Prognostic role of the histological subtype of melanoma on the hands and feet in Caucasians.

Acral melanoma (AM) is associated with a poor prognosis in part because of delayed diagnosis, but probably also because of other intrinsic characteristics of location. The aim of this study was to review the specific characteristics and outcome of AM in Caucasians. This was a cross-sectional retrospective clinical-pathological study of 274 patients identified with AM in the database of a referral unit in Europe from 1986 to 2010. The mean age of the patients was 56.6 (SD 17.7) years. 269 cases could be histologically classified and included in the study. In all, 222 (82.5%) were located on feet. According to melanoma subtype, 165 (61.3%) were acral lentiginous melanoma (ALM), 84 (31.2%) were superficial spreading melanoma (SSM), and 20 (7.5%) were nodular melanoma (NM). SSM patients were characterized by female predominance (77.4%), younger age, and classic melanoma-risk phenotype (fair skin and multiple nevi). Among the 198 invasive cases with a mean follow-up of 56.2 months, the mean (SD) Breslow's thickness was 3.1 (3.6) mm, being 1.4 (1.4) mm in SSM, 3.5 (4.1) mm in ALM and 4.9 (2.9) mm in NM (P<0.001). Ulceration was present in 33.3%, 2.9% in SSM, 38.6% in ALM, and 76.9% in NM (P<0.001). A total of 29.3% relapsed (7.3% of SSM, 35% of ALM and 55% of NM) and 24.2% died because of AM. In multivariate analysis, age at diagnosis, Breslow, and histopathological subtype were independent prognostic factors for both disease-free and AM-specific survival. The ALM and NM subtypes presented poorer outcome after weighting Breslow and age (P=0.02). Histological subtype of AM could have an impact on biological behavior, ALM and NM subtypes presenting a poorer prognosis after adjusting for age and Breslow's thickness.

Effect of time to sentinel-node biopsy on the prognosis of cutaneous melanoma.

INTRODUCTION: In patients with primary cutaneous melanoma, there is generally a delay between excisional biopsy of the primary tumour and sentinel-node biopsy. The objective of this study is to analyse the prognostic implications of this delay. PATIENTS AND METHOD: This was an observational, retrospective, cohort study in four tertiary referral hospitals. A total of 1963 patients were included. The factor of interest was the interval between the date of the excisional biopsy of the primary melanoma and the date of the sentinel-node biopsy (delay time) in the prognosis. The primary outcome was melanoma-specific survival and disease-free survival. RESULTS: A delay time of 40 days or less (hazard ratio (HR), 1.7; confidence interval (CI), 1.2-2.5) increased Breslow thickness (Breslow ⩾ 2 mm, HR, > 3.7; CI, 1.4-10.7), ulceration (HR, 1.6; CI, 1.1-2.3), sentinel-node metastasis (HR, 2.9; CI, 1.9-4.2), and primary melanoma localised in the head or neck were independently associated with worse melanoma-specific survival (all P < 0.03). The stratified analysis showed that the effect of delay time was at the expense of the patients with a negative sentinel-node biopsy and without regression. CONCLUSION: Early sentinel-node biopsy is associated with worse survival in patients with cutaneous melanoma.

In vivo reflectance confocal microscopy to monitor the response of lentigo maligna to imiquimod.

BACKGROUND: Imiquimod has been used for treating lentigo maligna (LM) in selected cases when surgery is not an appropriate option because of functional or aesthetic impairment. Reflectance confocal microscopy (RCM) is a noninvasive method that has not been validated for monitoring the treatment of LM with imiquimod. OBJECTIVE: We sought to evaluate the use of in vivo RCM to accurately monitor the response of LM to nonsurgical treatment with topical imiquimod. METHODS: Twenty patients with confirmed facial LM, not amenable to surgical treatment or radiation therapy, were included prospectively. Clinical evaluation was performed by dermoscopy, RCM, and histopathology. Patients applied imiquimod 5% for 8 weeks. The affected area was assessed using the previously described LM score on RCM, and target sample biopsies were performed to confirm or discard RCM findings. RESULTS: Fifteen of the 20 patients (75%) presented histologic tumor clearance. Confocal microscopy identified 70% of these responders with no false-negative results, and when compared with histopathology, there was no significant difference in evaluating the response to imiquimod. LIMITATIONS: The impossibility of examining the entire lesion by means of histopathology is a limitation. CONCLUSION: In vivo RCM evaluation was useful in accurately monitoring the response of LM to nonsurgical treatment with topical imiquimod in patients when surgery is contraindicated.

