Benvenuto Giannotti

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.

Primary cutaneous follicular centre‐cell lymphoma—a lymphoproliferative disease with favourable prognosis

In this study the clinico‐pathological and immunohistological features, the methods of treatment and follow‐up data of 11 patients with follicular centre‐cell (B‐cell) lymphoma primarily presenting in the skin are reported. All the patients had nodular, tumorous and/or papulonodular skin lesions on the trunk. In nine patients the disease was confined to a circumscribed area of the back. Small papulonodular or plaque‐like lesions, as well as large nodules or tumours, were biopsied in six of 11 patients. No clear‐cut correlation between the age and clinical morphology of the lesions and their histological growth pattern was found. Interestingly, however, a different immuno‐architectural pattern was observed in large, late lesions compared to small, early lesions. Initial treatment consisted of orthovolt radiotherapy (in two patients associated with surgical excision), resulting in complete remission in all patients. Only one patient developed extracutaneous disease, which was limited to a single drainage lymph node appearing simultaneously with a cutaneous relapse. Five other patients had recurrent disease in the skin close to the initial site. The median disease‐free period was 15·5 months. On relapse, radiotherapy alone or in combination with short courses of chemotherapy was performed. This resulted in a second complete remission. All the patients are still alive and in complete remission, with a median survival of 37 months. These results confirm the favourable prognosis of patients affected with primary cutaneous follicular centre‐cell lymphoma limited to the trunk. Orthovolt radiotherapy proved to be the most suitable treatment for both initial lesions and relapses limited to the skin.

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.

In situ expression of transforming growth factor beta is associated with melanoma progression and correlates with Ki67, HLA-DR and beta 3 integrin expression.

Transforming growth factor-beta (TGF beta), which is secreted by cultured melanoma cells constitutively, inhibits the proliferation of normal melanocytes and of most melanoma cells in vitro, but some melanoma cells from advanced stages of the disease develop resistance to TGF beta-dependent growth inhibition, without developing any change in TGF beta cell surface binding. In vitro TGF beta also downregulates the expression of HLA-DR molecules on melanoma cells, and upregulates the expression of the beta 3 integrin subunit on some cell lines. Immunohistochemical analysis of 53 melanocytic lesions (12 naevi, 30 primary melanomas and 11 metastases) revealed a trend of increasing expression of TGF beta and TGF beta receptor type III with tumour progression, and a significantly higher expression of both TGF beta (P < 0.0001) and the receptor (P < 0.05) in metastatic and thick (> 1 mm) primary melanomas compared with thin (< 1 mm) primary melanomas. The expression of TGF beta correlated with expression of a marker of proliferation, Ki67, and with HLA-DR and beta 3 integrin subunit expression. Coexpression of the four molecules was observed in all metastases and in most thick primary melanomas. These findings argue against an inhibitory effect of TGF beta on cell proliferation or HLA-DR antigen expression in melanoma, and suggest the upregulation of the beta 3 subunit. TGF beta protein appears to be a biological marker of melanoma progression in situ.

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.

Dermatoscopy in the diagnosis of pigmented skin lesions: a new semiology for the dermatologist.

Dermatoscopy or epiluminescence microscopy (ELM), is a noninvasive method that enables clinicians to evaluate fully – by means of a magnified oil immersion diascopy – numerous morphological features, not visible with the naked eye, which enhance the diagnosis of nearly all pigmented skin lesions. In recent years, a burst of research activity in this topic has been carried out, dealing with different aspects, and new frontiers, of this technique. First, a continuous refinement of dermatoscopic terminology is undertaken, paying particular attention to the diagnostic performance of dermatoscopy at peculiar anatomical sites and to the building of different dermatoscopic algorithms aimed at a simplified diagnosis of melanoma, even for less experienced observers. Another point of interest concerns the possible role of dermatoscopy in the pre‐operative assessment of melanoma thickness. Finally, promising data about the role of digital equipment in the follow up of melanocytic skin lesions as well as in the automated diagnosis of pigmented skin lesions have been recently reported. This paper should enable readers to become familiar with the procedure and terminology of ELM in the diagnosis of pigmented skin lesions encouraging a greater understanding of different methods (pattern analysis, algorithms) in the diagnosis of melanoma using ELM.

