Ultra-High-Frequency Ultrasound: A Modern Diagnostic Technique for Studying Melanoma

Abstract

The development of new ultra-high-frequency devices with a resolution of 30 μm makes it possible to use ultrasound in the study of new small anatomical units and to apply this tool to new fields of pathology. Cutaneous melanoma is a severe skin disease with an incidence of approximately 160 000 new cases each year and 48 000 deaths. In this paper, we evaluate the role of HFUS in the diagnosis of cutaneous melanoma, describe the sonographic appearance of skin layers in the pre-excision phase as well as of lesion features, and correlate the characteristics with pathological examination.

Learning objectives

• 1. Knowledge of ultra-high-frequency ultrasound

• 2. Understanding of the role of ultrasound in dermatologic disease

• 3. Understanding of the role of ultrasound in the diagnosis of melanoma

• 4. Description of our experience studying melanocytic lesions, including knowledge of surface anatomy and technical considerations

• 5. Conclusions

Introduction

Imaging of the skin layer is often tricky with conventional ultrasound (US). Therefore, clinical cutaneous US imaging has been limited to high-frequency probes with values of 18 to 20 MHz and millimetric spatial resolution.

Despite this technical limitation, US offers more powerful support in diagnostic procedures too. This has been made possible thanks to latest-generation ultra-high-resolution transducers recently introduced in routine clinical practice. These transducers, first developed for small animal imaging, can reach frequencies as high as 70 MHz.

Today, “ultra-high-frequency” refers to the best transducers currently available in medical ultrasound. Thanks to their excellent resolution, which is high enough to detect half a grain of sand, these transducers are revealing new never-before-seen scenarios in medical imaging.

Using greater frequencies than conventional US, it is possible to achieve increased spatial resolution but to the detriment of penetration depth, which corresponds to less than 1 cm from the outer skin layer when using 70 MHz frequencies.

This patented technology allows for the finest resolution of any general-purpose US system today.

This paper presents the role and the potential clinical applications of ultra-high-frequency ultrasound (UHFUS) in cutaneous imaging, based on our experience with a commercially available US system equipped with a 22 to a 70 MHz linear-array transducer. This method produces an image capable of depicting up to 30 μm within the first 3 cm from the outer body surface.

1. Knowledge of ultra-high-frequency ultrasound

Transducers routinely used for ultrasonography of superficial structures are linear-array transducers with frequencies of up to 20 MHz that provide excellent image detail (axial resolution of 250–500 μm) [1] [2] [3].

UHFUS allows the examination of small parts with high-resolution images with a dynamic, real-time, and comparative, where applicable, evaluation [4].

At the beginning of the 2000 s, UHFUS debuted in the clinical scenario as a diagnostic technique characterized by a frequency range between 30 and 100 MHz and a resolution up to 30 microns [5] [6] [7].

Compared to conventional ultrasound (CUS), UHFUS has superior spatial resolution even with the limitation of a low penetration depth, which is within 3–1 cm.

Probes with a frequency of 48 MHz have a penetration depth of 23.5 mm, whereas probes with a frequency of 70 MHz allow scanning of the first 10.0 mm under the surface.

With a probe with a frequency of 48 MHz, it is possible to evaluate lesions with a diameter between 1 and 2 cm, while with 70 MHz transducers, it is possible to assess lesions < 1 cm [8] [9] [10] [11] [12].

This method depends on the operator more than other methods, since the probes are extremely sensitive to the examiner’s hand movements. However, UHFUS has extreme versatility and applicability and is inexpensive, noninvasive, and repeatable. UHFUS literature is continuously developing. This promising technology overcomes many of the limitations of ultrasound examination seen in the case of lower frequency.

The term UHFUS is often misused in clinical language because of a lack of agreement about the cutoff value for discriminating between “very high” and “ultra-high” frequencies.

The CUS technique refers to probes with frequencies from 10 to 15 MHz. Bhatta et al. considered a frequency greater than 10 MHz to be high-frequency US (HFUS), whereas Polanska et al. considered 20 MHz to be the cutoff value for the definition of HFUS. Shung et al. defined HFUS probes as having frequencies > 30 MHz [13] [14] [15] [16].

