Miguel Cordova

Confocal Microscopy-Guided Laser Ablation for Superficial and Early Nodular Basal Cell Carcinoma A Promising Surgical Alternative for Superficial Skin Cancers

IMPORTANCE Laser ablation is a rapid and minimally invasive approach for the treatment of superficial skin cancers, but efficacy and reliability vary owing to lack of histologic margin control. High-resolution reflectance confocal microscopy (RCM) may offer a means for examining margins directly on the patient. OBSERVATIONS We report successful elimination of superficial and early nodular basal cell carcinoma (BCC) in 2 cases using RCM imaging to guide Er:YAG laser ablation. Three-dimensional (3D) mapping is feasible with RCM to delineate the lateral border and thickness of the tumor. Thus, the surgeon may deliver laser fluence and passes with localized control-ie, by varying the ablation parameters in sublesional areas with specificity that is governed by the 3D topography of the BCC. We further demonstrate intraoperative detection of residual BCC after initial laser ablation and complete removal of remaining tumor by additional passes. Both RCM imaging and histologic sections confirm the final clearance of BCC. CONCLUSIONS AND RELEVANCE Confocal microscopy may enhance the efficacy and reliability of laser tumor ablation. This report represents a new translational application for RCM imaging, which, when combined with an ablative laser, may one day provide an efficient and cost-effective treatment for BCC.

Intraoperative imaging during Mohs surgery with reflectance confocal microscopy: initial clinical experience

Abstract. Mohs surgery for the removal of nonmelanoma skin cancers (NMSCs) is performed in stages, while being guided by the examination for residual tumor with frozen pathology. However, preparation of frozen pathology at each stage is time consuming and labor intensive. Real-time intraoperative reflectance confocal microscopy (RCM), combined with video mosaicking, may enable rapid detection of residual tumor directly in the surgical wounds on patients. We report our initial experience on 25 patients, using aluminum chloride for nuclear contrast. Imaging was performed in quadrants in the wound to simulate the Mohs surgeon’s examination of pathology. Images and videos of the epidermal and dermal margins were found to be of clinically acceptable quality. Bright nuclear morphology was identified at the epidermal margin and detectable in residual NMSC tumors. The presence of residual tumor and normal skin features could be detected in the peripheral and deep dermal margins. Intraoperative RCM imaging may enable detection of residual tumor directly on patients during Mohs surgery, and may serve as an adjunct for frozen pathology. Ultimately, for routine clinical utility, a stronger tumor-to-dermis contrast may be necessary, and also a smaller microscope with an automated approach for imaging in the entire wound in a rapid and controlled manner.

Video-mosaicing of reflectance confocal images for examination of extended areas of skin in vivo

With cellular-level resolution comparable to histology, reflectance confocal microscopy (RCM) imaging is a promising approach both for diagnosis of skin cancer in vivo with high sensitivity and specificity1,2, and for pre- and intra-operative detection of cancer margins to guide treatment.3–5 However, RCM images are limited to a field of view (FOV) of 1 mm -by- 1 mm, much smaller than the typical size of skin lesions. Many diagnostic features cannot be reliably identified in such small FOVs. Moreover, clinicians rely heavily on visual context of the surrounding tissue to perform diagnoses. Thus, larger areas must be imaged to evaluate cellular and morphologic features with high accuracy and repeatability. To address this concern, mosaicing approaches, which increase the FOV by acquiring a matrix of adjacent images and stitching them together to display a large area, have been developed for confocal microscopy6. In standard mosaicing, images are acquired while mechanically translating the microscope lens relative to the skin along pre-determined linear (straight-line) trajectories. This approach was implemented in the RCM scanner used in the cited studies1–5, and, in fact, is now routinely used on patients. However, the mechanics of translation limit speed and coverage to pre-selected small rectangular-shaped areas, currently up to 8 mm-by-8 mm, imaged in ~4.5 minutes. Coverage and speed could be increased, of course, with larger and faster mechanical translation systems, but would add significant size and cost to RCM scanners, and would certainly not be practical for routine use on patients. Miniaturized confocal endoscopes have been developed that allow the operator flexible control for imaging in vivo, without the constraints of mechanical translation7,8 Similar flexibility is now possible for imaging skin with the recent advent of smaller and miniaturized handheld confocal microscopes9,10,11. The operator manually moves the microscope along a desired curvilinear trajectory, with the lens gently pressed against the tissue, while acquiring a video sequence of images. Video microscopy enables the operator to choose the trajectory in real-time, allowing adaptive coverage of areas that can be selected in real-time during acquisition. Thus, an area with any shape and size may be rapidly imaged, without the previous constraints of straight-line trajectories and rectangular coverage. However, observing a video, by itself, merely as a time-sequence of small FOVs, does not readily provide the necessary visual context from the surrounding tissue. In this paper, we present results from an approach for computationally transforming such videos into mosaics that display the entire imaged area. Algorithms for video-mosaicing have been developed in the fields of computational photography and computer vision12, and their use has previously been reported for confocal endoscopic imaging7,8.We report here application of video-mosaicing to reflectance confocal images of human skin lesions and margins in vivo.

