Morphological aspects of basal cell carcinoma vascularization

Abstract

Basal cell carcinoma (BCC) is a malignant skin cancer which commonly exhibits aberrant blood flow because of angiogenesis. Its invasiveness and lack of metastatic potential may be explained by the typical pattern of vascularization seen in BCCs, where blood vessels are absent in the tumor islands and prominent in the tumor’s periphery. From clinical point of view, high-frequency ultrasound (HFUS) is a useful tool for the evaluation of the lateral and depth extension of these tumors; furthermore, by employing color Doppler, important data regarding the vascularization degree of BCCs is provided. Knowingly, the sonographic vascular pattern of cutaneous tumors can aid in improving diagnosis and treatment by differentiating between benign and malignant lesions, between various types of cutaneous malignancies and also between various types of BCC (e.g., low risk versus high risk). Our aim was to perform a review integrating all currently known vascular properties of BCC as a tumor entity.

Introduction

Basal cell carcinoma (BCC) is the most frequent type of skin malignancy [ 1, 2, 3], and its prevalence during the past decades has grown continuously [ 1, 4]. Its incidence increases by age and by cumulative ultraviolet rays’ exposure [ 1, 2, 3]. The major risk factors are solar radiation, sun damage, such as burns, skin phototype and immunosuppression [ 1, 2, 3, 4]. Although more research is required, the existence of a high caliber artery close to a non-melanoma skin cancer is thought to be a potential risk factor [ 4]. Tumor progression may also be impacted by preferential arterial colocalization, more particular by arterial pulsatile flow [ 4]. To prevent BCC occurrence, we need a better knowledge of its etiology, development, and progression, which will help limit their rising incidence [ 4]. The head and neck region are the most common site of development for BBCs [ 1, 2, 3]. From all subtypes, the majority of BCCs are nodular, with the forehead, eyelids, cheeks, and nasolabial folds being particularly affected [ 1]. The second most common clinical subtype is represented by superficial BCC [ 1]. While all the other subtypes favor the head and neck region, superficial BCCs develop frequently on the trunk and extremities [ 1]. Though rare variants, infiltrative and morpheaform BCC are typically more aggressive in nature, when compared to nodular and superficial BCC [ 1, 2]. The potential for severe local invasion and destruction exists in infiltrative and in morpheaform BCC, which frequently display subclinical spread [ 1]. Because they are pigmented and can exhibit certain dermoscopic characteristics that are indicative of a melanocytic lesion, pigmented BCCs can be difficult variant to diagnose clinically [ 1]. Location of the tumor is a crucial factor in therapeutic decision-making as it is necessary to have an oncological outcome, to preserve function and have an aesthetic result in such a particular area as the body [ 1]. Although BCC does not usually metastasize, it is locally destructive and can cause functional and aesthetic damage [ 3]. This is especially significant due to the usual region of appearance on the face and neck [ 1, 3, 4]. BCC’s destructive local spread has the potential to result in substantial morbidity [ 1]. The current “gold standard” for BCC diagnosis is histology, providing morphological and structural characterization of the tumor [ 2]. To speed up clinical diagnosis and improve preoperative evaluation, novel in vivo investigational methods, such as skin high-frequency ultrasound (HFUS) have been employed [ 2, 3]. While HFUS cannot be relied on to confirm the diagnosis because it is unable to evaluate tumor’s cellularity, it does allow for a thorough preoperative study, providing information about the tumor, such as type, dimensions, depth of invasion, different lays and structures invasion and homogeneity [ 2, 3]. Moreover, the use of Doppler provides description of vascularization of the tumor itself but also of the surrounding tissue, thus aiding not only in clinical diagnosis but also in therapeutic planning [ 2, 3]. Another important information ultrasound (US) and Doppler examination can provide is about the histological subtype of BCC. The ability to distinguish between BCC’s many histological subtypes in a non-invasive manner may aid in care and enhance the lesion’s aesthetic outlook, especially in the situation where low and high-risk subtypes are encountered within the same lesion [ 3].