Sonographic properties in tissues are well known in the case of examinations conducted by machines at frequencies up to 20 MHz. However, in the case of US performed at frequencies between 20 and 100 MHz, the tissue proprieties are less well known since few studies regarding attenuation, backscatter, and speed of sound are available. However, these parameters seem to be closely related to the organization and concentration of collagen and other proteins.

Ultrasound provided a breakthrough in dermatology as soon as fixed-frequency equipment (20–100 MHz) became available. In fact, thanks to the technical capability of this equipment, it is able to distinguish skin layers. Despite the promising features, these transducers have a low penetration index (about 5 mm at 20 MHz) [6] [17]. Tumor thickness is one of the most important factors in determining surgical strategy in the treatment of melanoma. Highly accurate preoperative evaluation of cutaneous melanoma lesions is essential for establishing an optimal therapeutic approach. Today, multi-channel US machines have standard incorporated multi-frequency equipment with processors and probes whose frequencies vary from 15 to 22 MHz. This equipment uses sensitive color and power Doppler and slim probes that can successfully adapt to the skin contours in the different parts of the body. Moreover, hockey stick-shaped probes allow adequate contact with the surface when exploring complex regions of body, such as the face, the tongue, the ear pinna, or the fingernails. The main advantages of using variable-frequency ultrasound are the fair ratio between penetration and resolution, the real-time capability, and the ability to detect and sample both texture and blood flow changes. The limitations of this technique relate to melanin-like pigment detection, the detection of flat epidermal-only lesions, and the detection of ≥ 0.1 mm lesions [16] [17] [18].

2. Developing an understanding of the role of ultrasound in the diagnosis of dermatologic diseases

Probes over 14 MHz allow accurate diagnosis of several dermatologic pathologies thanks to the real-time examination of cutaneous and subcutaneous several layers. Moreover, some literature is reporting magnificent image detail in the US evaluation of the nail complex and its most common anomalies.

Based on the study conducted by Wortsman et al., there is high concordance between UHFUS and histology in the identification of skin annexes [19].

High-frequency US has also been shown to be capable of evaluating connective tissue disorders [20].

Skin thickness can be monitored in the follow-up of systemic sclerosis given that an increase in skin thickness is associated with disease severity and predicts visceral involvement risk, survival, and prognosis [21].

Skin epidermal and dermal thickness variations were analyzed by Firooz et al. [22].

Considering HFUS in other systemic disease, Chao et al. evaluated stiffness and total thickness of plantar foot in diabetic patients versus healthy ones [23].

UHFUS has also been used for the characterization and monitoring of glycosaminoglycan deposits and myxedematous inflammation in the eyelid and pretibial regions in patients with Graves’ disease before and after UVA-1 phototherapy treatment [24].

Many studies have already reported the possible use of UHFUS in different dermatologic disorders. Particularly, Chen et al. showed how 30 MHz UHFUS was capable of diagnosing lichen (atrophic and sclerotic) before histology, excluding the clinically suspected differential diagnosis of scleroderma (morphea) [25]. Using UHFUS, Murray et al. showed the echo-features of scleroderma. In particular, in 32 patients, they found the typical epidermal thinning and increased deeper perfusion of the morphea plaques [26]. Oranges et al. studied 50 patients suffering from hidradenitis suppurativa. 48 to 70 MHz probes can be used to identify previously unobservable findings [27]. Guerin-Moreau et al. explored the UHFUS features of pseudoxanthoma elasticum in 15 photoexposed and 11 photoprotected patients and also compared the results with 72 diabetic patients and 40 healthy subjects [28].

Preoperative UHFUS examination of non-melanoma skin neoplasia, such as squamous or basal cell carcinoma, demonstrated good correspondence with histology [29] [30] [31].

In a case report of basal cell carcinoma, UHFUS was used for presurgical mapping of tumor margins [32].

3. Developing an understanding of the role of ultrasound in the diagnosis of melanoma

As previously reported, UHFUS can be used to examine normal skin anatomy (layers and annexes) as well as pathologic conditions, such as cutaneous lesions, and also for the diagnosis of skin malignancies. UHFUS is a valid tool for most of dermatologic conditions thanks to its capability to provide real-time images of the epidermis and dermis layers as well subcutaneous layers [16] [18].