Clinical and Histopathological Characteristics between Familial and Sporadic Melanoma in Barcelona, Spain.

BACKGROUND: About 6 to 14% of melanoma cases occur in a familial setting. Germline mutations in CDKN2A are detected in 20 to 40% of melanoma families. OBJECTIVE: To characterise the clinical and histopathological characteristics of familial melanoma thus providing more information to clinicians and contribute to the understanding of the genetic-environment interplay in the pathogenesis of melanoma. METHODS: Clinical, histological and immunohistochemical characteristics of 62 familial melanomas were compared with 127 sporadic melanomas. RESULTS: variables associated with familial melanoma were earlier age at diagnosis (OR 1.036; 95% CI 1.017-1.055), lower Breslow thickness (OR 1.288; 95% CI 1.013-1.683) and in situ melanomas (OR 2.645; 95% CI 1.211-5.778). Variables associated with CDKN2A mutation carriers were earlier age at diagnosis (OR 1.060; 95% CI 1.016-1.105), in situ melanomas (OR 6.961; 95% CI 1.895-25.567), the presence of multiple melanomas (OR 8.920; 95% CI 2.399-33.166) and the immunopositivity of the tumours for cytoplasmic survivin (OR 9.072; 95% CI 1.025-85.010). CONCLUSIONS: Familial melanoma was significantly associated with the earlier age of onset, lower Breslow thickness and with a higher number of in situ melanomas; and also carriers of CDKN2A mutations were associated with a higher risk of multiple melanomas and cytoplasmic survivin immunostaining.

Ex vivo dermoscopy for biobank-oriented sampling of melanoma.

IMPORTANCE: In the era of targeted therapy for cancer, translational research identifying molecular targets in melanoma offers novel opportunities for potential new treatments. OBJECTIVES: To describe a method for sampling fresh tissue from primary melanoma and to test whether the area of maximal thickness can be identified with dermoscopy to ensure it remains available for routine histopathological diagnosis. DESIGN, SETTING, AND PARTICIPANTS: Tumors clinically suspicious for melanoma with diameter exceeding 5 mm were included. Dermoscopy-guided sampling was performed using a 2-mm to 3-mm punch through not the thickest part of the tumor. In vivo and ex vivo dermoscopic images obtained were available to the diagnosing pathologist. Melanoma samples were obtained in a referral melanoma unit. MAIN OUTCOMES AND MEASURES: In study 1, Breslow thickness in 10 melanomas was compared between sampled tissue and the remaining specimen to confirm that the area of maximal thickness remained available for the histopathological diagnosis. In study 2, forty-three additional melanomas were sampled for biobanking prospectively. Agreement between 2 independent observers on dermoscopic identification of the thickest part of the melanoma was studied. RESULTS: In study 1, the area of maximal Breslow thickness in all 10 melanomas was not sampled and remained in the main specimen. In study 2, sampling was performed by one of the investigators. Concordance was 93% between 2 independent observers for the dermoscopic selection of the thickest portion of the melanoma. Pathologists asserted that the sampling procedure did not compromise their ability to evaluate melanoma specimens. A limitation is that this is a single-center study. Each case required joint evaluation by expert dermoscopists and dermatopathologists. CONCLUSIONS AND RELEVANCE: In applying the dermoscopy-guided sampling protocol, we make the following 5 recommendations: Samples should only be obtained from areas that will not interfere with the pathologist's diagnosis and prognostic information. Sampling should not be obtained from tumors for which one suspects that the histopathological evaluation may prove difficult. Sampling should not be performed on small melanomas; we recommend a minimum diameter of 10 mm. All the dermoscopy-guided sampling should be documented with images, available to pathologists and clinicians, and reflected in the pathology report. Finally, the frozen biobank samples should be made available for routine hematoxylin-eosin histopathological evaluation until the final pathology report is produced. Ex vivo dermoscopy may serve to guide the procurement of small samples from primary melanoma for fresh tissue biobanking without compromising the histopathological evaluation.

