Umberto Maria Reali

Osteonectin expression correlates with clinical outcome in thin cutaneous malignant melanomas

Osteonectin, also termed BM40 or SPARC (secreted protein, acidic and rich in cysteine) is a multifunctional glycoprotein involved in tissue mineralization, cell-extracellular matrix interactions as well as angiogenesis. It has been suggested that osteonectin may play a key role in the process of tumoral invasion and metastasis in certain malignancies. In this study, we reviewed the clinical records and the histopathologic slides of 188 thin cutaneous malignant melanomas (< or = 0.75 mm). Among them, 12 cases underwent progression and were selected for the study. Osteonectin expression was investigated by immunohistochemistry in these 12 patients and 24 matched controls who did not undergo progression. Osteonectin staining was correlated with clinical outcome and other clinicopathologic parameters. Progression-free and disease-specific survival rates were calculated with the Kaplan-Meier method and their differences were evaluated by the log rank test. Overall, immunoreactivity for osteonectin was found in 23 (63.8%) cases. Eighteen cases (50%) displayed staining in 1% to 50% of neoplastic cells whereas five cases (13.8%) showed a diffuse positivity in more than 50% of the tumor cells. Osteonectin expression was significantly correlated with risk of progression (P = .01), incidence of distant metastases (P = .005) and survival (P = .03). There was a higher incidence of osteonectin-positive tumors in cases that did experience regional lymph node metastases versus those cases that did not, but that difference did not reach statistical significance (P = .06). No significant correlation was found between osteonectin expression and other clinicopathologic features, including age, sex, site, histotype, Clarks level, presence of regression, presence of inflammatory response, and tumor growth phase. Our data showed that osteonectin expression is a predictor of clinical outcome in thin cutaneous melanomas.

Inducible nitric oxide synthase expression in benign and malignant cutaneous melanocytic lesions.

Nitric oxide (NO) is synthesized by nitric oxide synthases (NOS) and plays an important role in tumour growth. In this study, inducible NOS (iNOS) expression was evaluated by immunohistochemistry in 34 melanocytic naevi (13 common melanocytic naevi, six Spitz naevi, and 15 so‐called ‘dysplastic naevi’), ten cutaneous melanomas in situ, 50 stage I invasive melanomas, and eight subcutaneous metastases of melanoma. In addition, four samples of melanocytic naevi and four samples of invasive melanomas were collected in order to perform western blot and northern blot analysis. By immunohistochemistry, melanocytic naevi never expressed iNOS. Among cases of melanoma in situ, two were negative, seven displayed staining in less than 20% of melanoma cells, and positivity was observed in 21–50% of melanoma cells in only one case. iNOS expression was detected in 46 out of 50 invasive melanomas (92%). Among these cases, 18 showed positivity in less than 20% of melanoma cells, 18 showed positivity in 21–50% of melanoma cells, and ten showed iNOS expression in more than 50% of cells. Statistical analysis revealed a significant difference in iNOS expression between melanocytic naevi and cutaneous melanomas (p<0.001). In addition, iNOS expression was significantly higher in invasive melanomas than in melanomas in situ (p=0.01). Among primary cutaneous melanomas, no significant correlation was found between iNOS expression and histopathological parameters (histotype, level, thickness and presence of regression/inflammatory infiltrate) and disease‐specific survival. In subcutaneous melanoma metastases, iNOS expression was diffuse in more than 50% of cells. Statistical analysis revealed that subcutaneous melanoma metastases showed greater iNOS immunoreactivity than invasive melanomas (p=0.02). Molecular analyses confirmed that iNOS mRNA and protein were highly expressed in melanoma samples. In conclusion, iNOS was constantly absent in melanocytic naevi, whereas it was frequently expressed in melanomas, with up‐regulation of the enzyme paralleling tumour progression. These data suggest that iNOS may play a role in the malignant transformation of melanocytes and in tumour growth. In addition, iNOS may be useful as an immunohistochemical marker for malignant melanocytic lesions. Copyright

