in cervical cancer. Cancer 98:2028-2038, 2003.
22. Hricak H, Lacey CG, Sandles LG, et al: Invasive cervical carcinoma: comparison of MR imaging and surgical findings. Radiology 166:623-631, 1988.
23. Seki H, Azumi R, Kimura M, et al: Stromal invasion by carcinoma of the cervix: assessment with dynamic MR imaging. AJR Am J Roentgenol 168:1579-1585, 1997.
24. Yamashita Y, Takahashi M, Sawada T, et al: Carcinoma of the cervix: Dynamic MR imaging. Radiology 182:643-648, 1992.
25. Wasnik AP, Mazza MB, Liu PS: Normal and variant pelvic anatomy on MRI. Magn Reson Imaging Clin N Am 19:547-566, 2011.
26. Rauch GM, Kaur H, Choi H, et al: Optimization of MR imaging for pretreatment evaluation of patients with endometrial and cervical cancer. Radiographics 34:1082–1098, 2014.
27. Bourgioti C, Koutoulidis V, Chatoupis K, et al: MRI findings before and after abdominal radical trachelectomy (ART) for cervical cancer: a prospective study and review of the literature. Clin Radiol 69:678–686, 2014.
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30. Sala E, Wakely S, Senior E, et al: MRI of malignant neoplasms of the uterine corpus and cervix. AJR Am J Roentgenol 188:1577-1587, 2007.
31. Gallup D: Glob. libr. women's med., in Aralkumaran S (ed): The Spread and Staging of Cervical Cancer. London, UK, 2008, ISSN: 1756-2228; DOI 10.3843/GLOWM.10231
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37. Hricak H, Powell CB, Yu KK et al: Invasive cervical carcinoma: role of MR imaging in pretreatment work-up – cost minimization and diagnostic efficacy analysis. Radiology 198:403409, 1996.
Tables and Figures
a.
b. Figure 1. Normal cervix. (a) sagittal T2 weighted MRI of the pelvis with vaginal gel demonstrates low-signal intensity of the normal cervix. (b) axial T2 weighted MRI of the normal cervix demonstrates normal zonal anatomy (in order from the center): high T2 signal intensity in fluid in the endocervical canal, intermediate high T2 signal intensity in columnar epithelium in the endocervix, low T2 signal intensity cervical stroma, and low-intermediate T2 signal intensity in the outer cervical stroma.
Figure 2. 45 year old female presenting with menorrhagia. Axial oblique T2 thin section through the cervix reveals a large tumor with preservation of a thin rim of cervical stroma (white arrow). Metastatic right internal iliac node (black arrow). Stage IB2.
a.
b.
c. Figure 3. Stage IB2 disease (a) sagittal T2 weighted MRI of the pelvis demonstrates an exophytic cervical tumor. (b) sagittal dynamic contrast enhanced MRI of the pelvis demonstrates the enhancing cervical tumor. (c) coronal T2 weighted MRI demonstrates full-thickness involvement of the cervical stroma without parametrial extension.
Figure 4. 45-year old female with pelvic pain. Axial T2-weighted MRI reveals a large cervical tumor with parametrial extension (arrows), rendering the patient stage IIB.
Figure 5. 32 year old female presenting with pelvic pain. Axial and coronal T2 weighted MRI demonstrates extensive left pelvic sidewall involvement with left hydroureteronephrosis. Stage IIIB
a.
b. Figure 6. (a) 54 year old female presenting with heavy intermenstrual bleeding, found to have stage IVA disease. Sagittal T2 weighted MRI of the pelvis with vaginal gel demonstrates a large tumor with invasion of the posterior bladder wall (short arrow) and early rectal involvement (long arrow). (b) Sagittal dynamic post-contrast image of bladder invasion (arrow).
Figure 7. Lymph node evaluation. A T2-weighted MR image demonstrates an enlarged left external iliac lymph node.
a.
b. Figure 8. 24-year old female with intermittent vaginal bleeding. (a) Pre-treatment sagittal T2weighted MRI of the pelvis with vaginal gel demonstrates a stage 1B2 squamous cell carcinoma of the cervix (arrow). (b) Sagittal T2-weighted MRI of the pelvis of the same patient following chemoradiation. There is no visible residual tumor, and the cervical stroma has normal low-signal intensity (short arrow). Minor artifact is due to a radiation seed (long arrow).
