Emerging Novel Non-invasive Imaging



Fig. 14.1
RCM feature of LM: nonedged dermal papillae



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Fig. 14.2
RCM feature of LM: round large pagetoid cells


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Fig. 14.3
RCM feature of LM: atypical cells at the dermal-epidermal junction


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Fig. 14.4
RCM feature of LM: follicular localization of atypical cells



Table 14.1
RCM score for diagnosis of lentigo maligna
































RCM feature

Points

Major criteria

Nonedged dermal papillae

+2

Round large pagetoid cells

+2

Minor criteria

Nucleated cells in dermal papillae

+1

Atypical cells at DEJ

+1

Follicular localization of atypical cells

+1

Broadened honeycomb pattern

−1


Suspicious for at least melanoma in situ with score ≥2 (Guitera et al. [4])


Rossi et al. studied the use of a handheld confocal microscope and compared it to histopathology in the diagnosis of 60 equivocal pigmented lesions in patients concerning for LM. In this study, RCM and histopathology interpretations were concordant in 89 % of cases (56/63). While there were no false-negative outcomes on RCM, 7 false-positive results were seen, a majority being diagnosed on histopathology as pigmented actinic keratotis. Features suggestive of LM in the false-positive group include the presence of numerous hyperreflectile large cells at the dermoepidermal junction and follicular localization of these cells [23].

A recent meta-analysis found a sensitivity and specificity of 93 % and 76 %, respectively, for RCM when used as a second-level test for diagnosing pigmented lesions that are clinically equivocal [24]. Others have also reported sensitivities of 100 % using RCM to detect LM, further supporting the idea that RCM is a reliable method for diagnosing LM or monitoring for treatment failure in vivo [12, 14]. Using RCM to non-invasively identify LM without biopsy is an exciting improvement in the management of patients with chronically sun-exposed skin.

Another important function of RCM is to improve the ability to hone in on optimal areas for mapping biopsies and detect possible occult invasion in LM lesions. Blind mapping biopsies of LM are prone to sample bias and depend greatly on biopsy technique. Even adequate biopsies of LM can be challenging to definitively interpret under standard hematoxylin and eosin histology due to its occurrence in areas with a background of melanocytic hyperplasia. Studies have demonstrated that occult invasion in LM with standard biopsy technique was not consistently apparent until complete surgical excision was performed. For example, Agarwal-Antal et al. reported on 92 cases of LM of which 16 % were found to have unsuspected invasion on final excisional pathology [25]. Due to the cosmetically-sensitive nature of the lesions, physicians may feel discouraged to take numerous mapping biopsies, even in cases of large lesions. This makes it quite difficult to adequately evaluate the breadth of the lesion or detect occult invasion. Moreover, biopsies are subject to sampling error due to the heterogeneous nature of LM and its characteristic subclinical extension. The costs and morbidity associated with multiple biopsies in patients with a high burden of actinic disease can be substantial. Utilizing real-time video imaging of the dermoepidermal junction at the margin and within the lesion has allowed for the detection of deep atypical melanocytes suspicious for invasion to better hone in on suspicious areas and guide mapping biopsies. Being able to detect the relative depth of invasion pre-treatment through RCM imaging or by guiding mapping biopsies is essential for not only counseling the patient about disease risk but also imperative for choosing an appropriate treatment modality.



RCM for LM Management (Surgical)


Surgery is considered the first line treatment for LM; however, it is not without associated morbidity. Wide surgical margins, especially on cosmetically-sensitive areas such as the face, are not always possible to obtain, and become further complicated when trying to maintain adequate functional and aesthetic outcomes. The margins required for surgical clearance may not be straightforward for facial lesions. A study by Hazan et al. reviewed 117 cases of LM and LMM and found that the total surgical margin required for excision of LM was 7.1 mm and for LMM was 10.3 mm. Moreover, of the tumors that were initially diagnosed as LM on biopsy, 16 % were found to have unsuspected invasion [26].

As surgical excision remains the standard of care for LM, it is important to optimize surgical methods and because there may be extensive subclinical extension, there is a need for better pre-treatment margin evaluation in LM. RCM is emerging as an adjunct to existing technologies, including dermoscopy and Wood’s lamp, to better delineate borders. Utilizing RCM pre-surgically offers the benefit of surgical planning, as it helps define the extent of subclinical spread prior to initiating the surgery. This informs both the surgeon and the patient to assist in reconstructive design and patient expectations. While RCM may be used to show that margins need to be increased due to subclinical spread, it may also allow for confirming narrower surgical margins in critical anatomical areas, facilitating reconstruction and decreasing patient morbidity. Thus, RCM provides valuable clinical information to potentially guide surgical management, and may lead to favorable cosmetic outcomes and a better prognosis.

One approach to using RCM to guide surgical management of LM is to first demarcate the lesion clinically with the aid of Wood’s lamp and dermoscopy, followed by placing appropriate surgical margins at 5–10 mm depending on clinical and histologic criteria. RCM may then be used within the lesion to identify features of the melanoma, thus serving as a control. An imaging “map” (Fig. 14.5) may be made by dividing the lesion into quadrants and capturing RCM video imaging along the periphery of surgical margins of each quadrant at the level of the dermoepidermal junction (main region to detect features of LM and LMM). In areas where positive findings including hyperreflective dendritic cells, large, round pagetoid cells, and epidermal disarray are seen, the margins are extended out radially. Video capture can be used to recreate video mosaics by stitching together sequences of images captured to re-create a larger field of view. As such, RCM is a valuable adjunct to the clinical exam and dermoscopy to determine clinical margins and define the gross tumor volume.