Intraoperative real-time reflectance confocal microscopy for guiding surgical margins of lentigo maligna melanoma.

Lentigo maligna melanoma (LMM) represents a diagnostic and therapeutic challenge because of its heterogeneous nature with poorly defined borders, subclinical extension, and location on sun-damaged skin. Reflectance confocal microscopy (RCM) has advanced the authors’ ability to better diagnose and manage these lesions through noninvasive examination of skin on a cellular level. Herein, the authors report the first case of RCM used intraoperatively, in a multidisciplinary approach involving dermatology and head and neck surgery to manage a challenging LMM. A 77-year-old woman was referred for treatment of an LMM on the left malar cheek approaching the lower eyelid. The lesion had been present for 2 years and previously treated with cryotherapy. On examination, there was an ill-defined 2-cm patch with irregular contour and variegate shades of brown–gray bordering the left lower eyelid (Figure 1). A biopsy revealed spindle cell–type melanoma with a depth of 1.25 mm. Preoperative mapping with RCM identified 2 surrounding areas suspicious for melanoma with epidermal disarray, dendritic hyperreflective melanocytes, and rounded pagetoid cells (Figure 2). Biopsies found invasive melanoma and melanoma in situ. Wide excision in the operating room assisted by RCM with rush pathology and delayed reconstruction was planned. Figure 1 Clinical photograph showing the ill-defined hyperpigmented patch on the left malar cheek approaching the lower eyelid outlined in green. The yellow circles mark areas outside of the clinical lesion where RCM showed suspicious findings, later confirmed ... Figure 2 (A) Reflectance confocal microscopy showing dense areas of hyperreflective, atypical dendritic processes with adnexal tropism. (B) Reflectance confocal microscopy showing pagetoid infiltration within the epidermal layer surrounding the hair follicles. ... Preoperatively, surgical 1 cm margins were defined under Wood lamp. Because of the poorly defined borders, RCM imaging was performed under an institutional review board–approved protocol using a commercially available handheld RCM (VivaScope 3000; Caliber ID, Rochester, NY). The lesion was imaged at the clinical and surgical margins from the stratum corneum down to inside the papillary dermis. Scanning confocal video microscopy was performed to rapidly inspect the border. Reflectance confocal microscopy examination allowed enhanced delineation of the borders and subsequently increased the resection margins. An area around the 9-o’clock margin was suspicious for positivity under RCM because of the presence of sheets of atypical cells and epidermal disarray, but it was not excised for possibility that it was a false positive because it encompassed a separate cosmetic subunit. It was decided to not increase the surgical margin in this area because of the experimental nature of this technology and instead wait for rush permanent hematoxylin and eosin pathology confirmation. Excision of the lesion and margins down to subcutaneous fat was performed. Then, RCM was used to re-evaluate the periphery of the area of resection. The same region of concern, showing dendritic processes and round pagetoid cells around the 9-o’clock position, was highlighted. A video captured intraoperatively was converted into a mosaic by stitching together individual frames to provide a detailed overview of the peripheral margin, highlighting the atypical findings (Figure 3). Figure 3 Representative section from the mosaic created to assess outside of the surgical margin. Area in the blue rectangle represents normal-appearing tissue architecture. The area within the red circle highlights large atypical hyper-reflective cells at the ... Pathology revealed residual invasive and in situ melanoma within the lesion and melanoma in situ extending to the 9-o’clock margin as suspected on confocal microscopy. The patient returned for re-excision along this margin and closure with a cervical facial flap and full-thickness skin graft. No further melanoma was seen on pathology.

