Paolo Carli

Improvement of malignant/benign ratio in excised melanocytic lesions in the ‘dermoscopy era’: a retrospective study 1997–2001

Background  Because of the many limitations of studies based on the diagnostic setting of excised lesions, the impact of dermoscopy (epiluminescence microscopy, dermatoscopy) in melanoma screening during practice remains to be established.

Squamous cell carcinoma arising in vulval lichen sclerosus: a longitudinal cohort study.

Histological changes of lichen sclerosus (LS)—a chronic inflammatory disease—are frequently found in association with squamous cell carcinoma (SCC) of the vulva, suggesting that women with this disorder are at increased risk. However, follow-up studies have been less convincing, showing that the vast majority of these patients do not go on to develop cancer. In this study, a series of 211 women affected by histologically demonstrated vulval LS were treated with topical therapy (testosterone, clobetasol) and followed prospectively by repetitive vulval examination. Three patients developed SCC of the vulva (two invasive, one in situ) at the sites affected by LS during an average follow-up period of 1 year and 8 months. Compared with the reference population, the number of cases of invasive SCC detected significantly exceeded the number estimated to occur in a comparable age-matched group. The standardized incidence rate of vulval SCC in the LS cohort was 317 (95% CI 35.7–1146.2). Cumulative risk was 14.8% (0.06% in the general female population), with a relative risk of 246.6. In conclusion, these data support the view that LS is a precursor of SCC, although characterized by slight tendency to evolve to carcinoma. Medical treatment of LS, although useful in the control of severity of disease, did not seem to be able to prevent the evolution to malignancy.

Multidimensional non-linear laser imaging of Basal Cell Carcinoma

We have used a multidimensional non-linear laser imaging approach to visualize ex-vivo samples of basal cell carcinoma (BCC). A combination of several non-linear laser imaging techniques involving fluorescence lifetime, multispectral two-photon and second-harmonic generation imaging has been used to image different skin layers. This approach has elucidated some morphological (supported by histopathological images), biochemical, and physiochemical differences of the healthy samples with respect to BCC ones. In particular, in comparison with normal skin, BCC showed a blue-shifted fluorescence emission, a higher fluorescence response at 800 nm excitation wavelength and a slightly longer mean fluorescence lifetime. Finally, the use of aminolevulinic acid as a contrast agent has been demonstrated to increase the constrast in tumor border detection. The results obtained provide further support for in-vivo non-invasive imaging of Basal Cell Carcinoma.

Clinical and dermatoscopic criteria for the preoperative evaluation of cutaneous melanoma thickness

BACKGROUND Melanoma thickness measured according to the Breslow method is used to determine surgical margin and in patient selection for sentinel node biopsy. Previous studies did not confirm the reliability of melanoma palpability for clinical prediction of tumor thickness. Recently we reported the usefulness of epiluminescence microscopy (dermatoscopy) for in vivo detection of the phases of melanoma progression, as well as tumor depth. OBJECTIVE Our purpose was to determine whether the combination of clinical and dermatoscopic criteria could increase the accuracy in preoperative evaluation of melanoma thickness with respect to the clinical elevation and dermatoscopic assessments considered separately. METHODS In a blind retrospective study, 122 cutaneous melanomas were studied to evaluate the presence of several clinical and dermatoscopic criteria and their relation with the histologic thickness. An algorithm of combined criteria was constructed and statistically assessed. RESULTS Combinations of palpability, diameter of more than 15 mm, pigment network, gray-blue areas, and atypical vascular pattern allowed correct prediction of thickness in 89% of melanomas when categorized in two groups of less than 0.76 mm and more than 0.75 mm thickness, compared with 75% using palpability, and 80% using dermatoscopic criteria. Lower values were obtained in the further subdivision of melanomas into groups of 0.76 to 1.5 mm and more than 1.5 mm thickness. CONCLUSION The combination of clinical and dermatoscopic criteria is a more precise guide for the preoperative evaluation of melanoma thickness than either is alone. However, further studies are needed to verify its applicability in establishing the surgical approach to cutaneous melanoma.

MC1R variants increase risk of melanomas harboring BRAF mutations.

Melanocortin-1 receptor (MC1R) variants have been associated with BRAF (v-raf murine sarcoma viral oncogene homolog B1) mutations in non-CSD (chronic solar-damaged) melanomas in an Italian and an American population. We studied an independent Italian population of 330 subjects (165 melanoma patients and 165 controls) to verify and estimate the magnitude of this association and to explore possible effect modifiers. We sequenced MC1R in all subjects and exon 15 of BRAF in 92/165 melanoma patients. Patients with MC1R variants had a high risk of carrying BRAF mutations in melanomas (odds ratio (OR)=7.0, 95% confidence interval (CI)=2.1-23.8) that increased with the number of MC1R variants and variants associated with red hair color. Combining these subjects with the originally reported Italian population (513 subjects overall), MC1R variant carriers had a 5- to 15-fold increased risk of BRAF-mutant melanomas based on carrying one or two variants (P<0.0001, test for trend), and regardless of signs of chronic solar damage. In contrast, no association with BRAF-negative melanomas was found (OR=1.0, 95% CI=0.6-1.6). No characteristics of subjects or melanomas, including age, nevus count, pigmentation, and melanoma thickness or location on chronically or intermittently sun-exposed body sites, substantially modified this association, although results could be affected by the small numbers in some categories. This study confirms that the known MC1R-melanoma risk association is confined to subjects whose melanomas harbor BRAF mutations.