Aim

The aim of this review was to characterize the morphology of BCC vascularization from a histological to a clinical point of view. BCC vascularization plays a major role in tumor growth, invasiveness and in its metastatic potential. This article will provide information from decades ago to the current time. In our review, we discuss how determining the vascular pattern can improve tumor measurement, how analyzing vessel distribution can help differentiate invasive from non-invasive variants of BCC and how qualitative and quantitative information reading tumor vascularization plays a role for the surgical approach.

BCC origin and morphology

First described in 1827 as an “ulcer” located on the face, then as “ulcer rodens”, in 1851, by Jacob [ 5], BCC had different hypothesis regarding its definition and its origin. Krompecher considered BCC as a malignant locally invasive cancer and in 1900 used the term “carcinoma epitheliale adenoides” to describe it. He is also the one that hypothesized that BCC origin lays in the basal cell layer located in the epidermis or in the hair follicle [ 6, 7]. Mallory had a different theory, stating in 1910 that BCC is a “hair matrix tumor”, implying that the cell of origin is follicular [ 8]. Those two distinctive theories reveal the ongoing debate and ambiguity about the cellular origin of BCC. Throughout the past few years, researchers postulate that the origin of BCC resides within stem cells from the hair follicle [ 9, 10], although others state that the origin is not within the hair bulge itself rather within the stem cells from the interfollicular epidermis and the infundibulum [ 11]. According to some theories, different stem cell compartments may be targeted by distinct carcinogenic agents, which would then result in the development of BCC [ 10, 12, 13, 14]. BCC has 10 histological variants according to the latest World Health Organization (WHO) Classification of Skin Tumors and from a morphological point of view they all contain basaloid cells with hyperchromatic nuclei and small amount of cytoplasm, that constitute islands of cells separated by a fibromyxoid stroma that often retracts around tumor nests [ 15]. Because the therapy of BCC is based on the risk of recurrence, in the latest WHO Classification of Skin Tumors the authors point out the significance of low- and high-risk classifications [ 15]. Lesack & Naugler were able to show that the peritumoral stroma of several BCC subtypes differs quantitatively from one another [ 16]. Changes in extracellular matrix proteins and growth factors secretion by fibroblasts are among the stromal modifications encountered in the peritumoral area [ 16]. Also, thicker stroma and smaller tumor radii, along with a proportionally lower tumor-to-stroma ratio, were characteristics of the infiltrative subtype [ 16]. Moreover, in this subtype solar elastosis was more prevalent [ 16]. Another study by Lynch & Matrisian postulate that matrix metalloproteinases expressed by stroma potentially have an extensive impact on tumor growth and angiogenesis, and therefore on their metastatic potential as well [ 17]. The fibroblast alongside the inflammatory cells located in the peritumoral stroma secrete paracrine factors, growth factors and reactive oxygen species, which all together affect cancer growth [ 18]. Angiogenesis is facilitated by intricate connections between tumor-associated macrophages and activated fibroblasts [ 19].

Morphological characterization of BCC vascularization

Since 1971, it has been believed that angiogenesis is crucial for the formation of tumors [ 20, 21]. A tumor cannot proliferate past a size of 1–2 mm3 and cannot metastasize without the existence of angiogenesis [ 22, 23, 24]. Invasiveness and the potential for metastatic spread may both be explained by higher microvascularity [ 25]. Poorer prognosis has been associated with higher microvessel density (MVD) in tumor tissue and in the tumor–stroma interface [ 24, 25, 26, 27, 28]. A more complex angiogenesis is linked to vascular pleomorphism, and it is very predictive of malignancy [ 29]. Staibano et al. discovered that the angiogenic process is clearly seen at the boundary between tumor and stroma, right at the invasive front of BCC lesions (Figure 1), and between the sheets of invasive malignant cells [ 30].

Figure 1.

Basal cell carcinoma specific vascularization pattern: one to two vascular pedicles. Blood circulation is concentrated at the tumor’s base.

