Ultrasonographic Assessment of Depth Infiltration in Melanoma and Non‐melanoma Skin Cancer

The preoperative assessment of infiltration depth in melanoma and non‐melanoma skin cancer by means of high‐frequency ultrasound (≥18 MhZ) is essential for optimizing the therapeutic approach in our patients. Often, histologically confirmed skin tumors are directly referred to surgical departments for resection, and sonography is increasingly helping us identify those subjects who are no longer candidates for extensive surgical interventions. In cases of deep tumor infiltration, with potential surgical failure e.g. impairment of the quality of life and significant esthetic and functional complications, preoperative sonography can guide the surgeon to withstand from an operation and decide instead in favor of less mutilating radiooncological or medical treatment options. Furthermore, in melanoma patients, the preoperative knowledge of the tumor depth is essential for the determination of the therapeutic approach, the correct safety margins and the need of a sentinelnode biopsy. We herein encourage the use of preoperative sonography in dermatologic surgery whenever possible as it represents an easy, painless, “in vivo” method, which provides clinicians with significant clinical information that can influence the therapy and improve patient compliance.

the dermatologic surgeon, as in some cases the anatomical microinvasion of the tumor might involve vital structures and therefore even require an interdisciplinary approach. 2 BCCs usually appear on ultrasound as welldefined, hypoechoic lesions that often display hyperechoic spots (representing clusters of apoptotic cells or microcalcifications), while color Doppler shows low-flow arterial and venous vessels within or at the bottom of the lesions. The presence of hyperechoic spots in BCCs was shown to be significantly higher in high-risk tumors. 9 SCCs on the other hand are usually inhomogeneous, hypoechoic structures, with irregular borders, no hyperechoic spots, with increased central and peripheral vascularisation on ultrasound. 3 Furthermore, they often present a thickened hyperechoic line on the lesions' surface and a consequent posterior acoustic shadowing, findings associated with the presence of keratotic material or crusts on top of the lesions.
For malignant melanoma (MM), the deadliest type of skin cancer, ultrasound usually shows oval, well-defined, hypoechoic, hypervascular lesions and the preoperative knowledge of the tumor depth influences the therapeutic approach. 2,10 In this pictorial essay, we highlight the importance of HFUS in the preoperative setting in skin cancer patients, which enables clinicians to choose the best therapy for their patients, avoiding more expensive, time-consuming imaging methods, which can delay diagnosis and treatment. Furthermore, in borderline cases, where the resectability of the tumor is questionable, preoperative ultrasound can aid in establishing the infiltration depth of the tumor and potential cartilage/bone infiltration. This information is essential in deciding whether a potentially mutilating operation should be performed, or whether other less mutilating options, such as radiation therapy or systemic oncologic treatments are more indicated. 2 All the investigations described were carried out in accordance with the ethical standards of the 2013 Declaration of Helsinki. Informed written consent was obtained from all the patients. In all depicted cases, the same operator, acquiring longitudinal and transverse grey-scale and color Doppler images of the lesions, performed the sonographic assessment; for each case, the extension of the tumor and a potential infiltration of bone, cartilage or muscle was assessed. For image acquisition, a Philips eL18-4 ultra-broadband linear array transducer was used except for the MM case, where the Toshiba 17LH7 linear array transducer was employed.

