EDUCATIONAL UPDATE

Magnetic resonance imaging in oncology: an overview

F. WALLIS and F. J. GILBERT
Academic Dept of Radiology, University of Aberdeen, Foresterhill, Aberdeen, U.K.

This review discusses a growing area of imaging in oncology. Traditionally, the primary role of magnetic resonance imaging (MRI) has been in the investigation of neurological diseases and in the diagnosis of musculoskeletal abnormalities. With the increasing availability of MRI systems and with the advances in technology, the role of this modality outwith these areas is rapidly expanding. This review outlines the areas where MRI has a specific role in the imaging of patients with cancer. In particular, emphasis is placed on areas outside of the central nervous and musculoskeletal systems. This review describes the areas where MRI may be advantageous over other imaging modalities such as computerised tomography (CT). Specific emphasis is placed on the staging of abdominal and pelvic malignancies, the detection of recurrence and the impact of MRI in hepatic imaging. In addition this article reviews the value of dynamic contrast enhanced MRI sequences, as well as the importance of newer organ specific MR contrast agents in hepatic and lymph node imaging.

Keywords: magnetic resonance imaging (MRI), oncology, staging, dynamic gadolinium enhancement

J.R.Coll.Surg.Edinb., 44, April 1999, 117-125

INTRODUCTION

From its initial conception in 1973¹, nuclear magnetic resonance imaging (MRI) has evolved continuously over the last 25 years. The development of the clinical applications of MRI occurred on both sides of the Atlantic with much of the initial work being carried out in the United Kingdom in centres such as Aberdeen, Nottingham and London.^2,3,4 Initially, MRI was used predominantly for imaging the brain and spinal cord, and then the musculo-skeletal system. Abdominal and pelvic images had poor quality due to motion artefact caused by breathing and bowel peristalsis owing to the long acquisition times inherent in the early pulse sequences used. The total duration of each scan could be up to 30 minutes, which compared poorly with computerised tomography (CT) and ultrasound. Although good quality body images were produced as early as 1980⁵, thoracic, abdominal and pelvic imaging did not develop significantly until the last 10 years. Over the last 5 years particularly, advances in technology, specifically pulse sequence design, radiofrequency receiver coils and magnetic field gradient technology have advanced considerably the role of MRI outside the neurological and musculo-skeletal system. This article will outline the basic physics involved in magnetic resonance imaging. It will discuss the current applications of MRI in oncology, and specifically look at areas where MRI may be more valuable than other imaging modalities, emphasising the value of newer techniques such as dynamic contrast enhancement and specific MR contrast agents.

BASIC PHYSICS OF MRI

The physics of MRI is complex and challenging to under-stand. A short introduction is necessary to understand the advantages and limitations of this imaging modality. A basic MRI system comprises a powerful magnetic field created by a resistive or a superconducting magnet. Field strength in these systems varies between 0.2 and 4 tesla (T) with common commercial systems utilising field strengths of 1.0 or 1.5T. There are a series of gradient coils within the magnet, which are integral to sequence design, and necessary for the spatial localisation of the signal within the patient. Different radiofrequency receiver coils are available depending on which area of the body is being imaged, e.g. shoulder, body or head coil. The body coil is also often used to transmit radiofrequency signals when a peripheral radiofrequency coil (e.g. a shoulder coil) is being used. Advanced computer systems are vital with high-grade hardware and software specifications.

Magnetic resonance imaging is based upon the effect of large magnetic fields on protons i.e. hydrogen nuclei within the water and lipid molecules in tissues. When a patient is placed within a large magnetic field these protons partially align themselves along the main magnetic field, thus producing a net magnetic moment. These protons can be displaced from this north-south alignment with the application of a radio-frequency pulse at a specific frequency. This frequency is defined as the Larmour frequency and is dependent on the strength of the magnetic field. Once these protons are displaced in the main magnetic field they relax, to align back along the main magnetic field. It is during this process of relaxation that the spinning protons produce a radiofrequency electromagnetic signal, which can be detected by the receiver coil and amplified. The strength of the signal depends on several factors, including the hydrogen proton concentration

within the tissues being imaged. The relaxation rate is dependant on the interaction of molecules within their local environment and with adjacent molecules, the field strength, and the timing and strength of the radiofrequency pulses. Different tissues relax, that is, precess back to the main magnetic field, at different rates. It is this difference in relaxation between tissues, which enables an image to be created.

