Digital follow-up by means of dermatoscopy and reflectance confocal microscopy of actinic keratosis treated with Imiquimod 3.75% cream.

BACKGROUND: Imiquimod 3.75% cream (Zyclara® Meda, Stockholm, Sweden) is a new field-directed therapy for actinic keratosis (AK). OBJECTIVES: The aim is to evaluate efficacy and the morphologic dynamic changes induced by this treatment by means of dermatoscopy and reflectance confocal microscopy (RCM) of imiquimod 3.75% cream for the treatment of AKs of the face or scalp and to evaluate. METHODS: Thirty-two patients were treated with Imiquimod 3.75% cream. Demographic parameters, AK-FAS and AKASI scores and side-effects were collected. RCM and dermatoscopy on one target AKs were performed at each visit. We collected images at baseline (T0), after 1 week from the end of the first 2-week cycle (T1), after 1 week from the end of the entire treatment (T2) and 2 months after the end of treatment (T3). RESULTS: One target representative AK in the selected area of treatment of each patient was analysed. All dermoscopic and confocal parameters were reduced 2 months after the end of the therapy (T3) with a substantial reduction of AKASI and AK-FAS scores, and 17 cases (54.8%) were completely solved. Confocal microscopic analysis showed a reduction of keratinocytes disarray in 77.4% of cases; none showed crusts and parakeratosis. Inflammation was considerably decreased and was observed only in 12.9% of patients at the last visit. This improvement was not assessed on dermatoscopy because of inflammation and background erythema, which adversely influenced the assessments. LSRs were observed in almost all the patients during treatment being more severe after the first cycle of treatment (T1). CONCLUSIONS: Imiquimod 3.75% cream is effective in treating clinical and subclinical AKs with an easy management of side-effects. Dermatoscopy and mostly RCM allow non-invasive monitoring of treatment response in vivo.

External validation and comparison of four confocal microscopic scores for melanoma diagnosis on a retrospective series of highly suspicious melanocytic lesions.

BACKGROUND: In vivo reflectance confocal microscopy significantly improves melanoma diagnosis as compared to clinical/dermoscopic examination alone. Several confocal criteria have been described allowing to differentiate melanoma from nevi; by combining different criteria, three pure confocal scores (Pellacani 2005, Segura 2009 and Pellacani 2012) and one mixed dermoscopic/confocal score (Borsari 2018) were constructed. OBJECTIVE: Our aim was to externally validate and compare the performance of these confocal scores. METHODS: We retrospectively enrolled excised melanocytic lesions which underwent confocal examination in a 2-year period. Lesions located on the face and acral sites were excluded. Both dermoscopic and confocal criteria considered in the four scores were evaluated by experts. Subsequently, specificity and sensitivity levels for each score were calculated, together with the positive and negative predictive values and likelihood ratios; also, receiver operating characteristic curves were constructed. RESULTS: A total of 389 patients with 422 lesions were retrospectively enrolled, of which 162 (38.4%) were melanomas and 260 (61.6%) were nevi (189 common and 71 Spitz/Reed nevi). The highest sensitivity levels were recorded for Segura 2009 with cut-off ≥-1 (92.0%), while Pellacani 2005 with cut-off ≥5 achieved the highest specificity (69.6%). The score by Borsari et al. showed the highest levels of positive and negative predictive values (59.8% and 91.5%) and likelihood ratios (2.4 and 0.1) as well as the highest area under the curve values (0.76; 95% CI 0.72-0.81; P < 0.001). CONCLUSIONS: High levels of accuracy were found for each of the four considered scores. No differences were found among scores in confirming melanoma diagnosis when positive; however, the score by Borsari 2018 was the best in excluding melanoma diagnosis when negative.

Dermoscopy and reflectance confocal microscopy for monitoring the treatment of actinic cheilitis with ingenol mebutate gel: Report of three cases.