TABLE 1: International Federation of Gynecology and Obstetrics (FIGO) Staging of Cervical Cancer12 Stage I
Description The carcinoma is strictly confined to the cervix (extension to the uterine corpus should be disregarded).
IA
Invasive cancer identified only microscopically. (All gross lesions even with superficial invasion are Stage IB cancers.) Invasion is limited to measured stromal invasion with a maximum depth of 5 mma and no wider than 7 mm.
IA1
Measured invasion of stroma ≤ 3 mm in depth and ≤ 7 mm width.
IA2
Measured invasion of stroma > 3 mm and < 5 mm in depth and ≤ 7 mm width.
IB
Clinical lesions confined to the cervix, or preclinical lesions greater than stage IA.
IB1
Clinical lesions no greater than 4 cm in size.
1B2
Clinical lesions > 4 cm in size.
II
The carcinoma extends beyond the uterus, but has not extended onto the pelvic wall or to the lower third of vagina.
IIA
Involvement of up to the upper 2/3 of the vagina. No obvious parametrial involvement.
IIA1
Clinically visible lesion ≤ 4 cm
IIA2
Clinically visible lesion > 4 cm
IIB
Obvious parametrial involvement but not onto the pelvic sidewall.
III
The carcinoma has extended onto the pelvic sidewall. On rectal examination, there is no cancer free space between the tumor and pelvic sidewall. The tumor involves the lower third of the vagina. All cases of hydronephrosis or non-functioning kidney should be included unless they are known to be due to other causes.
IIIA
Involvement of the lower vagina but no extension onto pelvic sidewall.
IIIB IV
Extension onto the pelvic sidewall, or hydronephrosis/non-functioning kidney. The carcinoma has extended beyond the true pelvis or has clinically involved the mucosa of the bladder and/or rectum.
IVA
Spread to adjacent pelvic organs.
IVB
Spread to distant organs.
TABLE 2: Typical MRI Sequences Sequence T2
Scanning Plane
Purpose
Coronal (large FOV)
Assess for hydronephrosis, overview of lower abdomen and pelvis Assess lymph nodes
T2
Axial
Overview of pelvis Assess ovaries Overview of pelvis
T1
Axial (large FOV)
Evaluate nodes, bone marrow Assess for hematometra or other collections Measure primary tumor size
T2
Sagittal thin section (3-mm), small FOV (20-22 cm)
Assess tumor extent Assess extension into uterus, vagina, bladder, rectum
T2
DWI
Axial oblique (perpendicular to the endocervical canal),thin section (3-mm), small FOV (20-22 cm)
Axial (large FOV)
Measure primary tumor size Assess parametrial invasion
Highlight neoplastic tissue, localize very small tumors Evaluate response to therapy
Dynamic contrast enhanced T1
Sagittal, small field of view
Evaluate extent of myometrial and cervical involvement
MRI in the Diagnosis, Staging, and Surveillance of Cervical Carcinoma Catherine Devine MD, Carly Gardner MD, Tara Sagebiel MD, Priya Bhosale MD
www.elsevier.com/locate/enganabound
PII: DOI: Reference:
S0887-2171(15)00039-6 http://dx.doi.org/10.1053/j.sult.2015.05.004 YSULT633
To appear in: Semin Ultrasound CT MRI
Cite this article as: Catherine Devine MD, Carly Gardner MD, Tara Sagebiel MD, Priya Bhosale MD, MRI in the Diagnosis, Staging, and Surveillance of Cervical Carcinoma, Semin Ultrasound CT MRI , http://dx.doi.org/10.1053/j.sult.2015.05.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
MRI in the Diagnosis, Staging, and Surveillance of Cervical Carcinoma
Authors Catherine Devine MD, Associate Professor, Diagnostic Radiology, UTMDACC Carly Gardner MD, Fellow, Abdominal Imaging, Diagnostic Radiology, UTMDACC Tara Sagebiel MD, Assistant Professor, Diagnostic Radiology, UTMDACC Priya Bhosale MD, Associate Professor, Diagnostic Radiology, UTMDACC
Abstract Cervical carcinoma remains a common gynecologic malignancy. Magnetic Resonance Imaging is a useful and accurate tool in the diagnosis, staging, and follow-up of cervical carcinoma. This article will describe the optimal techniques for MR evaluation of the cervix, illustrate the role of MRI in patients with known or suspected cervical carcinoma, and describe key aspects of staging and management of cervical carcinoma.
