|Year : 2012 | Volume
| Issue : 1 | Page : 11-18
Functional magnetic resonance imaging in cervical cancer: Current evidence and future directions
Sayan Kundu1, Supriya Chopra2, Ashish Verma3, Umesh Mahantshetty1, Reena Engineer1, Shyam Kishore Shrivastava1
1 Department of Radiation Oncology, Tata Memorial Hospital, India
2 Department of Radiation Oncology, Advanced Centre for Treatment, Education and Research in Cancer (ACTREC), Tata Memorial Centre, India
3 Department of Radiodiagnosis, Advanced Centre for Treatment, Education and Research in Cancer (ACTREC), Tata Memorial Centre, India
|Date of Web Publication||19-Apr-2012|
Department of Radiation Oncology, Advanced Centre for Treatment Education and Research in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai - 410210
Source of Support: None, Conflict of Interest: None
Carcinoma cervix is one of the most common cancers amongst Indian women. Though treatment strategies continue to evolve, there are no established predictive biomarkers of prognosis or therapeutic response. Novel imaging techniques using magnetic resonance (MR) and positron emission tomography (PET) can facilitate time resolved spatial evaluation of biological characteristics (perfusion, permeability, cellularity, proliferation, oxygenation, and apoptosis) thereby serving as early surrogate biomarkers for prognosis and therapeutic response. Several of these imaging modalities such as dynamic contrast-enhanced MRI (DCE-MRI), diffusion-weighted MRI (DW-MRI), MR spectroscopy (MRS) and fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) are now being evaluated for gynecological oncology, with the majority of work being performed on cervical tumors. PUBMED database was searched for this review from January 1966 till February 2011. This review examines the basic principles of functional MR imaging for cervical cancer and its current status as a diagnostic and predictive biomarker for cervical cancer.
Keywords: Cervix, diffusion-weighted MRI, dynamic contrast-enhanced MRI, response assessment
|How to cite this article:|
Kundu S, Chopra S, Verma A, Mahantshetty U, Engineer R, Shrivastava SK. Functional magnetic resonance imaging in cervical cancer: Current evidence and future directions. J Can Res Ther 2012;8:11-8
|How to cite this URL:|
Kundu S, Chopra S, Verma A, Mahantshetty U, Engineer R, Shrivastava SK. Functional magnetic resonance imaging in cervical cancer: Current evidence and future directions. J Can Res Ther [serial online] 2012 [cited 2019 Sep 21];8:11-8. Available from: http://www.cancerjournal.net/text.asp?2012/8/1/11/95167
| > Introduction|| |
Cervical cancer is one of the most common cancers in developing countries.  Radical treatment involves surgery or concurrent chemoradiotherapy for early stages and concurrent chemoradiation alone for locally advanced stages. The outcome following standard therapeutic approaches is governed by primary tumor size, extent, and lymph node status.  Though various biomarkers have been investigated and proposed ,,, for monitoring therapeutic outcome, they remain to be validated in large scale studies. Developments in radionuclide imaging in the last decade have generated interest in evaluation of imaging biomarkers as predictive and prognostic factors. Systematic evaluation of 18 Flourine-deoxyglucose (FDG) positron emission tomography (PET) through prospective studies have reported maximum pelvic nodal standardised uptake value (SUVmax) as a sensitive imaging biomarker of response and prognosis.  However, lack of large scale availability of PET limits integration of this metric in routine clinical practice.
In addition to developments in radionuclide imaging, recent years have also witnessed rapid development in MR imaging. Multifunctional MRI namely dynamic contrast enhanced MRI (DCE-MRI), diffusion weighted (DW) MR, spectroscopy, blood oxygen level dependent (BOLD) have facilitated high resolution imaging of tumor permeability, perfusion, cellularity, metabolites, and oxygenation such that baseline differences in these metrics could predict for differential therapeutic response. Though extensively evaluated in neuro-pathologies , these techniques await validation as imaging biomarkers for cervical cancer. The present review is being undertaken to summarize the present and future role of multifunctional quantitative MR metrics as predictive/prognostic imaging biomarker for cervical cancer.
