Diffusion signal evaluated using different models of analysis: mono-exponential a intravoxel incoherent exponential model IVIM b , diffusion kurtosis imaging DKI c , and diffusion tensor imaging DTI d. DWI can offer multiple parameters depending on the model of analysis, including ADC, perfusion fraction f , or apparent kurtosis Kapp with a different biological meaning. Biological and physiological correlation of parameters obtained from analysis is not entirely clear and their clinical value may depend on tumor type.
Rectal cancer in a year-old woman. Note that this curve showed a marked attenuation of signal intensity at low b values red arrow due to the influence of tumor perfusion on diffusion. Diffusion measures the random Brownian motion of water molecules at microscopic level. However, diffusion is not free in tissues and is modified by interactions with cellular packing, intracellular organelles, membranes, and macromolecules and by macroscopic water movements e.
As a general rule, water diffusion decrease with the increased cellularity and cell size 24b. Negative correlations between the ADC values and cellularity or proliferation have been reported in many tumor types; though, there were no clear correlations in others [ 32 , 33 ]. It must be also considered that molecular mobility is anisotropic, not equal for all directions.
Based on this, diffusion tensor imaging DTI may describe the magnitude, degree, and orientation of diffusion anisotropy and may estimate the tissular microstructure. Characterizing the non-Gaussian diffusion MRI signal behavior may also provide valuable information on tissue structure and function. IVIM model allows the separation of pure diffusion characteristics from pseudodiffusion and perfusion features. The biological meaning of these parameters is not entirely clear.
However, the f values have been suggested to be related to the blood volume BV and have been significantly correlated with the percentage of arterial enhancement in different tumor types [ 34 , 35 , 36 ]. Most studies have also found a fair to good correlation between f and histological surrogate markers of angiogenesis, such as the microvessel density MVD , and parameters derived from perfusion imaging techniques [ 34 , 35 , 36 ].
The diffusion signal alterations serve as an excellent qualitative tool, providing an additional contrast mechanism to supplement routine conventional sequences.
Areas retaining high SI on high b values images suggest highly cellular tissues, such as tumors [ 28 , 29 , 30 , 31 ] Fig. This feature may be a useful clinical tool. A recent meta-analysis reported that visual assessment of tumor diffusion might be more accurate than ROI measurements of ADC for PCa detection [ 38 ].
A year-old man with lung adenocarcinoma. The ADC has served as a quantitative biomarker for the evaluation of diffusion in clinical practice. Calculation of an ADC value is typically performed utilizing a mono-exponential fit of the diffusion signal at different b values.
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There is a linear decay of the natural logarithmic diffusion SI as the b value is increased. Malignant lesions usually have lower ADC values compared to surrounding normal tissue, edema, and benign tumors [ 28 , 29 , 30 , 31 ].
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Unfortunately, there is considerable disparity in the published ADC values across different anatomies, vendors, or technical parameters of the acquisition causing that there are no unique cut-off ADC values that distinguish cancer from normal tissues. Besides, both well-differentiated tumors and necrotic poorly differentiated tumors may show high ADC values and some normal tissues including endometrium, bowel mucosa, testes, and normal LNs and nerves may show increased SI on high b value [ 28 , 29 , 30 , 31 ].
Finally, non-Gaussian models yield several quantitative parameters that may improve diffusion assessment. Malignant tumors are generally more cellular than benign tissues and show lower ADC values. However, false positive results may occur with abscesses and infective processes and false negatives may happen with cystic, necrotic lesions and in well-differentiated neoplasms particularly adenocarcinomas [ 27 , 28 , 29 , 30 ]. DWI has also demonstrated to be an effective tool for evaluating tumor response to therapies [ 40 , 41 , 42 , 44 ]. Successful treatment is usually reflected by increases in ADC values.
However, it depends on the mechanism of action of therapy given. This finding appears to be related to cellular swelling and reductions in tumor BF, extracellular space, and vasogenic edema. Accurate imaging response evaluations of oncologic patients are sometimes notoriously difficult with conventional imaging techniques, especially in the case of bone lesions. In this setting, whole-body WB -DWI MRI has shown clinical value for the assessment of therapeutic response in patients with metastatic bone disease, multiple myeloma, and lymphoma [ 41 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ] Figs.
A year-old woman with metastatic breast cancer treated with chemotherapy a. Red colored voxels represent untreated disease or those with no-detectable response. A year-old woman with metastatic breast cancer treated with an anti-HER2 agent and hormonotherapy. In this case, response assessment demonstrated a discrete change in ADC values predominantly yellow voxels.
IVIM represents an alternative to perfusion contrast-enhanced techniques without the use of contrast agents in oncologic imaging. IVIM has also shown promising results for monitoring therapy response especially antiangiogenic drugs or vascular targeting agents in clinical practice [ 21 , 35 , 55 ]. Published data suggests that DKI may provide additional information and may improve tumor diagnosis and characterization compared with conventional diffusion parameters in these tumor types [ 37 ].
Computed tomography and magnetic resonance tomography of intracranial tumors a clinical perspective
Up to now, SEM has been used in a limited way in the evaluation of tumors. Imaging specially MRI may allow the depiction of tumor composition. Several tumor types show characteristic imaging findings. For instance, melanin a paramagnetic substance shortens the T1 relaxation time, making melanoma appear hyperintense on T1-weighted images.
MRI fat quantification allows monitoring bone marrow BM composition in oncologic patients and BM changes that result from therapy. BM has variable composition and vascularization Fig. These features may be useful in the evaluation of patients with metastatic bone disease for diagnosis or therapy response assessment [ 43 , 50 , 53 , 56 , 57 , 58 ]. T1 mapping can detect important tissular characteristics such as excess of water e.