Melanocytic naevi with globular and reticular dermoscopic patterns display distinct BRAF V600E expression profiles and histopathological patterns

BRAF (v‐raf murine sarcoma viral oncogene homologue B) V600E mutations have been detected with high frequency in melanocytic naevi. Few studies have stratified analyses by naevus dermoscopic pattern.

Carbon dioxide laser ablation of basal cell carcinoma with visual guidance by reflectance confocal microscopy: a proof-of-principle pilot study

Laser ablation is an alternative, nonsurgical treatment modality for low‐risk basal cell carcinoma (BCC). However, lack of confirmative tumour destruction or residual tumour presence has been a limiting factor to its adoption. Reflectance confocal microscopy (RCM) provides noninvasive, cellular‐level resolution imaging of the skin and is capable of identifying tumour.

Handheld optical coherence tomography–reflectance confocal microscopy probe for detection of basal cell carcinoma and delineation of margins

Abstract. We present a hand-held implementation and preliminary evaluation of a combined optical coherence tomography (OCT) and reflectance confocal microscopy (RCM) probe for detecting and delineating the margins of basal cell carcinomas (BCCs) in human skin in vivo. A standard OCT approach (spectrometer-based) with a central wavelength of 1310 nm and 0.11 numerical aperture (NA) was combined with a standard RCM approach (830-nm wavelength and 0.9 NA) into a common path hand-held probe. Cross-sectional OCT images and enface RCM images are simultaneously displayed, allowing for three-dimensional microscopic assessment of tumor morphology in real time. Depending on the subtype and depth of the BCC tumor and surrounding skin conditions, OCT and RCM imaging are able to complement each other, the strengths of each helping overcome the limitations of the other. Four representative cases are summarized, out of the 15 investigated in a preliminary pilot study, demonstrating how OCT and RCM imaging may be synergistically combined to more accurately detect BCCs and more completely delineate margins. Our preliminary results highlight the potential benefits of combining the two technologies within a single probe to potentially guide diagnosis as well as treatment of BCCs.

Correlation of Handheld Reflectance Confocal Microscopy With Radial Video Mosaicing for Margin Mapping of Lentigo Maligna and Lentigo Maligna Melanoma