Because of angiogenesis, abnormal blood flow is typically seen in BCCs [ 31]. When compared to normal skin, Bowden et al. found increased expression of vascular endothelial growth factor (a potent proangiogenic factor) in BCC tissue, more specifically in the tumor cells located at the tumor front [ 32]. Lupu et al. also postulate that the peritumoral stroma immediately surrounding BCC is where the angiogenic response occurs [ 29]. Chin et al. postulates that there could be a relationship between the metastatic potential and intratumoral blood vessels of a malignancy and their argument lies in the fact that squamous cell carcinomas (SCCs) have intratumoral vascularization and an increased metastatic potential as opposed to BCCs, which do not have vascularization (both blood or lymphatic vessels) within the tumor nests itself and rarely metastasizes [ 25]. Also, they theorize that those rare cases of metastatic BCC would be a consequence of the presence of blood vessels within the tumor [ 25]. Lupu et al. also support the idea that the microvascularization of BCC is linked to its characteristic low metastatic potential and also to its local invasiveness ability [ 29]. Staibano et al. propose that the biological indolence of non-aggressive BCCs (which today would translate into low-risk BCCs) is due to poor angiogenesis in their periphery, similar to the vascularization of preinvasive solid tumors [ 30]. Furthermore, Chin et al. also state that nodular BCCs’ lack of blood arteries in tumor islands would be a plausible cause for why they are ulcerated [ 25]. They also postulate that the development of telangiectasia around the tumor nests would be attributed to the stromal angiogenic response [ 25]. Based on Holash et al. concept about the cooption and regression of blood vessels within tumors [ 33], Chin et al. support the idea that alongside the BCC stromal angiogenesis, there are blood vessels located somewhere within the tumor and its edge where they undergo complete regression and, in that situation, anti-angiogenic factors could be involved [ 25]. Capillaroscopy was used to characterize the BCC vascularization, in a study by Newell et al. When compared to sun-exposed non-tumoral skin, they showed that BCCs have a chaotic tortuous abnormal microvascularization, with increased number of wider (maximum 2.9 times wider in BCC than in perilesional skin) and longer blood vessels [ 34]. Those blood vessels produce an arborizing, chaotic network limited to the tumor bed and not present in the non-tumoral surrounding skin [ 34]. Moreover, they described that this abnormal vascular pattern ended suddenly at the tumors’ margin and afterward continued with a normal-looking vascularization [ 34]. Those changes were observed in all the BCCs included in the study [ 34]. Several studies support the idea that the highest microvessel number is located at the tumor’s periphery [ 35, 36] and that, that is the place where endothelial cell proliferation is maximal [ 37]. MVD was quantified in research. Carbone et al. used CD31 immunohistochemical staining for microvessels combined with anti-vascular endothelial growth factor (VEGF) antibodies for VEGF expression and showed that compared to the superficial variant, both measurements were greater in the morpheaform and nodular BCCs (with an average value of 28.3 vessels/mm2) [ 38]. Winter et al. noticed that intratumoral MVD was typically low and that peritumoral stroma values were higher and found similar results when comparing the MVD of morpheaform and nodular variants but a statistically significant difference between the nodular variant, Pinkus’s variant and trichoblastomas [ 35]. Infiltrative, adenoid, metatypical, and nodular variants all exhibit much increased MVD, but there is no discernible difference in VEGF expression, according to a study by Vuletic et al. [ 39]. Also, from all the variants included in the study, the infiltrative and metatypical subtypes had the highest levels of VEGF expression, while superficial BCCs showed the lowest [ 39]. These findings support the notion that the BCCs histological variant and its angiogenic capacity are connected (Figure 2).

Figure 2.

Low-risk and high-risk BCC vascularization pattern (100×): (a and b) Low-risk BCC (nodular variant) – (a) Characteristic histological aspect of nodular variant in HE staining; (b) CD31 IHC staining shows increased microvessel distribution in the stroma surrounding BCC islands; (c and d) High-risk BCC (infiltrative variant) – (c) HE staining shows fibrotic stroma with narrow and variably sized basaloid epithelial islands, a characteristic appearance of the infiltrative variant; (d) CD31 IHC staining shows an abundant MVD in the fibrotic stroma. BCC: Basal cell carcinoma; CD31: Cluster of differentiation 31; HE: Hematoxylin–Eosin; IHC: Immunohistochemical; MVD: Microvessel density.