Quantitative T1 mapping requires a series of images using different inversion times to derive a T1 recovery curve resulting in a map that describes the relaxation value on a pixel-by-pixel basis, expressed in milliseconds. In oncology, studies about the use of T1 values in tumors evidenced that this parameter was greater than in normal tissues due to an increased extracellular space.
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On the contrary, low tumor T1 values have been correlated to increased necrosis, low water content, and high levels of proteins [ 59 ]. Native T1 mapping could also represent an in vivo biomarker for the differentiation of tumor grade [ 60 ]. Significant changes in T1 were shown in several pre-clinical models in response to therapy [ 59 , 61 ]. The use of T2 mapping in oncology has been mainly focused on PCa.
Sabouri et al. An explanation of this feature may be the effect of normal prostate tissue interdigitated with malignant glands, which may reduce contrast between tumor and normal prostatic tissue [ 63 ]. Unfortunately, a reliable diagnosis of malignancy cannot be made on the basis of a quantitative evaluation of T1, T2, or proton density indexes. MT imaging and chemical exchange saturation transfer CEST can evaluate the presence of molecules other than water.
MT may be useful for evaluating tissues with significant water-macromolecule interactions. This technique has showed promising results as a possible tool for tumor assessment in prostate, testicle, rectal, breast, and brain tumors Fig. CEST can detect low concentrations of molecules through the presence of 1 H protons that are exchangeable with those of water causing a decrease of signal intensity.
APT values also varied between malignant groups and tumor grades [ 67 , 68 ]. An 8-year-old patient with high-grade tectal plate glioma white arrow. Note the reduction in the MT ratio histogram in b associated with response to treatment, accompanied by slight increase in size and enhancement of the tumor a. Neil P. Jerome, Norwegian University of Science and Technology]. Spectral CT also enables material identification calcium, fat, etc. In this setting, for example, Kosmala et al. The biology of tumors can no longer be understood simply by evaluating tumor cells but instead must include the contributions of the tumor microenvironment TME to tumorigenesis.
TME is a complex, heterogeneous, and dominant component of solid tumors. TME includes the acellular component named the extracellular matrix, ECM and different co-opted cell types, including cancer-associated fibroblasts, mesenchymal cells, and immune infiltrate. TME plays critical roles in both promoting the malignant progression of solid tumors and modifying the response of solid tumor cells to therapy.
Pathological TME usually shows insufficient oxygenation hypoxia and acidosis. Multiple imaging modalities have been employed to evaluate the TME, but most of them are still at the pre-clinical phase of testing [ 71 , 72 , 73 ]. Desmoplastic reaction in a year-old patient with pancreatic adenocarcinoma. These findings were secondary to the predominance of fibrosis within the lesion.
Apart of the study of tumor vascularization, imaging evaluation of tumor stroma has been scarce. The stroma can make up a significant proportion of a tumor volume, and differs from normal stroma, showing a high number of fibroblasts, deposition of type I collagen and fibrin, and a marked infiltration of inflammatory cells. Stroma may deeply influence imaging findings of tumors Fig. Although these tumors usually show increased angiogenesis on histological analysis, tumor imaging findings are deeply modified by stromal fibrosis, a feature which explains that pancreatic adenocarcinomas usually show a diminished enhancement in the early phase of dynamic contrast-enhanced imaging techniques and gradual enhancement in the late phase Fig.
BOLD sequence and tumor oxygenation.
Progress on the diagnosis and evaluation of brain tumors
These features evidence the presence of radiosensitive areas within the tumor with increasing pass of oxygen from blood to the tissue. Interactions between tumor cells and immune cells are involved on the initiation, progression, therapy-resistance, and prognosis of cancer. Besides, immunotherapy has successfully been introduced in the clinic for many cancer types especially in cancer types with high mutation rates. To date, there is a limited experience with the evaluation of tumor-infiltrating immune cells and responses to immunotherapy in clinical practice and there is a lack of imaging tools to measure the behavior of immune cell populations, which is hampering the optimization and individualization of immunotherapy [ 74 ].
Tumor hypoxia leads to treatment resistance, enhanced tumor progression, and has a negative impact on patient prognosis and survival in cancer. Hypoxia changes the pattern of gene expression resulting in a more aggressive tumor phenotype [ 75 ]. Uncontrolled cell proliferation and the inability to form normal blood vessels results in impaired blood supply and low oxygen tension within tumors.
Hypoxia activates adaptive cellular responses and genomic instability that contribute to tumor progression and is associated with poor prognosis and resistance to different therapies, potentially contributing to poor patient survival. Two main types of tumor hypoxia are recognized [ 76 , 77 ]: 1 acute perfusion-related hypoxia resulting from inadequate BF in tumors due to structural and functional abnormalities of tumor vasculature and 2 chronic hypoxia, which is the most relevant type in oncology.
Two fundamental mechanisms of chronic hypoxia can be differentiated: diffusion-limited hypoxia caused by increased oxygen diffusion distances due to tumor growth and hypoxia due to a compromised perfusion due to inefficient and leaky microvessels. BOLD-MRI contrast derives from variations in the magnetic susceptibility of blood due to changes in the concentration of deoxyhemoglobin. This change in magnetic susceptibility produces local magnetic fields around blood vessels, changing signal intensity on MR images Fig.
BOLD provides an indication of tumor blood oxygenation, but is also sensitive to vessel density, blood flow hematocrit, and pH [ 77 ]. Theranostic in oncology with PSMA. PET image evidenced a difuse metastatic involvement.
FMISO enters cells under hypoxic conditions and becomes trapped at rates that are inversely proportional to the local pO 2.