Importance The management of lentigo maligna (LM) and LM melanoma (LMM) is challenging because of extensive subclinical spread and its occurrence on cosmetically sensitive areas. Reflectance confocal microscopy (RCM) improves diagnostic accuracy for LM and LMM and can be used to delineate their margins. Objectives To evaluate whether handheld RCM with radial video mosaicing (HRCM-RV) offers accurate presurgical assessment of LM and LMM margins. Design, Setting, and Participants This prospective study included consecutive patients with biopsy-proven LM and LMM located on the head and neck area who sought consultation for surgical management from March 1, 2016, through March 31, 2017, at the Dermatology Service of the Memorial Sloan Kettering Cancer Center. Thirty-two patients underwent imaging using HRCM-RV, and 22 patients with 23 LM or LMM lesions underwent staged surgery and contributed to the analysis. Main Outcomes and Measures Clinical lesion size and area, LM and LMM area based on HRCM-RV findings, surgical defect area estimated by HRCM-RV, and observed surgical defect area. In addition, the margins measured in millimeters estimated for tumor clearance in each quadrant based on HRCM-RV findings were calculated and compared with the surgical margins. Results Among the 22 patients (12 men and 10 women; mean [SD] age, 69.0 [8.6] years [range, 46-83 years]) with 23 lesions included in the final analysis, the mean (SD) surgical defect area estimated with HRCM-RV was 6.34 (4.02) cm2 and the mean (SD) area of surgical excision with clear margins was 7.74 (5.28) cm2. Overall, controlling for patient age and previous surgery, surgical margins were a mean of 0.76 mm (95% CI, 0.67-0.84 mm; P < .001) larger than the HRCM-RV estimate. Conclusions and Relevance Mapping of LM and LMM with HRCM-RV estimated defects that were similar to but slightly smaller than those found in staged excision. Thus, mapping of LM using HRCM-RV can help spare healthy tissue by reducing the number of biopsies needed in clinically uncertain areas and may be used to plan treatment of LM and LMM and counsel patients appropriately.

Handheld Reflectance Confocal Microscopy for the Detection of Recurrent Extramammary Paget Disease

Importance Extramammary Paget disease (EMPD) is commonly refractory to surgical and nonsurgical therapies. Identifying recurrent or persistent EMPD is challenging because the disease is multifocal, and multiple blind scouting biopsies are usually performed in this setting. Handheld reflectance confocal microscopy (HRCM) has been used to diagnose and map primary EMPD and therefore may be used to identify EMPD recurrences. Objective To evaluate HRCM’s diagnostic accuracy in the setting of recurrent or persistent EMPD as well as its potential diagnostic pitfalls. Design, Setting, and Participants This prospective case series study included patients referred to the Dermatology Service at Memorial Sloan Kettering Cancer Center between January 1, 2014, and December 31, 2016, with biopsy-proven EMPD in whom HRCM was used to monitor treatment response. Five patients were included, and 22 sites clinically concerning for recurrent or persistent disease were evaluated using HRCM and histopathologic examination. In 2 patients, video mosaics were created to evaluate large areas. Main Outcomes and Measures Sensitivity and specificity of HRCM in identifying recurrent or persistent EMPD; causes for false-negative results according to their location, histopathologic findings, and previous treatments. Results Of the 22 clinically suspicious sites evaluated in 5 patients (4 men, 1 woman; median [range] age, 70 [56-77] years), 9 (40.9%) were positive for recurrent disease on HRCM and histopathologically confirmed, and 13 (59.1%) sites were negative on HRCM, but 3 of the 13 were positive for EMPD on histopathological examination. In general, HRCM had a sensitivity of 75% and a specificity of 100% in identifying recurrent or persistent EMPD. False-negative results were found in 2 patients and occurred at the margins of EMPD, close to previous biopsy sites. Creating video mosaics (or video mosaicking) seemed to improve the detection of EMPD. Conclusions and Relevance Handheld reflectance confocal microscopy is a useful auxiliary tool for diagnosing EMPD recurrences and can be used to guide scouting biopsies, thus reducing the number of biopsies needed to render a correct diagnosis.

Radiation therapy for synchronous basal cell carcinoma and lentigo maligna of the nose: Response assessment by clinical examination and reflectance confocal microscopy

Radiation therapy (RT) is a noninvasive treatment for a variety of skin cancers. Although surgery is often preferred for basal cell carcinoma (BCC) and lentigo maligna (LM), these conditions often affect patients that are medically inoperable, who decline surgery, or have lesions in challenging anatomic locations. Although nonsurgical treatments can be employed, close monitoring for disease recurrence and progression is of utmost importance. Typically, this is carried out by clinical examination, without adjunctive imaging. Reflectance confocal microscopy (RCM) is an emerging imaging technology that is proving useful to aid in the assessment of treatment response and disease recurrence (Fig 1). RCM has a high