Impact of sunscreens on preventing UVR-induced effects in nevi: in vivo study comparing protection using a physical barrier vs sunscreen.

IMPORTANCE: Sun damage is the most important environmental factor associated with malignant melanoma. To address the health threat, as well as the economic burden, primary prevention and early detection are crucial. OBJECTIVE: To test the efficacy of a topical sunscreen in the prevention of UV-induced effects in nevi. DESIGN: Prospective study of nevi protected by sunscreen vs a physical barrier. SETTING AND PATIENTS: Twenty-three nevi from 20 patients attending a referral hospital. INTERVENTION: Half of each nevus was protected by either a physical barrier or a sunscreen. Lesions were completely irradiated by a single dose of UV-B. MAIN OUTCOMES AND MEASURES: In vivo examination before and 7 days after irradiation and histopathologic-immunopathologic evaluation after excision on the seventh day. RESULTS: The most frequent clinical changes after UV radiation were pigmentation, scaling, and erythema; the most frequent dermoscopic changes were increased globules/dots, blurred network, regression, and dotted vessels. Both physical barrier- and sunscreen-protected areas showed some degree of these changes. More than 30% (7) of nevi did not show any change on clinical examination, and 18% (4) had no dermoscopic change. Immunohistopathologic differences between the halves of each nevus were demonstrable even when in vivo examination detected nothing. Parakeratotic scale, increased number and activation of superficial melanocytes, and keratinocyte proliferation were the most remarkable features. The only difference between both barriers was more enhanced melanocytic activation and regression features in the sunscreen group. No phenotypic features were found to predict a specific UV-B response. CONCLUSIONS AND RELEVANCE: Both physical barriers and sunscreens can partially prevent UV-B effects on nevi. Subclinical UV radiation effects, not always associated with visible changes, can develop even after protection. Sunscreens are not quite as effective as physical barriers in the prevention of inflammatory UV-B-induced effects.

Characterization of 1152 lesions excised over 10 years using total-body photography and digital dermatoscopy in the surveillance of patients at high risk for melanoma.

BACKGROUND: The combined use of total-body photography and digital dermatoscopy, named "two-step method of digital follow-up," allowed the detection of incipient melanoma as a result of dermatoscopic or macroscopic changes during follow-up. OBJECTIVE: We sought to assess dermatoscopic features and dynamic changes leading to excision of melanocytic lesions during our 10-year experience of monitoring patients at high risk for melanoma. METHODS: We analyzed 1152 lesions excised during the surveillance of 618 patients at high risk for melanoma from 1999 to 2008. RESULTS: A total of 779 excised lesions had been previously recorded: 728 were removed because of dermatoscopic changes during follow-up and 51 were removed even though no significant change was noted. The remaining 373 excised lesions were new or undetected on previous total-body photography. A total of 98 melanomas were detected, 60 in the monitored lesions, and 38 among the "new" lesions. The most frequent dermatoscopic changes detected were asymmetric enlargement in almost 60% (n = 418), focal changes in structure in 197 (27%) and in pigmentation in 122 (17%), the latter two being more frequently seen in melanomas than in nevi (both P < .001). No significant differences were detected between dermatoscopic or histopathological characteristics of the melanomas in each group, with a considerable proportion of melanomas misclassified as benign in both groups (26.3% and 38.3%, respectively). LIMITATIONS: The dermatoscopy pattern of stable lesions and the histopathology of lesions not removed were not included in the study. CONCLUSION: The most frequent dermatoscopic features associated with melanoma were focal change in pigmentation or structure. Melanomas detected by dermatoscopic changes were remarkably similar to those detected in total-body photography. Almost 40% of melanomas diagnosed in individuals at high risk corresponded to lesions that were not under dermatoscopic surveillance.