Regarding the pattern of BCC blood vessel distribution, Emiroglu et al. have reported arborising vessels as the most common (42.9%) second by arborizing microvessels (21.4%) and short fine telangiectasia (15.3%) in that order [ 40]. Moreover, a study by Maurya et al. stated that the telangiectasia has a serpiginous arborising distribution [ 41]. Relating to BCC variants, studies found that arborising microvessels were often found in nodular variant and short fine telangiectasia and arborizing microvessels had greater incidence in the superficial variant [ 40, 42]. Also, in comparison to nodular BCCs, the diameter of the arborizing vessels was smaller (less than 0.2 mm) in superficial ones [ 40].

Ultrasound and histology

With numerous studies regarding the use of US in dermatology, authors such as Wortsman et al., Bobadilla et al. and Uhara et al. state that, because of its definition and penetration, which produce clearly defined images of the skin and deeper layers involvement, US is regarded as a first-line imaging method for the examination of BCC [ 43, 44, 45, 46]. In this regard, high and statistically significant correlations between BCC US depth measurements and histological depth of invasion have been found in multiple research [ 45, 47, 48]. By determining the size of the tumor, US enables for customized surgical planning for BCC, and it can assist in monitoring early BCC recurrence [ 49, 50, 51]. Moreover, other morphological data such as tumor width, length and aspect can be identified on HFUS examinations and patients’ therapy can be impacted by this (e.g., if HFUS identifies a superficial BCC, therapies such as photodynamic therapy and cryotherapy can also be used) [ 45, 47, 48, 52]. In a study by Desai et al., because of HFUS they had better therapy results with a clearance rate of 90% [ 52]. This finding is especially relevant in high-risk BCC and in difficult areas on the face and neck. When comparing HFUS to histology, certain artefacts and particular situations must be taken into consideration. Abundant tumor inflammatory infiltrate can determine bigger US measurements [ 52, 53]. The shrinkage of tissue due to formalin fixation can determine smaller histological measurements in comparison to the US ones [ 45]. Gray scale examination also provides information about tumors appearance, and it can correlate with the histological variant [ 47, 48, 54]. Due to its non-invasive ability to detect lesions’ depth and dimensions, invasiveness, and vascularization patterns, US can be helpful in the selection of the ideal BCC treatment in an individualized manner, in monitoring non-invasive medical treatments [ 45] and in recurrence evaluations [ 49, 50, 51]. Regarding BCC vascularization, Doppler US is used in conjunction to gray scale HFUS to enhance lesion classification as benign or malignant or as melanoma or non-melanoma skin cancer and also in determining the type of skin cancer (e.g., BCC, SCC) [ 55, 56].

HFUS in dermatology

In the late 1970s, skin ultrasonography was first proposed as a preoperative diagnostic procedure and its purpose was the measurement of tumor tissue, especially tumor thickness [ 1, 55]. The first recorded time in history when HFUS was used as an imaging method for describing skin tumors was in the early 1990s [ 55]. The early diagnosis process of cutaneous lesions, non-invasive techniques conquer more and more usefulness [ 57]. Every organ has certain characteristics and specific location. These proprieties are particular to skin lesion, limiting the use of laboratory tests, such as US imaging [ 43]. Medical imaging of skin lesions offers a three-dimensional view of tumoral and surrounding tissue [ 43]. The basic principle of ultrasonography is sound wave reflection within tissue structures [ 1]. HFUS is a type of US imaging method which uses higher frequencies, with values bigger than 15 MHz [ 1, 58]. The use of high frequency allows visualization of superficial structures, such as the skin, thus making cutaneous tumor accessible to US evaluation [ 58]. Layers of the skin and subcutaneous structures can be identified and characterized by means of HFUS [ 58]. In addition, this type of US can provide data about tumors, because tumors appear as hypoechoic structures within hyperechoic peritumoral tissue. Furthermore, tumor vascularization can be described when using color Doppler function [ 1, 58]. The use of variable frequency when assessing the skin gives information regarding various skin structures (epidermis, dermis, hypodermis, and subcutaneous tissue such as muscle, tendons, or bones). Thus, change in the frequency, when examining tumors provides information regarding deeper tissue involvement, tumor dimensions, tumor thickness, depth of invasion, but also about superficial aspects of the tumor such as tumor ulceration, presence of horny cyst as so forth [ 43].