By varying the repetition time (TR) between radiofrequency cycles, and the time to sample the signal, the echo time (TE) it is possible to "weight" the image, that is to alter the contrast between different tissues. There are three basic types of weighting used in clinical practice: T1; T2; and proton density weighting. T1 weighting is good for anatomical detail, while T2-weighted images which give high signal for tissues with a higher content of free unbound water and are essential in imaging inflammation or neoplastic tissue. Tissues with high free water molecules take longer to relax and, therefore, have high signals on long TR sequences, i.e. T2 weighting, (see Figure 1). Proton density weighting depends on the hydrogen proton concentration of tissues and has minimal T1 and T2 contrast-based effects.

Figure 1a: T4 right laryngeal squamous cell carcinoma demon -strating intermediate signal on T1 weighted spin echo (arrow)	Figure 1b: The tumour has high signal on T2-weighted spin echo sequence (arrow)

Initially, abdominal and pelvic MRI gave poor image quality when compared to CT. This was due to poor signal-to-noise ratio and spatial resolution from the images. Marked motion artefact and long scanning times caused degradation of abdominal, pelvic and head and neck images. However, in recent years, with the development of faster imaging sequences, better gradients and magnet designs coupled with advanced transmit and receive coils these problems to a large extent have been overcome.6 It is now possible to obtain high quality hepatic, abdominal or pelvic MRI examinations with single breath hold acquisitions. The patient can be imaged in any defined plane such as axial, coronal, para-sagital etc, depending on the clinical indication. With such a multi-planar capability, lack of ionising radiation and advanced processing systems, MRI now competes well with other modalities and compliments other investigations such as spiral CT, allowing MRI to become a critical diagnostic tool in imaging in oncology.

MRI AS A STAGING MODALITY

There have been numerous studies, which have investigated the role and value of MRI in the initial staging of many different types of tumours.^7-11 Most of these studies have compared MRI with other conventional modalities such as CT or ultra-sound. It would be impossible to review the staging of each type of tumour, but emphasis will be placed in tumours where MRI should be considered as the primary modality in the initial pre-operative staging.

The inherent superior soft-tissue contrast resolution of MRI in comparison to CT can improve tumour localisation and nodal staging. MRI has made significant advances in recent years in the staging of pelvic malignancy. It has challenged the role of CT in the staging of some of the more common pelvic malignancies such as bladder, cervix and uterine carcinoma. In bladder carcinoma, MRI appears to be more accurate in the overall staging of the primary lesion, due to the greater ability of MRI to detect perivesical spread and local invasion of structures as well as in the assessment of penetration of the lesion through the deep muscle layers of the bladder.^12,13,14 In the critical clinical area where cystectomy is being considered and the detection of perivesical spread is essential, MRI is advocated as the staging modality of choice. The multiplanar capability of MRI is particularly useful in this disease and in planning therapy.

In patients with proven uterine carcinoma MRI can accurately detect myometrial invasion (see Figure 2). The depth of myometrial invasion defines patient prognosis, as patients with greater than 50% myometrial invasion have a significant poorer prognosis, with an increased incidence of metastatic pelvic lymphadenopathy.^15,16 MRI, therefore, can aid both in prognostic information and local staging, and thereby enable critical decisions to be made regarding the type and extent of surgery, including pelvic para-aortic lymphadenectomy. Similarly, in patients with cervical carcinoma, MRI has been shown to be more accurate than either transrectal ultrasound or CT, specifically in the area of parametrial extension and local invasion of adjacent structures. MRI has a significant role to play in the follow-up of patients following radical radiotherapy and in the detection of recurrence in these patients.¹⁷

Figure 2: Sagital T2 spin echo of a patient with endometrial carcinoma. Note excellent contrast resolution enabling accurate assessment of myometrial extension (arrow); note associated pyometria (arrowhead)

The multiplanar facility of MRI is especially useful in the staging of head and neck carcinoma. The use of gadolinium-enhanced T1-weighted images and fat suppressed T1-weighted images have been found to be particularly useful in depicting local infiltration of nasopharyngeal squamous cell carcinoma. Suspected intracranial extension can be demonstrated on a coronal sequence.¹⁸ However, in patients with tumours of the larynx and hypopharynx, MRI, although having greater contrast resolution, suffers due to the degree of motion in this area as a consequence of the patient's disease. The decision on whether to use CT or MRI in head and neck cancer often depends on the local availability the scanners and radiological expertise.¹⁸