Cutaneous melanoma histologically associated with a nevus and melanoma de novo have a different profile of risk: results from a case-control study.

BACKGROUND Histopathologic association between melanocytic nevus and melanoma has been reported in approximately 10% to more than 50% of melanoma cases. Whether melanomas in contiguity with a nevus have a different natural history and pathogenesis from melanomas without a nevus is still to be determined. OBJECTIVE The present study was undertaken to clarify whether melanocytic nevus-associated melanomas (MN[+]) have a different risk factor profile from cases without histopathologic evidence of melanocytic nevus association (MN[-]). METHODS The study population consisted of 131 invasive melanoma cases with a thickness of 4.00 mm or less and 174 control cases without melanomas. The whole series was evaluated for the following risk factors: phenotypic traits; the number of common, atypical, and congenital nevus-like nevi; and freckling and history of sunburns. Melanoma cases were revised for the presence of associated melanocytic nevi. The analysis of risk factors was performed by a case-control approach comparing cases, classified by histologic association with nevus, to the group of controls. Possible differences in risk factor distribution between MN(+) cases and MN(-) cases were evaluated with a polychotomous logistic regression model and a likelihood ratio test for heterogeneity. RESULTS Histopathologic association between melanocytic nevus and melanoma was found in 27 cases (20.6%). Phenotypic traits were shown to be more powerful predictors of risk for MN(-) than for MN(+) cases (blond/red hair; odds ratio, 7.4 and 1.2, respectively; likelihood ratio test for heterogeneity, 4.13; P < .05). Conversely, history of frequent sunburn was a risk factor only in MN(+) cases (more than 5 sunburns; odds ratio, 6.7; 95% confidence interval, 1.3-33.7), but not in MN(-) cases (odds ratio, 1.2; 95% confidence interval, 0.3-4.0; likelihood ratio test for heterogeneity, 4.2; P < .05). Where melanocytic nevi are concerned, an increased number of common nevi was a predictor of melanoma risk in both MN(+) and MN(-) cases, but with a different magnitude of risk, higher for MN(+) cases (number of common nevi, 10-30; odds ratio, 14.4 and 4.7, respectively; likelihood ratio test for heterogeneity, 3.7; P = .055). CONCLUSION This study showed that, although MN(+) and MN(-) melanomas share many risk factors, there is a different strength of association between the 2 groups. The effect of a history of sunburn as a predictor of risk was found only for nevus-associated melanomas, suggesting a possible role of sunburns in the neoplastic transformation of nevi.

The density of melanocytic nevi correlates with constitutional variables and history of sunburns: a prevalence study among Italian schoolchildren.

In several studies from northern Europe, north America and Australia, melanocytic nevi are correlated with pigmentary traits and with intense sun exposure in a way similar to malignant melanoma. However, it is unclear if these data can be extrapolated to populations in other geographic locations and with different prevalent phenotypes. Our study was conducted among schoolchildren aged 13–14 years in 16 Italian cities. The parents of 3,127 children of a total of 3,160 (99%) consented to our study. A structured questionnaire was used to collect information about sun exposure and lifetime history of sunburns. Children were also examined by trained dermatologists to assess pigmentary traits and to make a count of melanocytic nevi. The median nevus density was higher among boys than girls. Areas that are usually chronically exposed to the sun exhibited a higher density of nevi compared to intermittently and rarely exposed areas. A higher density of nevi was found in children with lighter skin, blond hair and blue eyes. Red‐haired children had a remarkably lower nevus density compared to the other color categories. The density of nevi increased with an increased number of reported episodes of sunburns. The results concerning nevi ≥6 mm in diameter paralleled those obtained for the total nevus density. However, at variance with total nevus density, a significant relation was also observed between larger nevi and freckling. Our study confirms that, in Italian schoolchildren, there is a relation between pigmentary traits, history of sunburns and the density of melanocytic nevi. Melanocytic nevi and malignant melanoma share a similar risk factor profile.

