Introduction to Oncological Imaging

Cancer is one of the major causes of death in the Western world. The worldwide incidence of cancer is continuing to increase both in developed and developing countries, related to factors such as an ageing population, a shift towards a more Western lifestyle, smoking and environmental factors.

In 2012, there were 14.1 million new cancer cases, 8.2 million cancer deaths and 32.6 million people living with cancer worldwide; 57% of new cancer cases and 65% of the cancer deaths were in developing countries. Lung cancer is the commonest cancer, followed by breast, colorectal and prostate cancer. Lung cancer remains the biggest killer, accounting for one in five cancer deaths worldwide.

The economic burden of cancer on society is substantial. In addition to health care costs associated with cancer prevention and management, there are costs associated with lost earnings due to the inability to work, and the costs of ‘unpaid’ care provided by relatives and friends. A population-based cost analysis found that the estimated cost of cancer was €126.2 billion for the European Union and €14.4 billion for the United Kingdom for 2009. Lung cancer had the highest economic cost of €18.8 billion, 15% of overall cancer costs. UK health care costs were estimated to be €5.4 billion.

From both patient and health economics perspectives, prevention and screening are important aspects of cancer care. Evidence from randomised controlled trials that a screening programme is effective in reducing mortality or morbidity is prerequisite for adoption. Screening programmes have been established for breast, cervical and colorectal cancer in the UK. Once cancer is established, the aim of cancer therapy is to cure where there is limited disease, or to extend progression-free survival where disease is advanced, while maintaining a good quality of life.

In recent years there has been a major shift in the approach to assessing and treating cancers, related to a better understanding of tumour genomic and molecular heterogeneity, and clonal evolution. There has been a greater focus on early diagnosis, and ‘personalised oncology’ including genomic and molecular testing, to guide individual patient management. There has been an expansion in available therapeutic options ( Table 62.1 ) for locoregional and metastatic disease, including targeted therapies such as antiangiogenic therapies.

TABLE 62.1

Current Therapeutic Options for Cancer Patients

Disease Extent	Treatment	Aim of Treatment
Locoregional disease	Surgery	Curative treatment: removal of tumour and local nodes yet minimising morbidity and maintaining a good quality of life
	Interventional oncology	Curative treatment: ablation of primary tumour where disease is limited and surgery is not possible
	Radiotherapy	Curative treatment: includes 3D conformal radiotherapy, intensity-modulated radiotherapy, stereotactic radiosurgery (CyberKnife, Gamma Knife) and proton therapy
Metastatic disease	Drug therapy, including chemotherapy, targeted therapy or immunotherapy	To reduce disease burden, improve symptoms and maintain quality of life
	Radiotherapy	Palliative treatment: to reduce symptoms or prevent significant complications
	Surgery	Curative treatment: removal where limited disease present Palliative treatment: to reduce symptoms or prevent significant complications

The landmark approval in 2004 of bevacizumab, an antiangiogenic therapy targeted to vascular endothelial growth factor (VEGF), for first-line metastatic colorectal cancer, has paved the way for an increasing number of licensed molecular targeted therapies. These include targeted HER-2 (human epidermal growth factor receptor 2) therapy (trastuzumab) for HER-2 overexpressing breast cancer and gastric/gastro-oesophageal cancer; targeted EGFR (epidermal growth factor receptor) therapy (cetuximab) for RAS wild-type colorectal cancer; targeted EGFR therapy (gefitinib or erlotinib) for EGFR mutated non–small cell lung cancer; crizotinib for ALK (anaplastic lymphoma kinase) gene rearrangement non–small cell lung cancer (present in approximately 5% of adenocarcinomas); and multikinase inhibitors (pazopanib, sorafenib, sunitinib) or mTOR inhibitors (everolimus) for advanced renal cell cancer.

More recently an increasing number of immunotherapies have been licenced for advanced cancer. The body's immune system plays an important role in cancer development. Evasion of the immune system is a hallmark of cancer and an important mechanism in its progression. Immunotherapies aim to re-engage the immune system in its fight against cancer cells, by neutralising immune suppressor mechanisms. Examples of drugs include ipilimumab, a ‘cytotoxic T-lymphocyte–associated protein 4’ (CTLA4) targeted antibody; and nivolumab, a ‘programmed cell death 1’ (PD1) targeted antibody. These have been licensed for advanced stage IV melanoma and non–small cell lung cancer.