| > Materials and Methods|| |
Published data for this review was identified by systematically searching PUBMED database from 1966 - February 2011 with the following Medical Subject Heading (MeSH) terms: "cervical cancer", "MRI", "DW-MRI", "DCE-MRI", "MR Spectroscopy", "biomarkers", "treatment response" using boolean search algorithms. Any study reporting the use of anatomical or functional MRI for cervical cancer either alone or in combination with other biomarkers or imaging modalities was reviewed. A preliminary search identified 112 potential articles. All pertinent articles in English language were retrieved and relevant studies were considered for the purpose of this review. Original studies were included only if they dealt with diagnosis, response assessment using DWI or DCE or spectroscopy of cervical cancer. Studies dealing with endometrial or uterine cancers or describing only anatomical MRI for diagnosis and response evaluation or using MRI for external beam radiation or brachytherapy planning were excluded. Initial abstract screening eliminated 61 studies. Subsequently two authors (SK, SC) independently reviewed each study for its relevance and inclusion in this review.
| > Results and Discussion|| |
Diffusion is a physical process by which microparticles are transported from one part of a system to the other as a result of random translational molecular motions.  In human body, diffusion of various ions and molecules is crucial for maintenance of homeostasis. Water molecules being the main component of any living system are the predominant diffusing entity in a human body. The process is however 'highly anisotropic' due to the 'selective permeability' of the plasma membrane, inter-molecular magnetic and electronic interactions. DWI allows creation of image contrast dependent on intravoxel diffusion of water during diffusion sensitised period of MR pulse.  Pathologic processes tend to alter the magnitude of structural organization either by destruction of cell membrane or by a change in tissue cellularity. Membrane expansion related to cellular swelling may also increase trapped water, hence reducing water diffusion.  Early alterations in water diffusivity can be easily measured through DWI, making DWI a forerunner in predicting cellular pathologies. Quantitative metrics of diffusion like apparent diffusion coefficient (ADC) can predict for alteration in cellular density and hence the quantity and diffusivity of water. ADC values can be displayed as parametric maps generated by gray scale or color mapping of the average intra-voxel diffusion during the DWI pulse sequence acquired at least at two different b-values (or strength of diffusion gradient).  Though contributions from intravascular perfusion may impact measured diffusion, advanced MR techniques incorporating higher strength of diffusion gradient and multiple b values (including low b values, e.g., b 50 and 100) ensure that the effect of flow/perfusion is minimised and the obtained maps represent true changes in cellular morphology.  An example of ADC map is depicted in [Figure 1] and [Figure 2]. While DWI has been extensively utilised to map cerebral ischemia,  its role in oncological imaging is currently evolving. ,, The ability to map cellular alterations without exogenous contrast, short imaging time make DWI an attractive method for evaluating pretheraputic intratumoral heterogeneity and therapeutic sensitivity. ADC values of malignant tumours are commonly lower than those of its benign counterparts or normal tissues, due to increased cellularity. However, the inverse relationship between cellularity and ADC remains to be systematically evaluated in cervical cancer.
|Figure 1: (a) T2W image demonstrating postoperative recurrence of cervical cancer. (b) Relative blood volume (RBV) map at spatially corresponding location. Note the bright region of increased blood flow within the tumor, (c) ADC map at spatially corresponding location. Note the region of restricted diffusion within the tumor (black arrow), (d) T2 W image with gross tumor (red) and superimposed sub-volume of restricted diffusion (orange) and restricted bl ood fl ow (green)|
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|Figure 2: (a) T2W image demonstrating tumor involving the cervix (b) Diffusion map showing regions of restricted diffusion within the tumor. While the blue region has restricted diffusion, that in the yellow region shows comparative facilitation, (c) Relative blood flow map in a patient with early cervical cancer. Notice that there are no regions of increased blood volume, (d) Spectroscopy image demonstrating a choline peak in the region containing tumor|
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DW-MRI in cervical cancer
Malignant cervical tissue demonstrates restricted diffusion and hence reduced ADC values when compared to normal tissue. DWI and ADC maps allow differentiation of benign from malignant zones of cervix with high sensitivity and specificity. ,,,, Preliminary data demonstrates the ability of ADC to differentiate histological type and grade. , In a prospective study  statistically significant difference was observed in ADC values of normal and malignant cervix (1.7 × 10 -3 mm 2 /sec vs 1.1 × 10 -3 mm 2 /sec; P < 0.001). Well differentiated tumors had higher ADC values than poorly differentiated tumors (1.2 × 10 -3 mm 2 /sec vs 1.1 × 10 -3 mm 2 /sec; P = 0.01). Similar results have been observed in another study  evaluating correlation of ADC and tumor grade. However, heterogeneity has been observed in ability to differentiate histological subtype. While one study  identified ADC of squamous carcinomas to be lower than adenocarcinomas, another study reported no difference in ADC between different histological subtypes.  Further studies are however needed to confirm these results.