Pigmented spindle cell nevus: clues for differentiating it from spindle cell malignant melanoma. A comprehensive survey including clinicopathologic, immunohistochemical, and FISH studies.

Pigmented spindle cell nevus (PSCN), also known as Reed nevus, is a distinctive melanocytic tumor that can show worrisome clinical and histologic features mimicking a malignant melanoma. From a series of 46 pigmented spindle cell melanocytic lesions, including 22 PSCN and 24 spindle cell malignant melanomas (SCMMs), we collected clinical and histopathologic characteristics and evaluated cell cycle and apoptosis regulators by immunohistochemistry. Moreover, fluorescence in situ hybridization (FISH) using probes targeting 6p25 (RREB1), 11q13 (CCND1), 6q23 (MYB), and centromere 6 was performed. PSCN presented in younger people, frequently in women, and were small lesions under 7 mm in diameter affecting the lower limbs, whereas SCMMs arose more frequently in the trunk, upper limbs, and head and neck region. Histologically, symmetry, good lateral demarcation, and uniformity of cellular nests were significantly differential features of PSCN, whereas pagetoid and adnexal spread were frequently seen in both tumors. Immunohistochemical markers that significantly differed from melanomas were Ki-67, cyclin D1, and survivin. FISH was positive in 1 of 15 PSCN and was negative in 4 of 15 SCMMs. These results correlated to a sensitivity of 73% and a specificity of 93%. In conclusion, in the evaluation of pigmented spindle cell melanocytic tumors, the integration of clinical and histologic assessment is essential. However, ancillary techniques such as proliferation antigen Ki-67, cyclin D1, survivin, and FISH can be useful as adjunctive tools.

Early stages of melanoma on the limbs of high-risk patients: clinical, dermoscopic, reflectance confocal microscopy and histopathological characterization for improved recognition.

Early stages of 36 melanomas on limbs were morphologically characterised. Most occurred in high-risk patients (multiple and/or familial melanoma) attending a referral unit for melanoma and pigmented lesions. None of the tumours was clinically suspicious for melanoma (mean diameter of 4.3 mm). The tumours were classified into four dermoscopic groups: (i) prominent network (n = 16); (ii) delicate network (n = 5); (iii) hypo-pigmentation with dotted vessels (n = 10); and (iv) diffuse light pigmentation with perifollicular pigmentation (n = 5). Confocal microscopy performed in 12 cases allowed the identification of atypical, single cells within epidermal layers. Histopathology showed marked large atypical cells in a pagetoid spreading pattern in most cases. Significant associations were detected between the third dermoscopic group and naevoid histological appearance and delay in detection, and between the fourth group and lentigo-maligna-like features. Dermoscopy allowed an increase in the suspicious threshold in these difficult melanomas in high-risk patients and enabled the subclassification of early melanomas on the limbs, with a correct confocal and histopathological correlation. Although the biological behaviour of these incipient tumours remains uncertain, the most appropriate treatment seems to be recognition and proper excision.

Adult xanthogranuloma mimicking basal cell carcinoma: dermoscopy, reflectance confocal microscopy and pathological correlation.

Juvenile xanthogranuloma in adulthood is an infrequent non-Langerhans cell histiocytosis, which may simulate malignant tumors such as basal cell carcinoma (BCC) or amelanotic melanoma. Dermoscopy has been described as a useful tool in the preoperative diagnosis of xanthogranuloma. We report a xanthogranuloma on the suprapubic area of a 48-year-old female, which clinically and dermoscopically mimicked a BCC with a yellowish hue and arborizing vessels. Reflectance confocal microscopy exhibited large highly refractive atypical cells in the dermis, some of them with pleomorphic nuclei, corresponding to Touton cells in the histopathological study. To our knowledge this is the first description of the clinical, dermoscopic and confocal microscopy correlations of a xanthogranuloma.

Alveolar soft part sarcoma presenting with cutaneous metastases: report of a case with immunohistochemical and molecular characterization.