Role of Ultrasonographic Assessment of Depth Involvement in NMSC
We live in an age of demographic change in the western world. Patients with NMSC increasingly present as elderly persons and have consecutive co-morbidities. 11 This entails an increasing demand of individual personalized dermato-oncologic treatment decisions.
Since the Corona pandemic, we, as a tertiary referral center, see an increasing number of patients with clinically inapparent, but locally advanced, deep infiltrative NMSC referred to our dermatosurgery unit for an operation. While many of these patients are operable, a minority reveals itself as being complex presentations and preoperative HFUS does allow us to identify those patients where surgery might not suffice or where other options ought to also be considered. Twenty years ago, besides micrographic surgery and radiotherapy there was no other available option for NMSC patients, but nowadays many new alternatives for locally advanced tumors have arisen. First to mention is the modern immunotherapy, then modern irradiation protocols based on small seeds, then targeted therapies and finally combinations of the before mentioned, all of them being successfully used in this patient population where surgery is not any longer the method of choice. 12,13 Immune checkpoint inhibitors (ICI) have been shown to have promising results in locally advanced and metastatic NMSCs, as most of these tumors are hypermutated due to chronic UV damage and hence have a very high tumor mutation burden. Cemiplimab, a PD1-inhibitor was approved by Food and Drug Administration (FDA) for locally advanced or metastatic SCCs where surgery or radiation therapy is not an option. 14 In 2021, it was also authorized for patients with locally advanced or metastatic BCCs, which have progressed or were intolerant to a hedgehog-inhibitor therapy (HHI). 15 Furthermore, it was shown that the combination of ICI with radiation therapy (RT) could enhance the immune response and improve the response rates in these tumors. 16 In patients with locally advanced or metastatic BCCs (<0.6%), HHI (Vismodegib and Sonidegib) are approved as systemic agents, showing good response rates. 17 For patients with reduced performance status, where the administration of ICI/HHI is not possible, radiation therapy alone can be used in locally advanced cases in a curative or palliative intent; however, the local tumor control and disease-specific survival are knowingly lower. 18

Bone Involvement
The presence of bone invasion in NMSC immediately upstages a tumor into an advanced TNM stage: T3 in case of superficial bony invasion or T4, in case of macroscopical bone invasion, being a known poor prognostic factor for these patients. 19 In cases of sonographically identified bone involvement or bone erosion by the tumor mass, surgery surely remains a treatment possibility; however, procedures such as a hemicraniectomy are mutilating and can lead to significant postoperative complications and increased morbidity. Complicated cases with bone involvement demand an interdisciplinary tumor board and for such patients, alternative options such as modern combinations of radiation therapy and systemic treatment such as ICI should be discussed. 20 As previously mentioned, if the patient is in an adequate performance status, radiotherapy used in combination with ICI, such as Cemiplimab, has been shown to be very effective in terms of local tumor control. 12,21 For patients with reduced performance status or multiple comorbidities, radiation therapy alone can be used in cases of bone infiltration in a palliative intent, however with not long-lasting response rates (Figure 1). 18

Muscular Involvement
In cases of NMSC infiltrating the muscle, as identified by means of HFUS in the preoperative setting, the resection and defect coverage require greater efforts than with superficial tumors and thus the necessary surgical approach can be discussed with the patient in advance, improving patient compliance. Furthermore, the preoperative knowledge of muscular infiltration in NMSC is essential for the surgeon and can spare unnecessary surgical steps by immediately removing the involved muscular area (Figure 2).
In other cases of tumors infiltrating deep into the muscles and sometimes also adjacent vascular structures, preoperative ultrasound can aid in deciding whether a radical resection should be performed, as both muscle and arteries are vital structures, which, once resected, may leave a potentially larger functional deficit behind that can significantly impair life quality in the remaining lifespan.
Therefore, in such situations, although potentially operable, preoperative sonographic assessment of the local tumor extent together with the general performance status of the patient, can help in choosing the best therapeutic approach. In the case depicted in Figure 3, a decision was made against radical resection because of significant comorbidities and extensive perioperative risk of the patient; instead, a primary radiation therapy was initiated.
Similarly, extensive tumors with sonographically identified muscular involvement, which, once resected, bear the risk of a significant impairment of the functionality and quality of life of old and frail patients, as depicted in Figure 4, can also benefit from ICI therapies and the therapeutic response can be monitored regularly by means of HFUS.