Other areas are more controversial. The role of MRI in prostatic cancer is not clear-cut. Staging of prostatic cancer is normally based on digital rectal examination, PSA levels and Gleeson score. MRI using the body coil has been shown to be as accurate as transrectal ultrasound (TRUS) (see Figure 3).¹⁹ The addition of phased array coils and dynamic contrast enhanced sequences has demonstrated an improvement in the accuracy of staging.²⁰ In addition to local staging, MRI has the additional benefit over TRUS of being able to assess for pelvic lymphadenopathy. In patients who are being considered for radical prostatectomy, some centres advocate MRI as the staging modality of choice, in order to detect extracapsular spread. It is, however, necessary to undertake prostatic MRI with state of the art equipment, including either phased array body coils or local endorectal coils. Dynamic gadolinium enhancement of prostatic tumours has demonstrated that this technique, using quantitative data, may aid in the staging and, more interestingly, in the prediction of tumour grade itself.^21,22

Figure 3: Axial T2-weighted image of patient with a small area of prostatic carcinoma (arrowhead). The tumour appears of low signal in comparison with the normal high signal of left peripheral zone (arrow)

MRI may be used to further clarify detail or answer specific questions raised by other modalities. For example, in patients with low rectal carcinoma, MRI, due to its multiplanar capabilities and increased soft tissue contrast, can assess extension of tumour to the anal sphincter or invasion of levator ani, which are well seen on the coronal plane and can significantly alter surgical management.²³ Similarly, although MRI has failed to fulfil its early promises as a staging modality in lung cancer, it is useful in the assessment and management of suspected superior sulcus tumours and in the assessment of mediastinal invasion by central tumours. However, overall, MRI has not been shown to be any more accurate in the critical assessment of patients with lung cancer, especially in the assessment of resectability in comparison with standard imaging modalities.²⁴

MRI IN HEPATIC IMAGING

The role of MRI in liver imaging has advanced greatly with the development of faster sequences incorporating breathold techniques, which significantly reduce motion artefact.³¹ This allows information on the vascularity of liver lesions to be obtained of similar quality to dual phase contrast enhanced spiral CT. Recent development of specific MRI hepatic contrast agents has shown great potential to improve the accuracy and sensitivity of hepatic imaging.

In an assessment of liver MR imaging in oncology, several distinct groups of patients must be considered. The first group is those suspected of having a primary hepatic neoplasm, such as hepatocellular carcinoma (HCC) or a cholangiocarcinoma. Studies have shown little significant difference in the detection or staging of these tumours between CT and MRI, although the present perception is that dynamic contrast-enhanced MRI is marginally superior.^25,26 A scenario, which is much more frequently encountered in clinical practice, occurs with the detection of an incidental isolated hepatic lesion in a patient with a known malignancy. Although a combination of CT and ultrasound will characterise a majority of these lesions as either cysts or haemangioma, it can be extremely difficult to differentiate small metastases from these lesions or from areas of focal fatty infiltration. MRI using specific protocols has a 90% sensitivity and specificity in the evaluation of haemangioma, which is in part due to their inherent higher T2 values than metastatic deposits, as well as their appearances on dynamic gadolinium-enhanced T1-weighted sequences.^27,28 In areas of suspected focal fatty infiltration, specific opposed phase and in-phase sequences can demonstrate the presence of focal fatty change and aid in the differentiation from neoplasms.²⁹ In patients with equivocal hepatic lesions, we advocate MRI for further evaluation and characterisation prior to biopsy.

Another key area is the detection of hepatic metastases in those patients with colorectal carcinoma. Up to 30% of these patients will have isolated liver metastases, where surgical resection can offer a potential cure or improved survival.^30,31 Although only a minority of these patients will be suitable for resection, imaging plays a critical role in assessing and choosing which patients would be suitable for such surgery. Detection of other lesions within the potential remaining liver segments is vital. Currently, the technique with the highest sensitivity at over 90% is helical CT performed during arterial portography (CTAP).³² This is an invasive procedure, involving selective cannulation of either the splenic artery or superior mesenteric artery and infusion of iodinated contrast, resulting in maximal portal venous contrast and hepatic parenchymal enhancement. Hypovascular colorectal metastases become more conspicuous as a result. However, CTAP has potential pitfalls, with associated false positive results due to transient perfusion abnormalities as a consequence of local portal venous stenosis, obstruction, or segmental hyperperfusion due to accessory hepatic vessels.