These advances have resulted in improvements in patient outcome, particularly for early-stage disease. As a consequence, there has also been a greater focus on ‘survivorship’, aiming to address the long-term effects of cancer and its treatment. The subspeciality of oncological imaging has evolved in tandem with this. Typically, cancer is managed by a multidisciplinary team of specialists—including nurses; dieticians; physiotherapists; doctors such as surgeons, medical and clinical oncologists, physicians, radiologists, pathologists—that are experienced in the specific cancer type in order to optimise clinical management.

Oncological imaging now forms a significant proportion of the workload of a radiology department, with subspecialty cancer radiologists. Imaging plays a major role at different stages along the cancer patient pathway, including screening, diagnosis, staging, assessment of treatment response and surveillance; radiologists have a key role in the multidisciplinary delivery of care and multidisciplinary team meetings (‘tumour boards’). This chapter introduces key concepts in the imaging of cancer patients. The role of imaging in diagnosis, staging, response assessmen and surveillance is described.

Imaging Techniques for Cancer Imaging

Cross-sectional imaging techniques form the backbone of oncological imaging. Each imaging technique has advantages and disadvantages ( Table 62.2 ) and the ‘best’ imaging strategy will depend on the tumour type, tumour site, clinical indication (diagnosis, staging, treatment response assessment or surveillance), and availability, as well as the cost of the imaging technique.

TABLE 62.2

Summary of the Different Imaging Techniques Available for Clinical Cancer Imaging

Technique	Mechanism	Advantages	Disadvantages
Anatomical
Plain film	Attenuation of x-rays by tissue structures	Availability Low cost	Limited resolution
Ultrasound	Attenuation of sound waves by tissue structures	Availability Low cost No radiation burden	Dependent on observer expertise
Computed tomography	Attenuation of x-rays by tissue structures	Availability Cross-sectional ability High spatial resolution	Radiation burden Relatively low contrast resolution
Magnetic resonance imaging (MRI)	Absorption of radiowaves by atomic nuclei (most commonly hydrogen)	Cross-sectional ability High spatial and contrast resolution No radiation burden	Magnetic field effects and heating (particularly with high field systems)
Functional
Diffusion weighted MRI	Diffusion of water molecules	High spatial and contrast resolution No radiation burden Surrogate marker of tumour cellularity	Magnetic field effects and heating
Dynamic contrast-enhanced MRI	Kinetic modelling of gadolinium-based contrast agent to quantify vascular leakage	High spatial and contrast resolution No contrast burden Surrogate marker of angiogenesis	Magnetic field effects and heating
Blood oxygen level–dependent MRI	Paramagnetic effect of deoxyhaemoglobin; surrogate marker of hypoxia	Surrogate marker of hypoxia (hypoxic blood volume)	Magnetic field effects and heating
Dynamic contrast-enhanced computed tomography (CT)	Kinetic modelling of iodine-based contrast agent to quantify perfusion and vascular leakage	High spatial resolution Surrogate marker of angiogenesis and hypoxia	Radiation burden
Fluorodeoxyglucose (FDG) positron-emission tomography	Uptake of ¹⁸ F-FDG, analogue of endogenous glucose	Cross-sectional ability May be combined with CT or MRI Quantification of tumour metabolic activity possible	Radiation burden Poorer spatial resolution compared with CT or MRI Relatively high cost

Computed Tomography

Computed tomography (CT) remains the mainstay of oncological imaging practice, due to its high spatial resolution, clinical availability and relative cost-effectiveness. In the United Kingdom, approximately 5 million CTs are performed a year, 50% for cancer-related indications. Current CT systems are sophisticated scanners, allowing the whole body to be imaged in seconds with sub-millimetre isotropic spatial resolution. High-quality multiplanar reformats and volume rendering are now standard. Advanced software including computer-aided detection is available, for example, to support CT screening for lung nodules and colonic polyps. Physiological imaging can also be undertaken, for example with dynamic contrast-enhanced CT imaging, to assess tumour perfusion and angiogenesis, both relevant biological biomarkers for cancer.

There has also been resurgent interest in techniques such as spectral CT imaging for tissue differentiation and characterisation following the introduction of Dual Source CT scanners in 2006. Currently clinical spectral imaging can be achieved using the following methods: (a) two x-ray sources running at different voltages with two corresponding detectors; (b) fast kilovoltage switching using a single x-ray source; (c) pre-filtered twin beam from a single x-ray source; and (d) layered detectors with sensitivity to different x-ray spectra. In cancer patients this has led to improvements in care through improved lesion detection and characterisation: for example, within the liver and kidney.