FIRST RECURRENCE ANALYSIS OF 840 CUTANEOUS MELANOMAS : A PROPOSAL FOR A FOLLOW-UP SCHEDULE

Aims and background A correct follow-up schedule for patients who underwent an excision for stage I cutaneous melanoma might allow the early detection of local and distant metastases. At present, there is no general agreement on follow-up protocols. In order to work out a follow-up guide, we have retrospectively evaluated the records of 840 stage I cutaneous melanoma patients surgically treated and followed during the postoperative period in the Division of Plastic Surgery of the University of Florence from 1975 to 1992. Methods We evaluated the patients’ records by analyzing time, pathway and site of any first recurrence in relation to the main prognostic factors such as patient sex, site, histological type and depth of invasion of each primary melanoma. A statistical analysis was performed. Results To summarize, the salient results were the following: 80% of relapses occurred in the first 3 years and they occurred significantly earlier when the primary melanoma was localized in the trunk and significantly later when the melanoma was localized in the lower limbs and for < 1.5 mm lesions. The first recurrence occurred earlier by the lymphatic than by the hematic pathway regarding the overall number of patients. The hematic pathway was the most frequent (with respect to the overall percentage of hematic metastases) for the melanomas localized in the head and neck region and for lentigo malignant melanomas, whereas the lymphatic pathway was most frequent for melanomas of the lower limbs and > 3 mm in thickness. Conclusions We suggest a follow-up schedule taking into consideration the postoperative behavior of stage I cutaneous melanoma patients (in terms of time and pathway of the first recurrence) in relation to the site and depth of invasion of the tumor.

Thick cutaneous malignant melanoma: a reappraisal of prognostic factors.

&NA; The prognosis of patients with thick (> 3 mm) cutaneous malignant melanomas is generally poor; however, some cases survive far longer than expected. Thus tumour thickness cannot serve as the only predictor of disease course in the individual patient. The aims of the current study were to evaluate the clinical outcome of patients with thick (> 3 mm) cutaneous melanoma and test the prognostic value of a series of clinicopathological parameters on disease‐free and cause‐specific survival. We retrospectively evaluated 140 patients with stage I cutaneous melanoma > 3 mm in thickness. Disease‐free and cause‐specific survival rates (Kaplan‐Meier method) were compared using the log rank test. A multivariate analysis (Cox proportional hazards model) was used to determine the independent effect of each variable on prognosis. The overall 5‐year and 10‐year disease‐free survival rates were 35.5% and 29.3%, respectively, whereas the overall 5‐year and 10‐year cause‐specific survival rates were 55.3% and 47.7%, respectively. In the univariate analysis, the following factors were found to be significantly associated with the disease‐free and cause‐specific survival: tumour thickness, mitotic rate/mm2, type of invasive front, ulceration, thickness of the nodular component and predominant cell type. In addition, the presence of vascular invasion was significantly correlated with the risk of metastases but not with survival. In the multivariate analysis (Cox proportional hazards model), only tumour thickness (both as a continuous variable and > 7.5 mm), infiltrating invasive front, presence of ulceration and mitotic rate/mm2 (both as a continuous variable and > 10 mitoses/mm2) were significant independent predictors of poorer clinical outcome.

Spatial association of melanocytic naevus and melanoma

A series of 233 consecutive primary cutaneous melanomas was histologically and clinically studied. Histologically, 53 melanomas (22.7%) were associated with naevus cells. Such a high degree of association suggests that melanocytic naevus may be a precursor of a large number of melanomas. Analysing the cases according to Clarks levels and Breslows index, a decrease in the naevus-melanoma association was seen with tumour progression, suggesting that advanced tumours may overgrow pre-existing nevus cells, appearing as de novo melanomas. The comparison between histological and clinical data suggest some interpretations of the natural history of melanoma.

Incidence of cutaneous melanoma in the centre of Italy: anatomic site distribution, histologic types and thickness of tumour invasion in a registry-based study.