Actinic cheilitis (AC) can precede the development of squamous cell carcinoma (SCC) of the lip, a location with higher risk of invasiveness and metastasis. Herein, we reported the use of ingenol mebutate (IngMeb) 0.015% gel on three consecutive days to treat three patients suffering from AC. All the three patients achieved complete clearance of AC with rapid clinical effect, favorable safety profile, good patient's compliance related to short time of applications, and few local skin reactions. So IngMeb is an attractive new therapy for AC. Moreover, the present case report adds further evidence to the usefulness of dermoscopy and Reflectance confocal microscopy (RCM) in the assessment and monitoring of treatment outcome.

Basal cell carcinoma: the utility of in vivo and ex vivo confocal microscopy.

The use of confocal microscopy is possible using two different modalities: first, at patient's bedside for a rapid in vivo diagnosis of basal cell carcinoma and second, in the operating room directly on freshly excised specimen for a fast ex vivo margin-controlled surgery. In the current review, we report the main application of confocal microscopy for basal cell carcinoma diagnosis and management in both modalities.

Reflectance confocal microscopy and optical coherence tomography for the diagnosis of bullous pemphigoid and pemphigus and surrounding subclinical lesions.

BACKGROUND: Diagnosis of bullous pemphigoid (BP) and pemphigus is based on clinical features, histology, immunofluorescence and laboratory data. OBJECTIVES: To evaluate features of BP and pemphigus at reflectance confocal microscopy (RCM) and optical coherence tomography (OCT) in order to provide a rapid non-invasive bed-side diagnosis. Secondary objective was to evaluate the detectability of clinically non-visible lesions. METHODS: This was an observational, retrospective, multicentre study in which patients with suspicious lesions for BP or pemphigus underwent clinical assessment, RCM, OCT, blood tests and skin biopsy for histological and direct immunofluorescence examinations from January 2014 to December 2015. A total of 72 lesions in 24 selected patients were evaluated. Additionally, apparently unaffected skin at two different distances [near (1-2 cm) and far (2-3 cm)] from each lesion was examined to test subclinical lesion detectability. RESULTS: RCM was able to detect subepidermal and intra-epidermal blisters, respectively, in 75% and 50% of the patients affected by BP and pemphigus. At OCT, the exact blister level was identified in all patients. Acantholytic cells were observed only at RCM in pemphigus (62.5%). Fibrin deposition inside the blisters was only found in BP, evidenced both at RCM and OCT. Among patients with BP, subclinical blisters were detected in nine (9.4%) clinically healthy skin, while among patients with pemphigus were observed in 10 (20.8%) apparently unaffected skin. CONCLUSION: RCM and/or OCT provide useful information for a rapid diagnosis of BP and pemphigus and for the identification of biopsy site. Combined use of RCM and OCT is optimal because associates the higher resolution of RCM with the greater penetration depth of OCT. OCT could be an optimal tool for treatment monitoring, especially in the cases of subclinical lesions. However, histopathologic and immunologic examinations remain the gold standard for establishing the final diagnosis.

In vivo dermoscopic and confocal microscopy multistep algorithm to detect in situ melanomas.

BACKGROUND: Although several dermoscopic features of in situ melanoma have been identified, data on confocal features of in situ melanoma are still lacking. OBJECTIVES: To identify reflectance confocal microscopy (RCM) features of in situ melanoma and to develop a diagnostic score combining dermoscopy and RCM. METHODS: In total, 120 in situ melanoma and 213 nevi (test set) were retrospectively analysed to assess the presence of dermoscopic and RCM criteria. Facial and acral lesions were excluded. Spearman's correlation, univariate and multivariate regression models were used to identify features significantly correlated with in situ melanoma diagnosis. Multivariate results on the test set allowed the development of a multistep algorithm, that was tested on a validation set of 100 lesions. RESULTS: The dermoscopic findings of an atypical network and regression were independent predicting factors for in situ melanoma diagnosis [odds ratio (OR) 3·44, 95% CI (confidence interval) 1·70-6·97 and OR 4·17, 95% CI 1·93-9·00, respectively]. Significant confocal predictors for malignancy were epidermal pagetoid spread (OR 2·83, 95% CI 1·32-6·04) and junctional cytological atypia (OR 3·39, 95% CI 1·38-8·30 if focal, OR 8·44, 95% CI 3·21-22·16 if widespread). A multistep diagnostic algorithm able to predict in situ melanoma with a sensitivity of 92·5% and a specificity of 61% was developed. The validation set confirmed the high diagnostic value (sensitivity 92%, specificity 58%). CONCLUSIONS: An easy and reproducible multistep algorithm for in situ melanoma detection is suggested, that can be routinely used in tertiary centres.