Extensive clinical background knowledge and semeiotic ultrasonographic imaging findings are mandatory for the routine usage of this technique.

With respect to skin neoplasms, UHFUS is capable of detecting the skin cancer level in the case of invasion of deep layers, any satellite lesions, subcutaneous metastases, and nodal locations. UHFUS allows visualization of the relationship between the primary disease location and other anatomical structures such as adjacent nerves and fat-fascia borders. Thus, it can provide supporting information for presurgical local staging [33]. It is reasonable to predict a more widespread role in this field for UHFUS in the not-too-distant future, thereby allowing more accurate evaluation of skin lesions involving deeper layers [33] [34] ([Fig. 1a]).

Fig. 1 Normal skin. In a UHFUS of normal skin at 70 MHz shows different distinctive layers of epidermal “entry echo,” dermis, and subcutaneous tissue. A copious amount of gel was applied to the skin’s surface without using a spacer or other devices. In b pilifer bulbs are visible (arrowheads).

Cutaneous melanoma (CM) has a high incidence rate, even among young people, with an incidence in 2013 of about 76 250 new cases and 9180 deaths, according to Scally et al., and in 2014 of about 76 100 new cases in the USA according to Li et al.

Males are approximately 1.5 times more likely to develop melanoma than females. However, according to other studies, the different prevalence among the two sexes must be analyzed in relation to age. The incidence rate of melanoma is more significant in women than men until they reach the age of 40 years. Then, by the age of 75 years, the incidence is almost 3 times as high in men versus women. The leading risk factors for melanoma oncogenesis are ultraviolet (UV) exposure, melanocytic nevi, genetic susceptibility, and family history. Artificial UV exposure may also play a key role in melanoma development. About 1 in 10 patients with a prior history of melanoma is likely to develop multiple primary melanomas. Cutaneous melanoma prognosis basically depends on vertical growth corresponding to the histopathological Breslow index. This index positively predicts the possibility of node involvement as well as distant metastasis risk. Other important histologic prognostic factors are the Clark level, mitotic rate as the number of mitotes/mm2, and the possible presence of ulcerations. Age, male sex, and location are also associated with a bad prognosis. Highly accurate preoperative evaluation of cutaneous melanoma lesions is essential for improving the survival rate and establishing an optimal therapeutic approach [35].

High-resolution US helps to assess all aspects of locoregional melanoma [36].

High-frequency transducers are capable of estimating tumor depth, defined as the Breslow index. A Doppler modality is able to detect intra-tumor vessels and characterize their distribution, thereby improving diagnostic accuracy ([Fig. 2]).

Fig. 2 Melanocytic skin lesion UHFUS study. UHFUS shows well-defined, superficial, hypoechoic, heterogeneous lesion (a) with low superficial Doppler sign (b).

Modern UHFUS equipment gives details similar to histology in the visualization of the skin layers and appendages. Standard two-dimensional linear US with a frequency from 40 to 100 MHz allows imaging of the epidermis. Probes ranging from 15 to 22 MHz allow imaging of the epidermis and dermis, including the adjacent tissues 1 to 2 cm deep with respect to the basal dermal layer. Thanks to recent US technology advances, in particular multi-channel color Doppler with probes able to reach more than 15 MHz, it is now possible to observe skin layers with good resolution and define echo structure patterns of the epidermis and dermis. Moreover, despite sonography limitations with respect to detecting melanin-like pigments, UHFUS is pivotal in noninvasive tumor assessment and it contributes to the assessment of critical decision management due to its capability to evaluate skin thickness and blood flow. The literature increasingly includes ultrasound semiotics with respect to primary melanoma lesions.

4. Description of our experience in the study of melanocytic lesions, including knowledge of surface anatomy and technical considerations

In this paper, we evaluated the role of HFUS in the diagnosis of cutaneous melanoma and the description of skin layers in the pre-excision phase, as well as the US appearance of these lesions in correlation with pathological examination.

Ultra-high-frequency ultrasound is important for identifying skin layers and for characterizing skin lesions. Its usage increases the accuracy of lesion thickness measurement, which is an essential preoperative evaluation for establishing the best therapeutic approach.

Images included in this article were acquired using a commercially available US system (Vevo MD; Fujifilm Visual Sonics, Amsterdam, the Netherlands) with a 25–48–70-MHz linear-array transducer ([Fig. 3]).