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Fig. 14.5
RCM “map” created to delineate surgical margins of LM

Advancements have been made in RCM technology, overcoming limitations of earlier iterations of the device. The newer, handheld Vivascope 3000 (Caliber ID, Rochester, NY) offers the advantage of real-time assessment in areas that may not have been amenable to previous versions of the device. Employing RCM during the initial consultation may help clinicians characterize subclinical spread of LM and therefore better counsel patients about the extent of their lesion. Additionally, Hibler et al. described the use of the handheld Vivascope 3000 intraoperatively to provide the surgeon with real-time assessment of tumor margins in vivo [27]. This may be a valuable approach for large cases of LM being performed in the operating room under general anesthesia, where the benefits of obtaining immediate visual confirmation of margins to ensure clearance may prevent a return trip to the operating room, saving costs and avoiding risks of additional anesthesia. Using RCM in this mapping fashion could ultimately allow for improved clearance of LM, thereby decreasing the likelihood of recurrence and the need for re-excision, while also maximizing tissue conservation and lowering morbidity.


RCM for LM Management (Non-surgical)


While surgical excision is the treatment of choice for LM, factors including advanced patient age, multiple comorbidities, large lesion size in functionally or aesthetically-sensitive areas, and indiscriminate borders on photodamaged skin may make surgical excision complicated or not a feasible option. For patients unable to pursue surgical treatment and in cases where surgery would cause excess morbidity or deformity, multiple nonsurgical treatment options have been pursued. The use of superficial radiation or off label use of topical therapies, i.e. Imiquimod, has been reported in the literature as alternative non-surgical treatment options [28, 29]. However, the lack of histological confirmation, and possibility for undetected invasive spread have been limits to these modalities. Similarly, close monitoring for disease recurrence and progression is of utmost importance. Typically this is carried out by clinical examination, without adjunctive imaging beyond dermoscopy. RCM is emerging as an imaging technology that is proving useful to aid in the assessment of disease extent, treatment response and disease recurrence for LM after non-surgical therapy [1]. This is illustrated in Fig. 14.6.

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Fig. 14.6
RCM used to detect recurrent LM. (a) Pre-confocal mapping of brown pigmentation along scar from excision of invasive lentigo maligna melanoma 15 years prior. ‘V’ indicates sites where images were captured in the z-plane. (+) indicates features of lentigo maligna on confocal microscopy. (b) Reflectance confocal image: Yellow circles indicate suspicious features for lentigo maligna: hyper reflective dendritic cells surrounding hair follicles. (c) Shave biopsies (blue circles) guided by confocal all showed melanoma in situ and patient opted for treatment with Imiquimod to avoid surgical morbidity

In the same way that RCM may provide enhanced delineation of lesion margins for surgical intervention, it may also be capable of better defining a treatment field for radiation or topical therapies (Fig. 14.7). LMs treated with radiation or non surgical treatment modalities need close follow-up to detect recurrences [28]. Detecting recurrence can be a challenge clinically, as the lesion may recur as an amelanotic lesion, or can be further obscured by radiation-induced inflammation and post-radiation pigment changes. Because RCM allows for the same area of skin to be re-examined over time, this technology can also be applied to monitor for recurrence in LMs [30]. Changes in tissue architecture have been observed in LMs after radiation, including: superficial necrosis and apoptotic cells, dilated vessels, and increased inflammatory cells in both the dermis and epidermis [10]. After radiation, LM-specific large pagetoid cells were decreased or even resolved in the epidermis, dermal-epidermal junction, and in the follicles [10]. When using RCM to monitor for recurrence post-treatment, it is important to wait until the inflammation and post treatment changes have subsided to ensure any acute radiation-induced changes in skin architecture have resolved and will not cause false positives [31]. Epidermal regeneration post-radiation therapy begins 3–5 weeks after treatment and heals within 1–3 months, suggesting that radiation-induced changes on RCM might persist for this duration of time, although this has not been formally studied [32]. The ability to visualize and define changes during and after RT suggest RCM may be useful for monitoring for treatment failure. Examination with RCM may augment our ability to better define the radiation field pre-treatment and has been shown to be capable of detecting areas concerning for residual or recurrent disease post-treatment before clinical repigmentation [33].

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Fig. 14.7
RCM used to plan radiation treatment margins. (a) Initial lesion with irregular pigmentation confirmed as lentigo maligna on biopsy. Patient elected treatment with Imiquimod due to her advancing age and medical comorbidities. Follow-up biopsies found melanoma invasive to 0.37 mm and patient underwent surgery to excise the invasive melanoma but in situ LM remained at surgical margins. (b) Reflectance confocal mapping for radiation therapy planning. Yellow circles indicate areas of dendritic pagetoid hyper reflecticle cells suspicious for lentigo maligna. (c) RCM map at 1 cm and 2 cm margins from surgical scar created to guide further radiation planning. ‘v’ indicates stacks of images captured in the z-plane. (+) indicates findings suspicious for lentigo maligna

In a similar manner, RCM may be utilized to monitor response after treatment with off label Imiquimod cream [34]. While the use of Imiquimod for LM has been well documented in the literature, the application, duration of therapy, and response to treatment vary greatly. Furthermore, factors accurately predicting a positive response to treatment have yet to be fully elucidated, as the degree of inflammatory response and erythema have not correlated well with overall clearance. The benefit of RCM after topical therapy is that it represents a non-invasive modality to monitor response to treatment and may help assess the need for increased duration of treatment. Moreover, similar to the changes induced post-radiation, treatment with Imiquimod may cause an alteration of the clinically apparent pigment, and it is therefore difficult to assess treatment success by clinical inspection alone. The use of RCM before, during, and after treatment provides a longitudinal assessment of the lesion, and may augment our ability to determine treatment success or failure.

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Jul 13, 2017 | Posted by in Dermatology | Comments Off on Emerging Novel Non-invasive Imaging

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