HFUS of BCC: morphology and vascularization aspects

Preoperative assessment of BCC using HFUS provides data about deep layer involvement and vascular pattern in a non-invasive way, data which can improve surgical planning and outcome, thus making HFUS a valuable diagnostic tool [ 45, 48, 59]. Gray scale HFUS assessment of BCCs reveals a hypoechoic structure, with inhomogeneous appearance and well-defined borders, though in infiltrative and morpheaform of BCCs, margins are poorly defined [ 1, 43, 59]. Within the tumor, hyperechoic dots can be present [ 1, 43, 48]. Doppler US is a real-time imaging method which can visualize blood flow in motion, therefore completing the regular gray scale US imaging with motion data [ 55, 58]. The principle on which Doppler US is based is the movement in respect to one another of the transductor and the reflector [ 55]. The proximity of the origin of movement determines frequencies that are analyzed by Doppler tools [ 55, 59]. Doppler US imaging consists of several manners of functioning which give out different types of information regarding blood flow, vascular pattern and distribution and number of vascular pedicles [ 55, 58]. These manners consist of conventional stationary US, pulsed wave Doppler, duplex, and continuous wave Doppler [ 55]. Depth of moving object is assessed using pulsed wave Doppler [ 55]. The presence of movement is highlighted by continuous wave Doppler [ 55]. Pulse Doppler can differentiate between types of blood vessels by measuring velocity [ 59]. Blood flow is seen using duplex Doppler, which consists of B-wave imaging combined with pulsed wave Doppler. Blood flow can be seen as colors (color Doppler) or as amplitudes (power Doppler) [ 55]. Tumor vascularization can be characterized by type, diameter, flow, peak systolic flow and also by distribution pattern [ 43]. Mapping of the tumoral vessels provides knowledge about malignant neoangiogenesis for instance the presence of vascular shunts between arteries and veins, disorganized and interrupted vascular pattern and distribution of vascular structures within malignant tissue [ 58, 59, 60]. Malignant tissue has the propriety of developing its own vascularization, determined by need of nutrients and oxygen [ 57, 61]. This occurrence is represented by angiogenesis and production of neovascularization [ 62]. BCC and other skin malignancies develop vascular proliferation, vascular dilatation, and changes in shape [ 62, 63, 64]. The higher the aggressiveness of the malignant tissue, the higher the vascular proliferation [ 57, 61, 65]. Histological and ultrasonographic aspects of BCC are statistically correlated; therefore, the morphological and vascular imaging are significantly overlaying [ 3]. Sometimes, measurement of tumor bed can be difficult on HFUS, making treatment a challenge, but the use of Doppler function resulting in the visualization of tumoral vascularization can help determine tumor margins, thus proving itself of great importance in pretreatment assessment [ 45, 66]. In the late 1980s, blood flow pattern of skin tumors was beginning to show importance, especially in differentiating benign from malignant lesions [ 62]. The presence of blood flow was considered a strong argument for malignancy potential [ 62]. Nowadays, medical imaging technology has advanced and is able to provide more data about tumor vascularization [ 57, 67]. Macrocirculation of BCC seen using Doppler reveals prominent blood flow localized at the bottom of the tumor (Figure 3) and one to two vascular pedicles [ 43, 59]. Perfusion pattern is high in BCC and is seen as uniformly distributed within tumor tissue, whereas peritumoral tissue shows low perfusion rates [ 57, 62]. Also, the presence of abundant arteries and of disorganized vascular pattern is known to be characteristic to malignant tissue [ 59].

Figure 3.