Fig. 3 Ultrasound scanner with three ultra-high-frequency probes (25–48–70-Mhz) by Vevo MD, Fujifilm Visual Sonics (a). Linear probe of 70 MHz (b).

The probe used was UHF 70 MHz, which can automatically select frequencies based on the analyzed structure ([Fig. 4], [5]).

Fig. 4 UHFUS example of a superficial skin lesion appears as a linear hypoechoic lesion within the hyperechoic epidermis and the dermis (a). Histological examination of the lesion confirms malignant melanocytes confined to the epidermis and epidermal adnexal structures (melanoma in situ) (b).

Fig. 5 a UHFUS longitudinal view of fusiform hypoechoic lesions that involve the epidermis and dermis. b UHFUS transverse view shows superficial spreading with Breslow of 0.44 mm in the epidermis and superior dermis by proliferation of melanocytic lesion, with irregular distribution in a case of melanoma.

Based on our experience, we have mainly evaluated flat melanocytic lesions and only a few nodular exophytic lesions.

Based on clinical dermatoscopic features strongly indicative of melanoma, different melanocytic lesions were analyzed, and excisional biopsy was requested.

Ultrasound was performed preoperatively before excision.

Technical aspects

The exam starts with systematic inspection of the external surface of the skin at the site being examined. Later, a thick layer of gel is applied between the skin and the probe in order to obtain the best focal point. To avoid phenomena caused by the compression of superficial structures, it is essential to be as delicate as possible when handling the probe in terms of pressure applied to the outer surface of the skin. In the case of ulcerative lesions, sterile gel should be used.

A dermatologic HFUS exam properly performed by a specialist includes identification of the exact topography in the exam followed by evaluation of the different skin layers, their thickness and vascularization, and any pathology-related findings.

Sagittal and axial B-mode images are to be acquired in order to obtain data on lesion features and borders. Blood flow can be explored with the use of US color Doppler.

The evaluation of lesions, when present, should be performed with a three-dimensional evaluation in order to determine size, depth and thickness, calcifications or necrosis foci, content (e. g., cystic, solid, mixed), involvement of adjacent structures, exact location vascularization, exact location, presence of satellite and transit metastases, and the relative vascularization (using Eco-Color Doppler).

US features

Healthy Skin

Knowledge of the ultrasonographic appearance of normal skin is necessary in order to evaluate abnormalities.

Skin characteristics may vary based on anatomical region, race, and age.

The epidermis, dermis, and hypodermis are the three layers of skin tissue.

Every layer has its own echogenicity depending on its main molecular component: keratin (epidermis), collagen (dermis), and fat lobules (subcutaneous).

The epidermis presents as a hypoechoic line; the dermis as a hyperechoic band that is less shiny than the epidermis; and the subcutaneous tissue as a hypoechoic layer with the presence of hyperechoic horizontal lines corresponding to fibrous septa therein ([Fig. 1a]).

Echogenicity and thickness may vary according to the patient’s age.

It is slightly hypoechoic in newborns. With increased age, due to actinic exposure and damage, it is possible to identify the epidermal band of low echogenicity as a hypoechoic line between the epidermis and the dermis. This is the sonographic finding corresponding to the histological representation of laxity of the papillary dermis and elastosis.

Hair follicles in non-glabrous skin areas are observed as hypoechoic fusiform structures obliquely arranged and localized in the dermis or subcutaneous tissue, depending on hair-cycle stage ([Fig. 1b]).

In the palmoplantar region between the granular and corneous layers, there is an additional layer called the stratum lucidum. HFUS evaluation of this additional layer shows as bilaminar hyperechoic structure, probably resulting from the contrast between the epidermis and a sharp stratum corneum. HFUS findings for other skin layers are similar to those of non-glabrous skin.

Skin tumors

Skin neoplasms, whether malignant or benign, are seen as hypoechoic areas naturally contrasting with the surrounding healthy tissue. During the examination, besides echogenicity, it is necessary to evaluate the three-axial measures, the lesion shape, and any involvement of deeper layers (muscle, cartilage, bones). Color Doppler may be useful in the study of vascularization by making it possible to examine the distribution and size of intra-tumoral vessels.