Alveolar soft part sarcoma (ASPS) is an uncommon neoplasm of uncertain histogenesis that usually behaves as a painless, slow-growing mass that metastasizes early. We report a 21-year-old woman with cutaneous metastases of ASPS, whose histologic characteristics gave rise to a wide range of differential diagnoses of both primary and metastatic cutaneous neoplasms. The tumor failed to show a characteristic immunoprofile using routine immunohistochemical procedures, but was strongly and diffusely positive for the TFE3 antibody. The molecular study identified a type 2 alveolar soft part locus-transcription factor E3 (ASPL-TFE3) fusion, secondary to der(17)t(X;17)(p11.2;q25) translocation. A computed tomography scan performed after the diagnosis was made disclosed a 13-cm primary tumor in the left buttock. Cutaneous metastases presenting as the first sign of ASPS have not been reported previously. We emphasize the difficulties in making the diagnosis of ASPS when it presents in an unusual manner.

Development of a two-step method for the diagnosis of melanoma by reflectance confocal microscopy.

BACKGROUND: Reflectance confocal microscopy (RCM) has been shown to improve accuracy in the differentiation of nevus from melanoma, but only a few studies have evaluated both melanocytic lesions (ML) and non-ML. OBJECTIVE: We sought to develop an algorithm for the in vivo diagnosis of skin tumors by RCM. METHODS: In 143 patients we evaluated 154 skin tumors (100 melanocytic, 54 nonmelanocytic) by RCM before their excision. We analyzed RCM features on stored images and performed univariate and multivariate analyses to determine the association of RCM features with tumor types. RESULTS: Four confocal features differentiated ML from non-ML: cobblestone pattern of epidermal layers, pagetoid spread, mesh appearance of the dermoepidermal junction, and the presence of dermal nests. Within ML, the presence of roundish suprabasal cells and atypical nucleated cells in the dermis was associated with melanoma, and the presence of edged papillae and typical basal cells was associated with nevi. Based on the correlation of RCM features with dermatoscopy and histology, we developed a two-step algorithm for the diagnosis of skin tumors by RCM. LIMITATIONS: This is a preliminary study, and the results must be validated in further studies with a larger number of cases. CONCLUSION: RCM appears to be helpful in improving the presurgical diagnosis of difficult skin tumors.

In vivo microscopic features of nodular melanomas: dermoscopy, confocal microscopy, and histopathologic correlates.

OBJECTIVE: To characterize nodular melanoma (NM) using dermoscopy, in vivo reflectance-mode confocal microscopy, and histopathologic analysis. DESIGN: Consecutive pure NMs and superficial spreading melanomas (SSMs) with nodular or blue areas were studied using dermoscopy and confocal microscopy, and a correlation with histopathologic findings was performed. MATERIALS: Ten NMs, 10 SSMs with a nodular area, and 10 SSMs with a blue palpable but not yet nodular area. MAIN OUTCOME MEASURE: Confocal differences within the nodular component between pure NMs and SSMs with a nodular area, hypothesizing different biological behaviors. RESULTS: Whereas NMs had predominantly nonspecific global dermoscopic patterns, SSMs exhibited a multicomponent pattern and higher dermoscopic scores. Globules, blue-white veil, atypical vessels, and structureless areas were frequent in NMs and in nodular areas from SSMs. At confocal microscopy, NMs exhibited few pagetoid cells within a typical epidermal architecture in the superficial layers in most cases, differing from SSMs frequently characterized by epidermal disarrangement and pagetoid infiltration. At the dermoepidermal junction, dermal papillae were rarely seen in nodular areas both from NMs and from SSMs, frequently substituted by nonaggregated atypical cells distributed in sheetlike structures. In the upper dermis, all groups exhibited plump bright cells, dense dishomogeneous cell clusters, and atypical nucleated cells, whereas cerebriform clusters were characteristic of NMs. Conclusion Distinctive dermoscopic and confocal features seen in NMs compared with SSMs are helpful in making the diagnosis and suggest different biological behavior.