Tracking actinic keratosis of face and scalp treated with 0.015% ingenol mebutate to identify clinical and dermoscopic predictors of treatment response.

BACKGROUND: Ingenol mebutate (IngMeb) 0.015% gel is an approved field treatment option for non-hyperkeratotic non-hypertrophic actinic keratosis (AK) of face and scalp. Efficacy of IngMeb has been assessed only on a clinical ground, in the majority of studies. Dermoscopy is a pivotal tool for the diagnosis of AK, while its role in evaluating the response to non-surgical therapies for AK has not been fully defined. OBJECTIVES: Our study aims to determine whether some dermoscopic features of AK of the face and scalp areas may independently predict the response to IngMeb therapy. METHODS: Clinical and dermoscopic responses, 1 month after 0.015% IngMeb therapy, were retrospectively evaluated using a per-patient and per-lesion approach. Safety was evaluated through local skin reaction composite score calculation. Demographic, clinical and dermoscopic factors were then evaluated via univariate and multivariate logistic regression analysis to assess independent predictors of response. RESULTS: Fifty-five patients with 245 AKs were enrolled. Clinically, per-patient response evaluation identified 25 (45.4%) poor/partial and 30 (54.5%) complete responders, corresponding on a per-lesion approach to 66 (26.9%) and 179 (73.1%) AKs, respectively. Dermoscopy reclassified 14 patients in the per-patient and 48 AKs in the per-lesion analysis from complete to poor/partial responders. Multivariate logistic regression analysis showed that AKs dermoscopically characterized by red pseudonetwork and located on the face were independently associated with a complete dermoscopic response to 0.015% IngMeb therapy, while microerosions were negative predictors. CONCLUSION: Specific dermoscopic features of AK may predict the response to 0.015% IngMeb therapy, together with the location on the face.

Integration of dermoscopy and reflectance confocal microscopy for distinguishing melanomas from nevi of the breast area.

BACKGROUND: Nevi of special sites encompass a class of benign lesions characterized by the presence of atypical clinical and histopathological features that can be difficult to distinguish from melanoma. Dermoscopy and reflectance confocal microscopy may improve the clinical assessment of melanocytic lesions to avoid unnecessary excisions. OBJECTIVES: The aim of this study was to assess the value of specific dermoscopic and confocal criteria in distinguishing melanomas from nevi of the breast area. METHODS: Dermoscopic and confocal images from consecutive patients with at least one clinically and/or dermoscopically equivocal melanocytic skin lesion of the breast area were retrospectively evaluated. In this case-control study, only histopathologically proven melanomas (cases) and nevi (controls) were included. Spearman's coefficients were first calculated to flag significant correlation; then univariate and multivariate logistic regression analyses were performed to assess which factors were independently associated with the histopathological diagnosis. Finally, a mixed dermoscopic/confocal score was created to distinguish nevi from melanomas on the breast area. RESULTS: The study population included 55 skin lesions of the breast area, 34 (61.8%) nevi and 21 (38.2%) melanomas. Among dermoscopic criteria, atypical network and irregular pigmentation resulted independently associated with melanoma diagnosis (OR: 11.1; 95% CI 1.0-119.9; P:0.048 and OR: 6.5; 95% CI 1.1-37.5; P:0.037, respectively). Furthermore, on RCM examination, the presence of pagetoid cells was an independent positive predictor for melanoma (OR: 38.5; 95% CI 3.9-379.6; P:0.002). The mixed score showed high levels of sensitivity and specificity, 95.2% and 82.4%, respectively, which were higher than dermoscopic and confocal evaluations alone. CONCLUSION: The combined use of dermoscopy and confocal microscopy in the triage of pigmented lesions of the breast area may help in increasing the diagnostic accuracy and avoiding unnecessary excisions.

Improving diagnostic sensitivity of combined dermoscopy and reflectance confocal microscopy imaging through double reader concordance evaluation in telemedicine settings: A retrospective study of 1000 equivocal cases.

