The diagnostic value of Superb Microvascular Imaging in identifying benign tumors of parotid gland

Parotid gland tumors account for 3–6% of head and neck tumors [1]. 80% parotid gland tumors are benign tumors, in which pleomorphic adenoma (PA), Warthin’s tumor (WT) and basal cell adenoma (BCA) account for the top three [2]. Different types of parotid gland tumors have different biological behaviors; therefore, different types of parotid gland tumors have different operation principle. PA has complex components, often presents multicenter growth, tends to infiltrate into the surrounding tissues and may recur after resection. Additionally, 2–25% PA has malignant tendency. In order to ensure the complete resection of tumors, reserve normal tissues maximumly and reduce recurrence and postoperative complications, tumor resection including superficial parotid gland resection is recommended for PA. WT is often bilateral and multifocal and has relatively simple components and less postoperative recurrence. Thus, exenteration of the tumor is recommended. Some BCAs can grow in a multicentric and multifocal manner, and 4% BCAs have malignant tendency. Thus, all involved tissues need to be completely removed during the operation for BCA. Although basal cell adenoma was first reported by Kleinsasser and Klein in 1967, until 1991 it was first time that the WHO classified basal cell adenoma (BCA) as a independent solid tumor type. There are many studies on parotid PA and WT, but few reports on BCA. Actually, BCA is not rare in clinic, while the misdiagnosis rate for BCA is as high as 50% [3].

Preoperative differential diagnosis is important, particularly for surgical decision making. However, there are many ultrasonic similarities between these three types of parotid gland tumors [3, 4]. Although high-frequency color doppler ultrasonography has become the preferred method of parotid gland imaging examination and has certain value in providing tumor location diagnosis and blood flow information, it has limited ability in the differential diagnosis of parotid gland masses. Contrast-enhanced ultrasound (CEU) can provide the perfusion of micro vessels in the tumor, and the characteristic curve of CEU can be used to analyze relevant parameters to improve the diagnostic accuracy of the tumor [5‐7]. However, CEU is expensive and time-consuming. Superb microvascular imaging (SMI), as a new ultrasound technology, is able to use adaptive algorithm to separate low-speed blood flow signals from slow mixed clutter signals, so as to display the micro-low-speed blood flow signals clearly and completely. Recent studies show that, compared with color doppler flow imaging (CDFI). It can display the low-velocity blood flow in breast and kidney tumors more sensitively [8‐10]. It is saving time and no extra cost, as well as can carry out true and meticulous microangiography of the lesion site without contrast enhancement.

Micro vessel density (MVD) is an important indicator reflecting tumor angiogenesis [11], which was proposed by Weidner in 1991. It is also a quantitative analysis method of tumor angiogenesis capacity. So MVD is widely used in most angiogenesis studies. This method is based on the immunohistochemical analysis of postoperative pathological tissue paraffin section specimens. The number of micro vessels under high magnification is the gold standard for the evaluation of tumor micro vessels. CD34 antigen had highest specificity for vascular endothelial cells. Therefore, at present, most studies on tumor angiogenesis use CD34 to label vascular endothelial cells and calculate the MVD value of microvascular density.

At present, there are few clinical studies on ultra-micro angiography of parotid gland tumors [12]. In this study, we compared the diagnostic performance of SMI and CDFI, and analysis correlation between SMI, CDFI and MVD, so as to explore the clinic value for SMI assess micro vascular density.

High-frequency ultrasound is a first-line examination method for the diagnosis of parotid gland tumor, which can provide information such as the location, size, shape, internal echo and the relationship with surrounding tissues, etc. However, due to the diversity of parotid gland tumor pathological types, ultrasound features overlap greatly, common ultrasound has high sensitivity but low specificity for differential diagnosis. In this study, there were no statistically significant differences in conventional ultrasound characters including tumor boundary, shape, cystic area and size between these three different parotid gland tumors. Generally, parotid gland tumor is small, with clear boundaries and regular shapes. They are round or oval, with complete capsule. Some of the parotid gland tumor have complex characters, which are lobulated and irregular in growth. Cystic changes may occur in larger tumors and in all three types of tumors, which is results from liquefaction necrosis, internal bleeding, or mucous retention secreted by tumor epithelium.

In this study, there were statistically significant differences in internal echogenicity among the three groups of parotid gland tumors. The internal echogenicity of PA and WT were more inhomogeneous. PA is a borderline tumor, with atypia, composed of myxoid epithelial tissue and (or) chondroid tissue. The internal echogenicity depends on tumor tissue, epithelia dominated tumors are usually hypoecho, mucinous or cartilaginous dominated tumors are usually extreme hypo-echo. WT is composed of epithelial tissues and lymphoid tissues, the echoes of lymphoid tissues are hypoecho, while the epithelial tissues of the tumor are functional and secrete some liquid, so the cystic area in the tumor are common, the internal echogenicity inside the tumor extremely-hypo, and some of them have “grid-like”. BCA are composed of a single cell, which constitutes the basal cell layer. The layers are relatively sole, without interstitial and cartilaginous matrix, and the internal echoes are more homogeneous. Echogenicity inside the tumor is helpful to distinguish BCA from PA and WT.