Comparison between different skin malignancies: (a–c) Color Doppler – (a) BCC, increased blood flow at tumor’s base with arborising pattern; (b) Cutaneous melanoma, hypervascularized tumor with parallel central pattern, with more than two vascular pedicles; (c) SCC, hypervascularized tumor with two vascular pedicles; (d–f) CD31 immunohistochemistry (200×) – (d) BCC, nodular variant, blood vessels surrounding tumor islands with no vessels present inside the islands; (e) Cutaneous nodular melanoma, increased intratumoral vascularization that spreads into nests; (f) SCC, increased intratumoral vascularization that spreads in tumor islands. BCC: Basal cell carcinoma; CD31: Cluster of differentiation 31; SCC: Squamous cell carcinoma.

Importance of Doppler in BCC diagnosis

The assessment of BCC using Doppler US has many advantages, such as differentiating between various BCC subtypes, between high- and low-risk BCC and between BCCs and other skin lesions (malignant and benign) [ 2, 56, 57, 58]. Another benefit of Doppler is the fact that it provides information regarding tumor and peritumoral tissue vascularization, which helps guide therapeutic procedures and estimate blood loss [ 57]. Studies show that abundant vascularization throughout tissue is a sign of malignancy [ 57]. This fact is also highlighted by the ultrasonographic aspect of BCCs [ 58]. By using Doppler examination, hypovascularity was seen predominantly in benign lesion, whereas hypervascularity was described in most malignant tumors [ 58]. If we compared benign tumors with BCC we will observe certain differences, such as the presence of multiple vascular structures in the malignant tissue and few vascular structures in the benign tissue, disorganized circulatory pattern throughout BCC tissue, while the pattern was organized in the benign lesion, the preference for central or mixed blood vessel distribution in the tumoral bed while the benign tumor presented peripheral blood flow and nonetheless blood flow velocity in BCC was higher than in benign tumor [ 59]. Another use of Doppler US is the fact that it can help distinguish high from low-risk BCC [ 2, 68]. BCCs can be roughly devised into two major classes: low risk (e.g., nodular BCC or superficial BCC) and high risk (e.g., morpheaform) [ 2]. These two classes of BCC show different recurrence rates, thus high-risk BCCs have a higher recurrence rate and require performing wider surgical excision [ 2, 68]. Therefore, knowledge about framing the tumor into one or another class is important in planning the optimal therapy for our patients [ 2, 68]. Consequently, Doppler can help in these situations, in two ways: it can determine blood blow velocity and location and it can improve hyperechoic spots count [ 2, 68]. In the case of high-risk BCCs, vascularity is prominent in the lower part of the lesion as opposed to low-risk BCCs where vascularity is uniformly spread throughout tumoral tissue [ 2]. Color Doppler US can be used for counting hyperechoic spots [ 2]. These spots are highly correlated to the presence of atypical basal cell nests, which usually appear in high-risk BCCs [ 2]. Differentiating between various types of skin malignancies is difficult, but there are certain ultrasonographic aspects that can ease the process [ 57, 69]. BCCs are vascularized, but neovascularization is less intense than other skin tumors (Figure 3). Thus, on Doppler US, BCCs appear less vascularized than other cancers [ 62, 69]. Although BCC has telangiectasia, perfusion rates are lower and flow velocity is lower than of other skin malignancies [ 57, 69]. As previously stated, BCCs arise most frequently in the head and neck region [ 1, 2]. Therefore, the therapeutic approach of these tumors must have an oncological result (negative surgical margins) as well as an aesthetic one [ 1, 68]. By providing a better view of tumoral bed, Doppler US helps in planning and choosing the most suitable therapeutic treatment [ 1, 68]. Furthermore, certain treatment methods can be improved by US investigations [ 69].