The available data demonstrates high sensitivity and specificity of DWI in identifying primary tumor and secondary nodal deposits [Table 1], its comparative or incremental performance over T2W imaging has not been systematically assessed. While vast majority of studies have imaged early stage tumors with ADC values ranging between 0.86-1.38 10 -3 mm 2 /sec [Table 1], there is a distinct possibility that large infiltrative tumors may be associated with higher average ADC values due to intratumoral necrosis and resultant increase in extracellular volume.
DWI has been extensively used to image morphological alterations following ischemia and reoxygenation in benign neuropathologies,  however, its role in identifying intratumoral oxygenation is not well established. McVeigh et al. evaluated correlation of pretherapeutic ADC values with pre-treatment intratumoral partial pressure of oxygenation (pO2) and proportion of measurements that were hypoxic (defined being <5 mm Hg(HP5)) in women undergoing chemoradiation for cervical cancer. No correlation was observed between tumor ADC values and pO2 or HP5. 
DWI and treatment response
Differences in baseline intratumoral diffusion can predict for difference in treatment response. In a prospective study Liu et al.  observed higher odds of complete response in those with lower baseline ADC values. While complete responders had an average baseline ADC of 0.80 × 10 -3 mm 2 /sec, those with partial response had an average ADC of 0.93 × 10 -3 mm 2 /sec (P = 0.005). While another study  suggests existence of this relationship, others failed to demonstrate the relationship of baseline ADC with treatment response  [Table 1].
The mean ADC of cervical cancer is known to increase during and after chemoradiotherapy such that early alterations in ADC can be used for prediction of early therapeutic response [Table 1]. Jianyu et al.  evaluated the changes in ADC value following chemoradiotherapy (1.5 Tesla; b = 0 and 800 s/mm 2 ). Pretherapeutic ADC value was identified to be significantly lower than posttreatment ADC (1.1 × 10−3 mm 2 /s vs 1.4 × 10−3 mm 2 /s, P < 0.001).
The optimal pretreatment and post-treatment ADC threshold values for distinguishing between normal cervical tissue and cervical carcinoma were 1.3 × 10−3 mm 2 /s and 1.5 × 10−3 mm 2 /s, respectively. Using these thresholds the response to chemoradiation could be predicted with sensitivity and specificity of 70% and 81.8%, respectively. 
In another prospective study in 20 women with locally advanced cervical cancer, Harry et al. investigated the correlation of baseline, midtreatment, and post-treatment ADC with percentage reduction of tumor size. For all patients, ADC maps were generated and region of interest (ROI) was delineated on central slice of tumor while observing T1 and T2 weighted images. Post-therapeutically, if no tumor was identified than ROI included normal residual cervix. While no correlation was observed with pre-treatment ADC, significant positive correlation was observed between increase in midtreatment ADC and percentage clinical (P = 0.009, r = 0.56) and radiological response (P = 0.04, r = 0.44). 
A summary of all DWI studies in cervical cancer is depicted in [Table 1] ,,,,,,,,,,,,, .
The available data demonstrates moderate to high reliability of DWI in discriminating malignant from normal tissue. However, heterogeneity in imaging protocols and methods of ROI delineation and ADC analysis (often restricting analysis to a single slice) has lead to wide range of mean ADC cut-off values such that there is an overlap between ADC values defined for benign and malignant cervix. Furthermore, incremental performance of ADC over T2 has not been assessed in any of the published studies.
Preliminary data indicates that baseline ADC or early ADC changes following therapeutic intervention could potentially be an imaging biomarker of therapeutic response assessment and should be investigated in future studies. Adherence to published recommendations  for performing DWI and uniform method for ROI delineation is recommended for inter-institutional comparisons. Future studies should also focus on evaluating performance of ADC in defining parametrial tumor extent and diagnosing early postoperative/postradiotherapy recurrences.
