Melanoma in the Italian Population and Regional Environmental Influences: A National Retrospective Survey on 2001–2008 Hospitalization Records

Objective: To assess the burden of regional environmental factors influencing the incidence of Melanoma in the Italian population and overcome the problem of partial population coverage by local cancer registries and thematic archives. Methods: We analyzed the Italian national hospitalization records from 2001 to 2008 provided by the Ministry of Health, excluding hospital re-admissions of the same patients, in order to assess the occurrence of Melanoma over a 8-year period. Data were presented by age groups (absolute number of cases from 20 to ≥80 years old) and per Region (rates per 100,000 inhabitants) for each year. Results: The overall number of new hospitalizations due to malignant Melanoma increased by 16.8% from 2001 (n = 4846) to 2008 (n = 5823), with the rate per 100,000 inhabitants passing from 10.5 to almost 12.0 at a national level. The majority of new diagnoses of malignant Melanoma was observed in two age groups: 61–70 years old (from 979 in 2001 up to 1209 in 2008, corresponding to 15.1 and 18.1 new cases per 100,000 inhabitants, respectively) and 71–80 years old (from 954 in 2001 up to 1141 in 2008, corresponding to 19.5 and 21.8 new cases per 100,000 inhabitants, respectively). The number of hospitalizations due to Melanoma increased in all age groups with the only exception of the youngest patients aged 20–30 years old. The highest increases over the 8-year period were observed in people aged ≥81 years old (+34%), 61–70 years old (+20%) and surprisingly in the age group 31–40 years old (+17%). Southern Regions showed lower hospitalization rates compared to Northern Italy and Region Lazio. The highest increases between 2001 and 2008 were observed in Trentino/Alto Adige, Friuli Venezia Giulia, Valla d’Aosta and Veneto Region. Conclusions: Hospitalizations due to malignant Melanoma in Italy seem to be influenced by environmental or population-related factors showing a decreasing incidence rate from the Northern to Southern Regions.


Introduction
Cutaneous malignant Melanoma (CMM) is a potentially lethal form of skin cancer. Although it accounts for only 3% to 5% of all skin cancers, it is responsible for approximately 75 percent of all skin cancer deaths [1]. CMM results from the malignant transformation of melanocytes, which are the pigment-producing cells responsible for the color of skin. The key triggers leading to malignant transformation of melanocytes have yet to be fully elucidated, but are known to be multifactorial and include UV radiation damage and genetic susceptibility. Melanoma was diagnosed in approximately 85,000 people globally in 2008 [2] and is in general confined to economically developed countries. In particular, there is a high incidence in countries with fair-skinned populations, such as Northern Europe, the US, Australia, New Zealand, and South Africa. The incidence of CMM is highest in white persons. This population is approximately 20 times more likely to develop the disease than black persons. It is rare in young persons, with only 2 % of Melanomas occurring in persons younger than 20 years and approximately 0.3 percent in children younger than 14 years [3]. Persons with an increased number of moles, dysplastic (also called atypical) nevi, or a family history of this disease are at increased risk compared with the general population.
According to the Italian Cancer Society, there is an annual average incidence of 12.5 new skin Melanoma diagnoses per 100,000 males and 13.1 per 100,000 females [4]. Incidence rates for skin Melanoma vary sensibly across Italy, with a decreasing trend moving from North to the South. Worldwide, Melanoma incidence and death rate have progressively increased during the last 30 years [5].
An important tool to assist in the evaluation of potential Melanomas for patients and health care professionals is the ABCDE mnemonic, which takes into account asymmetry, border irregularities, color variation, diameter, and evolution. Any suspicious pigmented lesion should be biopsied to determine the histologic depth of lesion penetration, which is known as the Breslow depth. The Breslow depth is the most important prognostic parameter in evaluating the primary tumor. Early detection and treatment can lead to longer survival. According to the American Academy of Dermatology Association and the Society for Investigative Dermatology, the estimated total direct cost associated with the treatment of Melanoma in 2004 was $291million, of which $101 million were for office visits, $76 million for hospital outpatient treatment, $78 million for prescription drugs, $35 million for hospital inpatient treatment and $1 million for emergency room treatment [6].
In Italy, a network of population-based local cancer registries has been established (Italian Association of Cancer Registries, AIRTUM, Roma, Italy) in order to set high qualitative standards in data collection that can result in reliable reports. However, the AIRTUM CRs cover about 35% of the Italian population, (19 million people out of 61 million inhabitants), with a remarkable difference in CRs population coverage among Northern (50.2%), Central (25.5%) and Southern areas of the Country (17.9%) [7].
Also for Melanoma, as well as for mesothelioma, advanced experiences of thematic registries are also available, despite being limited to some hospitals or regions. Because no complete data are available about the occurrence of Melanoma in the entire Italian population, our aim was to provide some first data about hospitalizations due to main diagnosis of Melanoma in Italy. Although Cancer Registries remain the gold standard methodology to collect epidemiological information on cancer at local level, we attempted to estimate the overall burden of Melanoma at regional level and for age groups by analyzing hospitalization records, which have already been used for this purpose in our previous studies about breast cancer and in other researches [8][9][10][11].