Introduction Cervical cancer is the third most common gynecological malignancy in females, following uterine and ovarian cancer. The number of cases of cervical cancer and the number of deaths from cervical cancer have decreased significantly in the past 40 years due to cervical screening.1 Currently, cervical cancer is diagnosed in one out of every 154 American women over her lifetime, with 12,900 new cases and 4,100 deaths estimated to occur in 2015.2 The five-year overall survival rates range from 93% for stage I disease to 15% for stage IV disease.3 Patients typically present in the fourth and fifth decades of life. Many patients with noninvasive cervical cancers are asymptomatic and are initially diagnosed due to screening with a Papanicolaou’s (Pap) smear. Patients with invasive cervical cancer frequently present with vaginal discharge and intermenstrual or postcoital bleeding. Human papilloma virus (HPV) infection is the most important etiologic factor in cervical cancer, and is present in nearly all cases of cervical squamous cell carcinomas.4 Several other risk factors have been reported, including early coitarche, multiple sexual partners, low socioeconomic status, and smoking.5
Histopathology There are 2 main histologic types of cervical carcinoma: squamous cell carcinoma, which accounts for the majority of cases, and non-squamous cell cancers, which account for only approximately 20% of cases.6 Squamous cell carcinomas arise from foci of dysplasia and atypia at the squamocolumnar junction. Nonsquamous cell cancers arise from the endocervical glands and include andenocarcinoma, adenosquamous carcinoma, adenocystic carcinoma, small-cell carcinoma, and lymphoma.7 While the incidence of
squamous cell carinomas has declined in recent decades, there has been an increase in relative and absolute incidence of adenocarcinoma and adenosquamous carcinoma of the uterine cervix during the same period.8 Adenoma malignum is a very rare subtype of cervical adenocarcinoma which carries a very poor prognosis. It is a multicystic lesion associated with copious watery vaginal discharge, and may be indistinguishable from nabothian cysts on MRI. Adenoma malignum is exceedingly uncommon and should not be diagnosed based on imaging findings alone.9
Anatomy The cervix is usually between 2-3 cm long and cylindrical in shape. The endocervical canal connects the uterine cavity and the lumen of the vagina via the internal os and external os, respectively. The lower part of the cervix, known as the vaginal portion, portio vaginalis, or ectocervix, is covered by stratified squamous epithelium as a continuation of the epithelial lining of the vagina. The endocervical canal is lined by columnar epithelium. These two epithelial linings meet at the squamocolumnar junction. Metaplasia at this junction results in squamous cell carcinomas. The squamocolumnar junction is located near the external os in young women, but migrates superiorly with advancing age. This movement accounts for a typical pattern of exophytic tumors in young women and endocervival tumors in older women.10 A thick layer of fibrous stroma underlies both types of epithelium. T2 weighted MR imaging demonstrates the distinct zones of the cervix: hyperintense mucous located centrally in the canal, hyperintense endocervical mucosa, and hypointense fibrous stroma forming the outer layer (figure 1). Cervical lymphatics initially drain to parametrial nodes. From this level, the drainage proceeds laterally to external iliac nodes, inferiorly to internal iliac nodes, or posteriorly along sacral nodes. All of these routes lead eventually to the common iliac nodes and the para-aortic nodes.7 There are three patterns of spread of squamous cell carcinoma of the cervix: direct invasion of adjacent organs, the most common; lymphatic dissemination to pelvic and para-aortic lymph nodes; and rarely, hematogenous spread to the lungs and bones.11