Contrast-enhanced MRI techniques
The perfusion and permeability of tumors can be interrogated with time dependent intravenous delivery of exogenous contrast agent. The kinetics of contrast enhancement of tumor depends on microvessel density, perfusion, permeability, and the extracellular-extravascular space composition. Typically any tissue with adequate blood supply will enhance but tumor tissues due to increased microvessel density will have higher signal intensity than its normal counterpart. The temporal changes in signal intensity brought out by dynamic imaging facilitate evaluation of permeability and perfusion of the tumor microenvironment.  Perfusion weighted MRI (PWI) broadly consists of two techniques, i.e., the dynamic susceptibility contrast PWI (DSC-PWI) and dynamic contrast enhanced PWI (DCE-PWI). The DSC-PWI relies on rapid serial measurements of the signal intensity of the region under interrogation on T2*W images acquired in sets of multiple phases, after injection of gadolinium based intravenous contrast media (I/V GD). I/V GD typically cause a fall in signal intensity (better known as negative enhancement) due to its susceptibility effect. This drop in tissue signal during the first-pass of contrast media, as compared to baseline pre-contrast intensity and the post-first pass, is plotted against time domain and is extrapolated to derive metrics indicative of contrast media dynamics in intravascular and extra-vascular compartment. Notably the denser the neo-angiogenetic tuft, the deeper the signal drop after I/V GD injection.  DCE PWI on the other hand, utilizes a fast multi-phasic T1W imaging data set and hence relies on measurement of post-contrast increase in tissue signal intensity, on lines similar to that mentioned above  Both these techniques have different software applications, limitations, and interpretation algorithms, discussion about which is beyond the scope of this article.
Systematic evaluation of PWI has focused on obtaining metrics related to contrast uptake time, rate of contrast uptake and washout. Semiquantitative and (heterogeneous) quantitative metrics have been utilized in various studies for quantifying PWI patterns. These include k ep (contrast rate flow constant between extravascular extracellular space and plasma), K trans (volume transfer constant between blood plasma and extravascular extracellular space), Relative Signal Intensity (RSI), amplitude, enhancing fraction and time-signal intensity plot obtained through DCE-PWI and relative blood volume (RBV) (volume of blood vessels within volume of tumour) obtained through DSC-PWI.  An example of RBV map obtained through DSC-PWI imaging is depicted in [Figure 1] and [Figure 2].
While we utilize DSC-PWI for imaging cervical cancers and deriving pretreatment RBV, most of the clinical studies in gynecological cancer have focused on DCE-PWI. Early studies evaluating immunohistochemical correlates have demonstrated that signal intensity on DCE-PWI correlates with microvessel density, ,,, VEGF expression  and pO2 levels.  While DCE-PWI has been extensively evaluated for breast, prostate, head, and neck tumours only few studies have evaluated its role for cervical cancer.
Early studies of DCE-PWI have focussed on evaluating sensitivity and specificity of stromal invasion. In a correlative study, the use of DCE-PWI was associated with higher sensitivity and specificity of diagnosing stromal invasion >3 mm than standard T2 weighted imaging (accuracy 98% vs 76%). 
Tumor microenviornment and cervical cancer
Intratumoral hypoxia is a major determinant of local failure and/or distant metastasis.  The development and validation of pretreatment noninvasive imaging methods is desirable. PWI provides avenues for non-invasive spatial three dimensional evaluation of cervical cancer oxygenation and angiogenesis. Tracer kinetic modelling and quantitative metrics derived from PWI imaging have been weakly correlated with tumor angiogenesis and aggressiveness. Preliminary validation studies have demonstrated that cervix cancer with low pO2 has low vascular density  and positive correlation has been observed between pO2 and level of contrast enhancement on PWI.  This was further validated through cervical cancer xenograft studies. Pharmacokinetic studies in cervical cancer xenografts have demonstrated unambiguous inverse relationship between K trans and fraction of radiobiologically hypoxic fraction  providing rationale for evaluation of intratumoral hypoxia through non-invasive PWI.
Intratumoral heterogeneity on DCE and therapeutic efficacy
Many studies have assessed the predictive role of pretreatment tumor enhancement. ,, Tumor enhancement or an increase in signal intensity within the first two weeks of treatment are associated with better tumor regression, ,, local control, disease-free survival, and overall survival. A summary of DCE studies evaluating tumor response is provided in [Table 2]. ,,,,,,,
|Table 2: Summary of studies correlating perfusion weighted imaging with tumor response|
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However, differences in opinion exist regarding baseline tumor enhancement, signal intensity, and clinical outcome. Unlike other studies, Hawighorst and colleagues reported that high contrast tissue exchange rate constant, i.e., >5.4 /min on presurgical DCE-MRI was associated with decreased survival probability. However, histopathologically high microvascular density which colocalised with high tissue exchange rate constant did not predict for decreased survival probability.  While it is difficult to draw conclusions regarding the predictive role of baseline contrast enhancement DCE-MRI, increased enhancement after initiation of treatment predicts for favorable therapeutic outcome [Table 2].