Malignant melanoma in Italy: Risks associated with common and clinically atypical melanocytic nevi

BACKGROUND Most epidemiologic studies on risk factors for cutaneous melanoma have been performed in predominantly fair-skinned populations. OBJECTIVE Our purpose was to assess by means of a case-control study the importance of common melanocytic nevi (CMN) and clinically atypical nevi (CAN) as risk factors for cutaneous melanoma in a Mediterranean population. METHODS One hundred six patients with invasive cutaneous melanoma and 109 population control subjects were included in the study. All subjects were younger than 70 years of age and were residents of the Florence area. RESULTS The adjusted odds ratios obtained by exact conditional analysis, accounting for age, sex, place of birth, and residence, were 2.6 (95 confidence interval [CI], 1.0 to 6.7) for 10 to 30 CMN, and 22.3 (CI, 4.8 to 215) for more than 30 CMN (chi 2 for trend, 25.41; p < 0.001), 2.9 (CI, 1.2 to 7.5) for large nevi, and 8.4 (CI, 2.2 to 31.4) for CAN. Tendency to freckle resulted in a twofold increase in risk (odds ratio, 2.2) (CI, 1.0 to 5.2). The relative risk associated with a large number of CMN was statistically significant after adjustment for all other variables. When adjusted for the number of CMN, none of the other variables showed a statistically significant increased risk. CONCLUSION A large number of CMN represents the most important risk factor for cutaneous melanoma in the Italian population. The presence of large nevi and CAN did not result in an increased risk when the number of CMN was considered.

Naevus-associated melanomas: cause or chance?

Controversies exist regarding the true incidence and significance of the histological association between melanocytic naevi and melanomas. The current study was undertaken to determine the incidence of melanocytic naevi histologically associated with melanomas, to compare the clinicopathological profiles of melanomas associated with a naevus (MN+) and melanomas not associated with a naevus (MN-), and to verify the interobserver reliability of classifying the naevus remnants as congenital or acquired. We evaluated 131 patients with invasive melanoma < or = 4 mm in thickness with a Clarks level < V. Histological evidence of an associated melanocytic naevus was found in 27 out of 131 melanoma cases (20.6%). MN+ were significantly more frequent among males compared with MN-(P = 0.002) and were predominantly located on the trunk (P =0.001). No significant differences between MN+ and MN- were found in the distribution of histotype, Clarks level and thickness. Among MN-, the naevus component showed acquired features in 14 cases (51.8%), whereas 12 cases (44.5%) had features of small superficial congenital naevi; in one case (3.7%) a confident distinction between congenital and acquired naevus could not be made. Overall, there was concordance among the three observers in the diagnosis of the type of naevus remnants in 81.4% of cases (kappa = 0.78; P<0.0001). We conclude that, although the majority of cutaneous melanomas arise de novo, in approximately 20% of cases an associated melanocytic naevus is found. Our observation that MN+ and MN- have different clinicopathological profiles suggests that, at least for some cases, a causal relationship between the two lesions may be present. However, when the naevus is histopathologically adjacent to the melanoma, the possibility of a collision event cannot be ruled out. Finally, we documented a significant concordance among examiners in the diagnosis of the congenital versus acquired nature of the associated naevus. This suggests that the histopathological criteria generally employed to distinguish between congenital and acquired naevi have good reproducibility.

Diagnostic significance of the blue hue in dermoscopy of melanocytic lesions: a dermoscopic-pathologic study.

In epiluminescence microscopy, the perception of a blue hue is generally considered a clue to malignancy, especially in clinically equivocal melanocytic skin lesions. However, melanocytic nevi can seldom show a blue hue under dermoscopy. The aim of the current study was to evaluate the histopathologic correlates of the blue hue seen in dermoscopy, to clarify its significance and diagnostic value. From a series of 224 consecutive pigmented skin lesions submitted to surgical excision, we selected all the melanocytic skin lesions (n. 36), blue nevi excluded, characterized by the presence of a blue hue dermoscopically. In agreement with recent refinement of dermoscopic semeiology, all cases were further classified in cases showing blue areas and cases showing blue-whitish veil by experts observers blinded to the final diagnosis. Histopathologically, the series included 23 (63.9%) melanocytic nevi and 13 (36.1%) melanomas. For each lesion, several histopathologic parameters related to both epidermal and dermal alterations were assessed. Blue areas were found in 21 melanocytic nevi and 7 melanomas, whereas blue-whitish veil was found in 6 melanomas and 2 nevi. Careful dermoscopic-histopathologic correlation demonstrated that blue areas are related to the presence of large amounts of melanin pigment, either within melanophages (in the context of areas of regression) or within pigmented melanocytes in the superficial dermis. Conversely, the histopathologic correlate of the blue-whitish veil resulted in the presence of an acanthotic epidermis with compact orthokeratosis overlying large amounts of melanin in the dermis. Such melanin was found not only within melanocytes but also in large clusters of melanophages within areas of regression in the dermis. In conclusion, the majority of melanocytic lesions characterized by the presence of blue areas were histopathologically diagnosed as melanocytic nevi whereas the presence of blue-whitish veil was highly indicative of malignant melanoma diagnosis (specificity 91% vs. 9% of blue areas; sensitivity 75% vs. 25% of blue areas). Thus, these two features of blue hue under dermoscopy cannot be longer considered as synonymous in dermoscopy setting, being associated with different histopathologic alterations and different diagnostic information.