Francesca Passarelli

Tumor-infiltrating lymphocytes predict cutaneous melanoma survival.

Understanding differences in survival across distinct subgroups of melanoma patients may help with the choice of types of therapy. Tumor-infiltrating lymphocytes (TILs) are considered a manifestation of the host immune response to tumor, but the role of TILs in melanoma mortality is controversial. The aim of this study was to investigate independent prognostic factors for melanoma mortality. We carried out a 10-year cohort study on 4133 melanoma patients from the same geographic area (Lazio) with primary cutaneous melanoma diagnosed between January 1998 and December 2008. The probability of survival was estimated using Kaplan–Meier methods and prognostic factors were evaluated by multivariate analysis (Cox proportional hazards model). The 10-year survival rate for melanoma decreased with increasing Breslow thickness (Pfor trend<0.0001) and with age (Pfor trend<0.0001) whereas survival increased with increasing levels of TILs (Pfor trend=0.0001). The 10-year survival rate for melanoma divided into TILs intensity as scanty, moderate, and marked was 88.0, 92.2, and 97.0%, respectively. In the multivariate Cox model, the presence of high levels of TILs in primary invasive melanomas was associated with a lower risk of melanoma death (hazard ratio 0.32; 95% confidence interval 0.13–0.82) after controlling for sex, age, Breslow thickness, histological type, mitotic rate, and ulceration. After including lymph node status in the multivariate analysis, the protective effect of marked TILs on melanoma mortality remained (hazard ratio 0.37; 95% confidence interval 0.15–0.94). The results of this study suggest that the immune microenvironment affects melanoma survival.

Interleukin-17 and interleukin-22 promote tumor progression in human nonmelanoma skin cancer.

Interleukin‐17 (IL‐17) and IL‐22 have been reported to play critical roles in autoimmunity and inflammation but information about their role in cancer is limited. In this study, we investigated the role of IL‐17 and IL‐22 in the progression of human skin basal‐cell carcinoma (BCC) and squamous‐cell carcinoma (SCC). We found that both tumor types are infiltrated with an high number of IL‐17+ and IL‐22+ T lymphocytes, as demonstrated by immunohistochemistry and by FACS analysis performed on peritumoral T‐cell lines isolated from skin biopsies. In vitro studies demonstrated that proliferation and migration of the BCC‐ and SCC‐cell lines M77015 and CAL27 were increased by IL‐17 and IL‐22. Moreover, IL‐17, alone or in combination with TNF‐α, was able to induce the production of two cytokines important for tumor progression, IL‐6 and IL‐8, in CAL27. We also showed that IL‐17 upregulated NF‐κB signaling, while IL‐22 activated the STAT3 pathway and the antiapoptotic AKT protein in M77015 and CAL27. Finally, in vivo experiments demonstrated that IL‐17 and IL‐22 enhanced tumor growth in nude mice injected with CAL27. Altogether, our findings indicate that high levels of IL‐22 and IL‐17 in the BCC and SCC microenvironment promote tumor progression.

Factors associated with large cutaneous squamous cell carcinomas

BACKGROUND Large cutaneous squamous cell carcinoma (SCC) is associated with a higher risk of disfigurement, local recurrence, and metastasis; however, little is known about factors associated with tumor size at diagnosis. OBJECTIVES We sought to evaluate factors associated with SCC size, including diagnostic/treatment delay and patient and tumor characteristics. METHODS We studied a stratified sample of 308 patients with SCC recently treated at a dermatologic referral center in Italy. Medical records were reviewed and telephone interviews conducted. Multiple logistic regression was used to examine factors associated with SCC size. RESULTS With univariate analyses, among both invasive and in situ cases, SCC greater than 2 cm was significantly associated with male gender, tumors arising in chronic lesions, and tumors located on not easily visible sites. Long delay before surgical removal was significantly associated with large SCC size only for invasive SCC (P < .001). Among patients with invasive SCC, when controlling for age and gender, multivariate analysis showed a significantly higher likelihood of SCC greater than 2 cm with a total delay longer than 18 months before surgical removal (odds ratio=4.18; 95% confidence interval 2.45-7.13) and for tumors arising in chronic lesions (odds ratio=6.42; 95% confidence interval 3.13-13.2). LIMITATIONS The study was cross-sectional and based on a single center. CONCLUSIONS Long total delay in removal significantly increased the likelihood of invasive SCC greater than 2 cm. Our findings highlight the importance of early detection and treatment to prevent large invasive SCCs, which are associated with a higher risk of disfigurement, recurrence, and metastasis. Particular attention should be paid to chronic skin lesions and not easily visible body sites during physician- and patient-performed examinations.

