13 Microcirculation and Tumor Perfusion

Tumor tissue is composed of stroma cell constituents, blood, and lymphatic vessels. The extracellular matrix consists mainly of collagen and hyaloroic acid and is predominantly responsible for the hardness of a malignant tumor. The different components of the tumor microenvironment may vary depending on the type of the tumor and its location, making each tumor unique.¹

In normal tissue, the need for oxygen supply and nutrients regulates its blood supply. As long as the tumor’s size is below 1 to 2 mm, its oxygen and nutrition supply will be managed by diffusion; however, angiogenesis is essential for enabling the tumor to grow. This depends on the release of angiogenic factors like vascular endothelial growth factor (VEGF), angiopoitin, and many others. The imbalance and dynamic changes of pro- and antiangiogenic signaling within tumors create an abnormal vascular network. Microvessel density varies widely with tumor type and within a tumor itself.² Contrary to normal vessels, tumor vessels have a loose basement membrane, nonfunctioning or less functioning pericyts, and anarchic, mostly chaotic, vessel architecture due to lack of smooth muscle.

For characterizing tumors, tissue contrast agents have added great value. This is because contrast bubbles have a size range of red blood cells and are stable enough to trespass the capillary bed of the lung and abdominal organs. Thus, perfusion into organ and tumor can be imaged and the change in bubble concentration can also be quantified over time. As long as the bubbles are not destroyed, even a single bubble can be detected under favorable scanning conditions.

13.2 Available Imaging Techniques

For imaging blood flow, Doppler-based ultrasound (US) techniques are first-line choices. Besides the classic Doppler US techniques like color, power, and pulse wave Doppler, novel techniques like B-flow, “superb microvascular imaging” (SMI), and vector-flow (see plane wave imaging in Chapter 21) offer some advantages and limitations at the same time. Limitations related to all these techniques must be considered: Vessel and flow detection, size, angle of insonation, signal to noise ratio, number of reflectors related to the backscatter signal strength, and attenuation due to deep vessel location. For Doppler techniques, color window, angle, pulse repetition frequency (PRF), and gain have to be optimized to the individual flow condition. Filter techniques may have to be applied in order to prevent tissue motion, which is detected as flow signals. A range of well-known artifacts linked to the Doppler techniques also limit their use (Fig. 13.1, Fig. 13.2).

B-flow and SMI have been added to the diagnostic armament, offering some advantages over conventional Doppler techniques (Fig. 13.2c, Fig. 13.3, Fig. 13.4).

13.3 Tumor Vasculature and Perfusion

Monitoring microcirculation over time is the most important noninvasive diagnostic contribution in characterizing malignant and benign tumors. All radiologic methods like computed tomography (CT) and magnetic resonance imaging (MRI) are also dependant on contrast agents. Receptor- or cell-specific contrast agents such as Sonazoid (approved in the US and some Asian countries but not for US) or gadoxetate disodium (Primovist) add value in detecting and characterizing liver tumors. Positron emission tomography (PET) can visualize metabolic activities of tissues by administering fluorodeoxyglucose (18F-FDG).

All Doppler modes depend on sufficient backscatter signal strength to image intravascular flow, while contrast-enhanced ultrasound (CEUS) is capable of imaging the microvasculature by just detecting single bubbles. Marked differences between color Doppler and CEUS studies may therefore be seen (Fig. 13.2).

Tumor vessels may branch irregularly and have a variable vessel caliber, thus slowing down intraluminal flow velocity down to zero—a condition causing ischemia and necrosis, which, on the other hand, is the greatest stimulus for neoangiogenesis (Fig. 13.3, Fig. 13.4, Fig. 13.5).

Compared to cancerous tumors with their mostly chaotic vasculature, the vasculature of lymphomas and reactive lymph nodes (LNs) differs greatly. It must be recognized that, in patients with NHL and reactive LN, these two entities cannot be distinguished based on the vascular pattern (Fig. 13.5). It is probably because, like in follicular lymphomas, vessels mostly have a mature phenotype (i.e., have pericyts) rather than an immature phenotype, as commonly reported in malignancies.³ It has also been reported that staining of vascular markers highlights a similar vascular distribution in reactive nodes and follicular lymphoma, while similar vascular pattern is not reproducible in diffuse lymphomas.⁴

A high vessel density with a regular architecture can also be seen in patients with soft tissue tumors like Merkel cell carcinoma (Fig. 13.6) and a highly aggressive neuroendocrine skin malignancy to mention a few. When using high frequency probes with a sensitive color Doppler technique—or other flow-detection modes—US is regarded as the best imaging tool for characterizing peripheral LNs and for describing their vasculature.

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