IMMUNOHISTOCHEMICAL EVIDENCE OF SKIN IMMUNE SYSTEM INVOLVEMENT IN VULVAR LICHEN SCLEROSUS ET ATROPHICUS

Biopsies taken from vulvar lesions in 12 women affected by vulvar lichen sclerosus et atrophicus (LSA) have been processed for immunohistological study. Activated (HLA-Dr+) T cells, associated with CD1a+ accessory cells, were found in the dermis in all cases, with architectural patterns varying in relation to the histological phase (early, well developed, old) of the lesion. Interestingly, the number of epidermal CD1a+ Langerhans cells (LCs) was increased in all cases, without any correlation with the amount of the dermal infiltrate and with the histological phase of the lesions. In fact, also in old lesions the number of epidermal CD1a+ LCs was increased, and the sparse dermal lymphoid cells showed a persistent HLA-Dr antigen expression. These data, indicating the persistent activation of epidermal antigen-presenting cells and lymphoid cells in all the evolutive phases of vulvar LSA, suggest a possible involvement of the skin immune system in the pathogenesis of LSA.

Topical corticosteroids and unwanted local effects. Improving the benefit/risk ratio.

SummaryThe main goal of pharmacological research in the field of topical corticosteroids (TCs) is to dissociate efficacy and adverse effects as much as possible. The optimal use of TCs, i.e. the careful evaluation of the benefit/risk ratio, depends on: (i) the chemical structure of the TC; (ii) the type of vehicle; (iii) the mode of application; and (iv) the features of the skin to be treated. The recent availability of TCs characterised by a good dissociation between efficacy and adverse effects makes the classic and widely used classification system of TCs based upon potency out of date. Indeed, TCs with increasing potency have been characterised up to now, as a rule, by an increasing risk of adverse effects. Therefore, a classification system taking into major account the benefit/risk ratio seems particularly needed for clinical use in dermatology.

Frequency and characteristics of melanomas missed at a pigmented lesion clinic: a registry-based study.

To ensure the removal of all melanomas at an early phase, a number of benign lesions are currently excised for diagnostic evaluation. Nevertheless, little is known about the frequency of melanomas missed (neither recognized nor excised for diagnostic verification) by early detection practices. This study aimed to investigate the diagnostic performance of a specialized pigmented lesion clinic (PLC) through linkage with a local cancer registry. In 1997, 1741 individuals resident in the area of Florence and Prato, Italy, the catchment area of the Tuscany Cancer Registry (RTT), were consecutively examined at a specialized PLC that has been running since 1992 at the Department of Dermatology of Florence. The outcomes of dermatological consultations retrieved from PLC case notes were compared with all the diagnoses of both in situ and invasive melanoma recorded by the RTT until 31 December 1999. The performance of the PLC in detecting cutaneous melanoma was evaluated in terms of sensitivity, specificity and predictive values, with the RTT data as the gold standard. In the population examined at the PLC, 15 newly incident melanomas, all histologically demonstrated, were recorded by the RTT. In 13 of the 15 cases, excision of the lesion had been recommended by PLC staff, while two melanomas, one in situ and one level II 0.60 mm thick invasive, were missed and were subsequently excised 586 and 824 days, respectively, after the first PLC examination. The clinical and dermoscopic features of the invasive lesion were in agreement with a ‘featureless’ melanoma, and lacked the well-established parameters of malignancy. A total of 67 benign pigmented skin lesions were excised for diagnostic evaluation. Thus the PLC showed a sensitivity in detecting cutaneous melanoma of 86.7% (95% confidence interval [CI] 85.1–88.3%), a specificity of 95.4% (95% CI 94.3–96.3%), a positive predictive value of 13.7% (95% CI 12.1–15.3%) and a negative predictive value of 99.9% (95% CI 99.7–100.0%). The ratio of melanomas to benign skin lesions excised was 1:5.1. In conclusion, specialized examination of pigmented skin lesions at the PLC offered good level of diagnostic performance, with an acceptable cost in terms of benign lesions removed and overall a low risk of missing melanomas.