BACKGROUND: Reflectance confocal microscopy (RCM) is an imaging device that permits non-invasive visualization of cellular morphology and has been shown to improve diagnostic accuracy of dermoscopically equivocal cutaneous lesions. The application of double reader concordance evaluation of dermoscopy-RCM image sets in retrospective settings and its potential application to telemedicine evaluation has not been tested in a large study population. OBJECTIVE: To improve diagnostic sensitivity of RCM image diagnosis using a double reader concordance evaluation approach; to reduce mismanagement of equivocal cutaneous lesions in retrospective consultation and telemedicine settings. METHODS: 1000 combined dermoscopy-RCM image sets were evaluated in blind by 10 readers with advanced training and internship in dermoscopy and RCM evaluation. We compared sensitivity and specificity of single reader evaluation versus double reader concordance evaluation as well as the effect of diagnostic confidence on lesion management in a retrospective setting. RESULTS: Single reader evaluation resulted in an overall sensitivity of 95.2% and specificity of 76.3%, with misdiagnosis of 8 melanomas, 4 basal cell carcinomas and 2 squamous cell carcinomas. Combined double reader evaluation resulted in an overall sensitivity of 98.3% and specificity of 65.5%, with misdiagnosis of 1 in-situ melanoma and 2 basal cell carcinomas. CONCLUSION: Evaluation of dermoscopy-RCM image sets of cutaneous lesions by single reader evaluation in retrospective settings is limited by sensitivity levels that may result in potential mismanagement of malignant lesions. Double reader blind concordance evaluation may improve the sensitivity of diagnosis and management safety. The use of a second check can be implemented in telemedicine settings where expert consultation and second opinions may be required.

Dermoscopic and reflectance confocal microscopy features of cutaneous squamous cell carcinoma.

BACKGROUND: Squamous cell carcinoma (SCC) of the skin is a highly prevalent neoplasm. The management and the prognosis of this tumour are dependent on its invasiveness and its grade of differentiation. OBJECTIVES: To evaluate whether specific dermoscopic and reflectance confocal microscopy (RCM) criteria can predict the diagnosis of invasive SCC vs. in situ SCC and poorly differentiated compared with well- and moderately differentiated SCC. METHODS: Dermoscopic and RCM images of SCC were retrospectively evaluated for the presence of predefined criteria. RESULTS: Among 143 SCCs, 121 cases had a complete set of images and thus were included in the study set. The head and neck area was the most frequently involved body site (74/121; 61.1%) followed by extremities (36/121, 29.7%) and trunk (11/121, 9.1%). Seventy tumours were in situ (57.8%), while 51 were invasive (42.1%), of these 11 were poorly differentiated (21.5%), 16 were moderately differentiated (31.3%), and 24 were well differentiated (47.0%). Chi-squared analysis demonstrated that invasive SCCs were characterized by polymorphic vessels, erosion/ulceration, architectural disarrangement, speckled nucleated cells in the dermis, irregularly dilated vessels and absence of hyperkeratosis. Buttonhole vessels, white structureless areas and dotted or glomerular vessels were significantly associated with in situ lesions. Poorly differentiated SCCs were typified by red areas, erosion/ulceration and architectural disarrangement. Well- or moderately differentiated SCCs were associated with white areas and speckled nucleated cells in the epidermis. CONCLUSION: Clinical, dermoscopic and RCM images provide useful information that should be integrated in order to achieve the optimal therapeutic management for the patient.

Dermoscopic features predicting the presence of mitoses in thin melanoma.