Methods
Information concerning all hospitalizations occurring in Italian public and private care setting are registered in hospital discharge records (HDR), which are collected in the Italian Ministry of Health national hospitalization database (SDO). These information are anonymous and include: region and hospital where the patients have been hospitalized, type of hospitalization (ordinary admission or day hospital), region and province where the patient come from, local health authority (ASL) who is paying for the hospitalization costs, patient's age, gender, main diagnosis, secondary diagnoses (up to five), procedures performed (main procedure and up to five additional procedures), diagnosis related group (DRG) and length of the hospitalization. It should be noticed that in the national hospitalization database, those people admitted at hospitals located in a region or province different from those where the patients live, are classified according to their home address. Hospitalization records are kept at a central level by the Ministry of Health from 1999 to date, but some records concerning the years 1999 and 2000 are missing and the national hospitalization database has been fully implemented for all Italian regions only from 2001. The Italian Ministry of Health has officially provided the full database concerning all hospitalizations occurred in Italy between 2001 and 2008 due to several diagnosis of Melanoma. The quality of these data is known to be very high and certified at central level by the Ministry of Health, with completeness and reliability of records (in terms of correspondence between hospitalizations and individual social security numbers, but also in terms of absence of errors or missing data) varying from 95.6% (year 2001) and 99.8% (for year 2008), respectively, as reported in our previous studies [10,11].
Our dataset included all hospitalized patients with major diagnosis of skin Melanoma based on the the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 172 (all extensions). Patients with Melanoma in other parts of the body were not captured in the analysis.
Based on social security numbers (which were treated anonymously), the Ministry of Health has allowed us to exclude all hospital re-admissions of the same patient over the entire study period, in order to minimize possible bias related to the overlapping between prevalent and incident cancer cases. To exclude hospital re-admissions from our analysis, we have considered as "index" hospitalization the first hospital admission of the patients for which repeated hospitalizations were recorded over the entire study period (2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008). Patients presenting the same social security number (treated anonymously) and the same major diagnosis were considered as the same person, and they were computed only one time. This methodology has been already used and certified by the Environment Protection Agency of Piemonte Region for the assessment of population heath indicators [12].
The absolute frequencies (number of hospitalizations) were computed for each Italian Region (Reg) and Province (Prov), by sex (S), year (y), and 10-year age groups (x):

Results and Discussion
As Reported in Table 1 100,000 inhabitants, respectively). The number of hospitalization due to malignant Melanoma increased in all age groups with the only positive exception of the youngest patients aged 20-30 years old. The highest increases over the 8-year period were observed in people aged ≥81 years old (+34%), 61-70 years old (+20%) and surprisingly in the age group 31-40 years old (+17%). Table 3 summarizes the number of hospitalizations per 100,000 inhabitants in the Italian regions and the corresponding standardized hospitalization rates, showing that the Southern regions and islands (Sicily and Sardinia) have lower rates compared to northern regions (8.4 and 13.3, respectively in year 2008). Southern regions presented also the lowest increase over the 8-year period. The number of hospitalizations recorded in the Lazio region were higher than those observed in other Central Italian regions. Friuli Venezia Giulia, Lazio, Veneto, and Valle d'Aosta presented the highest hospitalization rates due to main diagnosis of Melanoma (ranging from 16 to 24 per 100,000 in 2008), while Apulia was the region where the highest number of cases were observed in Southern Italy (Table 3).  Table 3 and displayed in Figure 2. Table 4 shows the Standardized Hospitalizations Rate (SHR) per 100,000 inhabitants in Italian regions per year (2001-2008) and age groups, highlighting that people aged 71-80 and >80 are usually more affected by skin Melanoma. However, the incidence in younger people is different according to the regions where people live.