Clinical Staging and Prognosis Staging of cervical cancer aims at assessing tumor resectability and is currently based on the guidelines of the International Federation of Gynecology and Obstetrics (FIGO) (table 1).12 The FIGO classification is a clinical approach based on findings from physical examination. Many studies have demonstrated the value of cross-sectional imaging over clinical staging, and MRI is significantly better than clinical examination in ruling out parametrial invasion.13,14 The most recent update to FIGO staging system encourages, but does not mandate the use of diagnostic imaging techniques.15 The FIGO staging system is used as a predictor of patient survival, but has limitations.16 Studies have shown a poor correlation between the clinical stage and surgical-pathologic findings. These limitations are due inaccurate estimation of tumor size, poor detection of parametrial, pelvic sidewall, bladder and rectal wall invasion, and non-detection of distant metastases.7 In addition, nodal status, known to be one of the most important prognostic factors, is not included in the current FIGO staging system.17,18
Accurate staging influences clinical management. Current FIGO guidelines suggest surgical treatment or radiotherapy alone for patients with early disease, stages IA, IB1, and IIA with tumor size less than or
equal to 4 cm. Patients who have more extensive early disease, stages IB2 and IIA with tumor size greater than 4 cm, may require radiation and/or chemotherapy. Furthermore, stage IIB (limited extrauterine extension to the parametrium) disease or greater precludes curative surgical treatment.
Imaging Modalities Physical examination remains the central component of cervical cancer evaluation, but often fails in the accurate estimation of tumor size, the detection of parametrial, pelvic sidewall, bladder and rectal wall invasion, and metastases to distant organs.7 CT, PET/CT, Ultrasound, and MRI all have roles in assessing local extent and distant spread of disease. The advantages of MRI include excellent soft tissue resolution, wide field of view, and lack of ionizing radiation. MRI is far more reliable than physical exam in assessing tumor size, with accuracy close to 90%.19 MRI has a high negative predictive value for parametrial invasion, approaching 100% in some studies.20, 21 The positive predictive value of MRI for parametrial invasion is lower, due to the difficulty in distinguishing benign reactive changes adjacent to the cervix from actual tumor invasion. MRI is highly accurate in diagnosing bladder and rectal invasion.22
MRI Technique Proper patient preparation and MR imaging technique are critical in obtaining high quality images. The patient should be instructed to fast for 4 hours prior to the study to reduce bowl motion artifact. Some institutions advocate the use of an anti-peristaltic agent, such as 1 mg of glucagon intramuscularly, to further minimize bowl motion. The bladder should neither be empty, nor uncomfortably full. A partially distended bladder can helpfully displace loops of bowel out of the pelvis. The patient should be imaged supine with a surface phased-array coil on a high field magnet (1.5 Tesla or higher). Once the patient is positioned on the table, approximately 20-30 cc of warm ultrasound gel is instilled into the vagina via a catheter. The high signal intensity of the vaginal gel creates excellent contrast, highlighting the contour of the vaginal portion of the cervix on the T2 weighted sequences. The T2-weighted sequences are the mainstay of cervical cancer imaging, namely sagittal and axial oblique thin-section, small field of view, high-resolution T2 weighted sequences. Dynamic gadoliniumenhanced T1-weighted imaging has been shown to improve detection of small cervical tumors and may be especially useful for the evaluation of depth of stromal invasion and bladder wall invasion.23, 24 Additional sequences may include an axial T1-weighted sequence with a large field of view to evaluate the entire pelvis and lower abdomen for lymphadenopathy and bone marrow abnormalities, a large field of view SSFSE T2 weighted sequence to include the kidneys, and diffusion weighted images. (Table 2)
MRI appearance of cervical cancer The normal cervix demonstrates three discrete zones on high-resolution T2-weighted images, a central hyperintense zone formed by the endocervical mucosa, a hypointense middle layer of fibromuscular stroma, and a low to intermediate signal intensity outer layer of fibromuscular stroma. The three layers cannot be distinguished onT1-weighted images, but after the administration of intravenous gadolinium contrast, the endocervical mucosa enhances more rapidly than the fibromuscular stroma.25