Advantages and disadvantages of HFUS examination of BCC

Many studies highlight the fact that histopathological examination remains the “gold standard” for the diagnosis of BCCs and that ultrasonography and other medical imaging techniques have a role in optimizing treatment and providing additional information [ 1, 43, 45]. Ultrasonography has advantages and disadvantages. Some advantages of the use of ultrasonography for examining skin tumors are its proprieties to be easily reproduced, to be repeated as many times as needed and the fact that it does not harm or cause pain for the patient [ 67]. Crişan et al. demonstrates the fact that HFUS findings have great concordance to histopathological examinations [ 59]. Another advantage of US examination is the fact that HFUS shows high quality images and precise anatomical details [ 3, 43]. Doppler US provides qualitative and quantitative data about tumor vascularization and this data can be reproduced as many times as needed and also be of use in the treatment of these tumors [ 59, 68]. If data provided by Doppler examination is not sufficient, contrast-enhanced ultrasonography can be used to complete the information [ 59]. Kuonen et al. studied the hypothesis that the BCC vascularization pattern can be influenced by the proximity to a large vessel [ 4]. They state that non-melanoma skin cancers have a localization predication, and they seem to arise close to arterial vessels [ 4]. To demonstrate their hypothesis, Doppler US and histological examination have been performed [ 4]. Although many non-melanoma skin cancers were located near arterial vessels, more studies have to be conducted, thus this study was able to affirm that blood flow has a great impact in the malignant tissue microenvironment [ 4]. Other studies highlight the usefulness of US and Doppler US in planning therapeutic approach [ 45]. BCCs can be surgically removed, but there are other treatment methods worth mentioning, such as cryotherapy, photodynamic therapy (with or without topic agents), electrodessication and so on [ 45]. Ultrasonography is operator dependent. There is a learning curve and a year-to-year experience to be taken into consideration. Therefore, operator skill and training are essential elements to consider [ 55]. There are studies that demonstrate the fact that the US can identify lesions which were not clinically visible. A study conducted by Wortsman & Wortsman recognized two BCCs and one malignant melanoma on US examination, that were suspected only on ultrasonography and were clinically unknown [ 43]. In a systematic review of the use of US imaging in examining BCCs, Laverde-Saad et al. conclude that US can aid in the diagnosis and treatment of BCCs and recommend its usage for tumor depth and extent measurements as well as tumor aggressiveness [ 70]. Giovagnorio et al. recommend the contract agents administration to improve standard ultrasonography [ 58].

Other approaches in BCC vascularization characterization

It is also necessary to acknowledge other skin imaging techniques, such as in vivo confocal microscopy, dermoscopy, magnetic resonance imaging, positron emission computed tomography (CT) and standard CT [ 43]. Dermoscopy and reflectance confocal microscopy are investigations that also bring to light BCC vascularization. Dermoscopy examination highlights a few vascular patters suggestive of BCC, but some of them are also corelated with various BCC variants, such as arborizing vessels (the most impressive vascular pattern seen in BCC), short fine telangiectasia (dermoscopic hallmark of superficial variant but also highly evocative of the diagnosis in other variants as well), arborizing microvessels (more likely observed in superficial variant), milky pink background (encountered in other lesions as well, therefore with low significant diagnostic value), comma vessels (minor vascular pattern), glomerular vessels (minor vascular pattern), loop vessels (although not pathognomonic to BCC being encountered in many other skin lesions, all BCC variants report them to some extent) [ 29, 42, 71, 72, 73, 74, 75]. Of all the vascular patterns, arborizing vessels and/or short fine telangiectasia are the ones that are the most helpful in the differential diagnosis of BCC [ 29]. Reflectance confocal microscopy of BCC typically shows superficial, horizontal, enlarged (both in number and diameter) blood vessels with irregular shapes that can sometimes have a parallel distribution [ 76, 77].

Conclusions

The morphological distribution of blood vessels in BCC accounts for its growth, invasiveness and could be a possible explanation for the low rate of metastasis of this particular malignancy. The use of HFUS examination prior to treatment leads to informed personalized therapeutic planning as well. Furthermore, HFUS can help determine the real dimensions of the tumoral tissue, which can appear enlarged on clinical examination due to peritumoral inflammatory reaction or other peritumoral lesions. Doppler US, together with gray scale US, elastography and contract enhanced US, help distinguish BCC from other tumors (benign or malignant), can help distinguish low from high-risk BCC and can improve therapeutic planning (especially surgical excision). Doppler US improves diagnosis of BCCs and, among side physical examination and dermoscopy, creates a comprehensive pre-treatment evaluation. Histological examination remains the “gold standard” in BCCs diagnosis.

Conflict of interests

The authors declare that they have no conflict of interests.