Cartilage Involvement
At nasal and auricular level, highly UV-exposed areas with a peak incidence of NMSC, the preoperative identification of a potential cartilaginous infiltration by the tumor can additionally guide the surgeon to an efficient surgical approach, since cartilage involvement usually requires a more extensive resection and, in some cases, cartilage transplantation for the defect reconstruction. The study by Bobadilla et al has shown this with respect to the nasal cartilage. Sixteen BCCs of the nasal area were assessed for invasion of nasal cartilage by means of ultrasound and none showed signs of tumor involvement, influencing the surgical decision to not remove any cartilage; the findings were consisted with the histological results ( Figure 5). 8,22 In other cases with clinically extensive and sonographically suspected cartilage involvement, as    seen in Figure 6, surgery might step behind targeted therapy, such as with HHIs for locally advanced BCC, in a neoadjuvant approach. 23

Role of Ultrasonographic Assessment of Depth Involvement in Melanoma
For MM, the primary tumor thickness (Breslow index) and the presence of an ulceration represent essential prognostic factors. MMs are divided by their Breslow index in thin (<1 mm), intermediate (1-4 mm) and thick (>4 mm) and this parameter determines the therapeutic approach, the excision margins, the need of a sentinelnode biopsy and the overall survival. The histological Breslow index usually correlates with the risk of lymphonodal or distant metastasis. 24 According to Gershenwald et al., the 10-years melanoma-specific survival probability according to the tumor depth decreases with the increase of the Breslow index: while MMs with a tumor depth 0.8-1 mm with/ without ulceration have a 10-years survival rate of 98% and 96% respectively, patients with a tumor depth of 1-2 mm have a survival rate of 92% (without ulceration) and 88% (with ulceration). In subjects with a Breslow index between 2 and 4 mm, the 10-years survival rate decreases to 88% (without ulceration) and 81% (with ulceration), and in patients with a depth index >4 mm, the rate decreases further to 83% (without ulceration) and 75% (with ulceration). 25 Surely, histology remains the gold standard for establishing the exact Breslow depth of MM; however, modern, new transducers with high frequencies also enable a very accurate measurement of the tumor depth, which in some cases can spare patients a more-step surgical approach. Our study group among others has shown that HFUS can preoperatively "in vivo" establish the tumor thickness of MM with high precision and correlation to the histological Breslow depth index (>98%). 4,10,24,[26][27][28] The preoperative knowledge of the tumor depth allows in certain cases a one-time excision of the melanoma with the requested safety margin, sparing the patient a second surgical intervention. 29 Furthermore, it also helps surgeons decide upon the necessity of a sentinelnode biopsy, which is usually recommended in patients starting with a tumor depth of 0.8 mm or even <0.8 mm in the presence of ulceration, allowing the detection of subclinic metastatic lymphonodal involvement. 30 Lately, due to the demographic change as well as the COVID outbreak, we are often confronted with very old, significantly impaired patients with thick, ulcerated melanomas, where a resection of the tumor with safety margins is often the only therapeutic surgical option. 31 The preoperative knowledge of a Breslow index below or above 2 mm is essential to determine the safety margins for this intervention (1 cm safety margin for MM ≤2 mm, 2 cm safety margins for MMs >2 mm).
In very old, impaired patients, where in vivo sonography of the tumor cannot be performed, an ex-vivo measurement of the tumor depth of the excised lesion is also possible. Having established the approximate tumor depth, an immediate re-excision with the required safety margins can be performed, avoiding a second admission and surgical intervention (Figure 7). 32

Conclusion
Ultrasound in the presurgical setting plays an increasing role in the objective assessment of skin tumor parameters such as the tumor dimensions and the degree of extension into neighboring structures, enabling clinicians to identify patients who are no longer candidates for standard micrographic surgery, but rather require immunooncological and/or radiation therapies. Furthermore, it allows us to optimize the therapeutic approach in MM patients, avoiding unnecessary surgical interventions, as well as a delay in diagnosis and treatment. High-frequency ultrasound is a fast, non-invasive, in vivo diagnosis method, which in the hands of trained physicians can spare patients not only more expensive and timeconsuming imaging methods such as MRI or CT, but also unnecessary operative procedures. Furthermore, sonography does not require a particular preparation of the patient in advance, and preoperative knowledge of the tumoral characteristics allows clinicians to provide an optimal counseling to their patients with regard to the suitable therapeutic procedures (eg, invasive versus non-invasive) and expected outcomes.