Ultrasonic Doppler signals are not only derived from the blood flow, but also from the motion artifacts (clutter) of tissues. The motion artifacts have high amplitude and low velocity, and are often mixed with the low-velocity blood flow signals, or even conceal the micro blood flow signals. The CDFI technology can’t distinguish motion artifact and blood flow signal, because its processing method is a one-dimensional filtering technology. Low-speed motion artifacts and low-speed blood flow information were filtered indiscriminately. Therefore, CDFI could only display vessels with diameter of > 0.2 mm and blood flow signals with relatively high flow velocity, and could only provide the general blood supply situation in the tumor [15]. CDFI lacks the ability to evaluate the small blood vessels in the tumor, and could not reflect the real microvascular situation in the tumor. The growth of solid tumors is vascular dependent. As an important component of tumor stroma, blood vessels interact with tumor cells to form a complete microenvironment. This study showed that the detection rate of SMI for benign parotid tumor blood vessels was significantly different from CDFI, and the overall detection rate of SMI for Grade 2 and 3 was significantly higher than CDFI. In clinic, SMI technology use adaptive algorithm to distinguish motion artifacts and slow blood flow, fully suppress noise using the unique processing technology, highlight slow blood flow signals intelligence, brings high sensitivity to subtle low speed blood flow. So it can clear display diameter > 0.1 mm microvascular blood flow signal at low speed, show the tiny blood vessels without using the contrast agent and achieve the similar imaging display effect. Thus, SMI can more truly present the microvascular condition in the tumor than CDFI [15].

The number of micro vessels inside the tumor is closely related to the pathological type of the tumor. Usually the blood supply of the benign tumor is less, if the blood supply of the benign tumor increases, it indicates the possibility of malignant transformation. In this study, CDFI showed more red and blue blood flow distribution in the interior and peripheral in WT, SMI showed more puncture vessels in WT, more dendritic blood flow, mainly central or mixed distribution, 73.5% of patients with Grade 2–3 blood supply, significantly more than other benign tumors in parotid gland. This is related to its pathologic structure. WT is composed by both epithelial tissue and lymphoid tissue, its epithelial components form irregular large glandular ducts or microcysts, and form nipple into cavity, hyperplasia of lymphoid tissue forming lymphoid follicles. Most of the WT mesenchymal percentage was near to epithelial, and micro vascularity was rich in lymphoid interstitial [16]. The higher the content of mesenchymal, the more abundant the distribution of micro vessels inside and outside the interstitial and capsule, which makes WT significantly different from other benign tumors in parotid gland in terms of blood supply. Because the lesion originates from the heterotopic glandular epithelial cells in the lymph node, the blood flow distribution is close to the lymphatic portal blood flow, so the blood flow is usually dendritic. PA is often circumscribed by the edge of blood flow, and the blood flow signals are not rich, mainly with no blood flow and peripheral blood flow, Grade 0 and Grade 1. Some PA blood flow signals are rich, even up to Grade 3. The reason is related to local tumor capsule infiltration, or focal growth to the capsule. Most blood flow of BCA are also rich, mainly peripheral and mixed distribution, Grade 2 and Grade 3, which is related to the pathological characteristics of the tumor. Pathologically, BCA has more characteristic vascular network arranged along the endothelium, mainly capillaries and venules, and blood flow is mostly peripheral distribution.

The occurrence and development of solid tumors need two stages: the perivascular phase stage and the vascular stage. The diameter of tumor in pre-vascular stage was < 2 mm, and the tumor grew slowly, mainly relying on osmosis to obtain nutrition. When the tumor continues to grow to > 2 mm in diameter, it enters the vascular stage, with a large number of micro angiogenesis, which mainly relies on angiogenesis to obtain nutrition [17]. Pathological MVD is the gold standard for evaluating tumor microvascular condition. At present, the main imaging methods for evaluating tumor micro vessels include CEU and enhanced MRI, which are highly correlated with MVD [18, 19]. However, there is no noninvasive imaging technique to evaluate the angiogenesis of parotid gland tumors in real time. Therefore, it is urgent to find an imaging method with good correlation with MVD and no trauma, which can evaluate tumor angiogenesis in the preoperative living state and provide valuable prognostic information for clinical use. SMI quantitative index VI can accurately detect the pixel ratio of blood flow signal in parotid gland tumor, and truly reflect the distribution density of low-velocity blood flow signal in the tumor, so as to intuitively reflect the microvascular condition of the tumor. In this study, VI value and MVD value of PA, BCA and WT were successively increased, and VI was significantly positively correlated with MVD, implied that VI could accurately and quantitatively reflect the micro-blood flow generation in parotid gland tumor.

Despite the parotid benign neoplasm in conventional ultrasonic features and CDFI have overlap, but the SMI evaluation can provides us with abundant diagnostic information on flow classification, distribution and blood flow in VI, to assist conventional ultrasound, the SMI can significantly improve the ability of ultrasonography in the differential diagnosis of parotid benign tumor, provide reference for clinical diagnosis and treatment decisions. In summary, SMI can provide low-velocity blood flow information that can’t be displayed by other blood flow imaging technologies, which is helpful for the differential diagnosis of common benign tumors of parotid gland, and is expected to be more widely used.