New hepatic specific contrast agents aimed at improving the accuracy and sensitivity of hepatic MR have shown a significant improvement in lesion detectability.^33,34 Two specific groups have been developed: reticuloendothelial agents; and hepatocellular agents. Reticuloendothelial agents consist of superparamagnetic iron oxide particles (SPIO) or ultra small superparamagnetic iron oxide particles (USPIO). The Kuppfer cells within the liver selectively take these molecules up by phagocytosis. The iron oxide particles cause marked shortening of the T2 relaxation of the liver, resulting in significant dropout in the signal of normal liver in T2-weighted sequences. Colorectal metastases following the administration of these agents appear of high signal against the low signal of normal liver (see Figure 4). Using state of the art equipment, these agents have begun to challenge the role of CTAP in this patient group in their ability to detect small metastatic liver lesions. In addition, at the time of the MRI examination, gadoliniu- enhanced gradient echo sequences in the oblique coronal plane and axial plane can elegantly demonstrate the vascular anatomy of the liver to allow surgical planning.

Figure 4a: Axial T2-weighted sequence of the liver with high signal metastasis in segment 6	Figure 4b: Following infusion of Endorem®, (Guerbert, UK), there is signal dropout in the normal liver, with increased definition of the metastasis

Figures 4a and 4b courtesy of Dr Adrian Knowles, Hull MRI Centre

Some authors have recently advocated the use of contrast-enhanced hepatic MRI using SPIO, along with gadolinium-enhanced T1-weighted imaging as the initial imaging technique in patients for potential hepatic resections. CTAP could be reserved for those patients who are unable to complete a MRI examination due to claustrophobia or those patients where the MRI is technically unsatisfactory.³⁵

Despite these advances, helical CT and ultrasound remain the most common used modalities for hepatic imaging in oncology patients, in the initial staging, reassessment and follow up. This has been due to the more widespread availability of these modalities compared to state of the art MRI and recently to the emergence of spiral CT technology. However, this balance is changing with an increased emphasis on the value and benefit of hepatic MRI. Currently, MRI plays a key role in the initial evaluation of staging of certain tumours. With the more widespread availability of MRI in the future, coupled with advancing technology, MRI will play a more significant role in the primary assessment of neoplastic diseases.

MRI IN TUMOUR ANGIOGENESIS

Angiogenesis is defined as the formation of new blood vessels through the development of capillaries from pre-existing micro-vessels.³⁶ This mechanism is normally strictly regulated, but neoangiogenesis can play a key role in the development of certain diseases. In tumours, neoangiogenesis has been shown to occur when a tumour reaches 2mm in diameter. The new vessels that are formed encourage tumour growth by increasing the local delivery of oxygen and nutrients to the lesion. These new vessels form rapidly and lack normal structure with no smooth muscle, and with larger than normal gaps between the endothelial cells. This results in rather a fragile and leaky vascular network throughout the tumour, which allows rapid movement of small molecules from the blood stream into the extra-cellular space surrounding the tumour.³⁶

In addition, the presence of these new vessels within tumours is one of the factors, which enable abnormal cells to enter the circulation, thus encouraging metastatic spread.^{37, 38}

There are a number of extra-cellular contrast agents currently used in MRI imaging. These gadolinium chelates act by shortening the T1 signal of permeable tissue due to the paramagnetic effect of the molecules. These contrast molecules transfer rapidly from the intravascular compartment into the extra-cellular space, where it rapidly and freely diffuses throughout the tissue. Gadolinium, at the lower doses that are used in human imaging (0.1 - 0.2mmol per kg), has an approximately linear relationship with the T1-weighted image signal in tissue, which allows correlation of change in signal with concentration of contrast. At higher doses with increased tissue concentration, the relationship loses its linearity. The linearity of concentration in relation to contrast is also dependent on the acquisition of the MR signal; for example, whether a 2D or 3D acquisition is used.³⁹ As there is considerable overlap between the T1 values of benign and malignant tissues, the addition of contrast improves the conspicuity of malignant lesions by shortening the T1 value of tumours in comparison with normal tissue. There is, however, a large degree of overlap in the signal alteration that occurs following contrast administration. The development of fast and ultra fast dynamic sequences following gadolinium administration has been advocated to improve both lesion detectability and specificity.

Dynamic gadolinium enhanced MRI has been evaluated extensively in certain neoplasms, especially breast, cervical, prostate, bladder and melanoma. The acquisition of data within a single or multiple slices, following the administration of a bolus of gadolinium, can give specific information regarding the tumour. Using time intensity curves, the onset of enhancement, the rate of enhancement, and the rate of washout can be calculated (see Figure 5). The differences in these parameters are partly due to the development of neovascularity within these tumours, and partially due to the permeability of these vessel walls to the contrast agent. This form of MRI not only improves lesion delectability and specificity, but also can deliver useful information regarding tumour differentiation, prognosis and response to therapy.⁴⁰ In addition to this data, using dynamic contrast MRI, it is also possible to calculate the permeability and leakage space of an area within a tumour based on a mathematical algorithm derived from analysis of MS plaques.⁴¹ This technique has the potential to non-invasively quantify neoangiogenic vessels within tumours. Recent studies have shown this technique to be useful in mice⁴², while further research has demonstrated the potential application of this model in humans.⁴³ This specific area of research is currently undergoing active investigation. Indeed, with the advent of antiangiogenic drugs, which are currently in phase 1 and phase 2 trials, the development of the clinical application of quantitative dynamic contrast enhanced MRI within tumours may be an important future development.