Discussion
Melanoma is the deadliest form of skin cancer. It is a malignant tumor of melanocytes, cells which arise from the neural crest and it is considered the fourth most common cancer in individuals between the ages of 0 and 44 years [4]. It can occur de novo or from a preexisting lesion usually located in skin areas exposed to the sunlight. The annual incidence has increased dramatically over the past few decades. According to the Italian Cancer Society Report 2006, there were an yearly average of 12.5 new skin Melanoma diagnoses per 100,000 males and 13.1 per 100,000 females, with incidence rates for skin Melanoma remarkably varying across Italy with a decreasing trend moving from North to South (2:1 ratio; total estimated incidence: 6000 new cases per year) [4].
These finding are almost comparable to our results (11.5-12.0 per 100,000 inhabitants) both overall (more than 5.800 cases in 2008) and for Northern/Central/Southern Italian regions. The differences in prevention campaigns and proper/early diagnosis cannot completely explain the existing gap between Northern and Southern Italian regions. At a European level the highest European Standardized Rates (ESR) incidence rates were reported for Denmark in 2010 (21.5 per 100,000 men and 26.1 per 100,000 females), with the lowest incidence observed in Portugal (4.6 per 100,000 males and 6.2 per 100,000 females) [13]. It is important to point out that usually the incidence of Melanoma is higher in women than in men [14]. A recent case control study, including 5700 cases of malignant Melanoma showed a complex relationship between risk of developing this skin tumor and the individual patterns of sun exposure (recreational/occupational), body sites and sunburns [15].
The issue of the latitude where the affected person is living has also been addressed in a recent paper [16]. Thus, environmental and native population-related factors (i.e., skin pigmentation) seem to play a crucial role in the incidence of malignant Melanoma. The prognosis and the treatment of this tumor depends on the type of Melanoma, the patient's age, the presence or absence of ulceration, the depth of invasion and the nodal status at diagnosis [17]. A prospective study showed the possibility of using ERβ expression as a prognostic indicator of Melanoma; in fact it is evidenced that thin Melanomas show significantly higher ER mRNA levels than thicker lesions [18]. While the majority of patients present with a primary cutaneous malignant Melanoma and are cured by surgical resection alone, metastasis to regional lymph nodes or distant sites occurs in a proportion and is associated with poor long-term survival [19]. Furthermore, in those with visceral metastatic disease, Melanoma is usually rapidly fatal, with an average survival of less than one year, and it is associated with much morbidity [19].
Prognosis from Melanoma is determined by traditional anatomical staging; the risk of relapse from a primary Melanoma correlates with features such as tumor thickness, ulceration, and mitotic rate, and in advanced Melanoma, worsened clinical outcomes are observed in those patients with visceral metastases and those with an elevated lactate dehydrogenase level, presumed to reflect a higher burden of metastatic disease [20]. Similarly, performance status was also found to be a prognostic variable in patients with stage IV Melanoma treated in clinical trials [20]. Palliative systemic therapy is the basis of management for metastatic Melanoma, and until very recently, a global standard was dacarbazine, an alkylating chemotherapy agent. However, metastatic Melanoma is regarded as being insensitive to cytotoxic chemotherapy, as evidenced by response rates to dacarbazine in the order of 10% and no proven survival benefit [21][22][23][24]. Immunotherapy, including cytokine and vaccine treatments, provides the only alternative to chemotherapy but does not benefit the majority of patients, although durable responses have been observed in a small proportion of patients treated with high-dose interleukin-2 [25]. The generally held view that metastatic Melanoma is refractory to systemic treatments was dramatically altered in 2010, when positive Phase III clinical trial results were reported for two novel agents [26]. Both the anti-cytotoxic T lymphocyte-associated antigen-4 antibody, ipilimumab, and the small molecule inhibitor of BRAF, vemurafenib (formerly referred to as PLX4032 and RG7204), were shown to improve overall survival in patients with advanced Melanoma in randomized controlled trials [27].

Conclusions
Hospitalizations due to malignant Melanoma in Italy show a decreasing incidence rate from northern to southern Italian Regions, being possibly influenced by environmental and population-related factors.