We have analyzed a nodular melanoma lesion including two hyperechogenic laminae separated by a hypo/anechoic space. This structure is probably a tumor vessel neoformation. This hypothesis is supported by the information obtained from Eco-Color Doppler.

Tumor thickness measures should be obtained at the site with the greatest thickness since cutaneous lesions may be heterogeneous.

Melanocyte lesions are generally viewed as homogeneous and hypoechoic tissue, appearing well-defined, oval or fusiform, with smooth edges, and a variable degree of vascularization. In cases of ulceration, the epidermis may show irregularities and discontinuity, and it is possible to see increased echogenicity in the subcutaneous tissue.

In the case of an in situ melanoma lesion, US examination shows the presence of a regular hyperechoic band at the border between the lesion and the dermis. This structure is probably indicative of the radial growth phase of the lesion, in which the cells have not yet acquired the ability to invade the deeper layers of the skin. The satellite lesions (less than two centimeters from the primary lesion) or in transit (located more than two centimeters from the primary lesion) are hypoechoic, have an oval or round shape, smooth or lobulated margins, and variable degrees of heterogeneity and vascularization ([Fig. 6], [7]).

Fig. 6 a Nodular melanoma study with UHFUS with 70MhZ probe. b UHFUS shows well-defined, solid, homogeneously hypoechoic malignant lesion in the dermis with measurement of thickness, invasion depth, and assessment of the borders of skin tumors.

Fig. 7 a UHFUS shows well-defined, solid, homogeneously hypoechoic malignant lesion in the dermis. b Color and power Doppler studies help to identify vascularity in the lesions.

In exophytic lesions the epidermal layer is generally markedly hyperechoic, appearing as an irregular and continuous line with jagged margins, below which the presence of hypoechoic tissue is interposed between the epidermis and the underlying dermis.

On the other hand, in the case of lesions with hypodermic development, the hypoechoic infiltration of the lesion below the hyperechoic skin line is well evident, which is visible above the hypoechogencity of the lesion itself. Thanks to US examination, the depth of the lesion and its diameter can be measured, and the margins of the lesion as well as any lymph node infiltrations can be evaluated.

In very small lesions contained in the subcutaneous tissue (flat lesions), the use of ultra-high-frequency allows evaluation of even millimeter-sized lesions, which appear as hypoechoic tissue with predominantly hyperechoic and well circumscribed margins.

Some factors should be considered as a possible cause of error in the measurement of tumor thickness with HFUS. The size of the tumor could be overestimated in the presence of inflammatory processes associated with cancer, or, prior to the examination procedure, in the case of hypertrophic perilesional glands and nevus-melanoma association. In contrast, the presence of ulceration may result in an underestimation of the tumor thickness.

Metastatic lesions should be examined at different frequencies since they could be visible with one particular frequency and completely invisible with another, depending on the site and size.

HFUS has better sensitivity and specificity than clinical examination in the detection of melanoma metastases in regional lymph nodes. On ultrasound, metastatic lymph nodes are round, with clear edges and a hypoechoic or echolucent center (necrosis), whereas reactive lymphadenopathy presents with an elliptical aspect with a hyperechoic center and central vascularization.

5. Conclusion

In conclusion, from our experience and the current literature, UHFUS has wide applicability in the study of melanocytic lesions. UHFUS is a noninvasive and repeatable imaging method, and a proper examination provides information on the possible role of UHFUS in the prevention, diagnosis, surgical planning, and follow-up of various pathological conditions. The literature on UHFUS is still evolving, but ultra-high frequencies appear to be the answer to several clinical problems related to the high-resolution investigation of both normal anatomy and pathological processes. Therefore, in melanomatous lesions, UHFUS represents a useful tool for dermatologists and provides good comparison with pathological anatomy.

Conflict of Interest

Declaration of financial interests

Receipt of research funding: no; receipt of payment/financial advantage for providing services as a lecturer: no; paid consultant/internal trainer/salaried employee: no; patent/business interest/shares (author/partner, spouse, children) in company: no; patent/business interest/shares (author/partner, spouse, children) in sponsor of this CME article or in company whose interests are affected by the CME article: no.

Declaration of non-financial interests

The authors declare that there is no conflict of interest.

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Publication History

Article published online:
17 April 2023