Figure 5a: Dynamic contrast enhanced T1-weighted gradient echo coronal image of both breasts. Regions of interest placed over suspicious lesion in right breast (arrowhead) and over adjacent fat (arrow)	Figure 5b: Curve of dynamic contrast enhancement of a breast lesion (straight line) and adjoining fat (broken line). Note rapid early enhancement, plateau, and washout of the breast lesion (arrows). Histologically proven breast carcinoma

LYMPH NODE EVALUATION WITH MRI

Overall, the difference in the accuracy, sensitivity and specificity between CT and MRI in the detection of metastatic lymphadenopathy is minimal.^7-11 Both modalities depend predominantly on an alteration in size and shape of a lymph node in order to predict the probability of metastatic spread to that node. The constant problem that has dogged imaging of lymph nodes in patients with cancer is the inability to detect metastatic disease in normal sized nodes. Generally, there is no significant T1 or T2 signal difference between metastatic and normal lymph nodes. Recent studies have demonstrated the potential of two specific applications of MRI to improve our detection of metastatic nodes. Dynamic contrast enhanced imaging using gadolinium-DTPA has demonstrated a rapid and increased enhancement in metastatic nodes over benign nodes in recent studies (see Figure 6).^44,45

Figure 6a: Oblique sagital T1-weighted image of the axilla in a patient with breast carcinoma. intermediate signal intensity of lymph node (small circle)	Figure 6b: Dynamic contrast-enhanced image demonstrating early enhancement of the lymph node, which can be suggestive of metastatic involvement (arrow)

In addition, the recent development of MRI lymph node-specific MRI contrast medium, using ultrasmall supraparamagnetic iron oxide particles, may prove extremely useful in this area. These particles are given as an infusion and are trapped within normal nodes. This causes signal drop out on T2-weighted imaging, and differentiation between metastatic and normal lymph nodes may be enhanced (see Figure 7). Current studies are evaluating the safety and efficacy of these agents, with encouraging results.⁴⁶

Figure 7a: Axial T2-weighted spin echo through the axilla in a patient with breast carcinoma. Note high signal node in level 1 (arrow)	Figure 7b: Following infusion of a MR specific lymph node contrast agent, a repeat scan at 24 hours demonstrates normal homogenous signal loss in the same node (arrowhead) in keeping with a benign node

MRI IN SUSPECTED RECURRENT DISEASE

The diagnosis of relapse is usually due to a combination of clinical findings, tumour markers and appropriate imaging. There are specific situations where MRI may be helpful. The distinction between post-operative fibrosis/scar tissue and recurrent tumour can be difficult. MRI using fast dynamic gadolinium-enhanced sequences and signal intensity curves can be used in these clinical settings. This technique has been useful in the assessment of pre-sacral masses in patients following surgery for colorectal carcinoma.⁴⁷

The detection of recurrence, or of a second primary in patients with breast cancer previously treated with wide local excision and radiotherapy, may be very difficult with conventional imaging. Dynamic gadolinium-enhanced sequences, with evaluation of the enhancement profiles of suspicious lesions, has been shown to distinguish between benign and malignant lesions at the site of previous surgery.⁴⁸

CONCLUSION

With the increasing availability and improved abdominal and pelvic imaging techniques, MRI will be used more often in diagnosis staging and follow up of patients with cancer. Alternative contrast agents may allow more accurate evaluation of the liver and lymph nodes, allowing more accurate staging of patients and, therefore, more appropriate treatment. The potential of dynamic contrast-enhanced imaging to monitor permeability of tumours may allow more tailored management.

ACKNOWLEDGEMENTS

Dr Wallis acknowledges the support of TENOVUS (Scotland).

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Copyright date: 22nd February 1999

Correspondence: Dr Fintan Wallis, Senior Lecturer, Academic Dept of Radiology, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, Scotland, UK

©1999 The Royal College of Surgeons of Edinburgh, J.R.Coll.Surg.Edinb., 44; 2: 117-125