BACKGROUND: The latest AJCC classification has included the number of mitoses as a factor for upstaging thin melanomas. Meanwhile, while dermoscopy has often been used to predict melanoma thickness, its value in predicting number of mitoses remains unknown. OBJECTIVE: Our aim is to evaluate the correlation between dermoscopic features and the presence of mitoses in a consecutive cohort of thin melanomas. METHODS: A case control study has been performed to identify specific dermoscopic parameters that could differentiate thin melanomas with 1 or more mitoses per mm2 from those without mitoses. RESULTS: Of 177 melanomas equal to or thinner than 1mm, 131 (74%) lesions had no mitoses and 46 (36%) lesions had at least 1 mitosis×mm2. Dermoscopic features associated with the presence of 1 or more mitoses were the following: peripheral streaks (OR 4.11; 95% CI 1.94-8.71) and black colour (OR 4.70; 95% CI; 2.28-9.68). In contrast, atypical pigment network (OR (0.30; 95% CI 0.15-0.61)) and brown colour (OR 0.36; 95% CI 0.18-0.75) were associated to melanomas without mitoses. The same variables were also associated to the increasing number of mitoses at linear regression. CONCLUSION: Black colour and peripheral streaks can predict the presence of mitoses in thin melanoma, while atypical pigment network and brown colour are associated to thin melanoma without mitoses.

Clinical and dermoscopic clues to differentiate pigmented nail bands: an International Dermoscopy Society study.

BACKGROUND: Longitudinal melanonychia might be difficult to differentiate and the use of dermoscopy can be useful for the preoperative evaluation and management decision. OBJECTIVES: The aim of our study was to investigate clinical and dermoscopic criteria of acquired longitudinal melanonychia in adults to identify the best predictors of melanoma using a multivariate analysis and to explore eventual new dermoscopic criteria for nail melanoma diagnosis. METHODS: In this retrospective observational study, 82 histopathologically diagnosed, acquired nail pigmented bands were collected and examined. All variables were included in the analysis and examined as possible predictors of nail melanoma. Both univariate and multivariable analyses have been performed. RESULTS: Among 82 cases, 25 were diagnosed as nail melanoma and 57 as benign lesions (including 32 melanocytic nevi and 25 benign melanocytic hyperplasia). Melanoma cases were significantly associated with a width of the pigmented band higher than 2/3 of the nail plate, grey and black colours, irregularly pigmented lines, Hutchinson and micro-Hutchinson signs, and nail dystrophy. Granular pigmentation, a newly defined dermoscopic criterion, was found in 40% of melanomas and only in 3.51% of benign lesions. CONCLUSIONS: Dermoscopic examination of longitudinal melanonychia provides useful information that could help clinicians to improve melanoma recognition.

Grading keratinocyte atypia in actinic keratosis: a correlation of reflectance confocal microscopy and histopathology.

BACKGROUND: Actinic Keratosis (AK) is the clinical manifestation of cutaneous dysplasia of epidermal keratinocytes, with progressive trend towards squamous cell carcinoma. OBJECTIVE: To evaluate the strength of the correlation between keratinocyte atypia, as detected by Reflectance Confocal Microscopy (RCM) and histopathology, and to develop a more objective atypia grading scale for RCM quantification, through a discrete ranking. METHODS: A total of 48 AKs and two control areas (photodamaged and non-photodamaged skin) were selected for this study. All these areas were documented by RCM and biopsied for histopathology. One representative image of the epidermis was selected for RCM and for histopathology and used for side-by-side comparison with purpose written software. The assessor chose which of two images displayed more keratinocyte atypia, and an ordered list from the image showing the least to the most keratinocyte atypia was generated. Three evaluations were obtained for RCM and two for histopathology. RESULTS: Good interobserver correlation was obtained for RCM and histopathology grading, with high concordance between RCM and histopathology grading. CONCLUSIONS: Expert rater scan consistently distinguish different grades of cytological atypia. Non-invasive RCM data from in vivo imaging can be graded for keratinocyte atypia, comparable to histopathological grading.

Melanoma and naevi with a globular pattern: confocal microscopy as an aid for diagnostic differentiation.