Cervical carcinoma appears as a high signal intensity mass on T2 weighted sequences, disrupting the normal T2 hypointense fibromuscular stroma. The tumor usually cannot be distinguished on T1-weighted images. Cervical carcinoma is hyperintense on diffusion-weighted images with corresponding low signal intensity on the apparent diffusion coefficient (ADC) map. While T2-weighed sequences provide the key images for staging, diffusion-weighted images can be helpful to localize very small tumors. MRI Staging Stage I Stage IA microinvasive tumors are not reliably visualized on MRI, although they may be detected as a focus of early enhancement on dynamic contrast-enhanced images. For macroscopic tumors, MRI provides excellent measurement of the size of primary tumor, coming within 5 mm of pathologic measurements of surgical specimens with 83-93% accuracy.26, 27 Treatment decisions hinge on the size of small tumors, which should be measured in all 3 planes. In early-stage cervical carcinoma (≤ IB1 and distance of >5mm from the internal os) treatment with trachelectomy (which removes the cervix, but leaves the uterine body intact) can be considered to preserve fertility. Involvement of the internal os is a contra-indication to such treatment. Tumor involvement of the internal os is best evaluated on sagittal T2weighed images, with reported sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 91%, 97%, 81%, 98% and 96%, respectively.28 (figures 2 and 3) Stage II Tumor which extends beyond the uterine cervix, but not to the pelvic sidewall or lower vagina, is classified as stage II. Tumor infiltration into the vagina can be seen as T2-hyperintensity interrupting the normally hypointense vaginal walls. The location should be described as anterior or posterior, and whether it is confined to the upper two-thirds, or extends to the lower one-third of the vagina. Physical exam is often more accurate than MRI in assessing the vaginal fornices.29 Once the tumor breaches the cervical stoma and extends into the parametrium, it is classified as IIB. (figure 4) The stromal ring is best evaluated with axial oblique T2 weighted images perpendicular to the long axis of the cervix. The presence of an intact cervical stromal ring excludes parametrial extension with a negative predictive value of 94-100%.7 With early parametrial extension, the interface between the cervix and the parametrium becomes irregular and spiculated. More advanced parametrial extension is seen as an actual mass in the fatty parametrium. MRI is superior to physical exam in detecting parametrial extension, particularly early extension, with reported sensitivity of 69% and specificity of 93%.30 MRI is prone to overestimate parametrial invasion in large tumors with an accuracy of 70% versus an accuracy of 96% in small tumors due to stromal edema caused by tumor compression and inflammation.30 Nonetheless, MRI is considerably more accurate for staging than physical exam, which as an accuracy of approximately 50%.7 Stage III Tumor which extends to the lower vagina or to the pelvic side wall is classified as stage III. Stage IIIA disease involves the lower vagina, but not the pelvic sidewall. Stage IIIB disease extends to the pelvic sidewall or causes hydronephrosis. Pelvic sidewall involvement can be seen as tumor coming within 3mm or less from the pelvic sidewall musculature. The internal obturator, levator ani, and pyriformis muscles will demonstrate hyperintense infiltration when involved with tumor. Encasement of the iliac vessels is an additional sign of pelvic sidewall involvement. Involvement of the ureters resulting in hydronephrosis is automatically stage IIIB disease. (figure 5)
Stage IV Tumor which involves adjacent organs (bladder or rectum) or has distant metastases is classified as stage IV. Adjacent organ invasion is suspected if there is loss of the plane of fat separation between the cervix and the bladder or rectum. Abnormal high signal intensity in the bladder wall is suspicious for tumor involvement, but must be confirmed with cystoscopy, as bullous edema can mimic tumor. Frank tumor growth invading the bladder or rectum is unequivocally stage IV. (figure 6)
Lymph Node Involvement Although not included in the FIGO staging system, nodal involvement is one of the most important prognostic factors in cervical cancer. In surgically treatable disease, survival rates decline from 85–90% to 50–55% if nodal metastases are present. 7,11 MRI determination of metastatic lymph nodes is primarily based on size criteria, with a short-axis diameter of 1 centimeter or more indicating metastatic involvement. The limitations of morphologic assessment are well known, as enlarged lymph nodes may be reactive, and small nodes may contain microscopic foci of disease. Nodal metastases are typically seen initially in the pelvis with an orderly progression superiorly to involve retroperitoneal nodes. Rarely there are direct metastases to para-aortic nodes.31 (figure 7)