Development of a human in vivo method to study the effect of ultraviolet radiation and sunscreens in melanocytic nevi.

BACKGROUND: Ultraviolet radiation (UVR) plays an important role in the development of melanocytic lesions. Sunscreens have shown an impact in the prevention of UVR damage; however, their role in melanocytes has not been well established. The aim was to design and validate an in vivo human model to study the influence of UVR and sunscreen protection on nevi. METHODS: A model describing clinical, dermoscopic, histopathological and molecular changes after UVR with or without protection was elaborated. Two UVB minimal erythema doses were irradiated on 4 nonsuspicious nevi from 4 patients; previously one half of each lesion was protected, in 2 cases with a physical opaque material and in the other 2 lesions by applying a high physical and chemical protection sunscreen (containing octocrylene, Parsol 1789, titanium dioxide, Mexoryl SX, Mexoryl XL). Lesions were excised 7 days afterwards. RESULTS: After 7 days, clinical and dermoscopic changes (more pigmentation, erythema, dotted vessels, blurred network) were noted comparing the lesions before and after irradiation, especially when comparing both sides of each nevus (protected and nonprotected). Histopathological and immunohistochemical studies demonstrated marked melanocytic activation on nonprotected areas and a high proliferation index of keratinocytes. Both physical and sunscreen protections seem to avoid these changes. CONCLUSION: A useful and secure human model to study the UVR influence, and efficacy of sunscreens, on melanocytic lesions was developed. In vivo and ex vivo differences between irradiated nevus versus irradiated nevus plus sunscreen or physical protection were found.

Dendritic cells in pigmented basal cell carcinoma: a relevant finding by reflectance-mode confocal microscopy.

BACKGROUND: Reflectance-mode confocal microscopy (RCM) is a new approach for the in vivo diagnosis of skin tumors. A few studies of RCM on basal cell carcinoma (BCC) have provided specific diagnostic criteria, but large studies on pigmented basal cell carcinoma are lacking. Proliferation of large dendritic-shaped cells within a melanocytic tumor has been associated with the diagnosis of melanoma by RCM. Benign melanocytes and Langerhans cells may populate BCC according to previous histological studies. We studied 3 consecutive pigmented BCC by means of RCM and performed a histological and immunohistochemical correlation focusing on the presence of dendritic structures. OBSERVATIONS: Reflectance-mode confocal microscopy revealed highly refractive dendritic structures within tumor nests that correlated with the presence of melanocytes within the tumor by immunochemical analysis. In 1 case, dendritic structures on the overlying epidermis corresponding to Langerhans cells were also noted. Leaf-like areas observed on dermoscopy correlated with low-refractive cordlike structures and nodules by RCM and corresponded to nests of basaloid cells, whereas blue-gray globules presented as bright oval structures with ill-defined borders corresponding to melanophages. CONCLUSIONS: Reflectance-mode confocal microscopy allows the study of pigmented BCC and the identification of specific criteria described previously. In these tumors, dendritic melanocytes can be easily identified with this technique.

Seborrheic keratosislike melanoma with folliculotropism.

BACKGROUND: Seborrheic keratosislike melanoma could be one of the most problematic melanoma simulators, and it may be incorrectly treated by electrocautery or cryotherapy. Dermoscopic examination of pigmented tumors improves the diagnostic accuracy in these challenging lesions. In these tumors, numerous comedolike openings are present. OBSERVATIONS: A 34-year-old man was seen for a conspicuous pigmented lesion on his back that clinically resembled a seborrheic keratosis because of the presence of multiple comedolike openings. Findings from dermoscopic examination showed distinct melanoma criteria (atypical pigmented network, asymmetric globules and dots, and a blue-whitish veil), in addition to multiple comedolike openings. Histopathological examination confirmed a peculiar melanoma variant characterized by prominent folliculotropism and minimal radial spreading. This tumor was not associated with chronic sun-damaged skin. CONCLUSION: Dermoscopy was useful in identifying a particular case of seborrheic keratosislike melanoma with folliculotropism, thus avoiding incorrect treatment.