BACKGROUND: Dermoscopically, one of the most common findings in melanocytic lesions is a globular pattern. A regular globular pattern is a common finding in naevi. Melanoma can also show a globular pattern, with globules typically irregular in size, colour and distribution. OBJECTIVES: To investigate the likelihood of diagnosing melanoma according to distinct dermoscopic and confocal aspects. METHODS: Dermoscopic and confocal aspects of 83 excised melanocytic lesions dermoscopically showing globules were analysed. RESULTS: Our study population included 39 acquired melanocytic naevi, 16 Spitz naevi and 28 melanomas. Univariate analysis showed that regular distribution of globules on dermoscopy is associated with a ninefold lower risk for melanoma, whereas an irregular distribution is associated with an almost 10-fold increased risk for melanoma. Concerning confocal features, dense nests are associated with a fivefold lower risk for melanoma, whereas loosely arranged nests are associated with an almost sixfold risk for melanoma; moreover, the presence of round cells is associated with a 17-fold lower risk for melanoma, whereas pleomorphic cells are associated with an almost 16-fold risk for melanoma. CONCLUSIONS: So that melanoma is not missed, clinicians should carefully analyse globular lesions in adults, focusing, in particular, on the distribution of globules and on the presence of confocal cytological atypia.

Dermoscopy uncovers clinically undetectable pigmentation in basal cell carcinoma.

BACKGROUND: The presence of pigmentation might influence the management of basal cell carcinoma (BCC), with pigmented BCC responding poorly to certain treatments. Clinical studies report on a generally lower frequency of pigmentation compared with dermoscopic and histopathological studies, but the true frequency at which pigmentation occurs in clinically nonpigmented BCC has not been studied in detail. OBJECTIVES: To compare the clinical and dermoscopic frequency of pigmentation in a series of histopathologically diagnosed BCCs and to correlate it with patient demographics, tumour location and histopathological subtype. METHODS: Clinical and dermoscopic images of histopathologically confirmed BCCs were retrospectively evaluated for the presence of pigmentation. Dichotomous outcome variables were clinically pigmented and dermoscopically pigmented BCC. All separate dermoscopic variables were included in the analysis. Differences in proportions were evaluated using Pearson's chi-square test. RESULTS: Five hundred and seven BCCs from 507 patients with a mean age of 67 years and a male-to-female ratio of 1.35 : 1 were included in the study. Clinically, 295 tumours were judged as nonpigmented. Of those, dermoscopy disclosed pigmentation in 88 cases (29.8%). Overall, blue-grey ovoid nests were the most frequent dermoscopic pattern (n = 184, 36.3%), followed by multiple blue-grey dots/globules (n = 147, 29%) and maple-leaf-like areas (n = 70, 13.8%). Superficial tumours exhibited mainly maple-leaf-like areas, spoke-wheel areas and brown dots, whereas pigmented nodular BCC was most frequently typified by the presence of blue-grey ovoid nests. CONCLUSIONS: Dermoscopy allows detection of pigmentation in about 30% of clinically nonpigmented BCCs, providing additional information that may aid the clinical choice of adequate treatment modalities.

Hyporeflective pagetoid cells: a new clue for amelanotic melanoma diagnosis by reflectance confocal microscopy.

BACKGROUND: Amelanotic melanoma represents a diagnostic challenge both clinically and dermoscopically. Few studies based on case series have explored the possibility of using reflectance confocal microscopy (RCM) to diagnose amelanotic melanoma. OBJECTIVES: To validate a new confocal feature, named hyporeflective pagetoid cells (HPCs), for the diagnosis of amelanotic melanoma. METHODS: A group of 20 amelanotic melanomas and a control population of nonpigmented melanocytic naevi (10), hypo/nonpigmented nonmelanocytic lesions (20) and pigmented melanomas (20), imaged by RCM, were retrospectively evaluated. The presence of HPCs and other diagnosis-specific confocal features was assessed and correlated with histopathology. RESULTS: HPCs were present, and usually abundant, in the majority of amelanotic melanomas (85%). As expected, they were also observed in Spitz naevi. On histopathology, they were correlated with pagetoid infiltration of hypomelanotic melanocytes in all melanocytic lesions. Few nonmelanocytic lesions (three squamous cell carcinomas, two seborrhoeic keratoses and one basal cell carcinoma) showed the presence of HPCs. In these cases, they corresponded to enlarged or dyskeratotic keratinocytes by histopathology. CONCLUSIONS: The identification of HPCs in the epidermis is a new parameter that is frequently found in amelanotic melanoma. Possible confounders are represented by atypical keratinocytes that can be present in nonmelanocytic lesions. However, the whole architecture and the presence of additional diagnostic criteria should be considered in order to obtain a correct diagnosis.