Expression of vascular endothelial growth factor-C in primary cutaneous melanoma predicts sentinel lymph node positivity

Vascular endothelial growth factor‐C (VEGF‐C), a lymphatic vessel growth factor, has been involved in the formation of lymph nodal metastases in different tumor types. Early evidences indicate that VEGF‐C expression in human primary melanoma could be predictive of lymph nodal metastases, whereas the role of lymphangiogenesis is still controversial.

Delay in Diagnosis and Treatment of Squamous Cell Carcinoma of the Skin

Advanced squamous cell carcinomas (SCC) of the skin can cause significant tissue destruction and may metastasize. Understanding the determinants of patient delay could help prevent advanced presentation. The purpose of the present study was to examine patient- and healthcare-related factors associated with delay before the detection and treatment of SCC. A sample of 308 patients with SCC treated at a dermatological referral centre in Italy were interviewed. Clinical data were obtained from the medical records. The highest quartile patients reported > 9 months delay between noticing the lesion and the first medical visit (defined as long patient delay). Multivariate analysis showed that SCC arising on pre-existing chronic lesions were associated with long patient delay (odds ratio = 3.17; 95% confidence interval 1.1-9.3). Controlling for confounders, the first physicians advice to remove the lesion immediately was associated with a shorter treatment delay (p < 0.001). In conclusion, our work emphasizes the importance of seeing a doctor about any change in a pre-existing lesion, particularly in light of the fact that SCC on chronic lesions are at greater risk of metastasis and recurrence.

Skin Cancer Knowledge and Preventive Behaviors among Patients with a Recent History of Cutaneous Squamous Cell Carcinoma

Aims: To evaluate skin cancer knowledge and preventive behaviors of patients recently treated for cutaneous squamous cell carcinoma (SCC) and to examine the factors associated with the adoption of preventive behaviors. Methods: Telephone survey on 315 SCC patients treated at a large dermatological hospital in Italy, evaluating skin cancer knowledge, sun protection and skin examination practices as well as medical recommendations received after SCC removal. Results: Skin cancer knowledge was fair/low for 48.9% of the participants. Doctors were the main source of skin cancer information for 24.4% of the patients. Of the patients assessed ≧12 months after SCC removal, 32.7% reported a total skin examination after removal. Of the participants, 41.6% never/rarely used sunscreens. In a multivariate analysis, the likelihood of having complete skin examinations was associated with a doctor’s advice to have an examination (odds ratio, OR = 2.29; 95% confidence interval, CI = 1.2–4.4), a higher knowledge level (OR = 2.05; 95% CI = 1.1–3.8) and past skin examinations (OR = 3.62; 95% CI = 1.9–7.0). Doctor’s recommendations increased the likelihood of adopting preventive behaviors. Conclusions: We found substantial knowledge gaps and limited adoption of skin cancer prevention, highlighting the need for interventions promoting knowledge and preventive behaviors, particularly among higher-risk patients.