The majority of epidemiological data on cutaneous melanoma (CM) derives from studies carried out in a predominantly fairskinned population. On the contrary, little is known of the epidemiological figures (including incidence data) in mediterranean populations. The aim of this study was to investigate the incidence rates of CM in a geographically-defined area of the centre of Italy, with particular attention to anatomic site distribution, histologic types and thickness of tumour invasion. After revision of the data base of the Tuscany Cancer Registry concerning the period 1985 to 1987, 282 incident cases of invasive CM (135 males, 147 females) were found in a resident population of 1,174,121 inhabitants. The mean annual age-standardized rates were 6.7/100,000 for males and 7.0/100,000 for females. Site-specific incidence rates showed an almost three-fold higher incidence of CM of the trunk In males than females (3.7/100,000 vs 1.4/100,000). Conversely, a four-fold higher incidence in females than in males was observed for the lesions of lower limb (2.1/100,000 vs 0.5/ 100,000). A statistically significant difference of Incidence rates was also observed for the thigh (females 1.1/100,000, males 0.2/100,000), a normally sun-exposed area. Concerning histologic types of CM, the incidence of the nodular type was higher in males than in females (1.8/100,000 vs 1.3/100,000), even if the difference was not statistically significant in any class of age. The most interesting finding of this study was related to the difference of the thickness of tumour invasion between sexes at the time of diagnosis: lesions with favourable prognosis (less than 0.75 mm in thickness) were more frequent in females than in males (1.4/100,000 vs 0.3/100,000); on the other hand, incidence rates of poor prognosis CM (> 3.0 mm) were higher in males than In females (2.1/100,000 vs 1.0/100,000). This study shows that in mediterranean populations the specific incidence rates for age and anatomic site are similar to a predominantly fair-skinned population, whereas the overall incidence is lower. In respect of the peculiarity of each sex, the striking difference between males and females of the thickness of tumour invasion at diagnosis should be considered to better tailor further information for secondary prevention.

The Use of High Resolution Ultrasound in Preoperative Evaluation of Cutaneous Malignant Melanoma Thickness

High resolution ultrasound (HRUS) was tested in 58 cutaneous malignant melanomas to check its validity in evaluating tumor thickness in vivo before surgery. The values obtained with this method were compared with histologic values (measured according to Breslow); a highly significant correlation was found (r = 0.895, p < 0.001). The accuracy of HRUS in distinguishing between low- and high-risk cutaneous malignant melanoma was also found to be quite high. Our data therefore justify the use of such a technique in the preoperative staging procedure.

BANS: a discussion of the problem.

The significance of the BANS location (upper Back, posterior Arm, Neck and Scalp) as a prognostic factor in patients with stage I melanoma is controversial. A meta-analysis performed by Weinstock et al. on their own and five comparable studies corroborated the hypothesis that this location is influential in the prognosis of intermediate thickness (0.76–1.69 mm) melanomas. Our study investigated the relationship between BANS subsites, thickness and prognosis in 1,082 stage I melanoma patients from two major Italian centres, Turin and Florence. A BANS primary was observed in 212 (19.5%) patients: recurrences occurred in 85 of them (40.1%) vs 309/870 non-BANS patients (35.5%). Overall survival probabilities were significantly shorter (p < 0.01) in the BANS group (69.1% vs 76.7% at 5 years; 59% vs 68.5% at 10 years). The prognostic value of the BANS location was confirmed by a multivariate analysis using the Cox proportional hazards model. Stratification of BANS and non-BANS groups by thickness clusters showed a significant difference in both survival (p < 0.001) and disease-free interval (p < 0.05) in the 3.01–4.00 mm thickness subset, due to the greater incidence of distant and visceral metastases. In the 0.76–1.69 mm thickness range the significance was p = 0.06.

Malignant melanoma associated with human immunodeficiency virus infection: a case report and review of the literature.

A case of malignant melanoma arising in a young patient suffering from human immunodeficiency virus (HIV) infection is reported, along with a review of the literature. The neoplasm was characterized by aggressive clinical behaviour and, histopathologically, by a peculiar retiform pattern of growth with neoplastic cells interspersed among collagen bundles in the dermis without evident fibroplastic stromal reaction. In addition, a complete absence of host inflammatory cell infiltrate was noted. We hypothesize that this unusual histopathological pattern of growth, which has never been reported in this clinical setting, might be associated to HIV disease, immunosuppression and poor clinical outcome.

Reconstruction of a Medial Canthus Defect with a Myocutaneous Flap

Defects in the inner canthal area are generally repaired by full-thickness skin grafts, V-Y advancement flap, or frontal flap. Each of these techniques may give some problems in restoring the functional or aesthetic features of that region, or both. To avoid these inconveniences, we performed the reconstruction of the medial canthal area after tumor excision by using a myocutaneous rotation flap from the upper lid joined to a rotation flap from the lower lid and cheek. No scar resulted inside the aesthetic unit and a fine result was achieved from both the functional and the aesthetic point of view.