Magnetic Resonance Imaging

In comparison to CT, magnetic resonance imaging (MRI) has superior soft-tissue contrast and does not have a radiation burden. The role of MRI has evolved in recent years within oncological practice. Previously reserved as a problem-solving tool, the primary use of MRI has increased, such that MRI is now the primary imaging assessment tool for many cancers and plays an important part in management decisions. It is the initial imaging technique for diagnosing prostate cancer, and for staging rectal, cervical and endometrial cancer. As a whole-body technique, MRI is currently recommended for the initial evaluation of myeloma and for bone metastases, for example, from prostate cancer.

MRI is a comprehensive technique allowing multiple contrasts (e.g. T ₁ weighted, T ₂ weighted), as well as physiology, to be evaluated in a single examination. Physiological sequences include diffusion-weighted MRI (water diffusion, a surrogate of tissue cellularity), dynamic contrast-enhanced MRI (tumour perfusion and vascular leakage, a surrogate of angiogenesis); and blood oxygenation level–dependent or tissue oxygenation level–dependent MRI (tumour oxygenation, a surrogate of hypoxia).

Positron-Emission Tomography

Molecular imaging techniques such as positron-emission tomography (PET) using positron emitters such as fluorine 18 or carbon 11 have gained significant traction for assessing cancer. Emitted charged positrons travel a short distance in tissue, dissipating energy, before annihilating with an electron to produce two 511-keV photons travelling in opposite directions; this is detected with PET imaging. With different tracers, PET provides targeted imaging of tumour physiology and biology. ¹⁸ F-fluorodeoxyglucose (FDG), an analogue of glucose, remains the commonest radiolabelled tracer in clinical use, assessing glucose metabolism. Other tracers, including ¹⁸ F- or ¹¹ C-choline, ¹⁸ F-fluorothymidine (FLT), ¹¹ C-acetate, ¹¹ C-methionine, ¹⁸ F-misonidazole (FMISO), ¹⁸ F-FAZA, ⁶¹ Cu-ATSM or ⁶⁴ Cu-ATSM, provide relevant information on tumour proliferation, lipogenesis, amino acid metabolism, angiogenesis and hypoxia, respectively. Good anatomical localisation is possible with hybrid imaging techniques such as integrated PET/CT and PET/MRI.

Summary Box: Imaging Cancer

Cross-sectional imaging is the mainstay of oncological imaging practice.
A multimodality imaging approach is typically undertaken in the initial assessment of cancer. The ‘best’ imaging strategy will depend on the tumour type, tumour site, clinical indication, clinical effectiveness and cost-effectiveness.
There has been a paradigm shift in imaging practice beyond anatomical imaging with functional and molecular imaging techniques being incorporated into imaging strategies.

Diagnosis and Imaging

Primary Diagnosis

In the majority of cases, a patient will present with symptoms and signs related to the cancer, and appropriate investigations will be arranged, including imaging. Usually there are only a few diagnoses that can be made with confidence from imaging characteristics: for example, an ovarian dermoid, or other fat-containing tumours, and lesions that are obviously cystic. In most cases there is a differential diagnosis, requiring pathological confirmation of the diagnosis.

Confirmation of Diagnosis

Confirmation of a diagnosis may be undertaken using a variety of techniques, including cytological examination of fine-needle aspiration samples, tumour specimens from automatic cutting needles and surgical biopsies ( Fig. 62.1 , Fig. 62.2A and B ). Fine-needle aspiration and core biopsies are commonly image guided. Core biopsies yield a higher tumour volume than fine-needle aspiration, and may be more suited for tumour biomarker analysis, often required by clinical trials.

Fig. 62.1, Diagram of Westcott-Type Needle.

Certain principles should be followed when needle aspiration or percutaneous core biopsy is being planned. The chosen technique should acquire sufficient tissue for a pathological diagnosis. The technique should be safe: for example, patient coagulation parameters should be checked and appropriate measures taken to minimise the risk of haemorrhage. For cytological specimens, a cytologist should be present to ensure enough material is present, and to stain and interpret the cytology samples immediately. For core biopsies, specimen preparation should be discussed with the examining pathologist. Most specimens can be placed in formalin but others may require preparation for special staining techniques.

If image-assisted tissue diagnosis is inconclusive, consideration of further percutaneous attempts or of open surgical biopsy should take into account the reason for diagnostic failure. For example, some tumours, such as pancreatic carcinoma, may have few malignant cells. The degree of risk involved in repeat biopsy, the technical ease with which the specimen was obtained and the likelihood of achieving positive tissue diagnosis on the second attempt are important considerations.