DNA repair enzymes and cytotoxic effects of temozolomide: Comparative studies between tumor cells and normal cells of the immune system

Abstract O6-alkylguanine-DNA alkyltransferase (OGAT) and the mismatch repair system (MRS) play a crucial role in the susceptibility of tumor cells to the cytotoxic effects of agents that generate O6-methylguanine in DNA, including the triazene compound temozolomide (TMZ). Studies performed with peripheral blood mononuclear cells (MNC) showed that TMZ was scarcely active on lymphocyte functions not dependent on cell proliferation (e.g. NK activity and cytokine-mediated induction of CD1b molecule in adherent MNC). In contrast, TMZ depressed proliferation and lymphokine activated killer (LAK) cell generation in response to IL-2. In this case, a reasonably good inverse relationship was found between OGAT levels of MNC and their susceptibility to TMZ. This study also analyzed the ratio of the toxic effect of TMZ on MNC and on tumor cells (i.e. “Tumor-Immune Function Toxicity Index”, TIFTI). A particularly favorable TIFTI can be obtained when OGAT levels are extremely high in MNC and markedly low in tumor cells. This holds true for MRS-proficient neo-plastic cells, but not for MRS-deficient tumors. In conclusion, strategies aimed at modulating OGAT and MRS may improve the clinical response to TMZ. However, the use of OGAT inhibitors to potentiate the antitumor activity of TMZ might result in a concomitant increase of the immunosuppressive effects of the drug, thus reducing the relative TIFTI.

High Expression of the Mismatch Repair Protein MSH6 Is Associated With Poor Patient Survival in Melanoma

OBJECTIVES The outcome of patients with primary melanoma (PM) cannot be completely explained based on currently adopted clinical-histopathologic criteria. In this study, we evaluated the potential prognostic value of mismatch repair protein expression in PMs. METHODS We examined the immunohistochemical staining of mismatch repair proteins in 18 benign nevi and 101 stage I to III PMs and investigated their association with tumor clinicopathologic variables and melanoma mortality. RESULTS Expression of MSH2, MLH1, and PMS2 was high in benign nevi and reduced in a subset of PMs. Conversely, MSH6 expression was absent or extremely low in benign nevi and increased in a subset of PMs. In the multivariate analysis, including sex, age, Breslow thickness, and ulceration, high MSH6 expression in PMs (ie, immunostaining in >20% of tumor cells) was significantly associated with an increased risk of melanoma mortality (relative risk, 3.76; 95% confidence interval, 1.12-12.70). CONCLUSIONS MSH6 protein expression can be a valuable marker to improve prognosis assessment in PMs.

Tumor-infiltrating lymphocytes predict cutaneous melanoma survival

Background Tumor-infiltrating lymphocytes (TILs) is considered a manifestation of the host immune response to tumor, but the role of TILs on melanoma mortality is controversial. Therefore, the aim of this study was to investigate the role of TILs on melanoma mortality, controlling for all known histological prognostic parameters. Materials and methods We conducted a 10-year cohort study among 4143 patients from the same geographic area (Lazio) with primary cutaneous melanoma diagnosed between January 1998 and December 2008. Survival probability was determined by Kaplan–Meier estimates, and prognostic factors were evaluated by multivariate analysis (Cox proportional hazards model). Results Survival decreased with increasing age (P for trend < 0.001) and Breslow thickness (P for trend < 0.001). In the multivariate Cox model, the presence of high levels of tumour infiltrating immune cells in primary invasive melanomas was associated with lower risk of melanoma death (RR: 0.32; 95%CI:0.13-0.82, P for trend <0.001), after controlling for sex, age, breslow thickness, histological type, mitotic rate and ulceration. Conclusions These results suggest that immune microenvironment affects melanoma survival. Understanding differences in survival across distinct subgroups of melanoma patients may help choosing types of therapy.

Amelanotic melanoma mimicking cutaneous epitheliomas

DERMOSCOPIC APPEARANCE The dermoscopic analysis (Fig 2) revealed peripheral dotted vessels, linear irregular vessels, milky red areas, and white streaks, suggestive of melanoma. However, there were no structures or vascular patterns found in cutaneous epitheliomas, such as leaf-like areas, blue-gray ovoid nests, or arborizing or glomerular vessels. It is noteworthy that no brown, black, gray, or blue structures that would be suggestive of a melanocytic origin were found.