Distant Metastases Cervical carcinoma metastasizes hematogenously to the lungs, liver, and bones. Bone metastases are typically lytic. Distant metastases indicate a poor prognosis with a 5-year survival rate of 16%.1
Imaging Treatment Response Early-stage cervical cancer is treated surgically. Locally advanced tumors are treated with external beam radiation therapy with concurrent chemotherapy and integrated brachytherapy.32 MR imaging is the modality of choice for monitoring treatment response and for evaluating recurrent disease.33 Following radiation therapy, cervical tumors decrease in size and T2 signal intensity. Treatment effect may be seen rapidly (3 months) or after a delay (6-9 months), particularly in larger tumors. Complete treatment response is indicated by the return of the normal low-signal intensity cervical stroma and normal cervical zonal anatomy.33 (figure 8) If MR imaging is performed prior to 3 months post-radiation therapy, it can be difficult to distinguish between residual tumor and post-radiation edema and inflammation, both of which are seen as high T2 signal intensity. Recurrent disease often occurs in the cervix itself, and in the vaginal cuff, parametrium, and pelvic sidewall.34 MRI is useful to detect recurrences and may be able to distinguish recurrent tumor from radiation-induced fibrosis. Recurrent tumors are often heterogeneous masses with high signal intensity on T2 weighted sequences and variable degrees of enhancement. Radiation fibrosis has lower signal intensity on T2 weighted sequences, does not enhance significantly, and should regress or remain stable over time.35 Recurrent disease may be treated with radiation if it recurs in a non-radiated field. When the recurrence develops in the radiated field, pelvic exenteration may be considered as salvage therapy. Pelvic exenteration is a radical surgery with en bloc resection or all pelvic organs, the distal urinary tract, and anorectum. Due to the extremely high morbidity of this radical surgery, an exenteration is performed with curative intent and only when a complete resection with disease-free margins is expected.36
Conclusion MRI is widely accepted as an ideal modality for local staging of cervical carcinoma, and it has very high accuracy when performed with appropriate technique and image quality. MRI is useful in determining the feasibility of fertility-sparing surgery, as well as determining whether or not a patient is a surgical candidate based on parametrial involvement. MRI is useful in treatment planning, monitoring response to therapy, and assessing for recurrent disease. Factors contributing to prognosis, such as nodal involvement, tumor volume, and advanced stage disease can be evaluated with MRI. Finally, MRI has been shown to be cost-effective by eliminating the need for additional imaging or surgical procedures.37
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Tables and Figures
a.
b. Figure 1. Normal cervix. (a) sagittal T2 weighted MRI of the pelvis with vaginal gel demonstrates low-signal intensity of the normal cervix. (b) axial T2 weighted MRI of the normal cervix demonstrates normal zonal anatomy (in order from the center): high T2 signal intensity in fluid in the endocervical canal, intermediate high T2 signal intensity in columnar epithelium in the endocervix, low T2 signal intensity cervical stroma, and low-intermediate T2 signal intensity in the outer cervical stroma.
Figure 2. 45 year old female presenting with menorrhagia. Axial oblique T2 thin section through the cervix reveals a large tumor with preservation of a thin rim of cervical stroma (white arrow). Metastatic right internal iliac node (black arrow). Stage IB2.
a.
b.
c. Figure 3. Stage IB2 disease (a) sagittal T2 weighted MRI of the pelvis demonstrates an exophytic cervical tumor. (b) sagittal dynamic contrast enhanced MRI of the pelvis demonstrates the enhancing cervical tumor. (c) coronal T2 weighted MRI demonstrates full-thickness involvement of the cervical stroma without parametrial extension.
Figure 4. 45-year old female with pelvic pain. Axial T2-weighted MRI reveals a large cervical tumor with parametrial extension (arrows), rendering the patient stage IIB.