To summarize, PWI may provide incremental value over standard T2-weighted imaging in assessment of extent of stromal infiltration in early tumors deemed suitable for surgery. The value of PWI in distinguishing malignant from reactive nodes needs to be systematically evaluated. Encouraging data is available correlating PWI data with therapeutic outcome. Standardized reporting of PWI indices may facilitate better comparison of inter-institutional data. Large studies evaluating prognostic factors for cervical cancer should integrate PWI metrics in an attempt to ascertain independent prognostic value over and above the existing prognostic factors. The role of PWI for diagnosing post treatment central and parametrial recurrences needs further investigation.
Tissue metabolites can be investigated as a result of metabolic and hence spectral differences in normal and malignant tissues. Combining spectral information with anatomical information may facilitate investigation of prespecified ROIs. The same has been made possible by the 3D-Chemical shift Imaging Technique (3D-CSI). Over the past two decades, MRS has been used extensively to investigate lesions in a number of anatomical sites but has had limited use in the abdomen and pelvis due to technical difficulties caused by movement associated with respiration and bowel peristalsis. Contamination of signal is also observed due to pericervical fat. Furthermore, low spectral resolution at clinical field strengths of 1.5 Tesla limits the clinical utility. This can be overcome by the use of ex vivo samples, which eliminates movement-related artifact but may not reflect the true biochemical picture of the in vivo state. Techniques like high resolution magic angle spinning (HR-MAS) improve the spectral quality by reducing magnetic field inhomogenieties.
Only few studies have investigated the use of in vivo and/or high field ex vivo MRS/MAS for diagnosis of cervical cancer. Delikatny  evaluated 159 cervical cancer samples (40 invasive and 119 preinvasive). While a high resolution lipid peak (1.3 ppm) was observed in patients with invasive cancer, the preinvasive specimens demonstrated little or no lipid spectra however had a strong unresolved resonance between 3.8 and 4.2 ppm. Mahon et al. evaluated the performance of MRS and correlated ex vivo spectroscopy with histopathology. The measured lipid levels were more than double in malignant cervical tissue when compared with benign cervical tissue; however, no correlation was observed between tumor load and lipid levels. Authors proposed that elevated in phase triglycerides may be used for in vivo detection of malignancy however the interpretation at times may be limited by out of phase lipid signal. ,,
Booth et al. evaluated the performance of MRS for benign and malignant cervical lesions on 3 Tesla MR. Choline peak was observed in 8/11 patients with cervical cancer; however, no difference was observed in the choline peak between benign and malignant lesions.  Other investigators have also reported lack of discrimination between benign and malignant cervix on spectroscopy.  Similar observations have been made by other investigators using in vivo spectroscopy. 
MRS for therapeutic response assessment
Only few studies have investigated the variations in metabolite peaks during the course of treatment or posttreatment response monitoring. Allen et al. investigated the role of in vivo MRS for pre and post treatment radiation response evaluation.  Resolution of choline peak has been observed in patients with complete clinical response, however uncertainty remains about the predictive value of immediate post treatment MRS. Zhu et al. reported reduction in peak values of choline with tumor regression and proposed the possibility of its integration for adaptive radiation planning.  MRS has also been used for response evaluation to neoadjuvant chemotherapy prior to radical hysterectomy. The reduction in tumor volume has been associated with reduction in triglyceride levels. 
Though available studies indicate limited role of in vivo and ex vivo MRS as a response biomarker for cervical cancer, its independent value remains to be assessed.
The role of multifunctional MR continues to evolve for cervical cancer. While clinical and anatomical MR metrics have been integrated for therapeutic response modeling for cervical cancer ,, the aforesaid functional imaging techniques need to be systematically integrated. As functional MR metrics may be a surrogate for early response, drug and radiation sensitizer development for cervical cancer (especially monoclonal antibodies and gold nanoparticles) should prospectively integrate multifunctional MR for early response assessment. Availability of real time MR imaging may also facilitate evaluation of delivery and pharmacokinetics of nanoparticles/monoclonal antibodies through gadolinium tagging of drug chelates. Future research should also focus on integrating these functional imaging for identifying high risk subvolumes, which may niche clonogenic cervical cancer cells. Meaningful interpretation of results from prospective studies necessitates uniform imaging protocols, standardized reporting nomenclature, and validation through spatial correlation with histopathology.
Multifunctional quantitative MR metrics may serve as "imaging biomarkers" and evolving imaging techniques provide an opportunity for multiple time point non-invasive spatial and temporal assessment of tumor biology. Hence, all efforts should be made towards ensuring conduct of quality assured prospective studies.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]
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