Staging

Once the cancer has been confirmed, it is important to stage it accurately for its subsequent management. That is, it is important to establish its locoregional extent as well as the presence/absence of distant metastatic disease. Staging systems that are used in clinical practice—for example, tumour–node–metastasis (TNM) or Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) classification systems—provide an indication of prognosis and guide appropriate management, although decision-making will be influenced also by other factors, including the histological grade of the tumour, its expected biological behaviour, and the age and general fitness of a patient. While clinical examination continues to have a significant role in the initial assessment of patients, imaging has a major role to play in the staging of cancer.

Staging Systems

An ideal staging system should be simple, precise, consistent, applicable to all clinical circumstances in oncology and convey some prognostic information to facilitate best practice. Over the years, many staging systems have borne the name of eminent doctors (e.g. the Robson staging classification of renal tumours, or Dukes’ staging classification of colorectal cancer), institutions (e.g. the Royal Marsden Hospital staging classification for testicular germ cell tumours) or organisations (e.g. the FIGO classification systems for cervical, uterine and other gynaecological neoplasms). More recently the TNM system, advocated by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer (UICC) has been adopted widely.

The TNM classification of malignant tumours and the AJCC cancer staging handbook are currently in their eighth editions. The system was originally devised by Pierre Denoix in the 1940s and modified over the subsequent decades. The ‘T’ category entails evaluation of local tumour extent. The ‘N’ category entails evaluation of nodal involvement. The ‘M’ category entails evaluation of disease at distant sites. There may be a prefix ‘c’ to indicate clinical staging; ‘p’ to indicate pathological staging or ‘y’ to indicate post-neoadjuvant radiotherapy staging.

The ‘T’ category has several standard forms of notation: Tx indicates that primary tumour cannot be assessed; Tis indicates in situ disease with no evidence of invasion; T0 indicates no visible evidence of primary tumour; T1 to T4 indicates increasing degrees of local tumour invasion. These divisions may be adapted with the addition of subdivisions indicated by letters (e.g. ‘a’ or ‘b’) for greater flexibility within different tumour types. Although staging of the primary from T1 to T4 follows broad principles and there are some similarities between tumour types, refinements and adaptations for individual tumours are usually needed.

The ‘N’ category has similar notation. Nx is where regional lymph nodes cannot be assessed, N0 is where no regional lymph node metastases are present, and N1, N2 and N3 indicate increasing involvement of regional lymph nodes by the cancer. Likewise, these divisions may include subdivisions indicated by letters (e.g. ‘a’ or ‘b’).

The ‘M’ category assesses distant metastasis where Mx indicates that distant metastasis cannot be assessed, M0 indicates there are no distant metastases and M1 indicates the presence of distant metastasis. The category M1 may be further specified indicating which organs are involved. For example, PUL indicates pulmonary metastases, OSS indicates osseous metastases and HEP indicates hepatic metastases. Again, subdivisions may be indicated by letters (‘a’ or ‘b’).

A number of general rules apply when using the clinical TNM staging system. Clinical stage is assigned by physical examination, imaging and other relevant investigations, but may be amended as pathological information becomes available, and given the prefix pTNM stage where microscopic extent of disease is known. If there is doubt what stage should be assigned, the lower category should be used. Therefore, an imaging investigation that is suspicious but not diagnostic of spread to the pelvic sidewall will be disregarded unless supplemented by further imaging or confirmation by histopathology.

Once assigned, the pre-treatment TNM stage is recorded in the patient's records and remains unchanged through subsequent treatment. For multiple synchronous primary tumours, the tumour with the highest ‘T’ category is used for staging purposes. For synchronous primary tumours arising in paired organs, each tumour should be assigned a separate TNM stage. In modern usage the TNM system has the advantages of clarity of communication, but is complex. This has led to a further system: the stage grouping, which is published within the AJCC system. Stage groups of 0 to 4 are assigned as tumour becomes more extensive and widespread.

National bodies such as the Royal College of Radiologists in the United Kingdom have published recommendations or guidelines on the choice of staging investigation (CT, MRI and PET/CT), recognising that local availability of advanced imaging techniques as well as the experience and preference of individual radiologists remain important considerations in clinical practice. A potential effect of advances in imaging technology over time is stage migration, for example, via improvements in tumour detection, resulting in upstaging, and artefactual improvement in subgroup prognosis, although overall survival will remain stable unless more effective treatment is given.

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