Figure 5. 32 year old female presenting with pelvic pain. Axial and coronal T2 weighted MRI demonstrates extensive left pelvic sidewall involvement with left hydroureteronephrosis. Stage IIIB
a.
b. Figure 6. (a) 54 year old female presenting with heavy intermenstrual bleeding, found to have stage IVA disease. Sagittal T2 weighted MRI of the pelvis with vaginal gel demonstrates a large tumor with invasion of the posterior bladder wall (short arrow) and early rectal involvement (long arrow). (b) Sagittal dynamic post-contrast image of bladder invasion (arrow).
Figure 7. Lymph node evaluation. A T2-weighted MR image demonstrates an enlarged left external iliac lymph node.
a.
b. Figure 8. 24-year old female with intermittent vaginal bleeding. (a) Pre-treatment sagittal T2weighted MRI of the pelvis with vaginal gel demonstrates a stage 1B2 squamous cell carcinoma of the cervix (arrow). (b) Sagittal T2-weighted MRI of the pelvis of the same patient following chemoradiation. There is no visible residual tumor, and the cervical stroma has normal low-signal intensity (short arrow). Minor artifact is due to a radiation seed (long arrow).
TABLE 1: International Federation of Gynecology and Obstetrics (FIGO) Staging of Cervical Cancer12 Stage I
Description The carcinoma is strictly confined to the cervix (extension to the uterine corpus should be disregarded).
IA
Invasive cancer identified only microscopically. (All gross lesions even with superficial invasion are Stage IB cancers.) Invasion is limited to measured stromal invasion with a maximum depth of 5 mma and no wider than 7 mm.
IA1
Measured invasion of stroma ≤ 3 mm in depth and ≤ 7 mm width.
IA2
Measured invasion of stroma > 3 mm and < 5 mm in depth and ≤ 7 mm width.
IB
Clinical lesions confined to the cervix, or preclinical lesions greater than stage IA.
IB1
Clinical lesions no greater than 4 cm in size.
1B2
Clinical lesions > 4 cm in size.
II
The carcinoma extends beyond the uterus, but has not extended onto the pelvic wall or to the lower third of vagina.
IIA
Involvement of up to the upper 2/3 of the vagina. No obvious parametrial involvement.
IIA1
Clinically visible lesion ≤ 4 cm
IIA2
Clinically visible lesion > 4 cm
IIB
Obvious parametrial involvement but not onto the pelvic sidewall.
III
The carcinoma has extended onto the pelvic sidewall. On rectal examination, there is no cancer free space between the tumor and pelvic sidewall. The tumor involves the lower third of the vagina. All cases of hydronephrosis or non-functioning kidney should be included unless they are known to be due to other causes.
IIIA
Involvement of the lower vagina but no extension onto pelvic sidewall.
IIIB IV
Extension onto the pelvic sidewall, or hydronephrosis/non-functioning kidney. The carcinoma has extended beyond the true pelvis or has clinically involved the mucosa of the bladder and/or rectum.
IVA
Spread to adjacent pelvic organs.
IVB
Spread to distant organs.
TABLE 2: Typical MRI Sequences Sequence T2
Scanning Plane
Purpose
Coronal (large FOV)
Assess for hydronephrosis, overview of lower abdomen and pelvis Assess lymph nodes
T2
Axial
Overview of pelvis Assess ovaries Overview of pelvis
T1
Axial (large FOV)
Evaluate nodes, bone marrow Assess for hematometra or other collections Measure primary tumor size
T2
Sagittal thin section (3-mm), small FOV (20-22 cm)
Assess tumor extent Assess extension into uterus, vagina, bladder, rectum
T2
DWI
Axial oblique (perpendicular to the endocervical canal),thin section (3-mm), small FOV (20-22 cm)
Axial (large FOV)
Measure primary tumor size Assess parametrial invasion
Highlight neoplastic tissue, localize very small tumors Evaluate response to therapy
Dynamic contrast enhanced T1
Sagittal, small field of view
Evaluate extent of myometrial and cervical involvement